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Int J Ment Health Addict
Int J Ment Health Addict
International Journal of Mental Health and Addiction
1557-1874
1557-1882
Springer US New York
972
10.1007/s11469-022-00972-1
Original Article
Remote Screening for Alcohol, Smoking, and Substance Involvement by Sex, Age, Lockdown Condition, and Psychological Care-Seeking in the Primary Care Setting during the COVID-19 Pandemic in México
http://orcid.org/0000-0001-9269-7877
Morales-Chainé Silvia [email protected]
1
Robles-García Rebeca 2
Barragán-Torres Lydia 1
Treviño-Santa-Cruz Claudia Lydia 3
1 grid.9486.3 0000 0001 2159 0001 Facultad de Psicología, Universidad Nacional Autónoma de México, Av. Universidad 3004 Copilco Universidad B212 Coyoacán, Ciudad de México, México
2 grid.419154.c 0000 0004 1776 9908 Instituto Nacional de Psiquiatría “Ramón de La Fuente Muñiz”, Mexico City, Mexico
3 grid.9486.3 0000 0001 2159 0001 Instituto de Biotecnología, Universidad Nacional Autónoma de México, Mexico City, Mexico
9 12 2022
128
18 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The COVID-19 pandemic has created a psychoactive substance use crisis in many countries, including México. Remote valid tools to identify high-risk groups in need for treatment are a prerequisite for cost-effective interventions in primary care settings. To determine the validity and correlates of the remote applications of the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) with sex, age, and psychological care-seeking, offered remotely in primary settings, during the COVID-19 pandemic in Mexico, a total sample of 19,109 Mexicans, with an average age of 34.38 years (SD = 12.28, range = 18–80), 65.8% of whom were women (n = 12,578), 29.6% in lockdown (5,660), 39.8% in partial lockdown (7,611), 30.60% not in lockdown (5,838), and 14.75% of whom were seeking psychological care (n = 2,819), completed ASSIST through a programmed Web application. The dimensionality of the scale to verify construct validity evidence was achieved through a confirmatory factor analysis model (CFA). We represented the distribution of subjects by sex, age, lockdown condition, and psychological care-seeking, based on their lifetime consumption in 2021. We also compared the total distribution by consumption risk level and recommended type of intervention, psychological care-seeking, and age. The tool included ten dimensions (one for each substance, such as tobacco use), confirmed through the CFA. In general, our findings indicated that men reported high lifetime psychoactive substance use and risky drug use levels. A high percentage of 18 to 19-year-old women reported lifetime tobacco and alcohol use. Additionally, a high number of all-age women reported lifetime sedative and opioid use. Also, a high proportion of partially lockdown participants reported lifetime drug use. Moreover, a high percentage of subjects seeking psychological care were at a moderate and high risk of drug use, which required brief or intensive treatment. Our findings indicate that it was possible to validate the factor structure of the programmed ASSIST for remote use. More men than women reported high lifetime psychoactive substance use and risky levels because of their consumption. At the same time, younger women reported similar and even higher lifetime tobacco, alcohol, and cocaine use than same-age men. More all-age women reported lifetime use of sedatives than all-age men. More all-age partially lockdown participants reported lifetime use of drugs. In general, subjects at greater risk and those requiring psychological care are more likely to seek care. Community and primary care screening will make it possible to implement effective early interventions to reduce the substance use risks associated with health emergencies. Future studies are required to determine the diagnosis of substance use disorders to evaluate the cut-off points in the screening test to discriminate between the presence and absence of symptoms and evaluate the effect of remote psychological care.
Keywords
Alcohol
Smoking
ASSIST
Psychological-care-seeking
COVID-19
DGAPA-PAPIITIV300121 Morales-Chainé Silvia
==== Body
pmcIntroduction
By November 12, 2022, over 180.8 million people had been diagnosed with COVID-19, and 2.9 million had died, equivalent to a 1.58% mortality rate in America alone (PAHO, 2022). Moreover, the Global Drugs Report, published by the United Nations Office on Drugs and Crime (GDR-UNODC, 2021), has indicated that 275 million people worldwide used psychoactive substances between May 2020 and June 2021. Thirty-six million people may subsequently develop drug use disorders and do not always seek psychological care (GDR-UNODC, 2021).
Accordingly, drug use may be experiencing a global increase. Forty-two percent of 77 countries have reported an increase in the use of drugs such as cannabis or nonprescription medical drugs (GDR-UNODC, 2021). In 2022, Mellos and Paparrigopoulos referred to increased alcohol, cannabis, and nicotine use trends during the COVID-19 pandemic. However, Bommelé et al. (2020) and Adinolfi et al. (2022) suggested that some people use more drugs while others use less. Layman et al. (2022) reported reductions in the prevalence of substance use among youth, suggesting monitoring and continued surveillance in the subsequent years and predicting an increase in drug consumption. The GDR-UNODC therefore predicts that there will be an 11% rise in the number people using drugs worldwide by 2030.
On one side, the rise in drug abuse is associated with a fourfold increase in drug availability and accessibility through the black market (Mellos and Paparrigopoulos (2022), which occurred between 2011 and 2020, even though control systems limit the spread of drug use (GDR-UNODC, 2021). On the other side, Layman et al. (2022) suggested that the decrease in drug use is due to the lockdown during the COVID-19 pandemic. They explained that substance consumption occurs outside the home environment and within the context of the peer group. Substance use is highly dependent on the availability and access to drugs and other substances. Therefore, the COVID-19 pandemic and lockdown conditions are related to the variability and diversity of the distribution channels of psychoactive substances reaching some people while limiting drug access to other communities.
In Mexico, the Mental Health, and Substance Abuse Observer System (MHSAMOS, 2021) has reported that 43.2% of men and 32.3% of women used drugs in 2021. During the COVID-19 pandemic, 32.5% of the population reported alcohol consumption, 24.6% tobacco use, and 14.6% cannabis use with a higher prevalence in men than women. Moreover, 16% of men and 9% of women reported cocaine use, and 16.4% of men and 9.6% of women reported using opioids during the pandemic (MHSAMOS, 2021).
Regarding intake, 18.7%, 19.8%, and 3.1% of the Mexican population have reported greater use of tobacco, alcohol, and other drugs, respectively (MHSAMOS, 2021). The reasons for this drug use were stress, anxiety, and lockdown during the COVID-19 pandemic rather than curiosity about experiencing the effects of using drugs. According to Layman et al. (2022), people experiencing increased stress and mental health problems are more vulnerable to using drugs as a coping mechanism during the COVID-19 pandemic. Bommelé et al. (2020) reported that tobacco use varies because of boredom, restrictions in movement, and concern about becoming severely ill. Moreover, Adinolfi et al. (2022) reported said alcohol consumption has also varied by sex, age, lockdown, COVID-19 status, violence, and comorbidity. Specific factors associated with fewer variations in the frequency of substance use before and during the COVID-19 pandemic were being male, having a different occupation from being a homemaker, and being single (Adinolfi et al., 2022). Therefore, monitoring not just alcohol but also other psychoactive substances use is essential for designing public policies to prevent and treat drug use disorders (Layman et al., 2022).
In the context of drug use studies during the COVID-19 pandemic, innovations have been implemented and prevention services adapted to increase treatment availability. Academics have developed a WebApp using a Technological Information System (TIS; Morales-Chainé et al., 2022) based on national and international guidelines for remote psychological care (APA-GPT, 2013). The context of TIS has been one where few people have sought evidence-based psychological care. It means authors have developed a tool to reduce the gap for based-evidence treatment. However, MHSAMOS (2021) reported that 62.7% of the subjects interviewed failed to seek treatment or even consider that they needed help because of their drug use. As a result, 17.5% have not sought psychological care despite needing it and just 7.7% have sought professional care for their psychoactive substance use.
Screening for psychoactive drug use in primary care helps narrow the gap in timely treatment initiation. TIS has been helping with the early detection of lifetime drug use and risk levels during frequent drug use. The World Health Organization (ASSIST-WHO, 2010) developed the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) to achieve early screening in community settings. Prior to the COVID-19 pandemic, Tiburcio et al. (2016) assessed the psychometric properties of ASSIST while identifying at-risk cases due to substance use in a sample of 1,176 undergraduate students in Mexico. The authors reported reliability coefficients for tobacco (alpha = 0.83), alcohol (alpha = 0.76), and cannabis (alpha = 0.73). They found significant correlations between alcohol and the Alcohol Use Disorders Identification Test (AUDIT; r = 0.72), a good balance of sensitivity and specificity in the alcohol subscale (83.8% and 80%, respectively), and the largest area under the curve (ROC = 81.9%) and established a cutoff score of 8 points. Moreover, Adinolfi et al. (2022) used the ASSIST to assess the associations between quarantine, the use of psychoactive substances, and symptoms of depression and anxiety. They described how the ASSIST helped to identify the associated factors to less frequency of drug use.
Since drug use varied widely during the COVID-19 pandemic, the aim of the study was to determine the validity of the remote application and correlates of the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) with sex, age, lockdown condition, and psychological care-seeking, offered remotely in primary settings, during the COVID-19 pandemic in Mexico. We expected to distinguish the level of drug use risks related to sociodemographic characteristics and to find high levels in men, early age groups, not lockdown conditions, and psychological care-seekers. This exploration led to the dissemination of evidence-based interventions for drug use disorders in primary care and community settings.
Method
Design
In this correlational study, through a cross-sectional design, subjects were invited to enter a programmed platform, WebApp, between December 13, 2020, and August 31, 2021. The link was available on the Mexican Health Ministry Website (announced on the radio, television, and the Internet).
Subjects were asked to read the following instructions: The risk of suffering from COVID-19 is an unprecedented social condition that affects us all. The current COVID-19 pandemic is a situation in which we must understand our feelings. As a result, we should find out what to do about it and where to find professional evidence-based help whenever required. We therefore invite you to answer the following questionnaire. You will receive feedback on your answers, and counseling to help you cope with your emotions, thoughts, and behaviors due to the current health contingency. Your participation is voluntary, and all the information you provide will be treated confidentially. Your information management will comply with the Mexican privacy policies for personal data treatment.
Subjects
We received questionnaires from 19,109 subjects, from December 14, 2020, to August 31, 2021. Regarding the study sample, we invited the subjects to participate through a public announcement on the official Health Ministry website and the institutional website of the leading public University in Mexico. They had to log into the system with their email to identify participation. Thus, subjects were invited to participate through press announcements and conferences on several media. The inclusion criteria were to accomplish the legal age and reside in Mexico. The exclusion criteria must be under 17 years old or a healthcare provider. We also considered the criteria for internet E-surveys such as data protection, development, testing, contact mode, advertising the survey, mandatory, voluntary, completion rate, cookies used, IP check, log file analysis, registration, and atypical timestamp considerations (Eysenbach, 2004). Therefore, since the technological system does not allow unresponsive rates, 100% of the subjects were volunteers who completed the questionnaire. As a result of this quota data collection, the sample was not homogeneous. Thus, the average age of the subjects was 34.38 years (SD = 12.28; range = 18–85), 65.82% were women (12,578), 29.6% were in lockdown (5,660), 39.8% were in partial lockdown (7,611), and 30.60% were not in lockdown (5,838). Moreover, 19.37% were aged between 20 and 24 (3,702), and 14.75% were seeking remote psychological care (2,819). Table 1 shows the distribution of the sample by sex, age, and psychological care-seeking.Table 1 Subjects distributed by sex, age, and psychological care-seeking groups
Not psychological care-seeking Psychological care-seeking Total
Men Women Subtotal Men Women Subtotal Men Women Subtotal
Age n % n % n % n % n % n % n % n % n %
18 − 19 444 37.53 739 62.47 1183 7.26 56 22.67 191 77.33 247 8.76 500 34.97 930 65.04 1430 7.48
20 − 24 990 33.09 2002 66.91 2992 18.37 195 27.46 515 72.54 710 25.19 1185 32.01 2517 67.99 3702 19.37
25 − 29 824 33.91 1606 66.09 2430 14.92 149 31.04 331 68.96 480 17.03 973 33.44 1937 66.56 2910 15.23
30 − 34 827 35.31 1515 64.69 2342 14.38 95 28.61 237 71.39 332 11.78 922 34.48 1752 65.52 2674 13.99
35 − 39 717 34.44 1365 65.56 2082 12.78 79 29.92 185 70.08 264 9.37 796 33.93 1550 66.07 2346 12.28
40 − 44 583 35.46 1061 64.54 1644 10.09 68 29.57 162 70.43 230 8.16 651 34.74 1223 65.26 1874 9.81
45 − 49 495 34.86 925 65.14 1420 8.72 55 26.44 153 73.56 208 7.38 550 33.78 1078 66.22 1628 8.52
50 − 54 344 34.89 642 65.11 986 6.05 42 32.31 88 67.69 130 4.61 386 34.59 730 65.41 1116 5.84
55 or over 507 41.87 704 58.13 1211 7.43 61 27.98 157 72.02 218 7.73 568 39.75 861 60.25 1429 7.48
Total 5731 35.18 10559 64.82 16290 85.25 800 28.38 2019 71.62 2819 14.75 6531 34.18 12578 65.82 19109 100.00
The table shows the number and percentage of men and women and whether they were seeking psychological care in five-year cohorts
Subjects agreed to answer the survey in accordance with the privacy policies established in the General Protection of Personal Information in the Possession of Obligated Parties Act (Spanish Acronym LGPDPPSO, 2017) and the General Office of the Community Care Guidelines of the National Autonomous University of Mexico (Spanish Acronym DGACO-UNAM). Data were asymmetrically encrypted in the WebApp. The database was held in the official university domain, with security locks to protect the information and guarantee their management in keeping with the subjects’ informed consent.
In the informed consent form, researchers told subjects that confidentiality would be maintained by calculating general averages. Subjects were informed that their data would be used for epidemiological research and that they had the right to decline the use of their information and drop out at any point in the study. Immediate feedback was supplied in the form of psychoeducational tools (infographics, videos, and Moodle ® courses on COVID-19, self-care, relaxation techniques, problem-solving, and socioemotional management skills). Phone numbers were provided to obtain remote psychological care from the Health Ministry and the UNAM Services. Finally, the benefits of accessing the WebApp or calling for help with dealing with mental health conditions were described. A data section, in which subjects could give their phone number or email so that they could be contacted, was included to enable them to request remote psychological care. The protocol was approved by the UNAM Psychology Faculty Ethics Committee on Applied Research on October 16, 2020.
Instruments
The WebApp was programmed through Linux®, PHP®, HTML®, CSS®, and JavaScript® software. First, we included the sociodemographic section asking about sex, age, lockdown condition, and remote psychological care-seeking (Morales-Chainé et al., 2022). We included categorical responses for subjects to identify as men or women, lockdown condition (totally, partially [working or going to the supermarket] or not at all lockdown), and indicate whether they were seeking psychological care. Thus, we programmed the ASSIST in the WebApp (The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST-WHO), 2010; Tiburcio et al., 2016).
The ASSIST section enabled us to determine the risk level for ten groups of psychoactive substances: tobacco (cigarettes, chewing tobacco, and cigars), alcoholic beverages (beer, wine, spirits), cannabis (marijuana, pot, grass, and hash), cocaine (coke, crack), amphetamine-type stimulants (speed, meth, and ecstasy), inhalants (nitrous, glue, petrol, paint, and thinner), sedatives or sleeping pills (diazepam, alprazolam, flunitrazepam, and midazolam), hallucinogens (LSD, acid, mushrooms, trips, and ketamine), opioids (heroin, morphine, methadone, buprenorphine, and codeine), and other drugs.
ASSIST consists of eight questions that screen for substance use: (1) lifetime use; (2) use in the past three months; (3) having a strong desire to use the drug in question; (4) health, social, legal, or financial problems; (5) failing to do what is expected because of the use of the drug in question; (6) other expressions of concern about the use of the drug in question; (7) attempts to reduce use of the drug in question; and (8) injecting any drug (non-medical use only). The first item has dichotomous options: yes (1) or no (0). Items two to five have a five-option-response: never, once or twice, monthly, weekly, and daily or almost daily. The score for each substance is calculated by adding the answers to questions two to seven. Neither question five on tobacco nor questions one or eight is used to calculate the score.
ASSIST has shown good validity and reliability coefficients for tobacco (α = 0.83), alcohol (α = 0.76), and cannabis (α = 0.73; Tiburcio et al, 2016). Confirmatory factor analysis (CFA) found a good factor structure for tobacco (X2[3] = 37,792, p = 0.28631; RMSEA = 0.016; CFI = 0.999; CI90% RMSEA = 0.000–0.057). CFA also indicated a good factor structure for alcohol (X2[7] = 39,479, p = 0.78576; RMSEA = 0.000; CFI = 1.000; CI90% RMSEA = 0.000–0.025).
In this study, our WebApp was linked to a feedback algorithm, referring to brief counseling (a score of 0–10 for alcohol or 0–3 for other drugs), intervention (10 to 26 for alcohol and 3 to 26 for other drugs), or more intensive treatment (up to 27 for all substances), following WHO guidelines (2010). In addition, the WebApp was programmed to display a section in which subjects were advised to seek psychological care. To obtain the service, subjects had to sign in, share their phone number or email, and select their preferred schedule to be contacted by an addiction psychology specialist.
Data Analysis
The statistical procedure involved several analytical steps. We examined the dimensionality of ASSIST to provide construct validity evidence. We used a 10-factor confirmatory factor analysis model (CFA) incorporating maximum likelihood to continuous variable data as an estimation method (Elhai & Palmieri, 2011). We considered tobacco, alcohol, cannabis, cocaine, stimulants, inhalants, sedatives, hallucinogens, opioids, and others as factors. We adjusted dimensional models to each factor of interest. The overall fit of the models was assessed using the chi-square goodness of fit test. Since the chi-square goodness of fit test is over-sensitive to large sample sizes, more emphasis was given to the CFI, TLI, RMSEA, and SRMR fit indices. Models with CFI and TLI with values over 0.90 and RMSEA and SRMR with values under 0.08 and 0.06, respectively, were considered indicators of adequate data fit (Browne & Cudeck, 1993; West et al., 2012). The second step involved examining the reliability of the scale using the Cronbach’s Alpha test.
The third step entailed analyzing the distribution of subjects in relation to lifetime substance use by sex, age, and lockdown condition. The fourth step also required calculating each risk-substance score and recodifying each mean value into a discrete variable, recommended by the The Alcohol Smoking and Substance Involvement Screening Test (ASSIST-WHO) (2010): low (0–10 for alcohol and 0–3 for other drugs—brief counseling), moderate (11 to 26 for alcohol and 4 to 26 for other drugs—brief intervention), or high (up to 27 for all substances—more intensive treatment). We therefore compared the distribution of subjects by risk level and psychological care-seeking. The chi-square test was calculated, considering p values under 0.05, to describe the statistical difference between groups. All analyses were conducted in RSTUDIO® 1.4.1106 and IBM® SPSS 25.0 software.
Findings
Confirmatory Factor Analysis
Results from the ten-factor model and for each dimension model are shown in Table 2. In general, the data fit for the whole sample was adequate, with an X2(1,583) = 50,863.65, p < 0.001, a RMSEA = 0.040, a SRMR = 0.032, a CFI = 0.920, and a TLI = 0.913, after 491 iterations. Table 2 also shows Cronbach’s coefficients for the total sample and the ASSIST dimensions. As can be seen, reliability values fluctuated between 0.80 for the alcohol dimension and 0.91 for stimulants.Table 2 ASSIST ten-factor model and by-dimension fit indices, chi-square results, and Cronbach’s alpha coefficients
X 2 df p ≤ RMSEA SRMR CFI TLI Cronbach´alph
Tobacco 301.051 4 0.001 0.062 0.014 0.994 0.985 0.85
Alcohol 506.945 8 0.001 0.057 0.020 0.986 0.973 0.80
Cannabis 294.768 7 0.001 0.046 0.015 0.994 0.987 0.84
Cocaine 926.589 8 0.001 0.078 0.014 0.988 0.977 0.89
Stimulants 242.728 5 0.001 0.050 0.009 0.997 0.991 0.91
Inhalants 436.077 5 0.001 0.067 0.016 0.991 0.974 0.81
Sedatives 600.599 7 0.001 0.067 0.021 0.988 0.974 0.85
Hallucinogens 857.115 7 0.001 0.080 0.028 0.979 0.955 0.81
Opiods 292.090 5 0.001 0.055 0.012 0.996 0.987 0.88
Others 733.908 6 0.001 0.080 0.021 0.986 0.965 0.85
Overall CFA 50863.651 1583 0.001 0.040 0.032 0.920 0.913 0.86
This table shows chi-square values by degrees of freedom below 0.0001. It also represents values of fitted indexes for the CFA models by dimension. All Cronbach’s alphas were obtained for coefficients over 0.80
The different degrees of freedom values (df) observed in Table 2 refer to the modification indices (MI) in the CFA, indicating that it was necessary to add a correlation between some items and obtain a structure factor model with a good fit. First, we correlated items (2) …how often have you used… and (3) … had a strong desire or urge to use with the tobacco, alcohol, cannabis, stimulants, inhalants, sedatives, hallucinogens, and other drug dimensions. Second, we correlated items (4) … how often has your use led to health, social, legal, or financial problems? and (5) … have you failed to do what was normally expected of you because of your use… with the cannabis, sedatives and opioids, and other drug dimensions. Third, we correlated items (6) … has a friend or relative or anyone else ever expressed concern about your use… and (7) … have you ever tried to cut down on using with the cocaine, stimulants, inhalants, and hallucinogens dimensions.
The MI also suggested adding a correlation between items: (5) … have you failed to do what was normally expected of you… and (7) …you ever tried to cut down on using… but failed?, between (2) … how often have you used substances… and (4) … has your use led to health … or financial problems?, and between (3) …have you had a strong desire or urge to… and (5) … have you failed to do what was normally expected of you because of your use of… ? for the opioid dimension.
Moreover, the MI indicated adding a correlation between items: (2) …how often have you used substances… and (7) … have you ever tried to cut down … but failed? and between (3) …have you had a strong desire or urge to… and (7) … have you ever tried to cut down on using… but failed? for the stimulant dimension.
The MI indicated adding a correlation between items: (3) … have you had a strong desire or urge to… and (4) … has your use led to health…or financial problems? and (2) …how often have you used substances and (6) Has a friend … ever expressed concern about your use for the inhalants dimension.
Finally, the MI indicated adding a correlation between items: (2) … have you used substances and (7) … have you ever tried to cut down… but failed? for the other drugs dimension.
Essentially, the adequate fit model showed factor loadings > 0.40 for all the ASSIST dimensions (see Appendix A).
Lifetime Use of Psychoactive Substances
The percentage of subjects who reported lifetime psychoactive substance use by age, sex, and lockdown condition in the total sample is shown in Tables 3 and 4. Worldwide, as can be seen in Tables 3 and 4, 43.06% of subjects reported lifetime use of tobacco, 72.34% of alcohol, 19.52% of cannabis, and 9.59% of sedatives.Table 3 Distribution of lifetime psychoactive substance use by age and sex, in the total sample
Scales Age Total Scales Total
Men Women Total Men Women Total
n % n % n % n % n % n %
Tobacco 18 − 19 156 31.20 292 31.40 448 31.33 Inhalants 3 0.60 9 0.97 12 0.84
20 − 24 602 50.80 1004 39.89 1606 43.38 24 2.03 20 0.79 44 1.19
25 − 29 541 55.60 841 43.42 1382 47.49 26 2.67 26 1.34 52 1.79
30 − 34 516 55.97 758 43.26 1274 47.64 21 2.28 20 1.14 41 1.53
35 − 39 472 59.30 660 42.58 1132 48.25 15 1.88 4 0.26 19 0.81
40 − 44 347 53.30 469 38.35 816 43.54 5 0.77 2 0.16 7 0.37
45 − 49 268 48.73 368 34.14 636 39.07 5 0.91 0 0.00 5 0.31
50 − 54 158 40.93 220 30.14 378 33.87 3 0.78 1 0.14 4 0.36
55 o more 266 46.83 291 33.80 557 38.98 6 1.06 1 0.12 7 0.49
Total 3326 50.93 4903 38.98 8229 43.06 108 1.65 83 0.66 191 1.00
Alcohol 18 − 19 301 60.20 567 60.97 868 60.70 Sedatives 16 3.20 69 7.42 85 5.94
20 − 24 910 76.79 1860 73.90 2770 74.82 80 6.75 219 8.70 299 8.08
25 − 29 786 80.78 1489 76.87 2275 78.18 81 8.32 226 11.67 307 10.55
30 − 34 765 82.97 1347 76.88 2112 78.98 68 7.38 173 9.87 241 9.01
35 − 39 649 81.53 1146 73.94 1795 76.51 79 9.92 160 10.32 239 10.19
40 − 44 506 77.73 825 67.46 1331 71.02 67 10.29 122 9.98 189 10.09
45 − 49 419 76.18 663 61.50 1082 66.46 48 8.73 133 12.34 181 11.12
50 − 54 274 70.98 407 55.75 681 61.02 34 8.81 81 11.10 115 10.30
55 o more 439 77.29 471 54.70 910 63.68 57 10.04 120 13.94 177 12.39
Total 5049 77.31 8775 69.76 13824 72.34 530 8.12 1303 10.36 1833 9.59
Cannabis 18 − 19 103 20.60 151 16.24 254 17.76 Hallucinogens 22 4.40 27 2.90 49 3.43
20 − 24 368 31.05 572 22.73 940 25.39 91 7.68 109 4.33 200 5.40
25 − 29 336 34.53 485 25.04 821 28.21 77 7.91 86 4.44 163 5.60
30 − 34 274 29.72 406 23.17 680 25.43 63 6.83 58 3.31 121 4.53
35 − 39 221 27.76 222 14.32 443 18.88 49 6.16 36 2.32 85 3.62
40 − 44 112 17.20 136 11.12 248 13.23 26 3.99 22 1.80 48 2.56
45 − 49 82 14.91 86 7.98 168 10.32 12 2.18 13 1.21 25 1.54
50 − 54 39 10.10 41 5.62 80 7.17 1 0.26 9 1.23 10 0.90
55 o more 63 11.09 33 3.83 96 6.72 43 7.57 1 0.12 44 3.08
Total 1598 24.47 2132 16.95 3730 19.52 384 5.88 361 2.87 745 3.90
Cocaine 18 − 19 15 3.00 16 1.72 31 2.17 Opioids 2 0.40 3 0.32 5 0.35
20 − 24 66 5.57 81 3.22 147 3.97 9 0.76 9 0.36 18 0.49
25 − 29 88 9.04 88 4.54 176 6.05 8 0.82 6 0.31 14 0.48
30 − 34 75 8.13 63 3.60 138 5.16 4 0.43 7 0.40 11 0.41
35 − 39 78 9.80 43 2.77 121 5.16 2 0.25 3 0.19 5 0.21
40 − 44 64 9.83 30 2.45 94 5.02 3 0.46 3 0.25 6 0.32
45 − 49 49 8.91 15 1.39 64 3.93 2 0.36 3 0.28 5 0.31
50 − 54 13 3.37 10 1.37 23 2.06 0 0.00 1 0.14 1 0.09
55 o more 15 2.64 2 0.23 17 1.19 1 0.18 0 0.00 1 0.07
Total 463 7.09 348 2.77 811 4.24 31 0.47 35 0.28 66 0.35
Stimulants 18 − 19 3 0.60 8 0.86 11 0.77 Other 11 2.20 28 3.01 39 2.73
20 − 24 24 2.03 35 1.39 59 1.59 43 3.63 75 2.98 118 3.19
25 − 29 42 4.32 46 2.37 88 3.02 35 3.60 57 2.94 92 3.16
30 − 34 40 4.34 44 2.51 84 3.14 28 3.04 44 2.51 72 2.69
35 − 39 32 4.02 28 1.81 60 2.56 37 4.65 47 3.03 84 3.58
40 − 44 22 3.38 20 1.64 42 2.24 25 3.84 42 3.43 67 3.58
45 − 49 12 2.18 15 1.39 27 1.66 19 3.45 34 3.15 53 3.26
50 − 54 2 0.52 6 0.82 8 0.72 7 1.81 17 2.33 24 2.15
55 o more 5 0.88 5 0.58 10 0.70 10 1.76 14 1.63 24 1.68
Total 182 2.79 207 1.65 389 2.04 215 3.29 358 2.85 573 3.00
This table shows the number and percentage of subjects, who reported lifetime substance use by drug. It also presents the number and percentage of men and women by lifetime drug use. Bold numbers show a significant difference in the X2 test with one degree of freedom for groups compared by sex and a p < 0.05.
Table 4 Distribution of lifetime psychoactive substance use by age and lockdown condition, in the total sample
Scales Age Total Scales Total
Lockdown Partially Not Lockdown Total Lockdown Partially Not Lockdown Total
n % n % n % n % n % n % n % n %
Tobacco 18 − 19 237 52.90 153 34.15 58 12.95 448 31.33 Inhalants 8 66.70 3 25.00 1 8.30 12 0.84
20 − 24 630 39.20 684 42.60 292 18.20 1606 43.38 12 27.30 22 50.00 10 22.70 44 1.19
25 − 29 341 24.70 645 46.70 396 28.70 1382 47.49 11 21.20 19 36.50 22 42.30 52 1.79
30 − 34 277 21.70 614 48.20 383 30.10 1274 47.64 11 26.80 14 34.10 16 39.00 41 1.53
35 − 39 231 20.40 528 46.60 373 33.00 1132 48.25 2 10.50 12 63.20 5 26.30 19 0.81
40 − 44 145 17.80 394 48.30 277 33.90 816 43.54 2 28.60 2 28.60 3 42.90 7 0.37
45 − 49 119 18.70 270 42.50 247 38.80 636 39.07 0 0.00 3 60.00 2 40.00 5 0.31
50 − 54 68 18.00 157 41.50 153 40.50 378 33.87 1 25.00 1 25.00 2 50.00 4 0.36
55 o more 123 22.10 207 37.20 227 40.80 557 38.98 0 0.00 4 57.10 3 42.90 7 0.49
Total 2171 26.40 3652 44.40 2406 29.20 8229 43.06 47 24.60 80 41.90 64 33.50 191 1.00
Alcohol 18 − 19 469 57.10 261 30.10 111 12.80 868 60.70 Sedatives 44 51.80 36 42.40 5 5.90 85 5.94
20 − 24 1187 42.90 1088 39.30 495 17.90 2770 74.82 125 41.80 126 42.10 48 16.10 299 8.08
25 − 29 584 25.70 1081 47.50 610 26.80 2275 78.18 89 29.00 152 49.50 66 21.50 307 10.55
30 − 34 499 23.60 1012 47.90 601 28.50 2112 78.98 70 29.00 120 49.80 51 21.20 241 9.01
35 − 39 385 21.40 826 46.00 584 32.50 1795 76.51 52 21.80 119 49.80 68 28.50 239 10.19
40 − 44 280 21.00 612 46.00 439 33.00 1331 71.02 43 22.80 99 52.40 47 24.90 189 10.09
45 − 49 203 18.80 462 42.70 417 38.50 1082 66.46 39 21.50 73 40.30 69 38.10 181 11.12
50 − 54 114 16.70 280 41.10 287 42.10 681 61.02 17 14.80 50 43.50 48 41.70 115 10.30
55 o more 175 19.20 331 36.40 404 44.40 910 63.68 45 25.40 61 34.50 71 40.10 177 12.39
Total 3923 28.40 5953 43.10 3948 28.60 13824 72.34 524 28.60 836 45.60 473 25.80 1833 9.59
Cannabis 18 − 19 139 54.70 88 34.60 27 10.60 254 17.76 Hallucinogens 29 59.20 18 36.70 2 4.10 49 3.43
20 − 24 367 39.00 419 44.60 154 16.40 940 25.39 68 34.00 96 48.00 36 18.00 200 5.40
25 − 29 216 26.30 412 50.20 193 23.50 821 28.21 47 28.80 80 49.10 36 22.10 163 5.60
30 − 34 162 23.80 350 21.50 168 24.70 680 25.43 32 26.40 67 55.40 22 18.20 121 4.53
35 − 39 100 22.60 233 52.60 110 24.80 443 18.88 18 21.20 48 56.50 19 22.40 85 3.62
40 − 44 56 22.60 126 50.80 66 26.60 248 13.23 15 31.30 25 52.10 8 16.70 48 2.56
45 − 49 42 25.00 79 47.00 47 28.00 168 10.32 4 16.00 15 60.00 6 24.00 25 1.54
50 − 54 15 18.80 41 51.20 24 30.00 80 7.17 2 20.00 6 60.00 2 20.00 10 0.90
55 o more 21 21.90 43 44.80 32 33.30 96 6.72 1 2.30 24 54.50 19 43.20 44 3.08
Total 1118 30.00 1791 48.00 821 22.00 3730 19.52 216 29.00 379 50.90 150 20.10 745 3.90
Cocaine 18 − 19 16 51.60 12 38.70 3 9.70 31 2.17 Opioids 3 60.00 2 40.00 0 0.00 5 0.35
20 − 24 42 28.60 67 45.60 38 25.90 147 3.97 7 38.90 5 27.80 6 33.30 18 0.49
25 − 29 40 22.70 82 46.60 54 30.70 176 6.05 7 50.00 6 42.90 1 7.10 14 0.48
30 − 34 39 28.30 61 44.20 38 27.50 138 5.16 3 27.30 5 45.50 3 27.30 11 0.41
35 − 39 22 18.20 57 47.10 42 34.70 121 5.16 2 40.00 3 60.00 0 0.00 5 0.21
40 − 44 15 16.00 50 53.20 29 30.90 94 5.02 2 33.30 2 33.30 2 33.30 6 0.32
45 − 49 5 7.80 42 65.60 17 26.60 64 3.93 1 20.00 3 60.00 1 20.00 5 0.31
50 − 54 3 13.00 13 56.50 7 30.40 23 2.06 1 100.00 0 0.00 0 0.00 1 0.09
55 o more 2 11.80 7 41.20 8 47.10 17 1.19 0 0.00 0 0.00 1 100.00 1 0.07
Total 184 22.70 391 48.20 236 29.10 811 4.24 26 39.40 26 39.40 14 21.20 66 0.35
Stimulants 18 − 19 4 36.40 4 36.40 3 27.30 11 0.77 Other 26 66.70 11 28.20 2 5.10 39 2.73
20 − 24 16 27.10 28 47.50 15 25.40 59 1.59 58 49.20 38 32.20 22 18.60 118 3.19
25 − 29 20 22.70 41 46.60 27 30.70 88 3.02 29 31.50 44 47.80 19 20.70 92 3.16
30 − 34 23 27.40 42 50.00 19 22.60 84 3.14 19 26.40 39 54.20 14 19.40 72 2.69
35 − 39 12 20.00 30 50.00 18 30.00 60 2.56 13 15.50 38 45.20 33 39.30 84 3.58
40 − 44 9 21.40 24 57.10 9 21.40 42 2.24 17 25.40 24 35.80 26 38.80 67 3.58
45 − 49 6 22.20 13 48.10 8 29.60 27 1.66 9 17.00 32 60.40 12 22.60 53 3.26
50 − 54 3 37.50 3 37.50 2 25.00 8 0.72 8 33.30 11 45.80 5 20.80 24 2.15
55 o more 0 0.00 6 60.00 4 40.00 10 0.70 5 20.80 11 45.80 8 33.30 24 1.68
Total 93 23.90 191 49.10 105 27.00 389 2.04 184 32.10 248 53.30 141 24.60 573 3.00
This table shows the number and percentage of subjects, who reported lifetime substance use by drug. It also presents the number and percentage of participants by lockdown condition and lifetime drug use. Bold numbers show a significant difference in the X2 test with two degree of freedom for groups compared by lockdown condition and a p < 0.05
Table 3 shows that, according to the chi-square test, more almost-all-age groups men than women used tobacco, alcohol, cannabis, and cocaine (X2 [1] > 3.58, p < 0.05). However, similar proportions of 18 to 19-year-old men and women reported lifetime tobacco, alcohol, and cocaine use. Interestingly, a high proportion of 18–34 and over-45-year-old women reported sedative use. At the same time, a high number of men aged 25 to 44 reported stimulant use, a high number of men aged 20 to 39, 45 to 49, and 55 or over reported inhalant use, and a high number of men aged between 20 and 44 or over 55 reported the use of hallucinogens.
Furthermore, more almost-all-age participants, partially in lockdown, used tobacco, alcohol, cannabis, cocaine, stimulants, sedatives, hallucinogens, and other drugs than the rest of the groups (according to chi-square test, X2 [2] > 10.94, p < 0.05; see Table 4). However, similar proportions of almost-all-age lockdown conditions groups reported lifetime inhalants and opioid use.
Substance Use Risk Levels
Figure 1 shows the distribution of subjects by psychological care-seeking, risk level, and type of intervention required (The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST-WHO), 2010). The chi-square test indicated the different distribution of subjects for all substances (X2 [2] > 8.14, p < 0.05), except for opioids. The number of not-at-risk subjects not seeking psychological care was proportionally higher (no intervention required) than that of subjects needing care who were seeking help. For example, 2.20% of subjects seeking psychological care proved to be at a higher risk because of their tobacco use, while 1.19% of subjects who did not seek help required intensive care treatment. Likewise, 29.12% of subjects seeking psychological care required brief intervention as opposed to 22.35% of subjects who did not seek help yet had a similar risk level because of their tobacco use. More subjects seeking help also needed brief or intensive treatment than those who did not seek psychological care. In other words, a high proportion of subjects proved to be at moderate to high risk because of their alcohol, cannabis, or cocaine use when they were seeking psychological care.Fig. 1 Percentage of subjects seeking psychological care by risk level and type of intervention required for all psychoactive substances. Significant differences by X2 test, with two degrees of freedom for comparison groups, were p < 0.05 for all psychoactive substances, except opioids
Figure 1 also shows that the proportion of subjects requiring and seeking psychological care because of their use of stimulants, inhalants, sedatives, hallucinogens, opioids, and other drugs was less than 2.77%. Appendix B shows the proportions of subjects seeking psychological care by age group and subjects in the total sample, for consultations.
Discussion
This study provided data on screening for substance abuse risk through the programmed Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) on an electronic device, by sex, age, lockdown condition, and psychological care-seeking, offered remotely in primary settings during the COVID-19 pandemic. Our findings indicated that it was possible to validate the factor structure of the Alcohol, Smoking, and Substance Involvement Screening Test through the CFA, using the chi-square, and CFI, TLI, RMSEA, and SRMR good index procedure (Browne & Cudeck, 1993; West et al., 2012). The self-applied ASSIST programmed to be used remotely during the COVID-19 pandemic, just as Adinolfi et al. (2022) found, also yielded robust Cronbach’s alpha coefficients. The factor structure of the ASSIST resulted in some items correlating because of the modification indices (MI). Consequently, our findings are consistent with those reported by Tiburcio et al (2016); they validated ten latent variables: risks from tobacco, alcohol, cannabis, cocaine, stimulants, inhalants, sedatives, hallucinogens, opioids, and other drug use.
Validating ASSIST with our sample yielded key facts. First, our findings suggest high proportions of subjects reporting lifetime use of tobacco, alcohol, cannabis, and cocaine. Mellos and Paparrigopoulos (2022) have already signed an increase in alcohol consumption among people with severe alcohol use and an increase in cannabis, nicotine, and cocaine use. So several social and demographic factors might explain the high frequency of participants using drugs. Mellos and Paparrigopoulos (2022) explained that those with high consumption levels had higher harmful emotionality mechanisms. Layman et al. (2022) suggested an impact of environmental factors which contribute to the odds of drug use among the population. Then, a high number of participants reporting lifetime drug use is consistent with the GDR-UNODC (2021) and Adinolfi et al. (2022) reference to the tendency to use drugs during the COVID-19 pandemic.
Thus, the percentage of subjects reporting lifetime psychoactive drug use was high for tobacco (43.06%), alcohol (72.34%), cannabis (19.52%), cocaine (4.24%), sedatives (9.59%), hallucinogens (3.90%), and other drugs (3.00%) in our sample during 2021. These were higher proportions than those reported by Mental Health and Substance Abuse Observer System (MHSAMOS) (2021), Layman et al. (2022), or Mellos and Paparrigopoulos (2022) but down to those reported by Adinolfi et al. (2022). In these reviews, researchers reported variability in the use of practically all psychoactive substances during the COVID-19 pandemic. Layman et al. (2022) reported reductions in use across alcohol, cannabis, tobacco, and other drugs during the pandemic, while Mellos and Paparrigopoulos (2022) reported an increase in people using those drugs. Layman et al. (2022) suggested that drug use variability might result from availability and stress factors. They suggested that people who live in challenging home situations or in resource-limited areas are more likely to be negatively affected by environmental changes and may turn to substance use as a coping mechanism. Additional factors related to increased or decreased drug use are restricted access to worksites, entertainment services, and mandates for physical distancing. Mellos and Paparrigopoulos (2022) referred that intermittent drug availability and trafficking difficulties have led users to search for other substances, increase experimentation and make online purchases high. Therefore, such varied findings suggest studying the factors that increase or decrease drug consumption and the spread of drug use because of the high availability and accessibility during the COVID-19 pandemic.
Besides, our findings also suggest that more men than women over 20 reported lifetime use of tobacco, alcohol, and cocaine, while more men than women over 18 reported cannabis use. These findings are consistent with those reported by Mental Health and Substance Abuse Observer System (MHSAMOS) (2021) but also with some detailed data reported by Adinolfi et al. (2022) regarding lifetime use, where men showed higher percentages of use related to all drugs. Layman et al. (2022) also suggested high use by men while addressing how drug use most often takes place outside the home environment and is dependent on availability and access to substances.
Our findings, nevertheless, indicate that a similar number of 18 to 19-year-old men and women reported lifetime tobacco, alcohol, and cocaine use. Moreover, more women than men aged 18 to 34 and over 45 reported lifetime sedative use. In that regard, Adinolfi et al. (2022) suggested that men show less variation compared to women. Thus, Layman et al. (2022) suggested that young people and women might show high vulnerability because of social determinants. They suggested that feelings of loneliness because of long-term social isolation and limited opportunities to interact with others, prevalent during COVID-19 in young people and women, might explain our findings about such drug use variability. Layman et al. (2022) suggested that it is essential to monitor the adverse psychological effects of the pandemic on the population, including the significant increase in the prevalence of clinical depression, suicidal ideation, and anxiety, all of which have the potential to contribute to an increased prevalence in substances use. The tendency in women to try tobacco, alcohol, cocaine, and sedatives at least once in their lifetime points to the need to also monitor the counseling, and brief and intensive treatment provided due to the current vulnerability of women. Furthermore, these results suggest that it is essential to consider factors related to stress, anxiety, COVID-19 conditions, violence, and comorbidity, which Layman et al. (2022), Mellos et al. (2022) suggest are related to the use of psychoactive substances such as alcohol, particularly affecting young people and women.
Nonetheless, our results also suggested that partial lockdown was associated with increased participants using drugs in their lifetime. Bommelé et al. (2020) suggested that restrictions during COVID-19 might explain such variability. Lockdown was related to low proportions of participants reporting lifetime drug use. Adinolfi et al. (2022) reported that it might be related to the events making it impossible to get and use drugs. Both studies also suggested that high proportions of participants using drugs in their lifetime are expected when people are partially or not at all lockdowns like in our study. Layman et al. (2022) suggested that the availability when people have the possibility of getting out is associated with the increased use of drugs. Thus, the high proportions of subjects using drugs in their lifetime while being partially or not locked down might result from stress conditions and from the access to psychoactive substances.
While some people are exposed to drug use, others might have been protected by the lockdown. Bommelé et al. (2020) suggested that while some people reported smoking less due to the COVID-19 pandemic, others reported smoking more. They reported such variability of the smoking tendencies, for example, related to boredom or restrictions in movement, stimulating increasing drug use. Bommelé et al. (2020) also suggested that the threat of contracting COVID-19 or becoming severely ill might motivates to quit drug use to improve physical health. Moreover, Layman et al. (2022) suggested that people experiencing increased stress and mental health problems might cope with the risk of using drugs. Therefore, future longitudinal studies must clarify the role of motivation or protective factors in helping to prevent drug use disorders. Some factors to explore might be those about the permissiveness inside home. Some family members show permissive attitudes and behaviors encouraging drug use (Layman et al., 2022). Thus, family dysfunction and domestic violence could predispose the onset of substance use and other violent behavior. Then, it is required to monitor the prevalence of substance use in the post-pandemic years.
In such sense, in third place, our findings suggest that a low proportion of subjects need brief or intensive treatment for their substance abuse risk or psychological care. There were fewer subjects needing psychological care who failed to seek it than those who requested help. Mental Health and Substance Abuse Observer System (MHSAMOS) (2021) reported that 62.7% of subjects failed to seek treatment for drug consumption. Our findings suggest the 23.54% of our sample that consumed tobacco, the 15.67% that used alcohol, the 5.93% that used cannabis, and the 4.98% using sedatives failed to seek the psychological care they required. Our findings are consistent with those of Mental Health and Substance Abuse Observer System (MHSAMOS) (2021), which found that 17.5% of those needing help failed to request it.
However, through our WebApp, we found that 31.32% of subjects with at-risk tobacco use, 20.82% of those with at-risk alcohol use, 10.64% of those with at-risk cannabis use, and 9.87% of those with at-risk sedative use were seeking psychological care. These findings were slightly higher than the 7.7% reported by Mental Health and Substance Abuse Observer System (MHSAMOS) (2021).
Consequently, the WebApp (Morales-Chainé et al., 2022) appears to provide an opportunity to obtain professional care when there is a risk derived from the use of legal and illegal drugs. The use of the WebApp has helped reduce the gap in evidence-based treatment for subjects who may be suffering from drug use disorders. The availability of treatment is another way to reduce drug use when people are ready to seek treatment (Layman et al., 2022).
Substance use risk was identified in community and primary health care scenarios in this study through the CFA of ASSIST, during the COVID-19 pandemic, thereby reducing the treatment gap. Tiburcio et al. (2016) and Adinolfi et al. (2022) have already reported the good balance of sensitivity and specificity in the test. Nevertheless, future studies should describe the diagnosis of substance use disorders through ASSIST, evaluating the cut-off points in the screening test. Future research should also explore the ability of ASSIST to discriminate between the presence and absence of a substance use disorder.
Nevertheless, our findings may be considered an effective attempt to screen for substance use in community and primary care settings, which could lead to effectively implementing early interventions to reduce the substance use risks associated with the current pandemic. Early treatment prevents mental health illness and promotes healthy development, reducing the risk of life-goal failure and chronic disease (Layman et al., 2022).
Conclusions
The factor structure of the programmed ASSIST can be used remotely. More men than women reported high lifetime psychoactive substance use and risk levels because of their use. Partially-or-not-at-all lockdown seemed to be a condition with high-subject proportions using drugs in a lifetime. However, younger women reported similar and even more lifetime use of tobacco, alcohol, and cocaine than same-age men. More all-age women reported lifetime use of sedatives than all-age men. Vulnerability, while being young or women, availability factors, and not being in lockdown may explain the high levels of use and risk of drug consumption. Also, stress and social factors during the COVID-19 pandemic might explain drug use variability in the community. In addition, subjects at greater risk and needing psychological care are more likely to seek care. Furthermore, community and primary care screening strategies could lead to implementing effective early interventions to reduce the substance use risks associated with health emergencies.
Limitations
The first limitation of the present study is that we did not use a diagnostic tool for drug use disorders. Moreover, it is not longitudinal. Consequently, future research should monitor the time lapse between the occurrence of stressful events and process of development of a drug use disorder, as well as other mental health risks, anxiety, and/or depression, through measurement tools such as the one used in this study.
In addition, a WebApp may lead to the risk of bias. Morales-Chainé et al. (2022) have already conducted a measurement invariance analysis of their electronic tools (such as PCL-C, anxiety, and depression). Future studies should therefore consider the measurement invariance of ASSIST, while comparing groups (for example, by sex), to show the bias in the questions that could be a result of other factors such as cultural or educational ones. Identifying the source of bias would increase the accuracy of ASSIST and halt the evolution of other mental illnesses. Future studies should monitor and address the consistency of the diagnosis, evaluating the effect of remote psychological help.
In addition, we should consider a strategy to increase the representativeness of our sample, to address the heterogeneity characterizing ours in the study. We were unable to achieve these conditions given that subjects participated voluntarily. A controlled study should therefore consider staggered sampling to generalize conclusions about psychoactive substance use and their relationship with sociodemographic characteristics. Moreover, subsequent studies should consider social determinants during the COVID-19 pandemic, such as unemployment, intra-familial violence, and the acceptance of drug use to understand how they contribute to the early onset of a drug use disorder (APA, 2013).
Appendix A
Standardized and non-standardized factor loadings according to the ASSIST dimensions, with model fit indices and chi-square analysis
Items Standardized factor loadings Non-Standardized factor loadings Items Standardized factor loadings Non-Standardized factor loadings
Tobacco Inhalants
2f 0.594 1.000
2a 0.822 1.000 3f 0.769 1.481
3a 0.816 1.023 4f 0.805 1.411
4a 0.626 0.519 5f 0.853 1.749
6a 0.723 0.688 6f 0.465 0.926
7a 0.657 0.874 7f 0.443 1.500
Alcohol Sedatives
2b 0.521 1.000 2g 0.758 1.000
3b 0.572 1.342 3g 0.760 1.013
4b 0.747 1.292 4g 0.602 0.493
5b 0.725 1.362 5g 0.660 0.695
6b 0.661 1.176 6g 0.614 0.512
7b 0.506 1.218 7g 0.691 0.894
Cannabis Hallucinogens
2c 0.727 1.000 2h 0.621 1.000
3c 0.746 1.019 3h 0.659 1.288
4c 0.655 0.567 4h 0.784 1.099
5c 0.698 0.731 5h 0.783 1.330
6c 0.663 0.645 6h 0.492 0.811
7c 0.551 0.766 7h 0.458 0.969
Cocaine Opioids
2d 0.890 1.000 2i 0.758 1.000
3d 0.859 1.065 3i 0.864 1.385
4d 0.907 0.721 4i 0.723 1.081
5d 0.797 1.028 5i 0.921 1.714
6d 0.624 0.757 6i 0.587 0.911
7d 0.614 1.045 7i 0.669 1.322
Stimulants Others
2e 0.779 1.000 2j 0.676 1.000
3e 0.814 1.086 3j 0.741 0.963
4e 0.876 1.016 4j 0.671 0.565
5e 0.850 1.189 5j 0.668 0.673
6e 0.669 0.839 6j 0.705 0.686
7e 0.611 0.962 7j 0.687 0.965
Model fit X 2(1,583)=50,863.65, p< 0.001, RMSEA=0.040, SRMR=0.032, CFI=0.920,TLI=0.913
Appendix B
Proportions of subjects seeking psychological care by age group and of the total sample
Non-seeking psychological care Seeking Psychological care Total
Total Total Total
Scales No intervention Brief intervention Intensive treatment Total No intervention Brief intervention Intensive treatment Total No intervention Brief intervention Intensive treatment Total
Age n % n % n % n % n % n % n % n % n % n % n % n %
Tobacco 18 − 19 996 84.19 185 15.64 2 0.17 1183 7.26 169 68.42 77 31.17 1 0.40 247 8.76 1165 81.47 262 18.32 3 0.21 1430 7.48
20 − 24 2278 76.14 694 23.20 20 0.67 2992 18.37 461 64.93 236 33.24 13 1.83 710 25.19 2739 73.99 930 25.12 33 0.89 3702 19.37
25 − 29 1774 73.00 620 25.51 36 1.48 2430 14.92 307 63.96 161 33.54 12 2.50 480 17.03 2081 71.51 781 26.84 48 1.65 2910 15.23
30 − 34 1696 72.42 608 25.96 38 1.62 2342 14.38 218 65.66 104 31.33 10 3.01 332 11.78 1914 71.58 712 26.63 48 1.80 2674 13.99
35 − 39 1533 73.63 513 24.64 36 1.73 2082 12.78 165 62.50 89 33.71 10 3.79 264 9.37 1698 72.38 602 25.66 46 1.96 2346 12.28
40 − 44 1252 76.16 373 22.69 19 1.16 1644 10.09 165 71.74 55 23.91 10 4.35 230 8.16 1417 75.61 428 22.84 29 1.55 1874 9.81
45 − 49 1117 78.66 283 19.93 20 1.41 1420 8.72 169 81.25 36 17.31 3 1.44 208 7.38 1286 78.99 319 19.59 23 1.41 1628 8.52
50 − 54 810 82.15 164 16.63 12 1.22 986 6.05 108 83.08 22 16.92 0 0.00 130 4.61 918 82.26 186 16.67 12 1.08 1116 5.84
55 o more 999 82.49 201 16.60 11 0.91 1211 7.43 174 79.82 41 18.81 3 1.38 218 7.73 1173 82.09 242 16.93 14 0.98 1429 7.48
Total 12455 76.46 3641 22.35 194 1.19 16290 100.00 1936 68.68 821 29.12 62 2.20 2819 100.00 14391 75.31 4462 23.35 256 1.34 19109 100.00
Alcohol 18 − 19 1012 85.55 162 13.69 9 0.76 1183 7.26 190 76.92 50 20.24 7 2.83 247 8.76 1202 84.06 212 14.83 16 1.12 1430 7.48
20 − 24 2455 82.05 470 15.71 67 2.24 2992 18.37 541 76.20 147 20.70 22 3.10 710 25.19 2996 80.93 617 16.67 89 2.40 3702 19.37
25 − 29 1917 78.89 436 17.94 77 3.17 2430 14.92 352 73.33 90 18.75 38 7.92 480 17.03 2269 77.97 526 18.08 115 3.95 2910 15.23
30 − 34 1920 81.98 369 15.76 53 2.26 2342 14.38 263 79.22 57 17.17 12 3.61 332 11.78 2183 81.64 426 15.93 65 2.43 2674 13.99
35 − 39 1743 83.72 284 13.64 55 2.64 2082 12.78 195 73.86 53 20.08 16 6.06 264 9.37 1938 82.61 337 14.36 71 3.03 2346 12.28
40 − 44 1408 85.64 200 12.17 36 2.19 1644 10.09 193 83.91 29 12.61 8 3.48 230 8.16 1601 85.43 229 12.22 44 2.35 1874 9.81
45 − 49 1266 89.15 136 9.58 18 1.27 1420 8.72 180 86.54 22 10.58 6 2.88 208 7.38 1446 88.82 158 9.71 24 1.47 1628 8.52
50 − 54 897 90.97 77 7.81 12 1.22 986 6.05 117 90.00 10 7.69 3 2.31 130 4.61 1014 90.86 87 7.80 15 1.34 1116 5.84
55 o more 1118 92.32 87 7.18 6 0.50 1211 7.43 201 92.20 15 6.88 2 0.92 218 7.73 1319 92.30 102 7.14 8 0.56 1429 7.48
Total 13736 84.32 2221 13.63 333 2.04 16290 100.00 2232 79.18 473 16.78 114 4.04 2819 100.00 15968 83.56 2694 14.10 447 2.34 19109 100.00
Cannabis 18 − 19 1082 91.46 97 8.20 4 0.34 1183 7.26 210 85.02 34 13.77 3 1.21 247 8.76 1292 90.35 131 9.16 7 0.49 1430 7.48
20 − 24 2711 90.61 260 8.69 21 0.70 2992 18.37 608 85.63 96 13.52 6 0.85 710 25.19 3319 89.65 356 9.62 27 0.73 3702 19.37
25 − 29 2201 90.58 212 8.72 17 0.70 2430 14.92 406 84.58 64 13.33 10 2.08 480 17.03 2607 89.59 276 9.48 27 0.93 2910 15.23
30 − 34 2159 92.19 168 7.17 15 0.64 2342 14.38 292 87.95 37 11.14 3 0.90 332 11.78 2451 91.66 205 7.67 18 0.67 2674 13.99
35 − 39 1976 94.91 101 4.85 5 0.24 2082 12.78 242 91.67 18 6.82 4 1.52 264 9.37 2218 94.54 119 5.07 9 0.38 2346 12.28
40 − 44 1584 96.35 57 3.47 3 0.18 1644 10.09 216 93.91 14 6.09 0 0.00 230 8.16 1800 96.05 71 3.79 3 0.16 1874 9.81
45 − 49 1383 97.39 34 2.39 3 0.21 1420 8.72 202 97.12 4 1.92 2 0.96 208 7.38 1585 97.36 38 2.33 5 0.31 1628 8.52
50 − 54 970 98.38 15 1.52 1 0.10 986 6.05 128 98.46 2 1.54 0 0.00 130 4.61 1098 98.39 17 1.52 1 0.09 1116 5.84
55 o more 1195 98.68 16 1.32 0 0.00 1211 7.43 215 98.62 3 1.38 0 0.00 218 7.73 1410 98.67 19 1.33 0 0.00 1429 7.48
Total 15261 93.68 960 5.89 69 0.42 16290 100.00 2519 89.36 272 9.65 28 0.99 2819 100.00 17780 93.05 1232 6.45 97 0.51 19109 100.00
Cocaine 18 − 19 1172 99.07 10 0.85 1 0.08 1183 7.26 240 97.17 6 2.43 1 0.40 247 8.76 1412 98.74 16 1.12 2 0.14 1430 7.48
20 − 24 2928 97.86 59 1.97 5 0.17 2992 18.37 689 97.04 20 2.82 1 0.14 710 25.19 3617 97.70 79 2.13 6 0.16 3702 19.37
25 − 29 2374 97.70 48 1.98 8 0.33 2430 14.92 455 94.79 24 5.00 1 0.21 480 17.03 2829 97.22 72 2.47 9 0.31 2910 15.23
30 − 34 2301 98.25 38 1.62 3 0.13 2342 14.38 321 96.69 10 3.01 1 0.30 332 11.78 2622 98.06 48 1.80 4 0.15 2674 13.99
35 − 39 2052 98.56 27 1.30 3 0.14 2082 12.78 254 96.21 9 3.41 1 0.38 264 9.37 2306 98.29 36 1.53 4 0.17 2346 12.28
40 − 44 1616 98.30 26 1.58 2 0.12 1644 10.09 223 96.96 7 3.04 0 0.00 230 8.16 1839 98.13 33 1.76 2 0.11 1874 9.81
45 − 49 1402 98.73 17 1.20 1 0.07 1420 8.72 205 98.56 3 1.44 0 0.00 208 7.38 1607 98.71 20 1.23 1 0.06 1628 8.52
50 − 54 980 99.39 5 0.51 1 0.10 986 6.05 128 98.46 2 1.54 0 0.00 130 4.61 1108 99.28 7 0.63 1 0.09 1116 5.84
55 o more 1205 99.50 6 0.50 0 0.00 1211 7.43 217 99.54 1 0.46 0 0.00 218 7.73 1422 99.51 7 0.49 0 0.00 1429 7.48
Total 16030 98.40 236 1.45 24 0.15 16290 100.00 2732 96.91 82 2.91 5 0.18 2819 100.00 18762 98.18 318 1.66 29 0.15 19109 100.00
Stimulants 18 − 19 1181 99.83 2 0.17 0 0.00 1183 7.26 244 98.79 3 1.21 0 0.00 247 8.76 1425 99.65 5 0.35 0 0.00 1430 7.48
20 − 24 2970 99.26 19 0.64 3 0.10 2992 18.37 700 98.59 9 1.27 1 0.14 710 25.19 3670 99.14 28 0.76 4 0.11 3702 19.37
25 − 29 2399 98.72 23 0.95 8 0.33 2430 14.92 472 98.33 6 1.25 2 0.42 480 17.03 2841 97.63 29 1.00 10 0.34 2910 15.23
30 − 34 2312 98.72 27 1.15 3 0.13 2342 14.38 326 98.19 5 1.51 1 0.30 332 11.78 2638 98.65 32 1.20 4 0.15 2674 13.99
35 − 39 2068 99.33 11 0.53 3 0.14 2082 12.78 260 98.48 5 1.89 0 0.00 264 9.37 2328 99.23 15 0.64 3 0.13 2346 12.28
40 − 44 1632 99.27 9 0.55 3 0.18 1644 10.09 226 98.26 4 1.74 0 0.00 230 8.16 1858 99.15 13 0.69 3 0.16 1874 9.81
45 − 49 1412 99.44 8 0.56 0 0.00 1420 8.72 208 100.00 0 0.00 0 0.00 208 7.38 1620 99.51 8 0.49 0 0.00 1628 8.52
50 − 54 983 99.70 3 0.30 0 0.00 986 6.05 130 100.00 0 0.00 0 0.00 130 4.61 1113 99.73 3 0.27 0 0.00 1116 5.84
55 o more 1208 99.75 3 0.25 0 0.00 1211 7.43 217 99.54 1 0.46 0 0.00 218 7.73 1425 99.72 4 0.28 0 0.00 1429 7.48
Total 16165 99.23 105 0.64 20 0.12 16290 100.00 2783 98.72 32 1.14 4 0.14 2819 100.00 18948 99.16 137 0.72 24 0.13 19109 100.00
Inhalants 18 − 19 1180 99.75 3 0.25 0 0.00 1183 7.26 247 100.00 0 0.00 0 0.00 247 8.76 1427 99.79 3 0.21 0 0.00 1430 7.48
20 − 24 2982 99.67 9 0.30 1 0.03 2992 18.37 705 99.30 5 0.70 0 0.00 710 25.19 3687 99.59 14 0.38 1 0.03 3702 19.37
25 − 29 2418 99.51 11 0.45 1 0.04 2430 14.92 473 98.54 7 1.46 0 0.00 480 17.03 2891 99.35 18 0.62 1 0.03 2910 15.23
30 − 34 2337 99.79 5 0.21 0 0.00 2342 14.38 329 99.10 3 0.90 0 0.00 332 11.78 2666 99.70 8 0.30 0 0.00 2674 13.99
35 − 39 2075 99.66 7 0.34 0 0.00 2082 12.78 264 100.00 0 0.00 0 0.00 264 9.37 2339 99.70 7 0.30 0 0.00 2346 12.28
40 − 44 1641 99.82 2 0.12 1 0.06 1644 10.09 230 100.00 0 0.00 0 0.00 230 8.16 1871 99.84 2 0.11 1 0.05 1874 9.81
45 − 49 1419 99.93 1 0.07 0 0.00 1420 8.72 208 100.00 0 0.00 0 0.00 208 7.38 1627 99.94 1 0.06 0 0.00 1628 8.52
50 − 54 984 99.80 2 0.20 0 0.00 986 6.05 129 99.23 1 0.77 0 0.00 130 4.61 1113 99.73 3 0.27 0 0.00 1116 5.84
55 o more 1209 99.83 2 0.17 0 0.00 1211 7.43 218 100.00 0 0.00 0 0.00 218 7.73 1427 99.86 2 0.14 0 0.00 1429 7.48
Total 16245 99.72 42 0.26 3 0.02 16290 100.00 2803 99.43 16 0.57 0 0.00 2819 100.00 19048 99.68 58 0.30 3 0.02 19109 100.00
Sedatives 18 − 19 1145 96.79 36 3.04 2 0.17 1183 7.26 222 89.88 25 10.12 0 0.00 247 8.76 1367 95.59 61 4.27 2 0.14 1430 7.48
20 − 24 2859 95.55 121 4.04 12 0.40 2992 18.37 645 90.85 64 9.01 1 0.14 710 25.19 3504 94.65 185 5.00 13 0.35 3702 19.37
25 − 29 2301 94.69 119 4.90 10 0.41 2430 14.92 427 88.96 48 10.00 5 1.04 480 17.03 2728 93.75 167 5.74 15 0.52 2910 15.23
30 − 34 2228 95.13 106 4.53 8 0.34 2342 14.38 301 90.66 30 9.04 1 0.30 332 11.78 2529 94.58 136 5.09 9 0.34 2674 13.99
35 − 39 1967 94.48 110 5.28 5 0.24 2082 12.78 234 88.64 26 9.85 4 1.52 264 9.37 2201 93.82 136 5.80 9 0.38 2346 12.28
40 − 44 1546 94.04 93 5.66 5 0.30 1644 10.09 205 89.13 22 9.57 3 1.30 230 8.16 1751 93.44 115 6.14 8 0.43 1874 9.81
45 − 49 1333 93.87 79 5.56 8 0.56 1420 8.72 182 87.50 22 10.58 4 1.92 208 7.38 1515 93.06 101 6.20 12 0.74 1628 8.52
50 − 54 918 93.10 67 6.80 1 0.10 986 6.05 118 90.77 9 6.92 3 2.31 130 4.61 1036 92.83 76 6.81 4 0.36 1116 5.84
55 o more 1130 93.31 73 6.03 8 0.66 1211 7.43 185 84.86 30 13.76 3 1.38 218 7.73 1315 92.02 103 7.21 11 0.77 1429 7.48
Total 15427 94.70 804 4.94 59 0.36 16290 100.00 2519 89.36 276 9.79 24 0.85 2819 100.00 17946 93.91 1080 5.65 83 0.43 19109 100.00
Hallucinogens 18 − 19 1168 98.73 15 1.27 0 0.00 1183 7.26 241 97.57 6 2.43 0 0.00 247 8.76 1409 98.53 21 1.47 0 0.00 1430 7.48
20 − 24 2940 98.26 49 1.64 3 0.10 2992 18.37 687 96.76 23 3.24 0 0.00 710 25.19 3627 97.97 72 1.94 3 0.08 3702 19.37
25 − 29 2388 98.27 41 1.69 1 0.04 2430 14.92 472 98.33 8 1.67 0 0.00 480 17.03 2860 98.28 49 1.68 1 0.03 2910 15.23
30 − 34 2321 99.10 21 0.90 0 0.00 2342 14.38 326 98.19 5 1.51 1 0.30 332 11.78 2647 98.99 26 0.97 1 0.04 2674 13.99
35 − 39 2070 99.42 11 0.53 1 0.05 2082 12.78 263 99.62 1 0.38 0 0.00 264 9.37 2333 99.45 12 0.51 1 0.04 2346 12.28
40 − 44 1639 99.70 4 0.24 1 0.06 1644 10.09 229 99.57 1 0.43 0 0.00 230 8.16 1868 99.68 5 0.27 1 0.05 1874 9.81
45 − 49 1415 99.65 5 0.35 0 0.00 1420 8.72 207 99.52 1 0.48 0 0.00 208 7.38 1622 99.63 6 0.37 0 0.00 1628 8.52
50 − 54 986 100.00 0 0.00 0 0.00 986 6.05 129 99.23 1 0.77 0 0.00 130 4.61 1115 99.91 1 0.09 0 0.00 1116 5.84
55 o more 1209 99.83 2 0.17 0 0.00 1211 7.43 218 100.00 0 0.00 0 0.00 218 7.73 1427 99.86 2 0.14 0 0.00 1429 7.48
Total 16136 99.05 148 0.91 6 0.04 16290 100.00 2772 98.33 46 1.63 1 0.04 2819 100.00 18908 98.95 194 1.02 7 0.04 19109 100.00
Opioids 18 − 19 1181 99.83 2 0.17 0 0.00 1183 7.26 247 100.00 0 0.00 0 0.00 247 8.76 1428 99.86 2 0.14 0 0.00 1430 7.48
20 − 24 2987 99.83 4 0.13 1 0.03 2992 18.37 708 99.72 2 0.28 0 0.00 710 25.19 3695 99.81 6 0.16 0 0.00 3702 19.37
25 − 29 2421 99.63 9 0.37 0 0.00 2430 14.92 478 99.58 2 0.42 0 0.00 480 17.03 2899 99.62 11 0.38 1 0.03 2910 15.23
30 − 34 2338 99.83 4 0.17 0 0.00 2342 14.38 331 99.70 1 0.30 0 0.00 332 11.78 2669 99.81 5 0.19 0 0.00 2674 13.99
35 − 39 2080 99.90 2 0.10 0 0.00 2082 12.78 264 100.00 0 0.00 0 0.00 264 9.37 2344 99.91 2 0.09 0 0.00 2346 12.28
40 − 44 1642 99.88 1 0.06 1 0.06 1644 10.09 230 100.00 0 0.00 0 0.00 230 8.16 1872 99.89 1 0.05 1 0.05 1874 9.81
45 − 49 1419 99.93 1 0.07 0 0.00 1420 8.72 208 100.00 0 0.00 0 0.00 208 7.38 1627 99.94 1 0.06 0 0.00 1628 8.52
50 − 54 986 100.00 0 0.00 0 0.00 986 6.05 129 99.23 1 0.77 0 0.00 130 4.61 1115 99.91 1 0.09 0 0.00 1116 5.84
55 o more 1210 99.92 1 0.08 0 0.00 1211 7.43 218 100.00 0 0.00 0 0.00 218 7.73 1428 99.93 1 0.07 0 0.00 1429 7.48
Total 16264 99.84 24 0.15 2 0.01 16290 100.00 2813 99.79 6 0.21 0 0.00 2819 100.00 19077 99.83 30 0.16 2 0.01 19109 100.00
Other 18 − 19 1167 98.65 15 1.27 1 0.08 1183 7.26 240 97.17 7 2.83 0 0.00 247 8.76 1407 98.39 22 1.54 1 0.07 1430 7.48
20 − 24 2951 98.63 36 1.20 5 0.17 2992 18.37 683 96.20 26 3.66 1 0.14 710 25.19 3634 98.16 62 1.67 6 0.16 3702 19.37
25 − 29 2400 98.77 26 1.07 4 0.16 2430 14.92 461 96.04 18 3.75 1 0.21 480 17.03 2861 98.32 44 1.51 5 0.17 2910 15.23
30 − 34 2304 98.38 33 1.41 5 0.21 2342 14.38 326 98.19 6 1.81 0 0.00 332 11.78 2630 98.35 39 1.46 5 0.19 2674 13.99
35 − 39 2048 98.37 33 1.59 1 0.05 2082 12.78 255 96.59 6 2.27 3 1.14 264 9.37 2303 98.17 39 1.66 4 0.17 2346 12.28
40 − 44 1617 98.36 23 1.40 4 0.24 1644 10.09 219 95.22 9 3.91 2 0.87 230 8.16 1836 97.97 32 1.71 6 0.32 1874 9.81
45 − 49 1396 98.31 24 1.69 0 0.00 1420 8.72 202 97.12 5 2.40 1 0.48 208 7.38 1598 98.16 29 1.78 1 0.06 1628 8.52
50 − 54 974 98.78 11 1.12 1 0.10 986 6.05 129 99.23 0 0.00 1 0.77 130 4.61 1103 98.84 11 0.99 2 0.18 1116 5.84
55 o more 1198 98.93 13 1.07 0 0.00 1211 7.43 216 99.08 1 0.46 1 0.46 218 7.73 1414 98.95 14 0.98 1 0.07 1429 7.48
Total 16055 98.56 214 1.31 21 0.13 16290 100.00 2731 96.88 78 2.77 10 0.35 2819 100.00 18786 98.31 292 1.53 31 0.16 19109 100.00
Author Contribution
SMR, RRG, and LBT contributed to the writing and data analysis, and CLTSC contributed to the data analysis review, discussion, and data interpretation. All authors contributed to the article and approved the submitted version.
Funding
We thank the University for the support from the DGAPA-IV300121.
Data Availability
The original contributions presented in the study are included in the article/supplementary material; further inquiries should be sent to the corresponding author/s.
Declarations
Ethics Approval
All procedures followed were in accordance with the ethical standard of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Thus, the protocol was reviewed and approved by the Ethics Committee of the Universidad Nacional Autónoma de Mexico.
Consent to Participate
The subjects provided their written informed consent to participate in the study.
Conflict of Interest
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Adinolfi, A. C., Gómez, B. A., Fernández, C. D., Alves, L. S. A., & Fernandes, G. J. C. (2022). Drug use frequency variation and mental health during the COVID-19 pandemic: An online survey. International Journal of Mental Health and Addiction. 10.1007/s11469-021-00546-7
American Psychiatric Association Diagnostic and statistical manual of mental disorders 2013 5 Autor
American Psychological Association (APA-GPT), Guidelines for the Practices of Telepsychology (GPT). (2013), reviewed July 27, 2020, in https://www.apa.org/practice/guidelines/telepsychology.
Bommelé, J., Hopman, P., Hipple, W. B., Geboers, C., Croes, E., Fong, G. T., Quah, C. K., & Willemsen, M. (2020). The double-edged relationship between COVID-19 stress and smoking: Implications for smoking cessation. Tobacco Induced Diseases, 18(63). 10.18332/tid/125580.
Browne MW Cudeck R Bollen KA Long JS Alternative ways of assessing model fit Testing structural equation models 1993 Sage Publications 136 162
Elhai JD Palmieri PA The factor structure of posttraumatic stress disorder: A literature update, critique of methodology, and agenda for future research Journal of Anxiety Disorders 2011 25 849 854 10.1016/j.janxdis.2011.04 21793239
Eysenbach G Improving the quality of Web surveys: The Checklist for Reporting Results of Internet W-Surveys (CHERRIES) Journal of Medical Internet Research 2004 6 e34 10.2196/jmir.6.3.e34 15471760
Ley General de Protección de Datos Personales en Posesión de Sujetos Obligados (LGPDPPSO). (2017). General Protection of Personal Information in Possession of Obligated Parties Act. reviewed on july 10th, 2020 in: http://www.diputados.gob.mx/LeyesBiblio/pdf/LGPDPPSO.pdf.
Global Drugs Report, the United Nations Office on Drugs and Crime of 2021 (GDR-UNODC). (2021) Reviewed February 28, 2021 in Informe Mundial sobre las Drogas 2021 de UNODC: los efectos de la pandemia aumentan los riesgos de las drogas, mientras la juventud subestima los peligros del cannabis. World Drug Report 2021 (United Nations publication, Sales No. E.21.XI.8)
Layman HM Thorisdottir IE Halldorsdottir T Sigfusdottir ID Allegrante JP Kristjansson AL Substance use among youth during the COVID-19 pandemic: A systematic review Current Psychiatry Reports 2022 24 307 324 10.1007/s11920-022-01338-z 35476186
Mellos E Paparrigopoulos T Substance use during the COVID-19 pandemic: What is really happening? Psyhciatriki 2022 33 17 20 10.22365/jpsych.2022.072
Mental Health, and Substance Abuse Observer System (MHSAMOS). (2021). Observatorio Mexicano de Salud Mental y Consumo de Sustancias Psicoactivas (OMSMCSP, 2021), reviewed March, 4, 2021 in INFORME_PAIS_2021.pdf.
Morales-Chainé S Robles-García R López MA Bosch MA Beristain AA Treviño SCCL Palafox PG Lira CIA Barragán TL Rangel GMG Screening tool for mental health problems during COVID-19 pandemic: Psychometrics and associations with sex, grieving, contagion, and seeking psychological care Frontiers Psychology 2022 13 882573 10.3389/fpsy.2022.882573
The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST-WHO). (2010). Manual for use in primary care. World Health Organization, 2010 ISBN 978 92 4 159938 2. La prueba de detección de consumo de alcohol, tabaco y sustancias (ASSIST) – Manual para uso en la atención primaria. Organización Mundial de la Salud, 2011. ISBN 978–927533236–8.
Tiburcio SM Rosete-Mohedano G Natera RG Martínez VNA Carreño GS Pérez CD Validez y confiabilidad de la prueba de detección de consumo de alcohol, tabaco y sustancias (ASSIST) en estudiantes universitarios Adicciones 2016 28 1 19 27 26990386
West SG Taylor AB Wu W Hoyle RH Model fit and model selection in structural equation modeling Handbook of structural equation modeling 2012 Guilford Press 380 392
| 0 | PMC9734572 | NO-CC CODE | 2022-12-14 23:28:29 | no | Int J Ment Health Addict. 2022 Dec 9;:1-28 | utf-8 | Int J Ment Health Addict | 2,022 | 10.1007/s11469-022-00972-1 | oa_other |
==== Front
Innov Syst Softw Eng
Innov Syst Softw Eng
Innovations in Systems and Software Engineering
1614-5046
1614-5054
Springer London London
516
10.1007/s11334-022-00516-9
S.I. : Low Resource Machine Learning Algorithms (LR-MLA)
Opinion classification at subtopic level from COVID vaccination-related tweets
Sadhukhan Mrinmoy [email protected]
1
Bhattacherjee Pramita [email protected]
2
Mondal Tamal [email protected]
3
Dasgupta Sudakshina [email protected]
2
Bhattacharya Indrajit [email protected]
4
1 grid.257435.2 0000 0001 0693 7804 Computer Science, Indira Gandhi National Open University, New Delhi, India
2 grid.440742.1 0000 0004 1799 6713 Department of IT, Government College of Engineering and Textile Technology, Serampore, West Bengal India
3 grid.511110.5 Computer Science and Engineering Department, D Y Patil International University, Pune, India
4 grid.440742.1 0000 0004 1799 6713 Department of Computer Application, Kalyani Government Engineering College, Kalyani, Nadia, West Bengal India
9 12 2022
112
14 6 2022
22 11 2022
© The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Coronavirus disease 2019 (Covid-19) is a contiguous disease which affected a large volume of population with a high mortality rate across the globe. For dealing with the recent spread of COVID-19, one of the prime measures was to vaccinate people in full extent. People across the globe have diverse opinion regarding the vaccination process, its side effect and effectiveness. Such opinions get located into different micro-blogging sites including twitter. Opinion mining through analyzing public sentiments of such micro-blogs is a common method for detection of public responses. This paper focuses on classifying the public opinions expressed related to COVID-19 vaccination at sub topic level. The procedure tries to find out different keywords regarding positive, negative and neutral sentences. From those keywords, different related query set was constructed using Rocchio query expansion algorithm for positive, negative and neutral sentiments. Later Extended query set is used to form subtopic using LDA algorithm to identify the nature of the tweets. The proposed LDA model came across with 0.56 coherence score with twenty subtopics, which is fair enough to classify the tweets in different classes. This trained model is finally used to classify the tweets in real time with Apache Kafka framework regarding different subtopic based on positive, negative or neutral sentiment.
Keywords
LDA
Rocchio-expansion
TF-IDF
Tweepy
COVID-19
Indexing
Kafka
==== Body
pmcIntroduction
Twitter is a micro-blogging platform that assists community to provide information and their opinions concisely regarding any topic. The said block of information or tweets conveys public opinion regarding various topics. From past two years due to the spread of COVID-19 , it has been observed that people have been remained stuck into their places and the only way to express their opinion was through different social media platforms [1, 2]. Twitter being a popular platform has seen a major rise in its usage and has provided a rich source of data for opinion mining [3]. As soon as the vaccines rolled out across the globe, we evidenced array of reactions among people. For getting a clear understanding about the thought process of general public in context to vaccination, such reactions should get mined in real time at sub topic level. In the past literature [4], various models and tools have been adopted [5] for analyzing sentiments from tweets. However, specifically the tweets have been classified in positive, negative and neutral scores. COVID-19 being a disease similar to influenza and much other flu like diseases has caused different kind of perception among people. Some thought of it as a mere flu and dismissed the importance of vaccines, while some took the disease seriously and were slightly more intent on taking the vaccine. The constant propagation of positive news regarding vaccine administration by health authorities helped to achieve high vaccine uptake [6]. After the uptake, several side effects were reported. These again caused a wave of changes in people’s attitude toward vaccine [6]. Some feared the disease, some the vaccine. To increase vaccine acceptance among people several notable users assured the safety of the vaccines through tweets [6]. The prime importance should be to evaluate attitude of the community toward accepting the steps to recover from COVID-19 pandemic. For that, effective policies should be adopted to spread the awareness by outreaching to the community either electronically or at ground level. However, in order to germinate such significant policies, one of the prime tasks should be to mine the opinions of the community at deeper to deepest level to make out their thought process periodically. Such an understanding would assist in implementing policies toward the safety drives of COVID-19 and any other epidemic or pandemic which might arrive in near future. In this work, we have developed such a classification model that would categorize the public opinions at subtopic levels in real time. Our contributions are modeled in three folds: Firstly, we have classified the tweets related to COVID-19 in positive, negative and neutral sentiments. Secondly, the topic modeling has been performed in order to extract the hidden topics or vectors from each class, which further act as the sub topics for respective the classes. Thirdly, a classification model is trained that would classify the real-world tweets related to vaccination in subtopic level based on their inner meaning and people’s opinion.
To accomplish this challenging task, we subdivide the proposed methodology in different sections. Introduction to the problem is presented in Sect. 1. We discussed the previous work on this problem in Sect. 2. Data collection part is presented in Sect. 3. Proposed technique is discussed in Sect. 4 and its subsections. In subsections, firstly we discussed outline of proposed methodology in Sect. 4.1. In Sect. 4.2, TF-IDF [7]-based feature extraction technique is discussed to select the word with the highest weight. Thirdly, we have formed query vector using Rocchio algorithm [8], which is discussed in detail in Sect. 4.3. LDA [9] algorithm is used for formation of subtopic related to different sentiment, which is described in Sect. 4.4. In Sect. 4.5, a brief description is given on how Apache Kafka [10] is utilized to build a real-time subtopic classification system . In Sect. 5, results and discussion of our work are presented, and in Sect. 6, conclusion and the future aspect of the work are described.
Literature survey
A number of works have been proposed on the field of natural language processing to identify the sentiment of tweets which are collected from different micro-blogging sites such as twitter. Number of researchers had used Machine learning and deep learning based technique for sentiment classification.
In machine learning-based sentiment classification approach different state-of-the-art models are used such as Random forest (RF) classifier, KNN (K nearest neighbor), SVM (Support vector Machine), Gaussian Naïve Bayes (G-NB), etc. Xiongwei Zhang et al. [10] proposed a real-time sentiment analysis system using Apache Kafka and Spark Streaming. The author has trained different machine learning algorithm SVM, RF, KNN on a pre-processed labeled dataset using Apache spark and choose the best model and use it for prediction of tweets which are coming in real time from twitter. For pre-processing of tweets, they perform noise removal, tokenization, normalization, and stemming to change the tweets in machine interpretable format. Bania [11] proposed TF-IDF and inductive learning based approach . Here author extracts the feature from pre-processed tweets using TF-IDF , uni-gram , bi-gram and tri-gram. Later these feature sets are used to train different machine learning models like Gaussian Naïve Bayes (G-NB), Bernoulli’s Naïve Bayes (BNB), Random forest (RF) and Support vector machine (SVM) and choose the model based on the accuracy for prediction purposes. Yuvraj Jain et al. [12] proposed sentiment analysis technique using Vader (Valence Aware Dictionary and Sentiment Reasoner). For pre-processing, they perform stemming, lemmatization, stop word removal, clearing text by removing hash-tag, @user and http link. After pre-processing, tweets are fit in Vader algorithm, which returns a polarity score of the tweets that can have any value as a decimal. The close the value is to ‘1’, the more positive the tweet is considered and vice versa. Koyel Chakraborty et al. [13] proposed the fuzzy rule-based sentiment analysis technique. They implemented a fuzzy rule based on Gaussian membership function and also triangular membership-based fuzzy inference system. Author chooses the best performing model for future prediction to correctly identify sentiments from tweets. Priya Iyer et al. [14] proposed a NB(naive Bayes) based sentiment analysis technique . For pre-processing, they perform removal of hashtags, white-spaces, hyperlinks and URL-address, HTML, special entities, usernames and removal of stop words and unicode strings from the tweets. After that, they use TF-IDF and bi-gram-based feature extraction technique to extract most important features. Later these tweets are used to train NB model. They obtained about 67% accuracy in time of prediction.
In deep learning-based sentiment analysis approach, we commonly found use of the LSTM (Long Short Term Memory), RNN (Recurrent Neural Network) and BERT (Bidirectional Encoder Representations from Transformers) [15] model. Nalini Chintalapudi et al. [15] uses pre-trained BERT model for sentiment analysis. They fine tuned the pre-trained BERT model on twitter data set which are labeled with sentiment. BERT model can accurately classify the tweets based on the sentiment like sad, joy, fear and anger. Rabindra Lamsal [16] proposed the large-scale tweet data collection technique based on geo-location and popular hash-tag. To analysis the data set, the authors used bi-gram to draw a network between different tweets. For sentiment analysis, they used LSTM-based deep network to calculate sentiment score. Later author replaces the LSTM with TextBlob [17] to get better accuracy. Harleen Kaur et al. [18] designed an algorithm called Hybrid Heterogeneous Support Vector Machine (H-SVM) for performing the sentiment classification. They collect the twitter data based on different hashtag COVID-19, coronavirus, deaths, new case, recovered, etc. The proposed algorithm can classify tweets in positive, negative and neutral sentiment with respective sentiment scores generated as output. They compared the performance of proposed model with RNN and SVM model in terms of accuracy. Soham Poddaret et al. [19] developed a unique way to investigate on specific user group who have posted tweets in Pre-COVID and COVID times. To classify the users from tweet set, they used CT-BERT++ a deep learning based model to accurately detect the Anti-Vax or Pro-Vax tweets and then identify those users who have posted it. Here author used LDA algorithm to identify the distinct topic and investigate how the exposure changes from pre-COVID time to COVID time.
Though some prior work showed that different authors had used machine and deep learning based technique for sentiment analysis. To our knowledge, none of the papers implement any method to analyze the sentiment at subtopic level. In this work, we provide a real-time method that can accurately classify each tweets with proper sentiment and then categorize them with proper subtopic.
Data collection
Various researchers have accumulated tweets on COVID-19-related vaccination from January 2020 to present and stored such collected tweets in the form of tweet ids into different data repositories1. For our work, we have utilized a data store of openICPSR2 for obtaining the tweet ids for collecting tweets. The mentioned organization had collected tweets from 28th January 2020 to 1st September 2021. Beside this, we have also collected tweets from October 2021 to March 2022 by using popular COVID-19-related hashtags, i.e. corona, covid19, coronavirus, quarantine, safety, covidcase, lockdown, sarscov2, pandemic, wearamask, socialdistancing, stayathome, stayhome, PfizerBioNTech, Covaxin and many more and also labeled them with proper sentiments by using Vader [12] sentiment analyzer with 0.96 percent accuracy for further research. The two data sets are merged into one data set for training the model. In Table 1, we give some examples for tweets which are collected from twitter and some tweets which are re-hydrated from collected tweet ids.Table 1 Samples of collected tweets
Description Sentiment
There currently are no vaccines, pills, potions, lotions, lozenges or other prescription or over-the-counter products available to treat/cure #coronavirus (#COVID19). Coronavirus-related ad claims will be subject to exacting scrutiny. More on the biz blog: https://t.co/U4jdCwy9AJhttps://t.co/u6HiUMuXN8 Positive
We desperately need a #coronavirus vaccine. For #BigPharma that means raise prices for private profit. Please sign this @GlobalJusticeUK petition demanding that public research money goes with the condition that any vaccine is cheap enough for all of us https://t.co/0NESauWJa8 Positive
We’ve seen excessive purchasing. This can negatively affect others. #COVID19 has us feeling anxious, but important to prepare, not panic. Guidelines suggest we have food/supplies for 2 weeks. Read abt effects of excessive #stockpiling from @AgriLifeTODAY. https://t.co/EzQfFoIVRihttps://t.co/6zAi3WQ7xQ Positive
Urgent travel warnings, supermarket chaos, and the hunt for a COVID-19 vaccine. Take a look at the latest coronavirus news. #9Today https://t.co/OdcA5ZyIw0 Negative
Today, Jennifer Haller, a healthy mother of two, became the first person in history to test a potential vaccine for COVID-19. We owe her and 44 other people stepping up for human trials a debt of gratitude Â- may their bravery save many lives. https://t.co/eF2StcxHlQ Positive
There is currently no vaccine to prevent #Coronavirus. The best way to prevent illness is to avoid being exposed to this virus. Here are some measures, Cimas recommends to reduce the risk. #CoronavirusAlert1?? #TogetherWeMakeADifference https://t.co/7JZ45Xz0Rf Negative
Stabilitech’s COVID-19 Vaccine Intended to Be Delivered in a Disruptive Thermally Stable Capsule safe, efficacious, self-administered vaccine capsules that’s inexpensive to produce, developed in weeks, thermally stable and can be posted direct to consumer. https://t.co/MvyZpxhvVO Positive
Tweets which are collected from twitter are not in valid format to use it in model for training and prediction purposes. Hence, we have to follow some techniques for pre-processing to clean the tweets. In the time of re-hydrate of tweet from tweet ids using twitter API, it returns a HTTP response in json format with multiple label and sub-label. From these labels, some of the them are useful for us. For this, we first convert this HTTP response in python dictionary format and from it necessary fields are fetched in a table for simplicity. In Table 1, the glimpse of HTTP response and collected tweets are given in tabular format. Tweets which are collected contain hash tags, @user, Http links, numbers, etc., which cannot be processed by natural language library. So, we have to pre-process them to make it useful for training. In Table 2, regex expressions which are used in pre-processing algorithm are presented in tabular format.
In Table 3 we have presented a step-by-step operation describing how the pre-processing algorithm works and cleaned tweets are made ready for further use in different algorithms.
After cleaning the tweets, stemming operations are applied to return the words in their root forms so that different words having same meaning could not create separate entity, while building the model. In Table 4, we have presented some tweets after stemming operation.
Proposed technique
Outline of proposed methodology
The proposed working model is depicted in Fig. 1. In this proposed architecture,3 pre-processed tweets which are rehydrated from tweet ids are supplied as input to train the LDA [9] model. The model can predict one tweet with its subtopic to classify the user opinion. In Fig. 1, we had tried to formalize the problem in a block diagram, from where we can easily understand different steps for implementation.Table 2 Steps of tweet pre-processing
Regex expression used for preprocessing
text->str(text)
text->regex(r'@\w+′,′′,text)
text->regex(r'#\w+′,′′,text)
text->regex(r'RT[\s]+′,′′,text)
text->regex(r'https?:\/\/\S+′,′′,text)
text->regex(r'[∧a-zA-Z#]+′,′′,text)
text->text.lower()
Checking of length of each word which is greater than 2.
Table 3 Step-by-step process to clean the tweets
Regex expression used for pre-processing Tweets after applying pre-processing rules
Raw tweets There currently are no vaccines, pills, potions, lotions, lozenges or other prescription or over-the-counter products available to treat/cure #coronavirus (#COVID19). Coronavirus-related ad claims will be subject to exacting scrutiny. More on the biz blog: https://t.co/U4jdCwy9AJhttps://t.co/u6HiUMuXN8
text->str(text) There currently are no vaccines, pills, potions, lotions, lozenges or other prescription or over-the-counter products available to treat/cure #coronavirus (#COVID19). Coronavirus-related ad claims will be subject to exacting scrutiny. More on the biz blog: https://t.co/U4jdCwy9AJhttps://t.co/u6HiUMuXN8
text->regex(r'@\w+′,′′,text) There currently are no vaccines, pills, potions, lotions, lozenges or other prescription or over-the-counter products available to treat/cure #coronavirus (#COVID19). Coronavirus-related ad claims will be subject to exacting scrutiny. More on the biz blog: https://t.co/U4jdCwy9AJhttps://t.co/u6HiUMuXN8
text->regex(r′#\w+′,′′,text) There currently are no vaccines, pills, potions, lotions, lozenges or other prescription or over-the-counter products available to treat/cure (). Coronavirus-related ad claims will be subject to exacting scrutiny. More on the biz blog: https://t.co/U4jdCwy9AJhttps://t.co/u6HiUMuXN8
text->regex(r'RT[\s]+′,′′,text) There currently are no vaccines, pills, potions, lotions, lozenges or other prescription or over-the-counter products available to treat/cure (). Coronavirus-related ad claims will be subject to exacting scrutiny. More on the biz blog: https://t.co/U4jdCwy9AJhttps://t.co/u6HiUMuXN8
text->regex(r'https?:\/\/\S+′,′′,text) There currently are no vaccines, pills, potions, lotions, lozenges or other prescription or over-the-counter products available to treat/cure (). Coronavirus-related ad claims will be subject to exacting scrutiny. More on the biz blog:
text->regex(r'[∧a-zA-Z#]+′,′′,text) There currently are no vaccines pills potions lotions lozenges or other prescription or over the counter products available to treat cure Coronavirus related ad claims will be subject to exacting scrutiny More on the biz blog
text->text.lower() There currently are no vaccines pills potions lotions lozenges or other prescription or over the counter products available to treat cure coronavirus related ad claims will be subject to exacting scrutiny more on the biz blog
Checking of length of each word which is greater than 2. There currently are vaccines pills potions lotions lozenges other prescription over the counter products available treat cure coronavirus-related claims will subject exacting scrutiny more the biz blog
Table 4 A snapshot of pre-processed and stemmed tweets
Description Sentiment
There currently are no vaccines pills potions lotions lozenges other prescription over the counter products available treat cure coronavirus related claims will subject exacting scrutiny more the biz blog Positive
Desperately need vaccine for that means raise prices for private profit please sign the petition demanding that public research money goes with the condition that any vaccine cheap enough for all Positive
Seen reports from colleagues across the country doorstep rogues claiming from the nhs providing covid vaccine scammers will take advantage the situation extort money gain access your home report any cold callers via Positive
Urgent travel warnings supermarket chaos and the hunt for covid vaccine take look the latest coronavirus news Negative
Today jennifer haller healthy mother two became the first person history test potential vaccine for covid owe her and other people stepping for human trials debt gratitude may their bravery save many lives Positive
There currently no vaccine prevent the best way prevent illness avoid being exposed this virus here are some measures cimas recommends reduce the risk Negative
Stabilitech covid vaccine intended delivered disruptive thermally stable capsule safe efficacious self-administered vaccine capsules that inexpensive produce developed weeks thermally stable and can posted direct consumer Positive
Fig. 1 Block diagram of the proposed model
Feature extraction using TF-IDF
Feature extraction is one of the important parts in the field of Natural Language Processing. For feature extraction purpose, we use TF-IDF (Term Frequency-Inverse Document Frequency) algorithm [7]. It is one of the most important techniques used for information retrieval to represent importance of a specific word or phrase in a given document. To calculate TF-IDF [7] for any word, we use count vectorizer to convert the tweets into bag of words which represents occurrence of each word in a document. Count Vectorizer also converts the each unique word into a numeric value which will be used in calculation of TF-IDF [7]. The TF-IDF value increases in proportion to the number of times a word appears in the document. TF-IDF [7] uses two statistical methods: First, is Term Frequency, and the other is Inverse Document Frequency. Term frequency refers to the total number of times a given word appears in the document against the total number of all words in the document and The inverse document frequency measure of how much information the word provides. TF measures the weight of a given word in the entire document. IDF shows how common or rare a given word is across all documents. TF-IDF [7] can be computed as tf * idf. We sort the word set according to there weight form high to low, and we take first 30 words as a feature and later it is used in Rocchio [8] query expansion as foundation to generate of extended query set. In Table 5 we have presented top 14 among 30 words feature set.Table 5 Top 14 words among 30 words Feature set calculated by TF-IDF
1 ID Word Count Weight
2 0 Covid 4667 243.906914
3 1 Store 3340 220.305497
4 2 Grocery 2942 207.898252
5 3 Supermarket 2886 193.077264
6 4 Prices 2964 189.122269
7 5 Food 2717 177.935706
8 6 Grocery store 2296 176.767438
9 7 Amp 2656 168.936069
10 8 Hand 1807 158.525416
11 9 People 2301 157.517270
12 10 Sanitizer 1658 152.005650
13 11 Consumer 2039 146.073079
14 12 Online 1765 139.648347
15 13 Like 1695 135.985668
Table 6 Extended query set
Initial query Extended query set
Store Store, brix,furlough,wore,pennysylvania,..
Price Price,crude,slash,opec,exorbit,slump,..
Food Food,insecur,beverag,destroy,combin, immigr,migrant,..
Covid Covid,amp,easter,youth,commission,destroy, disast,sanit,bacteria,..
Query vector formation
Here we use classical query expansion algorithm Rocchio [8] relevance feedback algorithm, based on vector space model. In this algorithm, we provide relevant set of tweets which are related to the input query vector and also provide non-relevant set of tweets. Then we form the relevance and non-relevance document vector as input to the Rocchio algorithm. After that, we apply query expansion formula which is depicted below.1 q→m=αq→0+β1|Dr|∑d→j∈Dnrd→j-γ1|Dnr|∑d→j∈Dnrd→j
Here α, β and γ are weights attached to it and q0 is the original query vector, Dr and Dnr are the set of known relevant and non-relevant documents respectively. If we have a lot of judged document, then we set the value of β and γ little higher. In our paper, we give more strength on the weightage of relevant documents than the non-relevant, for this we have to set the values of γ<β. Here we set α=1.0, β=0.75 and γ=0.15. In Rocchio [8] algorithm, when we provide one word or word pair as input , it will return 30 words as extended query set in output. In Table 6, an example is provided to show how the Rocchio [8] query expansion algorithm generating a extended query set. This extended query set is fed to LDA [9] algorithm as input for subtopic analysis. From Table 6, we can observe that if we provide covid word as a query, then Rocchio will return covid, amp, easter, youth, commission, destroy, disast, sanit, bacteria and many more as extended query set.
Generation of subtopic using LDA
Topic modeling is a kind of method to automatically organize the documents based on some hidden themes. A document can be part of multiple topics at a time with different contribution scores per topic and we choose dominant topic for the document, which is a kind of soft clustering. To analyze topic(or theme), here we used one of the state-of-the-art machine learning algorithm known as LDA(Latent Dirichlet Allocation) [9]. It is an unsupervised document classification algorithm. In this paper, we used LDA algorithm for topic modeling purposes to extract the inner theme of tweets. To construct the LDA model, we have used extended query vector which is provided by Rocchio [8] algorithm as a input . The model outputs the group of words classified with sub topics. In Fig. 2, an image is provided through which we can easily understand how LDA model has generated subtopics based on some inner themes. For each type of sentiment, we trained the LDA model separately with separate extended query set and store it for further use.Fig. 2 Clustering of different words based on inner themes
To determine the merit of LDA model, the coherence score of the model is observed. In our work, we set topic size at 20; for this, we observed the coherence score as 0.56, which is good enough for LDA model. We can also increase or decrease number of topics based on word set and document size. In Figs. 3, 4 and 5, we present scatter plot of topic vs coherence score for the positive, negative and neutral sentiment.
From Figs. 3, 4 and 5, we can observe that after 20 subtopics the coherence score remains constant, which is nearly 0.56; hence, we have chosen 20 as our number of sub topics. In Table 7, we represent some topic with its keyword which is classified by LDA model [9]. From Table 7, it can be observed that in the subtopic numbered 1, we have obtained some keyword such as covid, price, consum, demand, oil, and stop, which are related to each other.Table 7 Subtopic related to negative sentiment
Subtopic name Keywords
1 Covid, Price,consum,demand,oil,coronaviru,stop insight,survey,gold,webniar
2 Store,groceri,supermarket,worker,work,one,go easter,sunday,piece,mail
3 Amp,peopl,pandem,get,time,crisi,connect,walmart dump,distilleri,greater
4 Food,need,buy,suppli,stock,panic,inventori,snap,code
5 Shop,onlin,led,gift,bid,portal,institut,commit
Utilization of Apache Kafka and Apache Spark to build the classification model at subtopic level
Event streaming is the digital equivalent of the human body’s central nervous system, it is the practice of capturing data in real-time from event sources like databases, sensors, mobile devices, cloud services, and software applications in the form of streams of events; storing these event streams durably for later retrieval. Apache Kafka [10] is one the leading event streaming architecture. To accomplish our real-time subtopic level classification of tweets, we have used Apache Kafka and Apache Spark. In this step, we have used Twitter Streaming API to stream Twitter data filtered by COVID-19-related hashtags, i.e. corona, covid19, coronavirus, quarantine, safety, covidcase, lockdown, sarscov2, pandemic, wearamask, socialdistancing, stayathome, stayhome, PfizerBioNTech, covaxin and many more. and Apache Kafka [10] is used to ingest data from Twitter. Twitter Streaming API is used to retrieve tweets about coronavirus produced in real-time for classifying the tweets at subtopic level. For connecting to the API and retrieving Twitter data, we have used a python library called Tweepy. After the connection to Twitter Streaming API is established, streaming data are ingested form Twitter to Kafka’s topic. Spark [10, 20] streaming and machine learning capabilities are then utilized to process streaming tweets and use LDA model for subtopic-level analysis. In particular, Apache Kafka [10] streaming pre-processes the collected tweets related to coronavirus on-the-fly and categories them according to their sentiment using the Vader [12] sentiment analyzer. After that, Apache spark [10] is used to classify the tweets with different subtopic using pre-trained LDA [9] model and store them for future uses.Fig. 3 A coherence versus number of topic graph for positive sentiment
Fig. 4 A coherence versus number of topic graph for negative sentiment
Fig. 5 A coherence vs number of topic graph for neutral sentiment
Table 8 Distribution of different topics related to positive and negative sentiment
Sentiment Topic number Topic name Topic concept Top words Tweet
Negative 6 Medicine Price Rise Concerns about Medicine price hike due to covid 19 Covid, price, pandem, contract, youth, opec, ayurved, grip, medicine, hike Advice talk neighbors family exchange phone numbers create contact list phone numbers neighbors schools employer chemist set online shopping accounts poss adequate supplies regular meds order
Negative 6 Medicine Price Rise Concerns about Medicine price hike due to covid 19 Covid,price,pandem , contract, youth, opec, ayurved, grip, medicine, hike Reminder price gouging illegal califor nians protected experience illegal price gouging housing gas food essentials submit complaint office call
Negative 02 Unavailability of vaccine to prevent covid Concerns about unavailable of covid-19 vaccination Vaccine, prevent, illness, virus, exposed There currently no vaccine prevent the best way prevent illness avoid being exposed this virus here are some measures cimas recommends reduce the risk
Negative 11 Food Shortage Concerns about food shortage and price hike in super- market Pleas, supermarket , hazard, safe, food, stock, feb, egg, amp, panic Ready supermarket outbreak paranoid food stock litteraly empty serious thing please panic causes shortage
Positive 02 Human trials Concerns about the human trials of covid 19 vaccine Healthy, history, vaccine, human, trails, lives, save Today jennifer haller healthy mother two became the first person history test potential vaccine for covid owe her and other people stepping for human trials debt gratitude may their bravery save many lives
Positive 16 Increase demand Due to covid 19 demand became high for food products Food, increase, demand, stock, full, groceries Due to the Covid-19 situation, we have increased demand for all food products. The wait time may be longer for all online orders, particularly beef share and freezer packs. We thank you for your patience during this time
Positive 18 Social distancing People try to maintain their social distancing to stop covid spread Social, distance, covid, supermarket, spread, stop I would love to practice social distancing but my occupation doesn’t allow it I monitor the selfservice area in a retail store and to do that I am required to remain in that area and assist customers when needed My greatest fear is getting Covid 19 unknowingly and 1 4
Negative 20 Online scam Concerns related to online scam cases due to online payment at store or online shopping app Consumer, online, shopping, workers, scam, needs, thanks, groceries, foods, safety, pricing Corona prevention stop buy things cash use online payment methods corona spread notes also prefer online shopping home time fight covid
Table 9 Performance comparison of different topic modeling techniques
LDA NMF LSA BERT
Topic 1 Topic 2 Topic 1 Topic 2 Topic 1 Topic 2 Topic 1 Topic 2
Covid Store Covid Store Covid Worker Covid Groceri
Covid Groceri Price Supermarket Consum Groceri Demand Stroe
Consum Supermarket Oil Work Demand Store Price Work
Demand Worker Coronavirus One Oil Panic Consum One
Oil Work Stop Go Coronavirus Shop Coronavirus Go
Coronavirus One Insight Sunday Stop Online Stop Easter
Stop Go Price Survey Gift Insight Sunday
Insight Easter Mall Survey Price
Survey Sunday Gold Inventori
Gold Price Code
Fig. 6 Real-time Tweets Classification
Results and discussion
The main challenges of our work are to classify the tweets with proper sentiment and extract subtopics in real time. For this purposes, we have used the Vader [12] sentiment analyzer. Vader (Valence Aware Dictionary and Sentiment Reasoner) is a lexicon and rule-based sentiment analysis tool that is specifically attuned to sentiments expressed in social media. It is used for sentiment analysis of text which has both the polarities, i.e. positive/negative. In Vader [12], we calculate the intensity of any tweet; if the sentiment score is found to be greater than 0.05 it is marked as positive sentiment, if the sentiment score is less than -0.05 it is treated as negative sentiment otherwise it is classified as neutral sentiment. Here we mainly focus on the tweets with positive and negative sentiment. After sentiment analysis part, we have applied trained LDA [9] model according to tweets sentiment to classify tweets in different subtopic category based on underneath theme of word grouping. To implement it in real time, we first integrate Apache Kafka [10] with twitter API to collect tweets based on some hash-tag related to COVID-19. After that on receiving the tweets, Vader [12] classifies them and Kafka saves the tweets as a message streams in a topic. Now, Apache Spark [10] reads the massages upon subscribing the topic and classifies them according there subtopic with the help of trained LDA model. Thus we can achieve the speed for classifying the tweets in real time. In Table 8, we represent distribution of different topics related to positive and negative sentiment.
From Table 8, we can observe that, across different time frame people tweet different opinion which is happening around us in our country or world. People frequently complain about medicine price hike, supermarket charging extra price for foods due to high demand and low availability, different fraud cases happening around us and money deducted from bank account due to scam. These subjects are highly negative in sentiment. After sentiment analysis, we group these type tweets by using different subtopics. From Table 8, we can observe different types of topic such as, Topic 6 [Medicine Price Rise], Topic 11 [Food Shortage], and Topic 20 [online scam]. In the negativity around us, there are some positive parts also such as small shop keepers tweeting they are getting huge demand from retailers. People maintaining social distancing, etc. For positive tweets, some of the topics are Topic 18 [social distancing], Topic 16 [Increase Demand], etc. In Table 9, a comparison among the performance of LDA model with machine learning-based topic modeling technique such as NMF (Non Negative Matrix Factorization) [21], LSA (Latent Semantic Analysis) [21] and deep learning-based topic modeling technique is presented.Fig. 7 Relation between methodology and tools required
From Table 9, observation can be made that for same numbered subtopic, LSA model and NMF model clusters less number of words in comparison with LDA and BERT model. It can also be observed that the performance of LDA and BERT model is nearly comparable as they generate same number of subtopics with respect to a topic. BERT [15] model is not chosen in our case because, there is always a token limitation for training the model, and it can only achieved the highest accuracy score when trained on billion of data sets with huge number of parameters. But machine learning approach based on LDA model is a unsupervised probabilistic clustering algorithm which does not require such huge amount of data for training purposes and does not have any token limitation also. A snapshot is given in Fig. 6 describing the classification of tweets in real time.
From Fig. 6, we can observe that value contains the real-time pre-processed tweets, timestamp helps us to know when the tweets are generated or posted in twitter, and sentiment gives us sentiment perceived in the tweets that is calculated by Apache Kafka [10] framework. Subtopic represents the proof in which the upcoming tweets should belong to, which is evaluated by Apache spark framework [10].
A relation between the methodology and tools required for various activities is presented in Fig. 7.
From Fig. 7, we can observe that for sentiment analysis we have used VADER [12] sentiment analyzer and for query vector formation we have used Rocchio [8] algorithm. For subtopic creation, we have used LDA [9] algorithm, and for real-time classification of tweets we have used Apache Kafka and Apache Spark [10].
Conclusion
This work systematically analyzes how the tweets are finally classified in different subtopics based on the word grouping. This might help to understand the inner theme of tweets posted regarding COVID-19 by analyzing the subtopic name. Essentially the proposed work provides a framework to use live tweet data related to COVID-19. The framework can automatically process the upcoming tweet and is categorized into different sentiments which is fed to the previously trained model to finally map it into appropriate subtopic level. This work would be helpful for the decision makers to identify the public sentiment related to COVID-19 vaccination, depending upon subtopic classification to make necessary decision regarding the vaccination process. In the future work, we like to build more advanced model which helps to visualize the changes of sentiment related to tweets in spatio-temporal way that might help to find the thought process of general people and their reaction regarding the COVID-19 vaccination process. Another future work might be to design a model that can accurately track a subtopic and detect whether the number of tweets related to it with different sentiments is increasing or decreasing.
Data availability
The tweet data are collected using twitter API, and some tweet ids is collected from openICPSR [22].
Declarations
Conflict of interest
Proposed work is self-funded and uses Google Colab free tier version for training purposes. There is no conflict of interest with other proposed state-of-art models.
1 https://github.com/lopezbec/COVID19_Tweets_Dataset
2 openICPSR: ’https://www.openicpsr.org/openicpsr/project/120321/version/V6/view?path=/openicpsr/120321/fcr:versions/V6/Twitter-COVID-dataset---Jan-2021’
3 The GitHub link of the project is given. GitHub: ’https://github.com/mrinmoy-sadhukhan/LDA-topic-Kafka’
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pramita Bhattacherjee, Tamal Mondal, Sudakshina Dasgupta and Indrajit Bhattacharya have contributed equally to this work.
==== Refs
References
1. Wong A, Ho S, Olusanya O, Antonini MV, Lyness D (2020) The use of social media and online communications in times of pandemic COVID-19. J Intensive Care Soc. 10.1177/1751143720966280
2. Website. https://www.statista.com/topics/7863/social-media-use-during-coronaviruscovid-19-worldwide/topicHeader__wrapper last visited: 17-April-2022
3. Wicke P, Bolognesi MM (2021) Covid-19 Discourse on twitter: how the topics, sentiments, subjectivity, and figurative frames changed over time. In: Frontiers in communication, year:2021. 10.3389/fcomm.2021.651997
4. Kharde VA, Sonawane SS (2016) Sentiment analysis of twitter data: a survey of techniques. In: Int J Comput Appl 139(11)
5. Blog. https://monkeylearn.com/blog/sentiment-analysis-of-twitter/ Last Visited On: 11-(April-2022)
6. Dai H, Saccardo S, Han MA, Roh L, Raja N, Vangala S, Modi H, Pandya S, Sloyan M, Croymans DM (2021) Behavioural nudges increase COVID-19 vaccinations. In: Nature, 02
7. Kim SW Gil JM Research paper classification systems based on TF-IDF and LDA schemes Hum Cent Comput Inf Sci 2019 9 30 10.1186/s13673-019-0192-7
8. Ye Z, He B, Huang X, Lin H (2010) Revisiting Rocchio’s relevance feedback algorithm for probabilistic models. In: Information retrieval technology—6th Asia information retrieval societies conference, year, pp 151–161. 10.1007/978-3-642-17187-1_14
9. Blei DM, Ng AY, Jordan MI (2003) Latent Dirichlet allocation. J Mach Learn Res
10. Zhang X, Saleh H, Younis EM, Sahal R, Ali AA (2020) Predicting coronavirus pandemic in real-time using machine learning and big data streaming system, In: Hindwai, Complexity, vol. 2020, Article ID 6688912, 10 p. 10.1155/2020/6688912
11. Bania RK (2020) COVID-19 public tweets sentiment analysis using TF-IDF and inductive learning models. In: INFOCOMP, vol 19(2), pp 23–41
12. Jain Y, Tirth V (2020) Sentiment analysis of tweets and texts using python on stocks and COVID-19. Int J Comput Intell Res 16(2), 87–104. 10.37622/IJCIR/16.2.2020.87-104
13. Chakraborty K, Bhatia S, Bhattacharyya S, Platos J, Bag R, Hassaniene AE (2020) Sentiment analysis of covid-19 tweets by deep learning classifiers—a study to show how popularity is affecting accuracy in social media. Appl Soft Comput. 10.1016/j.asoc.2020.106754
14. Iyer KBP, Kumaresh S (2020) Twitter sentiment analysis on coronavirus outbreak using machine learning algorithms. In: EJMCM, Volume 207, Issue 203, pp 202663–2676
15. Chintalapudi N, Battineni G, Amenta F (2021) Sentimental analysis of COVID-19 tweets using deep learning models. In: PMC, Apr 1. 10.3390/idr13020032
16. Lamsal R (2020) Design and analysis of a large-scale COVID-19 tweets dataset. In: Springer Nature. 10.1007/s10489-020-02029-z
17. TextBlob. https://textblob.readthedocs.io/en/dev/, last accessed on (May-2022)
18. Kaur H, Ahsaan SU, Alankar B, Chang V (2021) A proposed sentiment analysis deep learning algorithm for analyzing COVID-19 tweets. In: PMC, 2021
19. Poddar S, Mondal M, Misra J, Ganguly N, Ghosh S (2021) Winds of change: impact of COVID-19 on vaccine-related opinions of twitter users. In: arxiv, Sat, 20. 10.48550/arXiv.2111.10667
20. Apache Spark. https://spark.apache.org/, last accessed on (May-2022)
21. Kherwa P, Bansal P (2019) Topic modeling: a comprehensive review, In: EAI endorsed transactions on scalable information systems 24. 10.4108/eai.13-7-2018.159623
22. openICPSR. https://www.openicpsr.org/openicpsr/project /120321/version/V6/view ?path=/openicpsr/120321/fcr:versions/V6 /Twitter-COVID-dataset-Jan-2021, last accessed on (May-2022)
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Commentary
Connecting the Dots Among Science, Education, and STEM
http://orcid.org/0000-0001-8832-3223
Nazir Joanne [email protected]
grid.430529.9 Faculty of Humanities and Education, School of Education, University of the West Indies, St. Augustine, St. Augustine, Trinidad and Tobago
7 12 2022
17
18 10 2022
© Ontario Institute for Studies in Education (OISE) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Makerspaces, Innovation and Science Education: How, Why, and What For? is an attempt to interrogate questions about the history, philosophy, and sociology of science and schooling that have long troubled science educators. In crafting the book, the author, Michael Tan, uses the microcosm of makerspaces to move back and forth to interrogate questions about the nature of knowledge, nature of science, nature of pedagogy, and nature of schooling best suited for the times we live in. In the seven chapters that comprise the book, the author has worked out a consistent framework to answer these questions. This framework represents a strong academic opinion that is thought provoking.
Résumé
L’ouvrage intitulé « Makerspaces, Innovation and Science Education: How, Why, and What For? (Laboratoires ouverts, innovation et enseignement des sciences: comment, pourquoi et dans quel but ?)» tente d’obtenir des réponses aux questions portant sur l’histoire, la philosophie et la sociologie des sciences ainsi que sur l’enseignement qui ont longtemps tourmenté les éducateurs scientifiques. Dans l’élaboration de son livre, Michael Tan, utilise le microcosme des laboratoires ouverts pour aller et venir en s’interrogeant sur la nature de la connaissance, celle de la science, la nature de la pédagogie et celle de la scolarisation qui sont les mieux adaptées à l’époque dans laquelle nous vivons. Dans les sept chapitres qui composent le livre, l’auteur élabore un cadre cohérent pour répondre à ces questions. Ce cadre forme une opinion théorique forte qui suscite la réflexion.
Keywords
Science education
Nature of science
History, philosophy, sociology of science
STEM education
==== Body
pmcAs a young teacher, I read John Ziman’s (2000) Real Science: What it is and what it means. I was fascinated by the nature of science ideas this author discussed, and concerned about the implications for teaching science in schools that these suggested. At the time, I was working as a high school teacher in a post-colonial, developing country whose education system could best be described as content oriented and exam driven. Ziman’s work deeply disturbed me and started me on a quest to figure out how I could go about teaching science to my students in a more authentic, meaningful way.
A few years later, I moved on to graduate school to pursue a Masters and then a Doctorate in the field of education. As anyone who has been on a similar journey would appreciate, I read many courses in curriculum and general education. But my abiding interest in science education also led me to enroll in available courses that explored the history, philosophy, and sociology of science (HPSS); science, technology, society, and environments (STSE); teaching and learning science; and other contemporary issues in science education. I also read a lot in general, as one does, when pursuing postgraduate studies. During this time, my knowledge of the nature of science and education grew, and my concern became framed by two main questions: How could the gaps between science, technology, and society be bridged in high school science? And how could this type of authentic science education be made a practical reality for all types of learners despite variations in culture, location, ethnicity, and learning diversity?
My ruminations at the time led me in the direction of Science, Technology, Society and Environment (STSE) education, which seemed a good response to my concerns and resulted in a collaborative paper with my then supervisor Dr. Erminia Pedretti, entitled Currents in STSE Education: Mapping a Complex Field, 40 Years On (Pedretti & Nazir, 2011). In that paper, we tried to clarify the nature of STSE education by identifying, exploring, and critiquing six currents at work in the field. We created a typology and put it forward in the hope that it would serve as a heuristic/didactic tool for others to help bring about a practice of science education, that it represented the nature of science more realistically, and it would result in science learning that was more relevant and useful to students and society. At the time, that paper provided me a certain amount of personal mental respite from those big questions that had bothered me for so long.
I am currently a middle career academic. After completing my graduate studies at the Ontario Institute for Studies in Education (OISE) in Canada, I am once again in the context where I started: a content-oriented, exam-driven, post-colonial, developing country. This time, however, I work in a tertiary level institution where I teach teachers (mainly science teachers), and conduct research in education. My research interests have broadened to encompass both science education and sustainability education. While one can get caught up in the busyness of day-to-day academic life, there are times when my mind returns to those questions about the nature of science and science education that fascinated me as a young high school teacher.
I still grapple with understanding the true nature of science. Moreover, I find myself wondering about the nature of knowledge, the nature of schooling, and how all of these can align to best prepare young people for a world that can suddenly turn strange and a future that is largely unpredictable. As I write, the COVID-19 pandemic is ongoing. I am also acutely aware of the international political/economic instability engendered by the Russia-Ukraine war, and the undeniability of climate change facing the planet.
Michael Tan’s book Makerspaces, Innovation and Science Education: How, Why, and What For? is a refreshing attempt to answer those troubling questions in the present context. In crafting the book, he utilizes the microcosm of makerspaces, an aspect of the current Science, Technology, Engineering, and Mathematics (STEM) education movement that is most often seen as a means to teach the elusive “T” and “E” (technology and engineering aspects) within school science, and moves back and forth, microscopic to macroscopic to interrogate bigger questions about the nature of knowledge, nature of science, nature of pedagogy, and nature of schooling best suited for the times we live in. It is important to note that, for Tan, the work students do in makerspaces is more than the familiar hands-on activities or verification (cookbook) exercises that many teachers call practical work. Rather, they are spaces with multiple resources/materials available, where students are actively allowed to tinker, design, experiment, build, and invent in a student-directed, open-ended way.
Moreover, the role of the teacher in these spaces is cognitive coach and support rather than direct instructor. In other words, they are spaces of genuine inquiry, which, for this author, is a major deficiency of the usual science classroom. A most commendable thing is that, in the seven chapters that comprise the book, the author has worked out a consistent framework to link these ideas together. This framework is thought provoking, and presented as a way for educators to reorient science teaching and learning, especially if one accepts the underlying assumptions that run through the work.
Chapter 1 serves as an advanced organiser of the work. The author’s main antecedents, theoretical commitments, and ideas are presented in broad strokes, so that impatient readers can, as Richard Gunstone suggests, in the endorsement pages of the book, get a quick summary of the main ideas the author will be discussing by reading this chapter especially the closing paragraph:For the most part, schools tend to be associated with economic preparation of individuals (and, therefore, the community). In my opinion, this needs to be rethought. Yes, economic preparation is important, but it cannot be all there is to school. Schools can do a lot more, and science education in particular need not only concern itself with ‘conceptual acquisition’, and only at a cognitive psychological perspective. Science education can, and should, consider itself as a source of moral uplift, and I will discuss three principles of makerspace instruction that can help bring this about. (p. 10)
Put simply, one of the main aims of the book is to encourage readers to reconsider the place of technological design and engineering in traditional science education, especially how epistemological and cultural practices from these aspects of STEM, such as educating for innovativeness, the assumption of knowledge as having non-cognitive components, the need for deep learning, and the acceptance of utilitarian ethics, can help prepare students to solve present and future wicked problems, a much needed change that many science education scholars and researchers have been calling for, for some time now (e.g., Bencze et al., 2020; Calabrese Barton, 2003; Zeidler, 2014).
Chapter 2 explores the nature of knowledge and makes links to the nature of science that should frame science/STEM education. Tan begins by acknowledging that we are living in the post-truth era as a lead in to offer Michael Young as a major theorist worthy of consideration with respect to these. In particular, he reviews Young’s work about the relationship between knowledge and power and to justify science as a valuable form of powerful knowledge. He also discusses the notion that knowledge is socially constructed and contrasts it with a realist empirical position, philosophers about the nature of science traditionally endorse. Tan reconciles these two antithetical positions by suggesting school science adopt a middle position called social realism; that is, there is a reality out there that is discernible even through faulty social processes. This means, what stands the test of time is true:While social processes are responsible for making and adjudicating truth claims about the nature of reality as we may perceive it with our senses or with instruments, and while such social processes may be fallible because individual humans are fallible, the net effect of these processes is to produce a self-correcting mechanism that, over the long term, corrects itself, and represents humanity’s best knowledge. (p. 24)
This is a foundational position that the author builds upon in subsequent chapters.If we accept the social realist epistemological position, we already begin to see the importance of making for a complete STEM/science education. If our knowledge is in the form of socially generated truth claims grounded in stable reality, it matters that we increase access to the experiences of this stable reality, and that learners have opportunities to negotiate truth claims made up from their subjective experiencing of this reality. (p. 26)
Chapter 3 explores the nature of learning. The author draws upon Michael Polanyi’s (1967) aphorism of “knowing more than we can tell” (p. 4) to argue for learning as embodied cognition — the notion that the body’s interaction contributes to learning in significant ways. This idea implies learning involves more than discrete cognitive mental processes. Rather, it involves the complex interaction of both body and mind. Indeed, according to Tan, learning especially in STEM requires bodily experiences with the physical world and phenomena. While Tan does not expand on exactly how embodied cognition works, he contends that it should be driven by student interests and involve a spiraling cycle of doing and thinking reminiscent of David Kolb’s (1984) theory of experiential education.
In this chapter, he discusses makerspaces as ideal environments for embodied cognition to occur, since they contain physical resources that students are free to use to pursue their own inquiries and inventions. He is careful to note that makerspaces are not the STEM equivalent of the usual practical work often referred to by science educators as science labs, where scientific facts are verified, but rather places where students can be excited and learn deeply, and authentically about science, engineering and technology. He is also careful to note that makerspaces are not sites of manufacturing but spaces of doing where students can tinker, try, fail, and work together to generate artefacts to solve personally relevant problems or answer their own questions. To breathe life into this alternative understanding of STEM education, he provides examples of student projects he has observed in makerspaces in Singapore.
Chapter 4 follows from the epistemological and ontological considerations presented in the first three chapters. It explores the nature of teaching required to bring about the transformations in science education the book is concerned with. In this chapter, Tan advances design, as practiced in makerspaces, as a pedagogy for science and STEM education. This particular pedagogical practice draws on theories of engineering design and design education to include the social nature of knowledge creation and technology development, into the teaching–learning paradigm. The complexity of this type of pedagogy is used within the chapter to show the shortcomings of current science pedagogy and schooling. Tan goes further to suggest that the pedagogical ideas he is advancing can, not only transform science/STEM education, but serve as drivers for a new type of schooling overall, one that moves away from a traditional production line model and more towards an authentic, creative socially driven model for education.Design, is interested in the particular, as an interdisciplinary study of how and why intentions should be made real, stands before us as a candidate, mostly misunderstood within our schooling contexts obsessed with ahistorical decontextualised forms of knowledge. The role of makerspaces within such a framework of goals for schooling is as a site for contextualisation. Makerspaces fight the desire to reduce phenomena to mere representation. Representations attempt but will never express the fullness of the phenomena; makerspaces are sites of demonstration, decomposition of technologies to its constituent components so as to discern how they work, and crucially, the construction of alternative technologies that are driven by intentions other than what we currently possess. (p. 77)
Chapters 5 and 6 deepen the author’s framework for reorienting science/STEM education by exploring the type of axiology that should drive education for authentically preparing students for contemporary life. Chapter 5 delves into the problems of current STEM education bought about by inadequate/uncertain guidelines of how to treat with the ethical aspects inherent to the nature of science and science education. Tan begins by questioning if science itself is inherently flawed by having corruptible value components. However, he ultimately goes on to dismiss this criticism in favour of the argument that it is how science is taught that is the essential problem. He suggests that appropriate ethics can be taught by disrupting traditional pedagogies in STEM makerspaces and allowing for discussions of the communal aspects of design and group activity which tacitly but persistently encourage the creation of artefacts that are good for the many rather than good for few individuals. In this chapter, he offers evidence that such activities are practically possible by relating observational stories from his own research in Singaporean makerspaces.
Chapter 6 tackles the specific ethical dilemma of how the non-human world is treated by science/STEM practitioners and educators. Tan argues that, while science is about understanding and manipulating the physical world, this does not have to equate with unsustainably harming the non-human parts of the world. He draws upon Tim Ingold’s ideas about the textuality of making (p. 116) and Andrew Pickering’s mangle of practice (p. 122) to introduce notions that the process of creation entails a partnership between humans and materials, and that the non-human world has a substantial agency of its own in this process. He suggests how these characteristics can be used by science educators to challenge the false assumption that the world is a passive thing to be conquered. Tan concludes that makerspaces frontally allow students to work with materials in ways which allow them to experience material agency, and provide opportunities to learn to value non-human components of the world in more healthy ways.
Chapter 7 is the final chapter in the book. It summarises the main ideas proffered in Chapters 2–6, and seeks to tie the insights together in a consistent framework. The author begins by reiterating his criticism of traditional science education as mired in the past, and wrongheaded in its practices by comparing science educators to automatons working from old programming. He reiterates the fundamental ways in which STEM education, in his opinion, can change, through taking on a social realist epistemology, acknowledging the agency of the non-human world, and adopting a pedagogy that is experiential and driven by utilitarian ethics. For Tan, makerspaces are essential components of science/STEM education. He summarises ways makerspaces can be constructed to enact his framework, by focusing on inventing not manufacturing, people not things, and just in time teaching not just in case.
The main strength of the work has been noted early on in this review: more than simply criticizing theory and practice driving current science education, Tan provides an alternative framework to help address those problems. Moreover, that framework draws upon existing theories in the field and is internally consistent within itself. Among the myriad of ideas present in the academic sphere, the author has carefully selected ideas, presented them to the reader separately and then sewn them together with his own research findings to form a strong academic opinion on his chosen topic.
What is additionally commendable is that the author demonstrates what he purports. Within his writing, he takes on a social realist stance to explain why embodied cognition is the best way of learning, design the best pedagogy for contemporary science/STEM education, and what all of this means for schooling as a whole. Other strengths of the work have to do with the language and writing style of the author. Tan uses language that is accessible and engaging to present the reader with ideas that are complex. He does so by writing in a conversational manner which gives the reader the impression that she/he is talking to a familiar colleague rather than reading a dry academic treatise.
He often punctuates material that might be particularly dense with stories, aphorisms, and personal experiences in a bid to assist the reader in understanding what he is trying to say. For example, in Chapter 2, he gives the humorous example of Carol Beer, a character from a British sketch comedy series, to illustrate the public’s willingness to cede power to science and technology in everyday life. In taking on the issue of whether science is intrinsically ethical in Chapter 5, he uses a quirky story about the possible link between engineering education and jihadists to draw the reader in. These departures, other than lightening the work, demonstrate the breath of Tan’s reading and the depth of thinking he has expended in developing his thesis.
Still, despite its strengths, the work is not without its weaknesses. The book is a personal academic opinion that the writer is presenting for consideration to the reader. This feature is simultaneously a source of strength and weakness for the work. For this review, I will focus on three points that disturbed me during my reading of the book stemming from this essential characteristic. Firstly, Tan’s work is a progressive thesis made up of ideas that build one upon the other, and are interlinked in a dependent way. These ideas are riddled with tacit assumptions that readers need to agree with, to accept the thesis as a whole. If a reader does not agree with any one of these ideas or its underlying assumptions, then the internal consistency of the framework can disintegrate for that reader. For example, if one does not take on the social realist view of knowledge as he has presented in Chapter 2, then arguments about the need for bodily interaction with the physical world for learning to take place (embodied cognition) presented in Chapter 3 are difficult to agree with. Similarly, if one does not accept that the non-human world has agency as suggested by the textuality of materials and mangle of practice, then the ethical opportunities discussed in Chapter 6 lose tenure. This feature means that the reader has to be vigilant in discerning what Tan’s underlying assumptions are, and question if they hold true for them and for all contexts.
My second criticism is linked to the first. Tan’s work is concerned with fundamental questions: the nature of reality, the nature of science/science education, and the nature of schooling. These are quite longstanding, and have been answered in many ways by a variety of authors drawing upon many antecedents. For each of these questions, Tan attempts to give an overview of the variety of ideas that seek to explain or respond, but eventually picks certain theories to focus on. He inevitably presents his choices as the best response to bring about an overall goal of preparing students for life in our problem ridden world.
As I read, I kept wondering about the suitability of his choices as drivers for science/science education for all contexts. This unease was exacerbated by my observation of certain gaps in the author’s thinking. Throughout the work, Tan gives little consideration to spirituality and gender and what they might mean for science/science education. Indeed, in Chapter 5, he brusquely dismisses religion as having been disproved by science, and the feminist critique of the scientific method as unworthy of serious practical consideration. My third criticism has to do with the theoretical choices Tan has made. Most of the theories that form the basis of his framework come from white, western academics. This was surprising to me, especially since Tan situates himself in Singapore, which is a post-colonial, mostly non-white state in the Asia–Pacific region where ideologies of eastern origin are important cultural antecedents.
After reading the work, I found myself wondering whether there are ideas from scholars more representative of the sociohistorical context of these regions worthy of consideration for a thesis about science education and schooling? Since my own context is heavily influenced by non-western and post-colonial logistics, I found myself questioning the completeness of Tan’s thesis for me. For example, I wondered what someone reading explicitly from a post-colonial lens would make of this work. Would they see it as a prime example of non-white bodies continuing to privilege white ideologies, a continuing debilitating psychological effect of colonialism that Fanon (1967) described, and what Bristol (2012) calls plantation pedagogy with respect to education?
For any scholar, writing a whole book that summarises all one presently thinks about a topic is a remarkable achievement. In concluding this review, I would like to congratulate Dr. Michael Tan for having done so in a way that offers new understandings to longstanding important educational questions. Further, despite my critique above, I would recommend the book as a reading for anyone interested in science/STEM education. The work has a polyphonous character which means it has something to offer to various audiences. For the novel science educator/scholar, the book is a good introduction to the traditional history, philosophy, and sociology of science that seems to drive much of what happens in science education still.
While there are other good books that can serve similar purposes (e.g., Chalmers, 2013; Hodson, 2008; Losee, 2001; Ziman, 2000), Tan provides a cogent summary of salient points in a contemporary way that is easy to read. For mid-level to senior science educators/scholars, the book can provide novel ways of thinking about the nature of science and science education. For anyone working with the Next Generation Science Standards (National Research Council, 2013), which emphasize a deep understanding of science concepts and engaged inquiry, Tan’s work may suggest novel ideological directions to make these aims a practical reality. For those interested in STEM education in particular, the work provides a good description of the nature of makerspaces and how these might work to make the “T” and “E” in the acronym more apparent.
There are works we read that once finished, we leave behind. There are other things that we come back to over and over again, because they contain seeds of thought that feed the intellect or nag one to think in novel ways. I suspect that this book will be like this for me.
Acknowledgements
I have known Michael Tan for the past 15 years since we were both graduate students at OISE in the same cohort. I consider him a colleague and friend.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Bencze L Pouliot C Pedretti E Simmoneaux L Simmoneaux J Zeidler D SAQ, SSI and STSE education: Defending and extending “science-in-context” Cultural Studies of Science Education 2020 15 825 851 10.1007/s11422-019-09962-7
Bristol, L. (2012). Plantation pedagogy: A postcolonial and global perspective. Peter Lang Publishing.
Calabrese Barton, A. (2003). Teaching science for social justice. Teachers College Press.
Chalmers, A. F. (2013). What is this thing called science? Hackett Publishing.
Fanon F Black skin, White masks 1967 New York Grove Press
Hodson, D. (2008). Towards scientific literacy: A teachers’ guide to the history, philosophy and sociology of science. Brill.
Kolb DA Experiential learning: experience as the source of learning and development 1984 Englewood Cliffs, NJ Prentice Hall
Losee, J. (2001). A historical introduction to the philosophy of science. OUP Oxford.
National Research Council. (2013). Next Generation Science Standards: For States, By States. Washington, DC: The National Academies Press. 10.17226/18290.
Pedretti, E., & Nazir, J. (2011). Currents in STSE education: Mapping a complex field, forty ears on. Science Education, 95(4), 601–626.
Polanyi, M. (1967). The tacit knowledge dimension. Routledge & Kegan Paul.
Zeidler, D. L. (2014). Socioscientific issues as a curriculum emphasis: Theory, research, and practice. In N.G Lederman & S.K. Abell (Eds.), Handbook of research on science education, volume II (pp. 711–740). Routledge.
Ziman, J. (2000). Real Science: What it is and what it means. Cambridge University Press.
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Delivering Virtual Care to Patients with Cognitive Impairment within the Veterans Health Administration: Multi-level Barriers and Solutions
http://orcid.org/0000-0001-8901-2363
Gould Christine E. [email protected]
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Iyer Sowmya 13
Filips Julie 4
Alfaro Ana Jessica 12
Carlson Chalise 1
Trivedi Ranak 25
1 grid.280747.e 0000 0004 0419 2556 Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA USA
2 grid.168010.e 0000000419368956 Deptartment of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Palo Alto, USA
3 grid.168010.e 0000000419368956 Division of Primary Care and Population Health, Geriatrics Section, Stanford University School of Medicine, Palo Alto, USA
4 grid.484313.9 0000 0004 0420 8589 VISN 23 Clinical Resource Hub, VA Minneapolis Health Care System, Minneapolis, MN USA
5 grid.280747.e 0000 0004 0419 2556 Center for Innovation to Implementation, VA Palo Alto Health Care System, Menlo Park, CA USA
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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Older patients with cognitive impairment, including dementia, may benefit from virtual care that increases access to geriatric specialties. Here, we identify clinician-level strategies to address the numerous barriers that reduce utilization of virtual services. We describe two innovative programs in the Veterans Health Administration that deliver geriatric medicine and geriatric psychiatry services virtually. This commentary outlines concrete strategies addressing identified barriers, including technology access, digital literacy, and ambivalence and communication challenges during video visits. Two virtual care programs (tele-geriatric psychiatry consultation; tele-dementia care) that address complex medical and mental health issues in older adults with cognitive impairment are described. The Consolidated Framework for Implementation Research (CFIR) is used to categorize the clinician-level strategies and program elements as they relate to the implementation domains and constructs. Clinicians can use education strategies prior to and during virtual care visits to facilitate access to video, optimize the virtual experience, and promote information retention. These strategies rely on aspects of the inner setting, outer setting, and characteristics of individuals. The two virtual programs vary in their intervention characteristics and the inner setting, yet both programs share similar characteristics of individuals. Key elements contributing to adoption and sustainment of these virtual care programs for patients with cognitive impairment include the relative advantage of virtual care to leverage access to specialists over alternative solutions in each setting. Other factors to consider include the importance of communication, program champions, and the role of the Veterans Health Administration.
Keywords
Dementia
Older adults
Telehealth
Telemedicine
http://dx.doi.org/10.13039/100019294 Office of Rural Health
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pmcOne in 5 people aged 65 and older in the USA (20%) has mild cognitive impairment, and 1 in 9 (10.7%) has Alzheimer’s dementia (Langa & Levine, 2014; Rajan et al., 2021). Patients with cognitive impairment may present with complex medical and psychiatric comorbidities that necessitate care from specialties including geriatric medicine and geriatric psychiatry. Geriatric specialists often help clarify treatment plans when issues such as polypharmacy, behavioral and psychological symptoms of dementia, and caregiver stress may be present. These specialists, including interdisciplinary care teams, can promote non-pharmacological and pharmacological interventions to optimize the quality of life for patients with cognitive impairment and their caregivers. Unfortunately, these patients and their caregivers face multiple barriers to accessing in-person care due to transportation difficulties, logistical challenges, and behavioral challenges that may be exacerbated by unfamiliar clinical settings (Elbaz et al., 2021). Often specialists are located in urban medical centers (Juul et al., 2017), making access to care difficult for patients living in rural areas.
During the COVID-19 pandemic, additional factors complicated the receipt of specialty care for patients with cognitive impairment, who are particularly vulnerable to contracting COVID-19 (Numbers & Brodaty, 2021). Due to memory and attentional impairments, it is harder for patients with cognitive impairment to adhere to safeguarding procedures (i.e., physical distancing, restrictions, self-quarantine, and masking). Patients with advanced dementia may reside in institutional settings with higher COVID-19 transmission rates (Heras et al., 2021). Further, older patients in general have increased risk of complications and mortality from COVID-19 due to comorbidities such as hypertension, obesity, and diabetes (Tariq & Barber, 2018). This vulnerability compounded by the social isolation imposed by the pandemic and closure of respite options for caregivers makes it imperative to pursue virtual care for patients with cognitive impairment or dementia.
The rapid legislative changes to payment and privacy requirements made during the pandemic have increased access for a wider range of virtual care (Totten, McDonagh, & Wagner, 2020). These virtual care services (i.e., telehealth) include synchronous video visits to home or clinics, and audio only services (telephone visits). Video visits are generally encouraged and preferred (e.g., Chen et al., 2021; Nieman & Oh, 2020), particularly for patients with cognitive impairment (Iyer et al., 2021). However, research conducted within the Veterans Health Administration (VHA), the largest integrated healthcare system in the US serving 9 million veterans annually (Department of Veterans Affairs, 2022), has demonstrated gaps in access to video visits. One study found that older veterans were significantly more likely than younger veterans to have telephone visits for mental health both prior to and during the COVID pandemic (Connolly et al., 2022). An interview study about perceptions of telehealth in the VHA found that most patients valued seeing their providers during virtual visits (Chen et al., 2021). Particularly for patients with cognitive impairment, video allows the clinician to gather more information about the patient and their environment. Video also supports the clinician’s communication with the patient and caregiver through providing both visual and auditory input.
Barriers to virtual care were identified by reviewing the literature and incorporating the authors’ experience in delivering virtual care to patients with cognitive impairment and their caregivers. Barriers encompass lack of access to technology, broadband internet, limited digital literacy, and ambivalence about virtual care. Patients with cognitive impairment tend to be older and have lower rates of owning mobile devices and/or having broadband access (e.g., Choi et al., 2022). This, in turn, may be influenced by the cost of devices (e.g., smartphones and tablets) and internet services. Digital literacy is lower for older patients and may pose a challenge for caregivers as well (Schreurs et al., 2017; Wray et al., 2022). Notably, one study of Medicare beneficiaries found that 38% were unready for a video visit, primarily due to lack of experience with technology rather than access issues (Lam et al., 2020). Partaking in video telehealth requires navigation of complex health care systems to access appointments, including downloading apps or using patient portals to receive links to visits and to communicate with health care providers. Furthermore, age-related sensory changes to hearing, vision, and touch make interacting with a device interface more challenging. These factors taken together may contribute to providers offering telephone visits rather than video.
To address these barriers faced by patients with cognitive impairment and their caregivers, we apply the Consolidated Framework for Implementation Research (CFIR; Damschroder et al., 2009) in describing clinician-level strategies that facilitate virtual care. Then, we use CFIR to help characterize how two specialty virtual care programs were implemented within VHA for patients with cognitive impairment. CFIR is a comprehensive framework that is comprised of 5 domains (intervention characteristics, inner setting, outer setting, characteristics of individuals, and process) and 39 constructs that may affect implementation and related outcomes.
Clinician-Level Strategies
Clinicians play an essential role in helping older patients with cognitive impairment benefit from virtual care. The clinicians should consider the patient’s access to the internet and to video-capable devices (i.e., smartphone, tablet, computer with webcam). Further, clinicians are generally responsible for considering a patient or caregiver’s digital literacy. Digital literacy, defined as a person’s ability to understand and use information from different technology platforms effectively (Gilster, 1997), is a critical challenge related to virtual care for older patients with cognitive impairment. Additionally, engagement in and communication during virtual care is important to both the patient/caregiver experience and the effective use of virtual care by clinicians. The implementation strategies that clinicians may utilize to deliver virtual care to patients with cognitive impairment align with the 3 CFIR domains of inner setting, outer setting, and characteristics of individuals (see Table 1).Table 1 Clinician-level strategies to address barriers organized by CFIR domain
CFIR domain/constructs Barrier addressed Potential solutions
Inner Setting Available Resources Access to devices and reduced cost internet • Free tablets for eligible veterans through VHA
Digital literacy • Connect patients with free community-based technology training classes and drop-in programs at local organizations (e.g., Area Agencies on Aging, senior centers, libraries)
• Use peers and/or family members to train
Inner Setting Access to Knowledge and Information Unfamiliarity with virtual care platform • Schedule practice sessions ahead of visit
- Ensure the device is connected to the internet, positioning the webcam
- Test the microphone
- Ask caregivers to adjust sound for patients with hearing impairment
- Enlarge font for those with visual impairment
• Use handouts
Outer Setting External Policies and Incentives Access to devices and reduced cost internet • Federal program (Lifeline) or private companies (e.g., AT&T, Comcast, Verizon, Spectrum) provide free or low-cost technology for low-income seniors
Characteristics of Individuals Knowledge and Beliefs about the Intervention, Self-efficacy Addressing clinician knowledge and beliefs about virtual care, especially ability to address patient ambivalence regarding virtual care • Discuss rationale for virtual care
• Highlight potential benefits including:
- Video visits save time and travel costs
- May strengthen rapport with clinicians
- Include family and caregivers
- Can allow for faster access to specialists
Self-efficacy with technology needed to provide virtual care and address communication challenges during visit • Ensure adequate amplification
• Minimize background noise
• Use simple language; speak slowly and clearly
• Involve a caregiver in visit when possible
• Ensure that patients have their glasses
• Use teach back technique to check for understanding
• Provide written summary of information shared and follow-up recommendations after visit
• Screenshare images to explain complex concepts
• Type important takeaway messages
Inner Setting
The inner setting, that is, the clinic and larger health care system where clinicians deliver care, contributes to the extent to which implementation of virtual care by an individual clinician succeeds. With regard to clinician-level strategies, the constructs of available resources and access to knowledge and information facilitate clinicians in helping patients access and use technology for video visits.
Available Resources
Available resources refer to those resources that are dedicated for implementation, which may include money, time, training, and physical space. Some available resources within the inner setting that support implementation of virtual care includes programs within health care systems that provide tablets to patients in need or discounts to internet service. Clinicians can ask patients and their caregivers if they have access to technology and internet at home and direct them to these available local and federal resources. Programming available in the community at Area Agencies on Aging (Administration for Community Living, 2017), senior centers, and public libraries also can help older adults with learning to use technology. Utilizing trained support staff to offer practice sessions to patients and caregivers prior to a virtual visit may help to ensure that the patient’s equipment is working properly and may help reduce anxiety about using technology to connect to the visit.
Access to Knowledge and Information
Having access to knowledge and information such as patient/caregiver handouts may address education, sensory, and cognitive barriers to technology. Visual impairment may make seeing small symbols or icons on a smartphone difficult, whereas impaired working memory makes remembering those symbols and icons more challenging (Lee et al., 2011). Simple handouts with instructions can be shared with patients/caregivers to help facilitate the process of downloading apps or connecting to video visits (Gould et al., 2020). Practice sessions conducted by staff trained to address technology issues with novice users may facilitate virtual care use.
Outer Setting
The outer setting spans organizations, government, and other entities that extend beyond a specific health care system.
External Policies and Incentives
External strategies may facilitate the spread of virtual care and may be utilized by clinicians when facilitating the use of virtual care by patients with cognitive impairment. For example, in the USA, low-income seniors enrolled in programs such as Medicaid may be eligible for free or low-cost technology through federal and state assistance programs (e.g., Lifeline; Federal Communications Commission, 2022). Some private companies (e.g., AT&T, Comcast, Spectrum, Verizon; Oaks, 2022) have discounted rates for low-income seniors.
Characteristics of Individuals
The characteristics of the individuals involved in implementing virtual care are critical to its success. Notably, two key constructs that the clinicians may exhibit include knowledge and beliefs about the intervention and self-efficacy in using virtual care.
Knowledge and Beliefs
A clinicians’ knowledge and beliefs about whether older patients with cognitive impairment may benefit from virtual care affect the implementation of this modality. Additionally, it is important for clinicians to not assume low digital literacy based on the age of the patient and/or caregiver. Clinicians may pursue informal lines of questioning with patients and/or caregivers. These questions include “have you ever participated in a virtual care appointment” or “how comfortable do you feel using [specific technology].” While questionnaires such as the Mobile Device Proficiency Questionnaire (Roque & Boot, 2018) assess digital literacy among older adults, the psychometric properties with cognitively impaired patients have not been investigated.
Some patients may be hesitant to use mobile devices and computers due to declining physical and mental functional capacity. Other reasons underlying hesitancy may include being unsure about why video visits are particularly useful, lack of confidence in technology modality, and having concerns regarding privacy (e.g., Evangelista et al., 2019). Clinicians may use their knowledge about virtual care to help convey the rationale for use of video as a way of addressing patient and/or caregiver hesitancy. Benefits of virtual care that could be shared include the timeliness of virtual care, particularly for those residing in rural areas, and the saving of time and money for the patient by avoiding travel costs (Iyer et al., 2021). Compared with telephone calls, video visits enhance the patient’s experience by virtue of strengthening their rapport with their clinician. Video visits delivered to the patient’s home offer the patient an increased comfort level by remaining in their home environment and offer clinicians insights into a patient’s daily living circumstances. Including supportive family and caregivers from different locations highlights a unique benefit of virtual visits (Iyer et al., 2021). Using video visits also delivers information through multiple modes of communication for those with hearing-impairment. Reassuring patients and addressing concerns around ease of use, privacy, and available backups for the technology (i.e., alternative video platforms, telephone) can be helpful. The rationale for video visits may be tailored to include discussion of some or all of these factors.
Self-efficacy
The extent to which clinicians feel confident in using the technology themselves is an important factor when working with potentially novice technology users who also have cognitive impairment. Confidence in using technology likely helps clinicians effectively use the following strategies to address communication difficulties that may arise. Taking the time to establish rapport, assessing and addressing hearing loss, ensuring adequate amplification, minimizing background noise, using simple language, speaking slowly and clearly, and monitoring for cues that patient does not hear or understand (e.g., looking to a caregiver to respond, responding inappropriately) are important to ensure adequate communication. Using screenshare images for cognitive assessments or for explaining complex concepts can be very helpful for communication. Using the teach back technique asks patients and/or caregivers to summarize the received information back to the clinician (Agency for Healthcare Research and Quality, 2021). This technique may need to be used more than once to ensure satisfactory comprehension and understanding of information conveyed during the visit. Providing written follow-up to visits can be helpful to patients (Nieman & Oh, 2020). Thus, clinicians’ self-efficacy in technology is critical to successful implementation of virtual care particularly with patients with cognitive impairment.
Virtual Care Programs
It is imperative to establish, test, and implement virtual care programs that can enable those clinicians with expertise in geriatrics to reach the patients in need. We describe two innovative programs implemented in the Veterans Health Administration (VHA) to provide video telehealth care to patients with cognitive impairment and dementia and their caregivers. The first program utilizes a single geriatric psychiatrist who delivers tele-geriatric psychiatry consultation to outpatient and nursing home settings across more than 5 states. The second program is a tele-dementia care program delivering nonpharmacological and pharmacological dementia services to older adults in 8 clinic sites in a health care system.
Tele-geriatric Psychiatry Consultation
The program focuses on timely consultation such that the veteran’s care, diagnosis, and treatment plan can be addressed within 24 business hours of receiving the consult. This rapid turnaround is critical for long-term care settings where distress behaviors could cause significant difficulties for the patients themselves, professional caregivers, and fellow patients/residents. This consultation program began in a multi-state region in the Midwest through a geriatric psychiatrist responding to local and regional needs requesting evaluation and guidance on treatment plans for older patients presenting with cognitive impairment or dementia, psychiatric comorbidities (e.g., depression, PTSD, schizophrenia), and distress behaviors affecting a patient’s care or quality of life. In 2012, the geriatric psychiatrist began consulting for a State Veterans Home as a collateral duty, which then soon expanded to virtual consultations provided to VHA extended care and rehabilitation settings (i.e., community living centers). By 2015, the geriatric psychiatrist was serving outpatient, extended care, and acute inpatient settings across multiple health care systems. In 2018, the geriatric psychiatrist’s position was moved to a regional clinical telehealth hub where the operations challenges could be addressed and strategies to help patients connect to video can be implemented, thus freeing the consultant’s time to deliver specialty care.
E-consultation (chart review only with recommendations given to the referring provider), video-to-home telehealth, and clinical video telehealth (video-to-clinic) comprise the three modalities of care delivery. In the rare cases in which video cannot be arranged, audio only services are provided. A thorough diagnostic assessment is conducted as part of the video consultation. Veterans are almost always accompanied by either formal or family caregivers for the interview, both for assistance in communication (i.e., hearing loss necessitating the need for local caregiver to repeat questions) as well as getting a firsthand witness account of concerns regarding the veteran patient. In addition to the clinical interview with the patient and corroborating information from caregivers, the geriatric psychiatrist consultant conducts a medical record review often spanning more than 10 years of notes. These extensive chart reviews sometimes require up to 3 hours and may be particularly time-consuming if patients received care across multiple VHA sites. Next, the consultant speaks with the referring provider and health care team members depending on the setting.
The result of this assessment is a detailed treatment plan that may include specific medication recommendations (i.e., suggested dosing and titration schedule, deprescribing, gradual dose reductions), lab and diagnostic tests, behavioral recommendations, and environmental recommendations for patient and family safety. The consultant conveys recommendations through notes in the electronic medical record, supplemented with phone/video conference calls to the local teams/providers. At the request of some local teams, the consultant joins scheduled meetings where patients on rehabilitation units are reviewed for behavioral concerns. Local staff contact the consultant through secure video calls, phone calls, or encrypted email to discuss behavioral concerns as well. Informal consultations can take substantial time and typically cannot be billed; however, developing close relationships with local providers is essential in delivering timely patient care and in supporting local providers.
Tele-dementia Care
In late 2016, two geriatricians at VA Palo Alto Healthcare System began piloting tele-dementia management provided through telephone and video visits after finding that 95% of geriatric consultation requests were for cognitive-related issues. Assessment services included clarifying diagnoses with brief cognitive assessments, conducting functional assessments, and addressing underlying issues contributing to functional decline among frail, older patients. The geriatricians provided evaluation and management services including cholinesterase inhibitor evaluation and management, pharmacologic and non-pharmacologic management for behavioral and psychological symptoms of dementia, pharmacological management of depression in those with dementia, polypharmacy review and recommendations to reduce potentially inappropriate medications and dementia caregiver support. This program was designed with an understanding of the specific demands of primary care, including limited time to address multiple conditions in brief problem-focused primary care visits. This program provides an additional layer of support for primary care providers in the management of older patients with complex medical and cognitive concerns, regardless of where the patient lives, thereby increasing access to hard-to-find specialists.
This tele-dementia care program began with geriatricians and has expanded to include nurses, a social worker, and medical trainees. Prior to the visit, the care team employs many clinician-level strategies discussed in the previous section. A clinician coaches caregivers in preparing for virtual visits. If needed, this may include requesting a tablet for future use from a program in the VHA to provide veterans with tablets (Zulman et al., 2019). Practice sessions are conducted as needed. During the visit, the geriatrician provides education to the patient and caregiver using multiple methods of delivery to promote information retention. Depending on the content of the visit and desires of the caregiver, additional resources are sent after the visit and are tailored to the presenting concerns for each patient/caregiver.
Consults and dementia-related medication orders were placed by the consulting geriatrician thereby reducing burden of consult follow-up recommendations on primary care providers. Ongoing case management, including prescribing, deprescribing, and titrating medications, behavioral recommendations, and caregiver support occurs via telephone and/or video visits. In a small pilot, the caregivers reported that the most value came from being able to speak to the geriatrician alone when needed, without the person with dementia, and the ability to have an expert “co-manage” the dementia, resulting in a longitudinal relationship between specialists and dementia caregivers through disease progression. This relationship led to less time needed by the primary care providers to address dementia-related problems at outpatient visits. Without this virtual modality of care, specialty geriatrics care would only be available at the main medical center, which is 130 miles from the farthest outpatient clinic site.
Similarities and Differences Between Programs
Key factors underlying the programs, their similarities and differences, correspond to the CFIR domains of intervention characteristics, inner setting, outer setting, and characteristics of individuals (see Table 2).Table 2 Comparing virtual care programs across CFIR domains and constructs
CFIR domain/constructs Tele-geriatric psychiatry Tele-dementia Similarities & differences
Intervention characteristics
Evidence-base Individualized, evidenced-based pharmacological and non-pharmacological approaches to geriatric mental health disorders and dementia Individualized, evidenced-based pharmacological and non-pharmacological approaches to dementia management Tele-GP and Tele-D are both use evidence-based approaches and tailor services to individual patient needs
Relative Advantage Rapid consultation, often within 24 h of receipt. Increases access to geriatric psychiatry often not available at medical centers/clinics Primary care providers get assistance with patients who would require care beyond brief appointments. Geriatricians prescribe medications, place orders and consults Tele-D places orders in electronic medical record. Tele-GP provides rapid consultation and geriatric mental health access. Both programs provide advantages over existing services using virtual care
Complexity Comprehensive diagnostic assessment including clinical interview, extensive chart review, and conversations with care team. Actionable recommendations provided for care team to implement with consultant guidance Assess presenting behavioral concerns related to dementia. Works directly with patient/caregivers. Triage to ensure appropriateness for co-management The number of steps for intervention vary based on referral source and clinical question. Tele-GP often incorporates multiple steps involving information
Characteristics of individuals
Individual Identification with Organization Geriatric psychiatrist participates on regional dementia committee Geriatrician led local/regional dementia committee Both programs utilize experts with established roles and connections to VHA organization
Inner setting
Network and Communications Leverages virtual communication modalities to work with local teams to coordinate care Primarily focuses on patients rather than care teams Tele-GP uses network and communications to work closely with referring providers and teams. Tele-D uses EMR and communicates with referring providers, albeit less frequently
Compatibility Assists with particularly challenging cases that need specialized geriatric psychiatry care Aims to improve primary care workflow via separate dementia co-management visits Tele-GP and Tele-D are compatible with different needs of their inner settings
Leadership engagement Support received from regional geriatrics and mental health leaders Program initiated as demonstration project, expanding to larger region with leadership support Leadership support was critical to both programs’ expansion to cover larger regions
Outer setting
Patient needs Complex cognitive and psychiatric co-morbidities Dementia and related behaviors and psychological symptoms Tele-GP and Tele-D target patients with complex needs who need specialized, tailored care
Tele-GP tele-geriatric psychiatry; Tele-D tele-dementia
Intervention Characteristics
Intervention characteristics refer to aspects of the intervention itself that relate to the success of implementation of the intervention.
Evidence Strength and Quality
The programs are similar in their evidence strength and quality in that the programs use individualized approaches to patient care, pulling from existing evidence-based practices, but not relying on specific intervention protocols. The principles of these treatment plans may be similar across patients and across programs (i.e., behavior plans, environmental modification, deprescribing to reduce polypharmacy or use of potentially inappropriate medications and prescribing of medications to target distress symptoms or psychiatric symptoms), but the combination of interventions varies from patient to patient.
Relative Advantage
The interventions have similar relative advantages in their use of virtual care to leverage access to specialists for patients with cognitive impairment. For the tele-geriatric psychiatry program, the rapid turn-around is a perceived advantage compared with other existing services. In contrast, the tele-dementia management program’s co-management of the dementia related concerns is an advantage over those concerns being managed in primary care alongside other medical concerns.
Complexity
The two programs vary in their complexity of the procedures of the intervention. For the tele-geriatric psychiatry consultation, the assessment includes many different steps and sources of information to be integrated into the individualized case conceptualization and/or treatment plan. In contrast, the tele-dementia program requires fewer steps, but longer follow-up with patients.
Characteristics of Individuals
Individual Identification with the Organization
Both programs are led by expert medical providers with board certifications in their respective fields. Notably the program leaders have worked with local care teams through in previous roles at their facilities and through professional service (i.e., dementia committees), thus indicating the role of the individual identification with the organization.
Inner Setting
The programs differ in their approach to creating plans of care for patients with cognitive impairment (i.e., recommendations versus intensive case management), which is largely driven by their local needs, that is the inner setting. Three key constructs emerged as important within the inner setting domain: network and communications, compatibility, and leadership engagement.
Network and Communications
Both programs utilize frequent communication with referring providers and local champions to generate referrals. The geriatric psychiatrist informally interacts with referring providers and local teams through messages, phone calls, and attendance at select weekly behavior rounds. Because the tele-dementia program serves patients/caregivers who largely reside at home, there is less time devoted to communication with other providers or health care staff. These differences in network and communication also highlight how each program is compatible with the needs of the inner setting. The compatibility of the tele-geriatric psychiatry program focuses on consultation on particularly challenging cases; whereas the tele-dementia program focuses on using co-management to improve primary care workflow.
Leadership Engagement
Support from managers and leaders helped the implementation within the health care systems despite lower work productivity as a function of the visit complexity. Nevertheless, both programs provide substantial informal provider consultation, which makes it difficult for the consultants to attain productivity standards due to the complex needs of the patients. Challenges to providing these clinical services across health care systems include the need for substantial administrative time and operations support to get clinicians credentialed in each system and to schedule patients across systems. Leaders involved have recognized these challenges and have accommodated for this nonbillable work and administrative time.
Outer Setting
Patient Needs
Within the outer setting, both programs address similar patient and caregiver needs that encompass co-occurring cognitive impairment and medical and/or psychiatric needs.
Limitations
These findings and lessons learned may not be generalizable beyond the VA health care system due to several system-level facilitators unique to the VHA. The VHA provides tablets with data plans to those patients in need (Zulman et al., 2019). Furthermore, regional telehealth centers have the operations expertise to address barriers such as scheduling and privileging in multiple health care systems. An additional limitation for the tele-geriatric psychiatry program is that it utilizes a single provider to deliver the care with some support from a nurse case manager. Should the physician leader leave, the program could fail, which is a substantial drawback of the program in its initial iteration. Expansions of the program are underway with a second geriatric psychiatrist available for consultation and coverage.
Conclusion
Taken together, these clinician-level suggestions and virtual care programs demonstrate how individualized approaches help patients with cognitive impairment and their caregivers access virtual care. Factors potentially related to implementation and sustainability of these programs include the match between the intervention and the inner setting. These two programs have been adopted in three new VHA sites with evaluations of the programs ongoing. Future directions include the need to conduct more rigorous tests of these programs, which may include measuring efficacy and effectiveness and ability to prevent emergency room visits or delay institutional care. However, this need for rigorous testing is balanced with the pragmatic/real-world need to care for those patients who present with cognitive impairment and complex psychosocial needs, psychiatric comorbidity, and multiple medical conditions. The decreasing pool of geriatrics subspecialists nationwide (e.g., Juul et al., 2017; Lester et al., 2020) is an important consideration, as virtual care may be the only way to access these hard-to-find specialty providers. Using virtual care to collaborate with local interdisciplinary teams and the use of clinician-level strategies in delivering virtual care can help expand access to comprehensive geriatrics and geriatric mental health assessments, potentially improving the quality of life for patients with cognitive impairment and their caregivers.
Acknowledgements
Views expressed in this article are those of the authors and not necessarily those for the Department of Veterans Affairs or the Federal Government.
Funding
Funding support was received from the US Department of Veterans Affairs Office of Rural Health and VA GRECC Connect Virtual Geriatrics Program.
Declarations
Ethics Approval
This manuscript does not involve human subjects. Related ongoing program evaluations of the services described were reviewed by the Stanford University Institutional Review Board and determined to not be human subjects research.
Conflict of Interest
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Christine E. Gould and Sowmya Iyer contributed equally to the manuscript.
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References
Administration for Community Living. (2017). Area agencies on Aging [webpage]. Retrieved August 9, 2022: https://acl.gov/programs/aging-and-disability-networks/area-agencies-aging
Agency for Healthcare Research and Quality. (2021). Teach-Back: intervention. Retrieved October 18, 2022: https://www.ahrq.gov/patient-safety/reports/engage/interventions/teachback.html
Chen PV Helm A Fletcher T Wassef M Hogan J Amspoker A Cloitre M Lindsay J Seeing the value of video: A qualitative study on patient preference for using video in a Veteran Affairs telemental health program evaluation Telemedicine Reports 2021 2 1 10.1089/tmr.2021.0005 35720762
Choi NG DiNitto DM Marti CN Choi BY Telehealth use among older adults during COVID-19: Associations with sociodemographic and health characteristics, technology device ownership, and technology learning Journal of Applied Gerontology 2022 41 3 600 609 10.1177/07334648211047347 34608821
Connolly SL Stolzmann KL Heyworth L Sullivan JL Shimada SL Weaver KR Lindsay JA Bauer MS Miller CJ Patient and provider predictors of telemental health use prior to and during the COVID-19 pandemic within the Department of Veterans Affairs American Psychologist 2022 77 2 249 261 10.1037/amp0000895 34941310
Damschroder LJ Aron DC Keith RE Kirsh SR Alexander JA Lowery JC Fostering implementation of health services research findings into practice: A consolidated framework for advancing implementation science Implementation Science 2009 4 1 50 10.1186/1748-5908-4-50 19664226
Department of Veterans Affairs. (2022). Veterans Health Administration. Retrieved August 11, 2022 from https://www.va.gov/health/
Elbaz S Cinalioglu K Sekhon K Gruber J Rigas C Bodenstein K Naghi K Lavin P Greenway KT Vahia I Rej S Sekhon H A systematic review of telemedicine for older adults with Dementia during COVID-19: An alternative to in-person health services? Frontiers in Neurology 2021 12 761965 10.3389/fneur.2021.761965 34970210
Evangelista L Steinhubl SR Topol EJ Digital health care for older adults The Lancet 2019 393 10180 1493 10.1016/S0140-6736(19)30800-1
Federal Communications Commission. (2022) Lifeline Support for Affordable Communications. Retrieved June 19, 2022, from https://www.fcc.gov/lifeline-consumers
Gilster P Digital Literacy 1997 John Wiley & Sons Inc
Gould CE Loup JR Scales AN Juang C Carlson C Ma F Sakai EY Development and refinement of educational materials to help older veterans use VA mental health mobile apps Professional Psychology: Research and Practice 2020 51 4 414 423 10.1037/pro0000354 34465939
Heras E Garibaldi P Boix M Valero O Castillo J Curbelo Y Piqué JM COVID-19 mortality risk factors in older people in a long-term care center European Geriatric Medicine 2021 12 3 601 607 10.1007/s41999-020-00432-w 33245505
Iyer S Mehta P Weith J Hoang-Gia D Moore J Carlson C Gould C Converting a geriatrics clinic to virtual visits during COVID-19: A case study Journal of Primary Care & Community Health 2021 12 215013272110002 10.1177/21501327211000235
Juul D Colenda CC Lyness JM Dunn LB Hargrave R Faulkner LR Subspecialty training and certification in geriatric psychiatry: A 25-year overview The American Journal of Geriatric Psychiatry 2017 25 5 445 453 10.1016/j.jagp.2016.12.018 28214074
Lam K Lu AD Shi Y Covinsky KE Assessing telemedicine unreadiness among older adults in the United States during the COVID-19 pandemic JAMA Internal Medicine 2020 180 10 1389 1391 10.1001/jamainternmed.2020.2671 32744593
Langa KM Levine DA The diagnosis and management of Mild Cognitive Impairment: A clinical review Journal of the American Medical Association 2014 312 23 2551 2561 10.1001/jama.2014.13806 25514304
Lee B Chen Y Hewitt L Age differences in constraints encountered by seniors in their use of computers and the internet Computers in Human Behavior 2011 27 3 1231 1237 10.1016/j.chb.2011.01.003
Lester PE Dharmarajan TS Weinstein E The looming geriatrician shortage: Ramifications and solutions Journal of Aging and Health 2020 32 9 1052 1062 10.1177/0898264319879325 31583940
Nieman CL Oh ES Connecting with older adults via telemedicine Annals of Internal Medicine 2020 173 10 831 832 10.7326/M20-1322 32777187
Numbers K Brodaty H The effects of the COVID-19 pandemic on people with dementia Nature Reviews Neurology 2021 17 2 69 70 10.1038/s41582-020-00450-z 33408384
Oaks, R. (2022). Low-income internet plans for families, seniors, and students [webpage]. Retrieved August 10, 2022, from https://www.cabletv.com/blog/low-income-internet
Rajan KB Weuve J Barnes LL McAninch EA Wilson RS Evans DA Population estimate of people with clinical Alzheimer’s disease and mild cognitive impairment in the United States (2020–2060) Alzheimer’s & Dementia 2021 17 12 1966 1975 10.1002/alz.12362
Roque NA Boot WR A new tool for assessing mobile device proficiency in older adults: The Mobile Device Proficiency Questionnaire Journal of Applied Gerontology 2018 37 2 131 156 10.1177/0733464816642582 27255686
Schreurs, K., Quan-Haase, A., & Martin, K. (2017). Problematizing the digital literacy paradox in the context of older adults’ ICT use: aging, media discourse, and self-determination. Canadian Journal of Communication, 42(2), 359–377. 10.22230/cjc.2017v42n2a3130
Tariq S Barber PA Dementia risk and prevention by targeting modifiable vascular risk factors Journal of Neurochemistry 2018 144 5 565 581 10.1111/jnc.14132 28734089
Totten, A. M., McDonagh, M. S., & Wagner, J. H. (2020). The evidence base for telehealth: Reassurance in the face of rapid expansion during the COVID-19 Pandemic. Agency for Healthcare Research and Quality (AHRQ). Report No. 20-EH015. 10.23970/AHRQEPCCOVIDTELEHEALTH
Wray C Tang J Byers A Keyhani S Digital health skillsets and digital preparedness: Comparison of Veterans Health Administration users and other veterans nationally JMIR Formative Research 2022 6 1 e32764 10.2196/32764 35089147
Zulman DM Wong EP Slightam C Gregory A Jacobs JC Kimerling R Blonigen DM Peters J Heyworth L Making connections: Nationwide implementation of video telehealth tablets to address access barriers in veterans JAMIA Open 2019 2 3 323 329 10.1093/jamiaopen/ooz024 32766533
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Molino-Magtolis Joyce 3
1 grid.460955.b 0000 0004 0398 1000 School of Arts and Sciences, University of Central Asia, Naryn, Kyrgyz Republic
2 School of Graduate Studies, Biliran Province State University, Biliran Province, Naval, Philippines
3 grid.443276.0 0000 0001 0300 0370 College of Education, Leyte Normal University, Tacloban City, Philippines
3 12 2022
130
22 3 2022
24 11 2022
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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The COVID-19 pandemic has resulted in numerous setbacks in the different sectors of society until today (as of writing) including higher education institutions worldwide. Nevertheless, it also created opportunities to explore different aspects of pandemic prevention and preparedness. Specifically, this study attempted to explore predictors of COVID-19 pandemic preventive behavior including Views on the Nature of Science, belief on COVID-19 pandemic, and trust in the government among undergraduate students in one of the state universities in the Philippines. Following the survey research design, 389 undergraduate students answered a questionnaire whose items were adapted from literature. Data collected were analyzed through partial least squares–structural equation modeling using Smart PLS. The analysis allowed simultaneous assessment of measurement validity and reliability and hypotheses testing. Results showed that Views on the Nature of Science and belief on COVID-19 pandemic predicted COVID-19 pandemic preventive behavior. However, these two variables did not predict trust in the government nor did trust in the government predicted COVID-19 pandemic preventive behavior. A reflection on socio-scientific issues and the role of Views on the Nature of Science, synergy of beliefs, and public trust, science, and COVID-19 pandemic preventive behavior are provided.
Keywords
Views on the Nature of Science
Nature of Science
COVID-19 pandemic
COVID-19 pandemic preventive behavior
Trust in the government
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pmcIntroduction
The onset of the COVID-19 pandemic, first found in Wuhan, China, in November 2019, has resulted in an unprecedented disruption in all aspects of society including school operations at all levels. Informed by the past and most recent experiences of epidemics and pandemics, the World Health Organization (WHO) (WHO, 2020a) and governments of every nation like the Philippines (Republic of the Philippines, 2020) have developed and imposed protocols aimed at slowing down the spread of COVID-19. Such concerted effort is necessary to avoid the overwhelming of medical facilities especially the intensive care units, as well as the exhaustion of medical workers. In addition, it is hoped that these protocols would allow the governments to buy more time in developing effective vaccines and or medications.
While different governments have taken various approaches in response to the COVID-19 pandemic, from draconian measures involving the military in imposing a complete lockdown (Kupferschmidt & Cohen, 2020) to a more relaxed approach to achieving herd immunity (Vogel, 2020), some specific protocols and actions were found to be uniform for all. These include mandatory wearing of face masks, social distancing, use of hand sanitizers, and frequent handwashing (WHO, 2020b). In this study, the said specific protocols are collectively referred to as COVID-19 pandemic preventive behavior—actions/behaviors that are aimed at reducing the risk of infection and or containing the rapid spread of COVID-19. Notably, there is somewhat a common understanding that a collective pandemic preventive behavior may reduce the risk and vulnerability to COVID-19. Nevertheless, the acceptance and practice of COVID-19 pandemic preventive behavior appear to be differential.
The differential acceptance and practice of COVID-19 pandemic preventive behavior may not be completely surprising considering that existing theories in psychology have enumerated determinants of behavior such as values, beliefs, and norms (Ajzen, 1991; Rosenstock, 1974; Schwartz, 1977; Stern et al., 1999) which vary according to context including important socio-demographic variables (Stern, 2000) among others. In addition, experience including literature has consistently reported the influence of context (e.g. culture and tradition) in shaping many antecedents to a behavior (Matsumoto, 2007). In the context of the COVID-19 pandemic, varying degrees of context-specific and -related values, beliefs, and norms on the COVID-19 pandemic increase the differential vulnerability to COVID-19. This is in consideration of the uniform threat the pandemic is causing; therefore, apart from being urgent, an appropriate and concerted behavioral response to COVID-19 is imperative.
In this study, the researchers explored among undergraduates, the likelihood that one’s Views on the Nature of Science (VNoS), belief on COVID-19 pandemic, and trust in the government may predict COVID-19 pandemic preventive behavior. VNoS is defined as the belief in scientific knowledge and its development (Lederman, 1992). Meanwhile, belief on COVID-19 pandemic specifically refers to one’s awareness of consequences (Stern et al., 1999) of the COVID-19 pandemic (AC) and ascription to responsibility (Stern et al., 1999) in preventing the spread and stopping the COVID-19 pandemic (AR). Lastly, trust in the government refers to one’s support for and confidence in the government (Newton et al., 2018) during the COVID-19 pandemic.
Notably, the COVID-19 pandemic possesses the elements of a socio-scientific issue (SSI) (Sadler, 2009), referred to as a controversial social issue with conceptual and procedural links to science (Sadler, 2004). Recent studies such as the works of Herman and colleagues (2022) and Chadwick and McLoughlin (2022) have explicitly referred to the COVID-19 pandemic as an SSI. In science education, there has been increasing advocacy about the use of SSIs in teaching as it increases the engagement of the learners with real-world problems, hence making learning more meaningful. In dealing with SSIs such as the COVID-19 pandemic, one’s VNoS is imperative in making any actions related to it. However, there is a deficit in the literature on studies that explored the probability that one’s VNoS predicts COVID-19 pandemic preventive behavior. The researchers hypothesize the complementarity of scientific literacy (i.e., manifested through one’s VNoS) and the prevalence of COVID-19 pandemic preventive behavior. A higher level of VNoS may result in a more prevalent practice of COVID-19 pandemic preventive behavior. In the same way, less prevalent practice of COVID-19 pandemic preventive behavior may be evidence of low-level VNoS.
Similarly, behavioral theories (Ajzen, 1991; Schwartz, 1977; Stern et al., 1999) including the Health Belief Model (Janz & Becker, 1984; Rosenstock, 1974) has illustrated that one’s belief about health predicts health behavior. While the object of health belief and VNoS (i.e. belief in scientific knowledge and its development) are different, the fact that both refer to one’s held and accepted propositions bound with emotional commitment can be considered similar. That being so, the researchers hypothesize that belief on COVID-19 pandemic, specifically AC and AR may predict COVID-19 pandemic preventive behavior. Lastly, through observations and experiences about the different approaches taken by governments and the levels of success in containing the COVID-19 pandemic, the researchers hypothesize that trust in the government may also predict COVID-19 pandemic preventive behavior.
Some shreds of evidence from literature explored the influence of science and belief on health, as well as perceived trust in the government in the context of the COVID-19 pandemic in various contexts (Apeti, 2021; Oude Groeniger et al., 2021; Sulik et al., 2021); however, limited studies from literature collectively explored VNoS, belief, and trust in the government as possible predictors of COVID-19 pandemic preventive behavior, specifically among undergraduate students (Peng et al., 2020). More so in the study context.
In the Philippines, the Commission on Higher Education reported that during the academic year 2019–2020, around 3,408,425 students were enrolled in various undergraduate programs (Commission on Higher Education, 2020). This number comprises about three percent of the total population of the country and five percent of the adult population (Philippine Statistics Authority, 2022). While with certainty the undergraduates represent a unique group in society in general, the researcher thinks that they may be influential considering their relatively active lifestyle including voice and mobility. That being so, exploring VNoS, belief on COVID-19 pandemic, and trust in the government as predictors of the COVID-19 pandemic preventive behavior may be relevant. This study contributes to the body of knowledge on scientific literacy specifically on reflecting COVID-19 as an SSI. Moreover, it contributes to the body of knowledge on health behavior in times of pandemic specifically on the growing number of essential antecedents to pandemic preventive behavior. Finally, the model generated in this study may be informative to policymakers in universities and schools. These sectors experience a high vulnerability to the COVID-19 pandemic and related entities in making long-term solutions (e.g. pandemic preparedness).
COVID-19 Pandemic, a Socio-scientific Issue that Requires ‘Scientific’ Behavior
COVID-19 pandemic possesses the characteristics and elements of an SSI. SSIs are open-ended problems without clear-cut solutions that are intertwined with influential factors such as politics, economics, and ethics (Sadler, 2011). Moreover, SSIs tend to have multiple plausible solutions that may vary according to context including one’s VNoS, exactly in the case of the COVID-19 pandemic. A shred of evidence that the COVID-19 pandemic is a socio-scientific issue could be the different approaches undertaken by the government (Kupferschmidt & Cohen, 2020; Vogel, 2020) and the variation in beliefs, norms, and behavior of the public (Collis et al., 2022) that resulted in different increase/decrease of recorded cases and deaths per country. Some recent studies have explicitly referred to the COVID-19 pandemic as a socio-scientific issue. For example, the work of Herman and colleagues (2022) about university biology students’ perceptions of COVID-19 science as associated with COVID-19 behavior and other demographic variables. There is also the work of Betul Cebesoy and Chang Rundgren (2021) about the influences on preservice teachers’ perceptions and decisions about SSIs, and the work of Chadwick and McLoughlin (2022) on school science teachers’ perspectives on addressing the COVID-19 pandemic as an SSI.
In the last two decades or so, there had been increasing advocacy for the use of SSIs in teaching across levels. This is in consideration that SSIs link science to issues relevant to a learner’s life, the environment, and their role as a citizen (Hofstein et al., 2011). Similarly, it increases preservice teachers’ sense of efficacy (Yahaya et al., 2015), including their self-efficacy and learning-related beliefs, and improved their teaching practices (Maass et al., 2022). Moreover, it improves the informal reasoning skills of primary learners (Karpudewan & Roth, 2018), enhances the communication skills of 9th-grade learners (Chung et al., 2016), and increases conceptual understanding of water pollution of 7th-grade learners among others (Kiryak & Çalik, 2018). In a Delphi study conducted by Wan and Bi (2020), regarding what major SSIs to be focused on in the science curriculum, Chinese experts pointed out environmental issues, resources and energy, ecological systems, biotechnology, new materials, and safety and health such as the COVID-19 pandemic.
Related thereto, Lederman (1992) has put forward the concept of VNoS, defined as the belief in scientific knowledge and its development. Leaderman and colleagues (2002) have synthesized seven aspects of VNoS including (a) the empirical nature of scientific knowledge, (b) scientific theories and laws, (c) the creative and imaginative nature of scientific knowledge, (d) the theory-laden nature of scientific knowledge, (e) the social embeddedness of scientific knowledge, (f) myth of the scientific method, and (g) the tentative nature of scientific knowledge. The descriptions of aspects of VNoS in Table 1 were extracted from the works of Lederman and colleagues (2002).Table 1 Aspects of VNoS and their conceptualization (extracted from Lederman et al., 2002)
Aspects of VNoS Description
The empirical nature of scientific knowledge Science is partially based on observations; the validity of scientific claims is justified and explained by referring to observations of phenomena and observations are filtered by individual perceptions
Scientific theories and laws Scientific theories are well-established, highly substantiated, internally consistent systems of explanation while laws are descriptive statements of relationships among observable phenomena. Although cannot be tested directly, theories explain large sets of seemingly unrelated observations in more than one field of investigation
The creative and imaginative nature of scientific knowledge Generating scientific knowledge requires imagination and creativity as it involves the invention of explanations for observable phenomena or regularities in those phenomena under study
Theory-laden nature of scientific knowledge Science never starts with neutral observations considering that the theoretical and disciplinary commitments, beliefs, prior knowledge, training, experiences, and expectations influence the work of scientists
The social embeddedness of scientific knowledge Science is practiced in the context of a larger culture and scientists are a product of the culture, therefore science affects and is affected by social fabrics, power structures, socio-economic factors, philosophies, nd religion
The myth of the scientific method There is no single scientific method that would guarantee the development of infallible knowledge
The tentative nature of scientific knowledge Although reliable and durable, scientific knowledge is never certain. Facts, theories, and laws are subject to change as new evidence made possible by advances in thinking and technology are made
Behavioral theories suggest that VNoS impacts one’s perception and response to an SSI (Kim & Hamdan Alghamdi, 2021). That being so, the researchers hypothesize that the prevalent practice of COVID-19 pandemic preventive behavior is likely predicted by the strength of one’s VNoS. Therefore, the researchers hypothesize that VNoS may be a predictor of COVID-19 pandemic preventive behavior (H1), belief on COVID-19 pandemic (H2), and trust in the government (H3).
Belief and Health Behavior
Belief specifically refers to one’s consciously or unconsciously held propositions that are accepted as truth and imbued with emotional commitment, hence guiding one’s thought and or behavior (Borg, 2001, p. 186). Behavioral theories have established that the value placed by one on a goal and their belief of the likelihood that a given action will achieve the goal determine a specific behavior. If translated to health context, health behavior is determined by one’s desire to avoid illness and belief that specific actions will prevent illness as illustrated in the Health Belief Model (Janz & Becker, 1984, p. 2).
A more recent interpretation of the Health Belief Model postulated that general values and beliefs on health consequences influence health behavior. Mckellar and Sillence (2020) illustrated that if individuals perceive a threat to their health, and the perceived benefits outweigh perceived barriers, that individual is likely to undertake preventive health behavior.
In this study, two sub-dimensions of belief on the COVID-19 pandemic were assessed, AC and AR. Conceptually, AC refers to the individual’s perception of the consequences of the COVID-19 pandemic. Meanwhile, AR refers to the belief that one’s behavior can alleviate the consequences of the COVID-19 pandemic (Stern et al., 1999). The researchers think that as one of the antecedents to general behavior, COVID-19 pandemic-related beliefs may be an essential key driver toward pandemic prevention and preparedness. In addition, the researchers believe that one of the reasons for the differential vulnerability of communities and nations may be the differences in belief on the COVID-19 pandemic among the populations. That being so, the researchers hypothesize the likelihood that belief on COVID-19 pandemic may predict COVID-19 pandemic preventive behavior (H4) and trust in the government (H5), as well as its possible mediation between VNoS and COVID-19 pandemic preventive behavior (H7).
Trust in the Government and Pandemic Prevention
Trust refers to a relationship whereby a trustor voluntarily makes themselves vulnerable to the decision/action of a trustee with the aspiration of a more significant payoff than would be without trust (Coleman, 2000). Therefore, trust in the government may be conceptualized as how people perceive that the government produces an outcome consistent with their expectations (Hetherington, 2006). In short, it is the public support for and confidence in the government (Newton et al., 2018). Related thereto, LoMonte (2020) pointed out that public health depends on public trust. That being so, trust in the government may somewhat influence the acceptance and practice of COVID-19 protocols, hence imperative to COVID-19 pandemic prevention and preparedness.
Studies have revealed that trust in the government during the COVID-19 pandemic is important in predicting crisis management effects associated with low numbers of COVID-19 cases and deaths (Apeti, 2021). Moreover, it determines the frequency of following the recommended health protocol such as frequent handwashing of Swedes (Johansson et al., 2021) or the likelihood of practicing preventive measures such as support for stay-at-home requests and the use of contact tracing applications in Japan (Gotanda et al., 2021). Further, trust in the government is also associated with the adoption of health and pro-social behavior (Han et al., 2021) and COVID-19 vaccine acceptance and hesitancy in the case of New Zealand (Prickett & Chapple, 2021).
Nevertheless, studies showed that during the COVID-19 pandemic, different countries manifested different levels of trust in the government (Tan et al., 2021). Such levels may change over time (Nielsen & Lindvall, 2021; Oude Groeniger et al., 2021) as a result of the different approaches and measures taken by governments at the onset and during the COVID-19 pandemic, resulting in variation in public perception and opinion (Oude Groeniger et al., 2021). This phenomenon is interesting, and the researchers would like to further elucidate the importance of trust in the government as an antecedent to COVID-19 pandemic preventive behavior based on the Norm-Activation Theory.
Recalling the work of Schwartz (1977), the Norm-Activation Theory claimed that behavior is largely predicted by norms or the feeling of moral obligation. Literature established two types of norms. Personal norm refers to principles, rules, or cognitive heuristics in evaluating and prescribing behavior. It is experienced as feelings of moral obligation (Schwartz & Howard, 1981). Meanwhile, social norm refers to social pressures that individual experiences from other people that they consider significant or the society to engage in a specific behavior (Yadav, 2016) or simply the expectation that one is morally and ethically obliged to act (Choi et al., 2015). Along this line, studies of different behavioral contexts have illustrated the significantly considerable influence of norms as compared to other antecedents to behavior, including pro-environmental behavior (Stern, 2000; Stern et al., 1999) and disaster risk reduction (blinded for review).
With the onset of the COVID-19 pandemic, there was a need to shift daily activities among people, including the need to change habits and practices for prevention and reduction of the risk of contracting COVID-19. It was observed how some people willingly embraced the new normal while others stubbornly refuse to adhere to the new normal. Now the question is, in disaster situations like the COVID-19 pandemic, who sets the new norm that may result in concerted pandemic prevention and preparedness among the populations? The researchers think that it is the role of the government to establish the new norm during disaster situations as a form of social norm. During the COVID-19 pandemic, the strength and expertise of governments were unveiled and showcased through the different approaches they took against the COVID-19 pandemic that led to different outcomes. The said strength and expertise may be manifested through planning and implementing relevant rules and regulations, including assessment. It may significantly impact COVID-19 pandemic prevention and preparedness. Nevertheless, another related critical factor is people’s trust in the government.
Early on, Levi (1998) pointed out that the trustworthiness of the government influences its capacity to generate interpersonal trust among the population, and the amount of socially and economically productive cooperation in the society and turn affects the capacity to govern (pp87-88). In this study, the researchers think that undergraduates’ trust in the government during the COVID-19 pandemic significantly matters considering their relatively active representation in society. By representation, the researchers meant their aggressive voice on various platforms including social media and the Internet, as well as their mobility. That being so, the researchers hypothesize that trust in the government may be a predictor of COVID-19 pandemic preventive behavior (H6) and its possible mediation between VNoS and COVID-19 pandemic preventive behavior (H8), as well as between belief and COVID-19 pandemic preventive behavior (H9).
COVID-19 Pandemic Preventive Behavior
COVID-19 pandemic preventive behavior refers to a behavioral set to reduce the risk of contraction and rapid spread of COVID-19. At the onset of the COVID-19 pandemic in 2020, informed by past experiences of pandemics and epidemics, the WHO and other relevant health agencies such as the DOH have outlined recommended public protocol for safety and prevention of COVID-19 infection and rapid spread (Republic of the Philippines, 2020; WHO, 2020a). An earlier study of (blinded for review) attempted to determine the dimensions of COVID-19 pandemic preventive behavior that included (a) direct preventive behaviors, (b) healthy habits and lifestyle, (c) limited physical social contact, (d) COVID-19 curiosity, and (e) COVID-19 support. Similar past studies enumerated preventive behavior against pandemic influenza of 1918–1919 (Markel et al., 2007), SARS (Vartti et al., 2009), AH1N1 (Cowling et al., 2010; Zhang et al., 2014), anthrax, West Nile virus, and smallpox (Fischhoff et al., 2003). A few studies have enumerated and outlined COVID-19 pandemic behavior such as Lin and Chen (2021) in Taiwan, Breakwell and colleagues (2021) in England, Barakat and Kasemy (2020) in Egypt, and Gutu and colleagues (2021) in Ethiopia among others. Although may not be directly related to COVID-19 behavior, extant literature reported a variety of risk-taking and preventive health behaviors (Vickers et al., 1990) and health behavior representations (Shiloh & Nudelman, 2020) among others.
An in-depth understanding of COVID-19 pandemic preventive behavior is imperative because there is somewhat a common understanding that a collective COVID-19 pandemic preventive behavior may result in concerted pandemic prevention and preparedness. Consequently, the risk and vulnerability of the population to COVID-19 are significantly reduced.
Purpose and Hypotheses of the Study
The foregoing study aimed to explore the likelihood that VNoS, belief on COVID-19 pandemic, and perceived trust in the government predict undergraduates’ COVID-19 pandemic preventive behavior. As such, this study may contribute to the growing body of knowledge on antecedents to COVID-19 pandemic preventive behavior that could inform relevant policy-making bodies such as schools, universities, and similar entities to make relevant policies and decisions. The following hypotheses were tested in the study. The same hypotheses are illustrated in Fig. 1.VNoS predicts COVID-19 pandemic preventive behavior
VNoS predicts belief
VNoS predicts trust in the government
Belief predicts COVID-19 pandemic preventive behavior
Belief predicts trust in the government
Trust in the government predicts COVID-19 pandemic preventive behavior
Belief mediates VNoS and COVID-19 pandemic preventive behavior
Trust in the government mediates VNoS and COVID-19 pandemic preventive behavior
Trust in the government mediates belief and COVID-19 pandemic preventive behavior
Fig. 1 Model specifying the study hypotheses
Before this study, a pilot study was conducted to ensure the factor structure of the variables under study (to be reported elsewhere). That being so, in this study, VNoS is a second-order construct composed of six first-order constructs including NOS-A (NoS1 and NoS2), NOS-B (NoS3 to NoS5), NOS-C (NoS6 to NoS9), NOS-D (NoS10 to NoS14), NOS-E (NoS15 to NoS18), and NOS-F (NoS19 to NoS24). Similarly, belief on COVID-19 pandemic is also a second-order construct composed of four first-order constructs including AC-A (AC1and AC2), AC-B (AC3 and AC4), AC-C (AC5 to AC8), and AR (AR1 to AR5). Trust in the government is a first-order construct composed of 11 items (TrG1 to TrG11). Finally, COVID-19 pandemic preventive behavior is a second-order construct composed of five first-order constructs including CPPBa (CPPB1 to CPPB7), CPPBb (CPPB8 to CPPB13), CPPBc (CPPB14 to CPPB18), CPPBd (CPPB19 and CPPB20), and CPPBe (CPPB21to CPPB23).
Methodology
This quantitative survey was conducted in one of the state universities in the Eastern Visayas Region located in Tacloban City, the Philippines. Considering the numerous limitations faced during the data collection from September to November 2020, convenience sampling of participants was employed. After obtaining permission from the university administration, the assistance of 12 faculty was sought in data collection using a Google survey. A total of 410 participants responded to the survey and 389 entries (mean age = 20.16 years old; 72% female, 28% male) were retained after data cleaning.
To ensure that the number of participants was sufficient for statistical analysis through partial least squares-structural equation modeling (PLS-SEM), the gamma exponential method using the G*Power calculator that is available online was employed (Faul et al., 2009; Kock & Hadaya, 2018). With a 0.83 level of power, 0.20 effect size, p < 0.05, and three predictors, the study required a minimum of 63 participants (Hair et al., 2019; Sarstedt et al., 2019).
Instrument
A 5-point Likert scale questionnaire on VNoS, belief on COVID-19 pandemic, trust in the government, and COVID-19 pandemic preventive behavior was used in the study. Items were adapted from the works of Chen and colleagues (2013) for VNoS (Cronbach’s alpha = 0.85), Steg and colleagues (2005) for belief (i.e. AC and AR) (Cronbach’s alpha = 0.85 and 0.80, respectively), Grimmelikhuijsen and Knies (2015) for trust in the government (Cronbach’s alpha = 0.83–0.87), and (blinded for review) for COVID-19 pandemic preventive behavior (Cronbach’s alpha = 0.80–0.84).
The original VNoS questionnaire developed and validated by Chen and colleagues (2013) was composed of seven dimensions, namely, theory-ladenness (nine items), creativity (six items), coherence (11 items), tentativeness (nine items), durability (six items), science for girls (three items), and science for boys (three items). Meanwhile, the questionnaire on beliefs on COVID-19 pandemic adopted in this study was from the work of Steg and colleagues (2005) originally used to test the Value–Belief–Norm Theory in the context of energy policy acceptability. The questionnaire has two dimensions: awareness of consequences (six items) and ascription to responsibility (six items). Moving on, the items for trust in the government were adapted from the works of Grimmelikhuijsen and Knies (2015) on scale validation for citizens’ trust in government organizations. The questionnaire is composed of three dimensions namely benevolence (three items), competence (three items), and integrity (three items). The researchers added two items that were deemed relevant for the study. Finally, the items on COVID-19 pandemic preventive behavior were adapted from the works of (blinded for review). The original questionnaire was composed of six dimensions, namely, direct preventive behavior (five items), healthy habits and lifestyle (three items), limited physical social contact (five items), COVID-19 curiosity (three items), COVID-19 support (three items), and protecting others (two items). After the pilot study (to be reported elsewhere), the final instrument used in the present study included 37 items for VNoS, 13 items for belief, 11 items for trust in the government, and 29 items for COVID-19 pandemic preventive behavior.
Data Analysis
The study involved a hierarchical construct model (HCM) and was exploratory, therefore analyzing data through PLS-SEM using Smart PLS (Sarstedt et al., 2019) is most appropriate. It included an assessment of the measurement model whereby indicator reliability (outer loading ≥ 0.708), internal consistency (Cronbach’s alpha ≥ 0.70, composite reliability ≥ 0.70, Djikstra–Henseler’s rho ≥ 0.70), construct reliability and validity (average variance explained ≥ 0.50), and discriminant validity (heterotrait–monotrait ratio ≥ 0.50) were ascertained (Hair et al., 2019; Sarstedt et al., 2019). It was followed by an assessment of the structural model whereby collinearity (variance inflation factors ≤ 3.3), direct and indirect effects (p value ≤ 0.05, t value ≥ 1.654), predictive accuracy (R2 = 0.75 substantial, 0.50 moderate, and 0.25 weak), effect size (f2 = 0.35 substantial, 0.15 moderate, and 0.02 small), and predictive relevance (Q2 > 0.0) were measured (Hair et al., 2019; Sarstedt et al., 2019).
Results
Assessment of Measurement Model
The complete result of the indicator reliability, item consistency, and convergent validity and reliability of the constructs, VNoS, belief on COVID-19 pandemic, trust in the government, and COVID-19 pandemic preventive behavior is presented in Appendix 1. All items have outer loading ≥ 0.70 confirming individual indicator reliability. Except for NOS-A and NOS-B whose Cronbach’s alpha and Djikstra–Henseler’s rho values were < 0.70, the rest of the constructs of VNoS, belief on COVID-19 pandemic, trust in the government, and COVID-19 pandemic preventive behavior have Cronbach’s alpha, Djikstra–Henseler’s rho, and composite reliability that is ≥ 0.70 and average variance extracted that is ≥ 0.50, therefore ascertaining convergent validity (Hair et al., 2017). Nevertheless, NOS-A and NOS-B were retained considering that their respective composite reliability and average variance extracted fall within the acceptable thresholds of ≥ 0.70 and ≥ 0.50 respectively (Hair et al., 2017).
NOS-A refers to the belief that before observation, people already possess ideas of what to observe and all they need to do is prepare a table to fill up. Meanwhile, NOS-B refers to the belief that there are many ways in solving a problem and everyone has different ideas they want to prove through observation. NOS-C refers to the belief that there is only one method to solve a problem and that following a standard procedure is necessary. NOS-D refers to the belief about the need for creativity and imagination in scientific processes while NOS-E refers to the belief that scientific knowledge and processes are dynamic, that is, they change with time. Finally, NOS-F refers to the belief that scientific knowledge and processes are fixed and enduring, and hence will not easily change with time.
Moving on, along with the belief on COVID-19 pandemic, AC-A refers to the belief that the COVID-19 pandemic is a real concern of society today while AC-B refers to the belief that one’s efforts related to the COVID-19 pandemic can reduce the spread and impact of the disease. AC-C refers to the belief that lacking cooperation and knowledge, difficulty in preventing the spread of COVID-19, and the absence of medicine and vaccine are real concerns.
CPPBa refers to direct preventive behavior such as wearing a face mask, washing hands frequently, and using hand sanitizers while CPPBb refers to healthy habits and lifestyles like eating healthy food and taking vitamin C and food supplements including regular exercise and sleep. CPPBc refers to physical social distancing such as staying at home and avoiding travel. Meanwhile, CPPBd refers to exploring effective and new ways in preventing the spread of COVID-19. Finally, CPPBe refers to the readiness to contribute resources and support local government and non-government organizations working towards COVID-19 prevention (see Appendix 2 for a complete list of items).
Table 2 presents the heterotrait–monotrait ratio. Values are all within the acceptable threshold provided by the literature, hence confirming the discriminant validity (Hair et al., 2017).Table 2 Discriminant validity results (heterotrait–monotrait ratio)
AC-A AC-B AC-C AR CPPBa CPPBb CPPBc CPPBd CPPBe NOS-A NOS-B NOS-C NOS-D NOS-E NOS-F
AC-B 0.314
AC-C 0.653 0.294
AR 0.425 0.279 0.469
CPPBa 0.339 0.203 0.337 0.390
CPPBb 0.129 0.238 0.142 0.181 0.576
CPPBc 0.229 0.268 0.270 0.317 0.642 0.530
CPPBd 0.134 0.246 0.274 0.264 0.540 0.520 0.648
CPPBe 0.263 0.317 0.347 0.348 0.459 0.449 0.581 0.540
NOS-A 0.145 0.134 0.092 0.155 0.220 0.402 0.185 0.250 0.340
NOS-B 0.405 0.237 0.495 0.363 0.297 0.209 0.259 0.281 0.252 0.390
NOS-C 0.122 0.146 0.141 0.074 0.093 0.459 0.156 0.133 0.165 0.372 0.112
NOS-D 0.473 0.415 0.470 0.470 0.332 0.209 0.297 0.293 0.401 0.394 0.714 0.106
NOS-E 0.316 0.246 0.449 0.379 0.223 0.191 0.235 0.234 0.300 0.257 0.599 0.103 0.615
NOS-F 0.090 0.159 0.116 0.182 0.072 0.187 0.144 0.136 0.097 0.312 0.235 0.483 0.222 0.150
Trust 0.066 0.226 0.095 0.084 0.048 0.231 0.121 0.058 0.086 0.395 0.099 0.411 0.128 0.090 0.345
Assessment of Structural Model
Table 3 presents the inner and outer variance inflation factors during the first and second stage assessment, respectively. Notably, all values were below the stringent threshold of 3.3 (Hair et al., 2017), confirming no existing collinearity issues among the variables under study.Table 3 Collinearity, predictive accuracy, and predictive relevance
Inner VIF (first stage) Outer VIF (second stage) Inner VIF (second stage) R2 Q2
Belief CPPB Belief CPPB Trust
Belief 1.444 1.444 0.307 0.143
AC-A 1.454 1.407
AC-B 1.273 1.119
AC-C 1.589 1.452
AR 1.388 1.270
VNoS 1.000 1.496 1.444
NOS-A 1.141 1.186 1.143
NOS-B 1.476 1.519 1.481
NOS-C 1.214 1.297 1.217
NOS-D 1.635 1.925 1.643
NOS-E 1.431 1.496 1.430
NOS-F 1.236 1.301 1.236
Trust 1.300 1.048 0.045 0.029
CPPB 0.266 0.129
CPPBa 1.681
CPPBb 1.459
CPPBc 1.872
CPPBd 1.722
CPPBe 1.501
Tables 4 and 5 present the direct and indirect effects (i.e. β, T, p values, and confidence intervals bias-corrected) of the variables under study as illustrated in Fig. 2. Results revealed that VNoS (β = 0.202, p = 0.007) and belief (β = 0.380, p = 0.001) predicted COVID-19 pandemic preventive behavior. Moreover, VNoS also predicted belief on COVID-19 pandemic (β = 0.554, p = 0.001). Surprisingly, neither VNoS (β = 0.223, p = 0.040) nor belief on COVID-19 pandemic (β = − 0.018, p = 0.406) predicted trust in the government and trust in the government did not predict COVID-19 pandemic preventive behavior (β = − 0.036, p = 0.284). Further, results also showed that belief on COVID-19 pandemic mediated between VNoS and COVID-19 pandemic preventive behavior (β = 0.211, p = 0.001). However, trust in the government did not mediate between VNoS and COVID-19 pandemic preventive behavior (β = − 0.008, p = − 0.008) and between belief on COVID-19 pandemic and COVID-19 pandemic preventive behavior (β = 0.001, p = 0.001).Table 4 Direct effects
Hypotheses Mean, STDEV, T values, p values Effect size Confidence intervals bias corrected Decision
β Sample mean (M) Standard deviation (STDEV) T value p values f2 5.0% 95.0%
VNoS- > CPPB 0.202 0.215 0.082 2.470 0.007 0.037 0.057 0.324 Supported
VNoS- > belief 0.554 0.552 0.059 9.430 0.001 0.444 0.429 0.623 Supported
VNoS- > trust 0.223 0.217 0.127 1.749 0.040 0.036 -0.063 0.384 Not supported
Belief- > CPPB 0.380 0.383 0.081 4.713 0.001 0.136 0.215 0.489 Supported
Belief- > trust − 0.018 − 0.008 0.077 0.237 0.406 0.001 − 0.144 0.105 Not supported
Trust- > CPPB − 0.036 − 0.040 0.063 0.571 0.284 0.002 − 0.135 0.074 Not supported
Table 5 Specific indirect effects
Hypotheses Mean, STDEV, T values, p values Confidence interval bias corrected Decision
β Sample mean (M) Standard deviation (STDEV) T value p values 5.0% 95.0%
VNoS- > belief- > CPPB 0.211 0.213 0.055 3.864 0.001 0.094 0.283 Supported
VNoS- > trust- > CPPB − 0.008 − 0.006 0.016 0.507 − 0.008 − 0.039 0.012 Not supported
Belief- > trust- > CPPB 0.001 0.002 0.006 0.115 0.001 − 0.006 0.013 Not supported
Fig. 2 Direct effects (note: thick arrows confirm direct effects)
Moving on, Table 3 presents the predictive accuracy and predictive relevance of the variables under study. Belief on COVID-19 pandemic (R2 = 0.307) and COVID-19 pandemic preventive behavior (R2 = 0.266) had substantial predictive accuracy, while trust in the government (R2 = 0.045) had weak predictive accuracy (Cohen, 1988).
VNoS had a substantial effect size on belief (f2 = 0.444), a small effect size on COVID-19 pandemic preventive behavior (f2 = 0.037), and trust in the government (f2 = 0.036). Belief had a small effect size on COVID-19 pandemic preventive behavior (f2 = 0.136) and trust in the government (f2 = 0.001), while trust in the government had a small effect size on COVID-19 pandemic preventive behavior (f2 = 0.002) (Cohen, 1988; Hair et al., 2014). Nevertheless, belief, trust in the government, and COVID-19 pandemic preventive behavior had predictive relevance concerning the model specified, given that all Q2 values were greater than zero (Hair et al., 2014).
Discussion
Socio-scientific Issues and the Role of Views on the Nature of Science
VNoS as one of the predictors of COVID-19 pandemic preventive behavior established in this study confirms that the COVID-19 pandemic is indeed an SSI as pointed out earlier in the works of Herman and colleagues (2022), Betul Cebesoy and Chang Rundgren (2021), and Chadwick and McLoughlin (2022). That being so, to solicit an appropriate response, an SSI requires a certain level of VNoS, that is belief on scientific knowledge and its development from people such as the study participants. In this study, such belief includes the belief that before observation, people already possess ideas and assumptions that directs their observation of phenomena. It also includes the belief that there is no one method in solving a problem vis-à-vis the belief that there is one fixed method and solution to a problem. In addition, it includes the belief on the need and importance of creativity and imagination in generating scientific knowledge through experimentation, as well as the belief on the dynamic nature of scientific knowledge and processes vis-à-vis the enduring nature of scientific knowledge and processes.
Related thereto, the researchers infer that significantly low-level VNoS could be one of the reasons for one’s failure to decipher fake from legitimate news and information including the tendency to believe in conspiracy theories. This tendency is not surprising because one’s interpretation and trust in empirical data and scientific processes are influenced and informed by their respective VNoS. Hence, it is necessary to strengthen one’s VNoS.
This study, therefore, affirms the urgent call for advocacy for the inclusion and integration of critical scientific literacy (Sjöström et al., 2016) in teaching. Literature suggested that this can be achieved by integrating important and timely SSIs such as environmental issues, safety, and health among others (Wan & Bi, 2020). Studies reported that the use of SSIs in teaching can enhance habits of the mind (Çalik et al., 2014), improve the sense of efficacy (Yahaya et al., 2015), boost self-efficacy and learning beliefs, and upgrade teaching practices (Maass et al., 2022) among preservice teachers, increase conceptual understanding (Kiryak & Çalik, 2018) and enhance communication skills (Chung et al., 2016) of middle school learners, and improve informal reasoning of primary school learners (Karpudewan & Roth, 2018) among others.
The recent COVID-19 pandemic including the findings of this study that VNoS predicted belief on COVID-19 pandemic and COVID-19 pandemic preventive behavior necessitate to hasten the teaching and integration of critical scientific literacy. It justifies the need to put upfront the more complex and complicated dimensions of scientific literacy including character and values, science as a human endeavor, and metacognition, not to mention content knowledge and habits of the mind (Choi et al., 2011). Therefore, universities including schools, being in charge of formal education, play a key role along this line. Universities and schools alike should ensure that science curricula are effectively and efficiently used as platforms for critical scientific literacy.
On another note, along with governance, the researchers think that increased transparency and clarity in communication on the use of scientific knowledge and processes in all stages of development from planning, implementation, and assessment, as well as in providing solutions to emerging SSIs like the COVID-19 pandemic may aid in increasing trust in the government.
Synergy of Beliefs
This study revealed that belief on COVID-19 pandemic predicted COVID-19 pandemic preventive behavior and mediated between VNoS and COVID-19 pandemic behavior. In this study, belief on COVID-19 pandemic includes AC which refers to the belief that the COVID-19 pandemic is a real concern of society today. It also refers to the belief that lacking cooperation and knowledge, difficulty in preventing the spread of COVID-19, and the absence of medicine and vaccine are real concerns. It also includes AR which refers to the feeling of responsibility to prevent the spread of COVID-19 and the feeling of responsibility to develop the capacity of oneself, family, and other people to prevent the spread of COVID-19.
Therefore, it is imperative to strengthen and increase one’s beliefs on COVID-19 pandemic to increase the likelihood of practicing COVID-19 pandemic preventive behavior. It may be possible through appropriate and responsible awareness and information dissemination campaigns using different media platforms, including social media.
Furthermore, results showed that VNoS influenced belief on COVID-19 pandemic. This result is interesting because VNoS after all is also a form of belief (i.e. belief in scientific knowledge and its development). Increasing one’s VNoS will consequently increase one’s belief on COVID-19 pandemic resulting in an increased likelihood of prevalent practice of COVID-19 pandemic preventive behavior. Although one influences the other, increasing the synergy between and among VNoS and belief on COVID-19 pandemic may result in more robust, perhaps an unprecedented practice of COVID-19 pandemic prevention and preparedness or a more responsive and proactive action towards an SSI in general.
Noting that context, culture, and tradition are essential associates with one’s belief in general, it may be necessary to positively and boldly influence belief on empirical data and scientific processes. It is imperative to develop a reasonable balance between extreme skepticism and objectivity through careful observation and rationality. Though intricate and no one possible strategy, there is a need to increase the blending and intertwining of scientific knowledge and its development with culture, tradition, norms, and practices. The perception that science, culture, and tradition are separate entities needed to be reduced and possibly eradicated. Related thereto, the role of universities and schools may be crucial in developing objectivity and criticality in balancing between beliefs on empirical data and cultural/traditional beliefs. Being able to find the right balance between these two may result in a concerted effort to responsibly address SSIs such as the COVID-19 pandemic.
Trust in the Government, Science, and COVID-19 Pandemic
Results revealed that trust in the government did not predict COVID-19 pandemic preventive behavior. Similarly, VNoS and belief on COVID-19 pandemic did not predict trust in the government. These findings are interesting because the researchers hypothesized at the onset of the study that trust in the government would predict COVID-19 pandemic preventive behavior. Positively if trust in the government was high and negatively if trust in the government was low. Nevertheless, the results showed neither. It appeared that at least with the study participants, the government seemed to be an entity in a different dimension during the COVID-19 pandemic. With certainty, these findings may have certain implications and explanations. The researchers hypothesize that among the reasons could be that the participants could not or did not comprehend or perceive the role and function of the government during the COVID-19 pandemic or the participants’ lack of and disinterest in government-related affairs. Nevertheless, the interpretation of the findings about trust in the government found in this study requires extreme caution considering the fluidity of trust in the government as a variable. In this study, trust in the government was referred to as the whole government entity in general, but extant literature pointed out that government may refer to its leaders or the institutions per se (Nielsen & Lindvall, 2021), while Oude Groeniger and colleagues (2021) pointed out that trust in the government and science may be interpreted as confidence in the institution that takes action at times of crises.
Although the findings of this study are limited to its participants and context, still the researchers consider it agitating that the government has little influence on behavior in general during disaster situations such as the COVID-19 pandemic because it is expected to facilitate order and justice during crises. Literature has documented several ways to promote and maintain trust in the government. For instance, Lofredo (2020) pointed out that trust in the government may be promoted when the government shows that everyone matters, and is treated with respect, care, and concern. The same can be sustained through honest, fair, just, and humane governance, just and orderly distribution of resources, goods, and services, including maintenance of essential public service, order, and peace. During the COVID-19 pandemic, Liu and colleagues (2022) found that integrated government response policies, containment health measures, and economic relief were crucial to winning trust and support while the provision of impartial, transparent, and truthful government communication is vital to maintaining trust. Similarly, Han and colleagues (2021) found that the government perceived as well organized and disseminating clear messages, knowledge, and information about COVID-19 positively associated with high trust in the government. Following the study findings, it may be imperative for the government to develop new and improve existing communication protocols and strategies for young adults like the participants of this study. As mentioned earlier, undergraduates have relatively active lifestyles (i.e. aggressive voice and increased mobility). As such, they could create significant ripples and influence the people around them and their respective communities.
Limitations and Recommendations
This study is exploratory. The challenges posed by the COVID-19 pandemic have resulted in limitations in the study context, including participants and sampling. As such, it may be necessary to replicate the present study with larger and various groups of participants and look into the influence of important demographic variables such as age, gender, educational qualification, income, and development levels of countries (Adalı, 2022; Rieger & Wang, 2021; Xie et al., 2021). Moreover, it may also be interesting to explore further and in-depth through qualitative methods the reasons and explanations of the influences of the variables established in this study. In addition, the study was limited in exploring three antecedents to COVID-19 pandemic preventive behavior and analyzed through second-order PLS-SEM. The result gave a significant picture of the interaction between and among the second-order variables (i.e. VNoS, belief on COVID-19 pandemic, and COVID-19 pandemic preventive behavior), it may be interesting to explore in great detail the specific direct and indirect effects of the first-order variables on VNoS, belief on COVID-19 pandemic, and COVID-19 pandemic preventive behavior including trust in the government.
This study established the vital interaction of VNoS, belief on COVID-19 pandemic, and COVID-19 pandemic preventive behavior. Therefore, ways to effectively and efficiently strengthen VNoS and belief on COVID-19 pandemic must be explored. Along this line, SSIs in teaching and learning must be advanced.
In the study, trust in the government did not predict COVID-19 pandemic preventive behavior nor did trust in the government predicted VNoS and belief on COVID-19 pandemic as opposed to what was established in the literature. Therefore, it is interesting to dig deeper and understand the reasons and explanations related to that. This action is imperative considering the critical role of the government during disaster situations, especially in large-scale disasters such as the COVID-19 pandemic.
Finally, the model generated in this study may be used to develop policies on integration and inclusion of pandemic prevention and readiness in schools and universities and other similar entities.
Appendix 1
Indicator reliability and convergent validity results for VNoS and trust in the government. Outer loading Cronbach’s alpha Djikstra–Henseler’s rho Composite reliability Average variance extracted (AVE)
NOS-A 0.445 0.483 0.777 0.638
NoS1 0.713
NoS2 0.876
NOS-B 0.635 0.635 0.804 0.578
NoS3 0.775
NoS4 0.768
NoS5 0.738
NOS-C 0.709 0.712 0.820 0.533
NoS6 0.774
NoS7 0.702
NoS8 0.729
NoS9 0.713
NOS-D 0.842 0.843 0.888 0.614
NoS10 0.747
NoS11 0.769
NoS12 0.827
NoS13 0.788
NoS14 0.783
NOS-E 0.792 0.797 0.864 0.614
NoS15 0.790
NoS16 0.778
NoS17 0.805
NoS18 0.761
NOS-F 0.867 0.880 0.899 0.599
NoS19 0.788
NoS20 0.724
NoS21 0.809
NoS22 0.782
NoS23 0.764
NoS24 0.773
Trust 0.958 0.960 0.964 0.708
TrG1 0.702
TrG2 0.827
TrG3 0.857
TrG4 0.833
TrG5 0.874
TrG6 0.790
TrG7 0.855
TrG8 0.858
TrG9 0.876
TrG10 0.894
TrG11 0.874
Indicator reliability and convergent validity results for COVID-19 pandemic preventive behavior and belief on COVID-19 pandemic (awareness of consequences). Outer loading Cronbach’s alpha Djikstra–Henseler’s rho Composite reliability Average variance extracted (AVE)
CPPBa 0.890 0.907 0.913 0.601
CPPB1 0.718
CPPB2 0.736
CPPB3 0.740
CPPB4 0.730
CPPB5 0.869
CPPB6 0.857
CPPB7 0.759
CPPBb 0.838 0.846 0.881 0.552
CPPB8 0.728
CPPB9 0.726
CPPB10 0.809
CPPB11 0.730
CPPB12 0.727
CPPB13 0.734
CPPBc 0.824 0.847 0.874 0.581
CPPB14 0.704
CPPB15 0.715
CPPB16 0.841
CPPB17 0.792
CPPB18 0.751
CPPBd 0.899 0.903 0.952 0.908
CPPB19 0.957
CPPB20 0.949
CPPBe 0.875 0.878 0.923 0.801
CPPB21 0.863
CPPB22 0.916
CPPB23 0.905
AC-A 0.733 0.773 0.880 0.786
AC1 0.919
AC2 0.853
AC-B 0.917 0.921 0.960 0.923
AC3 0.964
AC4 0.957
AC-C 0.782 0.781 0.859 0.605
AC5 0.770
AC6 0.813
AC7 0.797
AC8 0.728
Indicator reliability and convergent validity results for belief on COVID-19 pandemic (ascription to responsibility). Outer loading Cronbach’s alpha Djikstra–Henseler’s rho Composite reliability Average variance extracted (AVE)
AR 0.919 0.923 0.939 0.755
AR1 0.836
AR2 0.883
AR3 0.913
AR4 0.846
AR5 0.866
Appendix 2
Items in the actual analysis. Views on the nature of science
NOS-A
NoS1 Before making observations, people already have ideas about what to observe
NoS2 Before making observations, people first prepare a table and then fill it out as they make their observations
NOS-B
NoS3 There are many possible ways to solve a science problem
NoS4 When doing an experiment, everyone has different ideas about it
NoS5 Everyone has his/her own ideas and wants to prove them when making observations
NOS-C
NoS6 When two scientists observe the same phenomenon, they will report the same results
NoS7 There is only one method and one set of steps to do an experiment
NoS8 When doing an experiment, I should follow the method given in the textbook. I should not try any other methods
NoS9 Everyone in the world has the same thoughts about science knowledge
NOS-D
NoS10 Yes, scientists need creativity and imagination to design and do experiments
NoS11 Scientists need creativity and imagination to innovate. For example, people have mixed ketchup and soy-bean sauce, but you can try to mix ketchup, soy-bean sauce, and vinegar to make something new
NoS12 I believe, scientists work like artists. They both need creativity and imagination
NoS13 Great scientists and inventors search for ideas from science knowledge and the universe using creativity and imagination
NoS14 The reason for having creativity and imagination is because there are many different ways to explain one event
NOS-E
NoS15 The advance of technology may lead to new findings and then it will change
NoS16 Better theories will be found and will replace some old theories because scientists will invent high technology machines to discover new findings in the future
NoS17 Scientific knowledge might change because other better explanations are given
NoS18 Scientific knowledge changes because people continue to change their views about the world and come up with new ideas
NOS-F
NoS19 Scientific knowledge will not be replaced because it has been proven by experiments and explanations
NoS20 Scientific knowledge will not be replaced, because scientists have used it to get to the moon
NoS21 Scientific knowledge cannot be gained in a short period of time; it has been accumulated over a long time. Therefore, scientific knowledge will not be replaced
NoS22 Scientific knowledge cannot be easily replaced because it has been confirmed by scientist
NoS23 Scientific knowledge which has been accepted by most people will not be replaced easily
NoS24 Scientific knowledge is acquired from precision machines so it cannot be easily replaced
Awareness of consequences
AC-A
AC1 It is certain that COVID-19 pandemic is a real concern today
AC2 COVID-19 pandemic is a concern of the society
AC-B
AC3 Efforts related to COVID-19 pandemic help reduce the spread of the disease
AC4 Efforts related to COVID-19 pandemic help reduce the impact of the disease
AC-C
AC5 Lacking cooperation among people against the COVID-19 pandemic is a real concern
AC6 Lacking knowledge and understanding about COVID-19 pandemic is a real concern
AC7 Difficulty in preventing the spread of COVID-19 pandemic is a real concern
AC8 Absence of medicine and vaccine against the COVID-19 is a real concern
Ascription to responsibility
AR1 I feel responsible for preventing the spread of COVID-19 pandemic
AR2 I feel responsible for developing my capacity to prevent the spread of COVID-19 pandemic
AR3 I feel responsible for developing the capacity of my family to prevent the spread of COVID-19 pandemic
AR4 I feel responsible for developing the capacity of other people to prevent the spread of COVID-19 pandemic
AR5 I feel responsible in actively taking a role to prevent the spread of COVID-19 pandemic
Trust in government organizations
TrG1 When it comes to COVID-19 pandemic, the government is capable
TrG2 When it comes to COVID-19 pandemic, the government is effective
TrG3 When it comes to COVID-19 pandemic, the government is skillful
TrG4 When it comes to COVID-19 pandemic, the government is expert
TrG5 When it comes to COVID-19 pandemic, the government carries out its duty very well
TrG6 When it comes to COVID-19 pandemic, if a citizen need help, the government will do its best to help them
TrG7 When it comes to COVID-19 pandemic, the government acts in the interest of citizens
TrG8 When it comes to COVID-19 pandemic, the government is genuinely interested in the well-being of citizens
TrG9 When it comes to COVID-19 pandemic, the government approaches citizens in a sincere way
TrG10 When it comes to COVID-19 pandemic, the government is sincere
TrG11 When it comes to COVID-19 pandemic, the government keeps its commitments
COVID-19 pandemic preventive behavior
CPPBa
CPPB1 I wear face mask every time I am outdoors
CPPB2 I wash my hands frequently
CPPB3 I bring with me hand sanitizer/alcohol all the time
CPPB4 I use hand sanitizer/alcohol from time to time
CPPB5 I take effort to protect myself from catching the COVID-19
CPPB6 I take effort to protect my family from catching the COVID-19
CPPB7 I take effort to protect other people from catching the COVID-19
CPPBb
CPPB8 I eat healthy food each day
CPPB9 I take vitamin C rich food every day
CPPB10 I take food supplements every day
CPPB11 I engage myself with physical exercise regularly
CPPB12 I get enough sleep every day
CPPB13 I consult the doctor regularly
CPPBc
CPPB14 I avoid travelling during the COVID-19 pandemic
CPPB15 I stay at home more often during COVID-19 pandemic
CPPB16 I encourage other people to stay at home more frequently
CPPB17 I encourage other people to cooperate with the orders of the government
CPPB18 I avoid going outdoor during the COVID-19 pandemic
CPPBd
CPPB19 I explore effective ways to prevent the spreading of COVID-19 pandemic
CPPB20 I explore new ways to prevent the spreading of COVID-19 pandemic
CPPBe
CPPB21 I am ready to contribute any resources that I have to help prevent the spread of COVID-19 pandemic
CPPB22 I am ready to support the local government in preventing the spread of COVID-19 pandemic
CPPB23 I am ready to support non-government organizations that works in preventing the spread of COVID-19 pandemic
Data Availability
The data used in this study are available and can be obtained from the corresponding author upon reasonable request.
Declarations
Ethics
Permission was obtained from the university research administration (Leyte Normal University) prior to the conduct of study. Participants were briefed of the study including its objectives. Participants were asked to sign informed consent form that outlines the extent of their participation, ensures anonymity of their responses, an option to skip items or quit the survey at any point while answering the survey if they feel uncomfortable, and a contact information of the university guidance office if there is a need to process undesirable feeling/emotion that may arise while answering the survey.
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References
Adalı, G. K. (2022). Measuring the attitudes of governmental policies and the public Towards the COVID-19 pandemic. In Ş. O. Çekirdekci, Ö. İ. Karkış, & S. Gönültaş (Eds.), Handbook of research on interdisciplinary perspectives on the threats and impacts of pandemics (pp. 163–187). IGI Global. 10.4018/978-1-7998-8674-7.ch009
Ajzen, I. (1991). The theory of planned behavior. Organizational Behavior and Human Decision Processes, 50(2), 179–211.
Apeti, A. E. (2021). Does trust in government improve Covid-19’s crisis management? MedRxiv, 2021.07.10.21260297. 10.1101/2021.07.10.21260297
Barakat, A. M., & Kasemy, Z. A. (2020). Preventive health behaviours during coronavirus disease 2019 pandemic based on health belief model among Egyptians. Middle East Current Psychiatry, 27(1). 10.1186/s43045-020-00051-y
Betul Cebesoy, U., & Chang Rundgren, S.-N. (2021). Embracing socioscientific issues-based teaching and decision-making in teacher professional development. Educational Review, 1–28. 10.1080/00131911.2021.1931037
Borg M Teachers’ beliefs ELT Journal 2001 55 2 186 187 10.1093/elt/55.2.186
Breakwell GM Fino E Jaspal R The COVID-19 preventive behaviors index: Development and validation in two samples from the United Kingdom Evaluation & the Health Professions 2021 44 1 77 86 10.1177/0163278720983416 33430623
Çalik M Turan B Coll RK A cross-age study of elementary student teachers’ scientific habits of mind concerning socioscientific issues International Journal of Science and Mathematics Education 2014 12 6 1315 1340 10.1007/s10763-013-9458-0
Chadwick, R., & McLoughlin, E. (2022). Irish secondary school science teachers’ perspectives on addressing the COVID-19 crisis as socioscientific issues. Disciplinary and Interdisciplinary Science Education Research, 4(1). 10.1186/s43031-022-00056-z
Chen S Chang W-H Lieu S-C Kao H-L Huang M-T Lin S-F Development of an empirically based questionnaire to investigate young students’ ideas about Nature of Science Journal of Research in Science Teaching 2013 50 4 408 430 10.1002/tea.21079
Choi H Jang J Kandampully J Application of the extended VBN theory to understand consumers’ decisions about green hotels International Journal of Hospitality Management 2015 51 87 95 10.1016/J.IJHM.2015.08.004
Choi K Lee H Shin N Kim S-W Krajcik J Re-conceptualization of scientific literacy in South Korea for the 21st century Journal of Research in Science Teaching 2011 48 6 670 697 10.1002/tea.20424
Chung Y Yoo J Kim S-W Lee H Zeidler DL Enhancing students’ communication skills in science classroom through socioscientific issues International Journal of Science and Mathematics Education 2016 14 1 1 27 10.1007/s10763-014-9557-6
Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Routledge. 10.4324/9780203771587
Coleman, J. S. (2000). Foundations of social theory. Belknap Press of Harvard Univ. Press.
Collis A Garimella K Moehring A Rahimian MA Babalola S Gobat NH Shattuck D Stolow J Aral S Eckles D Global survey on COVID-19 beliefs, behaviours and norms Nature Human Behaviour 2022 6 9 1310 1317 10.1038/s41562-022-01347-1
Commission on Higher Education. (2020). Higher education enrollment by discipline group: AY 2010–11 to 2019–20. Retrieved from https://ched.gov.ph/wp-content/uploads/Higher-Education-Enrollment-by-Discipline-Group-AY-2010-11-to-2019-20.pdf
Cowling BJ Ng DMW Ip DKM Liao Q Lam WWT Wu JT Lau JTF Griffiths SM Fielding R Community psychological and behavioral responses through the first wave of the 2009 influenza A(H1N1) pandemic in Hong Kong The Journal of Infectious Diseases 2010 202 6 867 876 10.1086/655811 20677945
Faul F Erdfelder E Buchner A Lang A-G Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses Behavioral Research Methods 2009 41 1149 1160 10.3758/BRM.41.4.1149
Fischhoff B Gonzalez RM Small DA Lerner JS Evaluating the success of terror risk communications Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science 2003 1 4 255 258 10.1089/153871303771861450 15040205
Gotanda H Miyawaki A Tabuchi T Tsugawa Y Association between trust in government and practice of preventive measures during the COVID-19 pandemic in Japan Journal of General Internal Medicine 2021 36 11 3471 3477 10.1007/s11606-021-06959-3 34159544
Grimmelikhuijsen S Knies E Validating a scale for citizen trust in government organizations International Review of Administrative Sciences 2015 83 3 583 601 10.1177/0020852315585950
Gutu, B., Legese, G., Fikadu, N., Kumela, B., Shuma, F., Mosisa, W., Regassa, Z., Shiferaw, Y., Tesfaye, L., Yohannes, B., Palanimuthu, K., Birhanu, Z., & Shiferaw, D. (2021). Assessment of preventive behavior and associated factors towards COVID-19 in Qellam Wallaga Zone, Oromia, Ethiopia: A community-based cross-sectional study. PLOS ONE, 16(4), e0251062. 10.1371/journal.pone.0251062
Hair JF Frisher J Sarstedt M Ringle CM When to use and how to report the results of PLS-SEM European Business Review 2019 31 1 2 24 10.1108/EBR-11-2018-0203
Hair, J. F., Hult, G. T. M., Ringle, C. M., & Sarstedt, M. (2014). A primer on partial least squares structural equation modeling (PLS-SEM). SAGE Publications Inc.
Hair, J. F., Hult, G. T. M., Ringle, C. M., & Sarstedt, M. (2017). A primer on partial least squares structural equation modeling (PLS-SEM) (2nd ed.). Sage.
Han, Q., Zheng, B., Cristea, M., Agostini, M., Bélanger, J. J., Gützkow, B., Kreienkamp, J., & Leander, N. P. (2021). Trust in government regarding COVID-19 and its associations with preventive health behaviour and prosocial behaviour during the pandemic: a cross-sectional and longitudinal study. Psychological Medicine, 1–11.10.1017/S0033291721001306
Herman BC Clough MP Rao A Socioscientific issues thinking and action in the midst of science-in-the-making Science & Education 2022 10.1007/s11191-021-00306-y
Hetherington, M. J. (2006). Why trust matters: Declining political trust and the demise of American liberalism. Princeton University Press.
Hofstein A Eilks I Bybee R Societal issues and their importance for contemporary science education - a pedagogical justification and the state-of-the-art in Israel, Germany, and the USA International Journal of Science and Mathematics Education 2011 9 6 1459 1483 10.1007/s10763-010-9273-9
Janz NK Becker MH The Health Belief Model: A decade later Health Education Quarterly 1984 11 1 1 47 10.1177/109019818401100101 6392204
Johansson, B., Sohlberg, J., Esaiasson, P., & Ghersetti, M. (2021). Why Swedes don’t wear face masks during the pandemic—a consequence of blindly trusting the government. Journal of International Crisis and Risk Communication Research, 4(2), 335–358. 10.30658/jicrcr.4.2.6
Karpudewan M Roth W-M Changes in primary students’ informal reasoning during an environment-related curriculum on socio-scientific issues International Journal of Science and Mathematics Education 2018 16 3 401 419 10.1007/s10763-016-9787-x
Kim, S. Y., & Hamdan Alghamdi, A. K. (2021). Saudi Arabian secondary school students’ views of the nature of science and epistemological beliefs: Gendered differences. Research in Science & Technological Education, 1–23.10.1080/02635143.2021.1961721
Kiryak Z Çalik M Improving grade 7 students’ conceptual understanding of water pollution via Common Knowledge Construction Model International Journal of Science and Mathematics Education 2018 16 6 1025 1046 10.1007/s10763-017-9820-8
Kock N Hadaya P Minimum sample size estimation in PLS-SEM: The inverse square root and gamma-exponential methods Information Systems Journal 2018 28 1 227 261 10.1111/isj.12131
Kupferschmidt, K., & Cohen, J. (2020, March). China’s aggressive measures have slowed the coronavirus. They may not work in other countries: Report from joint WHO-China mission takes detailed look at results of response in hardest hit country. Science. 10.1126/science.abb5426
Lederman NG Abd-El-Khalick F Bell RL Schwartz RS Views of nature of science questionnaire: Toward valid and meaningful assessment of learners’ conceptions of nature of science Journal of Research in Science Teaching 2002 39 6 497 521 10.1002/tea.10034
Lederman NG Students’ and teachers’ conceptions of the nature of science: A review of the research Journal of Research in Science Teaching 1992 29 4 331 359 10.1002/tea.3660290404
Levi, M. (1998). A state of trust. In V. Braithwaite, & M. Levi (Eds.), Trust and Governance (pp. 77–101). Russel Sage Foundation.
Lin HC Chen CC Disease prevention behavior during the COVID-19 pandemic and the role of self-esteem: An extended parallel process model Psychology Research and Behavior Management 2021 14 123 135 10.2147/PRBM.S291300 33603513
Liu, J., Shahab, Y., & Hoque, H. (2022). Government response measures and public trust during the COVID-19 pandemic: Evidence from around the world. British Journal of Management, 33(2), 571–602.10.1111/1467-8551.12577
Lofredo MP Social cohesion, trust, and government action against pandemic Eubios Journal of International and Asian Bioethics 2020 30 4 182 189
LoMonte, F. D. (2020). Casualties of a pandemic: Truth, trust and transparency. The Journal of Civic Information, 2(1). 10.32473/joci.v2i1.121552
Maass K Sorge S Romero-Ariza M Hesse A Straser O Promoting active citizenship in mathematics and science teaching International Journal of Science and Mathematics Education 2022 20 4 727 746 10.1007/s10763-021-10182-1 34177402
Markel H Lipman HB Navarro JA Sloan A Michalsen JR Stern AM Cetron MS Nonpharmaceutical interventions implemented by US cities during the 1918–1919 influenza pandemic Journal of the American Medical Association 2007 298 6 644 654 10.1001/jama.298.6.644 17684187
Matsumoto D Culture, context, and behavior Journal of Personality 2007 75 6 1285 1320 10.1111/j.1467-6494.2007.00476.x 17995466
Mckellar, K., & Sillence, E. (2020). Current research on sexual health and teenagers. In K. Mckellar & E. Sillence (Eds.), Teenagers, sexual health information and the digital age (pp. 5–23). Academic Press. 10.1016/B978-0-12-816969-8.00002-3
Newton, K., Stolle, D., & Zmerli, S. (2018). Social and political trust. In E. M. Uslaner (Ed.), The Oxford handbook of social and political trust (pp. 961–976). Oxford University Press. 10.1093/oxfordhb/9780190274801.013.20
Nielsen JH Lindvall J Trust in government in Sweden and Denmark during the COVID-19 epidemic West European Politics 2021 44 5–6 1180 1204 10.1080/01402382.2021.1909964
Oude Groeniger J Noordzij K van der Waal J de Koster W Dutch COVID-19 lockdown measures increased trust in government and trust in science: A difference-in-differences analysis Social Science & Medicine 2021 275 113819 10.1016/j.socscimed.2021.113819 33725488
Peng, Y., Pei, C., Zheng, Y., Wang, J., Zhang, K., Zheng, Z., & Zhu, P. (2020). A cross-sectional survey of knowledge, attitude and practice associated with COVID-19 among undergraduate students in China. BMC Public Health, 20(1). 10.1186/s12889-020-09392-z
Philippine Statistics Authority. (2022). Urban population of the philippines (2020 Census of Population and Housing).
Prickett, K. C., & Chapple, S. (2021). Trust in government and Covid-19 vaccine hesitancy. Policy Quarterly, 17(3), 69–71. 10.26686/pq.v17i3.7135
Republic of the Philippines. (2020). Memorandum from the executive secretary on community quarantine over the entire Luzon and management of the coronavirus disease 2019 (COVID-19) situation (18 March 2020).
Rieger MO Wang M Trust in government actions during the COVID-19 crisis Social Indicators Research 2021 10.1007/s11205-021-02772-x
Rosenstock IM Historical origins of the Health Belief Model Health Education Monographs 1974 2 4 328 335 10.1177/109019817400200403
Sadler TD Informal reasoning regarding socioscientific issues: A critical review of research Journal of Research in Science Teaching 2004 41 5 513 536 10.1002/tea.20009
Sadler TD Situated learning in science education: Socio-scientific issues as contexts for practice Studies in Science Education 2009 45 1 1 42 10.1080/03057260802681839
Sadler, T. D. (2011). Situating socio-scientific issues in classrooms as a means of achieving goals of science education. In T. D. Sadler (Ed.), Socio-scientific issues in the classroom: Teaching, learning and research (pp. 1–10). Springer. 10.1007/978-94-007-1159-4
Sarstedt M Hair JF Cheah J-H Becker J-M Ringle CM How to specify, estimate, and validate higher-order constructs in PLS-SEM Australasian Marketing Journal (AMJ) 2019 27 3 197 211 10.1016/j.ausmj.2019.05.003
Schwartz SH Normative influences on altruism Advances in Experimental Social Psychology 1977 10 221 279 10.1016/S0065-2601(08)60358-5
Schwartz, S. H., & Howard, J. A. (1981). A normative decision-making model of altruism. In P. J. Rushton & R. M. Sorrentino (Eds.), Altruism and helping behavior: Social, personality, and developmental perspectives (pp. 189–211). Lawrence Erlbaum.
Shiloh S Nudelman G Exploring dimensions of health behaviors’ representations Psychology & Health 2020 35 8 1017 1032 10.1080/08870446.2019.1707828 32202152
Sjöström J Eilks I Zuin VG Towards eco-reflexive science education: A critical reflection about educational implications of green chemistry Science and Education 2016 25 3–4 321 341 10.1007/s11191-016-9818-6
Steg L Dreijerink L Abrahamse W Factors influencing the acceptability of energy policies: A test of VBN theory Journal of Environmental Psychology 2005 25 4 415 425 10.1016/J.JENVP.2005.08.003
Stern PC Toward a coherent theory of environmentally significant behavior Journal of Social Issues 2000 56 3 407 424 10.1111/0022-4537.00175
Stern, P. C., Dietz, T., Abel, T., Guagnano, G. A., & Kalof, L. (1999). A value-belief-norm theory of support for social movements: The case of environmentalism. Human Ecology Review, 6(2), 81–97. https://www.scopus.com/inward/record.uri?eid=2-s2.0-0033393895&partnerID=40&md5=1a9c5ae06c72219c37572ce661ba412e
Sulik, J., Deroy, O., Dezecache, G., Newson, M., Zhao, Y., El Zein, M., & Tunçgenç, B. (2021). Facing the pandemic with trust in science. Humanities and Social Sciences Communications, 8(1). 10.1057/s41599-021-00982-9
Tan CL Chung MH Zaidon UHB Abdullah AB Chew PY Mathews NA Ligot DV Hamzah FAB Dunn AG Cross-country analysis of public trust towards government responses during COVID-19 pandemic SSRN 2021 10.2139/ssrn.3922113
Vartti AM Oenema A Schreck M Uutela A De Zwart O Brug J Aro AR SARS knowledge, perceptions, and behaviors: A comparison between finns and the Dutch during the SARS outbreak in 2003 International Journal of Behavioral Medicine 2009 16 1 41 48 10.1007/s12529-008-9004-6 19184625
Vickers RR Conway TL Hervig LK Demonstration of replicable dimensions of health behaviors Preventive Medicine 1990 19 4 377 401 10.1016/0091-7435(90)90037-K 2399221
Vogel, G. (2020, October 9). Sweden’s gamble: The country’s pandemic policies came at a high price and created painful rifts in its scientific community. Science, 159–163. 10.1126/science.abf1247
Wan Y Bi H What major “socio-scientific topics” should the science curriculum focused on? A Delphi study of the expert community in China International Journal of Science and Mathematics Education 2020 18 1 61 77 10.1007/s10763-018-09947-y
World Health Organization (WHO). (2020a). Advice on the use of masks in the community, during home care, and in health care settings in the context of COVID-19-Interim guidance. Retrieved from https://apps.who.int/iris/handle/10665/331493
World Health Organization (WHO). (2020b). COVID-19: Operational guidance for maintaining essential health services during an outbreak-Interim guidance. Retrieved from https://apps.who.int/iris/handle/10665/331561
Xie, X., Wu, T., Zhang, Y., & Guo, Y. (2021). Socioeconomic status and COVID-19-related psychological panic in China: The role of trust in government and authoritarian personality. International Journal of Environmental Research and Public Health, 18(20), 10888. 10.3390/ijerph182010888
Yadav R Altruistic or egoistic: Which value promotes organic food consumption among young consumers? A study in the context of a developing nation Journal of Retailing and Consumer Services 2016 33 92 97 10.1016/J.JRETCONSER.2016.08.008
Yahaya JM Zain ANM Karpudewan M The effects of socio-scientific instruction on pre-service teachers’ sense of efficacy for learning and teaching controversial family health issues International Journal of Science and Mathematics Education 2015 13 2 467 491 10.1007/s10763-014-9537-x
Zhang L Seale H Wu S Yang P Zheng Y Ma C MacIntyre R Wang Q Post-pandemic assessment of public knowledge, behavior, and skill on influenza prevention among the general population of Beijing, China International Journal of Infectious Diseases 2014 24 1 5 10.1016/j.ijid.2014.01.003 24735679
| 0 | PMC9734577 | NO-CC CODE | 2022-12-14 23:28:29 | no | Int J Sci Math Educ. 2022 Dec 3;:1-30 | utf-8 | Int J Sci Math Educ | 2,022 | 10.1007/s10763-022-10343-w | oa_other |
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Environ Sci Pollut Res Int
Environ Sci Pollut Res Int
Environmental Science and Pollution Research International
0944-1344
1614-7499
Springer Berlin Heidelberg Berlin/Heidelberg
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10.1007/s11356-022-24601-5
Short Research and Discussion Article
2030 Agenda: discussion on Brazilian priorities facing air pollution and climate change challenges
de Moura Fernando Rafael 12
http://orcid.org/0000-0002-7344-4679
da Silva Júnior Flavio Manoel Rodrigues [email protected]
12
1 grid.411598.0 0000 0000 8540 6536 LEFT - Laboratório de Ensaios Farmacológicos e Toxicológicos, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande - FURG, Av. Itália, Km 8, Campus Carreiros, Rio Grande, RS CEP 96203-900 Brazil
2 grid.411598.0 0000 0000 8540 6536 Programa de Pós Graduação em Ciências da Saúde, Universidade Federal do Rio Grande - FURG, Rua Visconde de Paranaguá, 102, Rio Grande, RS CEP 96203-900 Brazil
Responsible Editor: Philippe Garrigues
9 12 2022
115
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1 12 2022
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The advance of human activities in a disorderly way has accelerated in recent decades, intensifying the environmental impacts directly linked to these practices. The atmosphere, essential for the maintenance of life, is increasingly saturated with pollutants, offering risks to practically all the inhabitants of the planet, a process that, in addition to causing illness and early mortality, is related to serious financial losses (including in the production of goods), dangerous temperature increase and severe natural disasters. Although this perception is not recent, the global initiative to control the different mechanisms that trigger the commitment of biodiversity and irreversible climate changes arising from pollution is still very incipient, given that global initiatives on the subject emerged just over 50 years ago. Brazil is a territory that centralizes many of these discussions, as it still faces both political and economic obstacles in achieving a sustainable growth model as it was agreed through the United Nations 2030 Agenda. Even though there is little time left for the completion of these goals, much remains to be done, and despite the fulfillment of this deadline, the works will certainly need to be extended for much longer until an effective reorientation of consciousness occurs. Scientific researches and discussions are fundamental tools to the understanding of issues still little explored in this field.
Keywords
Contamination
Heat waves
Latin America
One health
Sustainable development goals
Wildfires
http://dx.doi.org/10.13039/501100003593 Conselho Nacional de Desenvolvimento Científico e Tecnológico 310856/2020-5 da Silva Júnior Flavio Manoel Rodrigues http://dx.doi.org/10.13039/501100002322 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 001 de Moura Fernando Rafael http://dx.doi.org/10.13039/501100004263 Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul 21/2551-0001981-6 da Silva Júnior Flavio Manoel Rodrigues
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pmcIntroduction
Recently, in Europe, it was released a final report listing several concerns related to climate change, the environment, and global health, which in the next decade should motivate research and the development of technologies in the context of the European Union, and as an extension, the whole world (Drakvik et al. 2022). In this sense, air pollution (and its relationship to local climates) is a fundamental concern because it centralizes several of these issues. People’s physical and mental health, economic and social progress, the overall image of the cities, as well as people’s livelihood and happiness index are all affected by the quality of the atmosphere. In the last decades, as people’s living standards have risen, and environmental consciousness has grown, air pollution has emerged as a severe environmental issue that has sparked widespread concern. As a result, conserving and improving the environment has become a top priority for the entire society.
According to Haq et al. (2021), the establishment of the 2030 Agenda by the United Nations in 2015, with its 17 SDGs, 169 targets and more than 200 indicators related to the different global challenges in the search for reducing inequalities, environmental impacts, and sustainable technologies, many countries have been taking actions in the quest to fit into these proposals, with some frequency adapting them according to the most critical needs of each location. Although many theorists criticized the 2030 Agenda for having too many goals and lacking prioritization, as mentioned by Rocha and Alexandre Weiss (2019), unfortunately, air pollution was one issue that was deemphasized. Air pollution’s position in SDGs is cloudy, and while climate change was highlighted in one of the goals (SDG13), there is no headline goal on air pollution. Air pollution is specifically cited in 3 targets, under health (SDG3), sustainable cities (SDG11), and responsible consumption (SDG12) but shares these targets with other issues. However, a broad perspective illustrates that air pollution is linked in principle to most of the SDGs, either in terms of causes (energy, industry, transport), the measurement of air pollution itself, or impacts such as damages to ecosystems and health.
Regarding climate-related changes, although it is not an unprecedented topic since more than 50 years ago the role of gases such as CO2 in this process was already under study (Benton 1970), and new implications have been raised as the technology of detection, modeling, and elaboration of forecasts based on the historical profile that has been traced and, especially, given the lack of an adequate and quick response to such effects (Atkinson and Jacquet 2022). Although SDG 13 deals directly with climate change, encompassing five targets, similarly to air pollution, only three other mentions are made on the subject, along with combating poverty (SDG1), eradicating hunger (SDG2), and sustainable cities (SDG11). Such a scenario raises concerns about the non-integration of objectives.
In recent years a concept called One Health (OH) has gained importance. Considered a holistic, transdisciplinary, and multisectoral concept, which encompasses human health, environmental health, and animal health, it is directly connected to aspects of public health, urbanization, legal framework, ecotoxicology, multifactorial diseases, and cultural practices, which in turn have direct influences on the quality of life, human rights, and institutional policies of companies and nations, although some of these aspects are often neglected (Destoumieux-Garzón et al. 2018; Ribeiro et al. 2019). Dye (2022) indicated that the OH approach is the most appropriate for achieving the complex and multiple aspirations of the SDGs of the 2030 Agenda, as this approach seeks to anchor health and development, demonstrating that social justice, environmental protection, and economic prosperity depend on and contribute to global health.
The OH approach is a very challenging strategy in developing countries like Brazil, especially to avoid setting goals that are too narrow or too broad, which lack prioritization of needs (Dye 2022). According to Espeschit et al. (2021), Brazil already has the necessary instruments to carry out interventions in the OH approach, but professional alienation, lack of financial resources, and lack of recognition of the intersection of human, animal, and environmental health remain obstacles to its articulation. Aiming to evaluate congruence points for different regions of the world, Laumann et al. (2022) grouped 181 countries into 35 groups based on their regional and economic affinities and found that SDG 17 (partnerships) had the highest number of mentions in connection with tackling climate change, prevailing on all continents except Oceania. Those authors also declared that fundamental variables such as air pollution and disorderly urbanization, with the growth of slums, were directly linked to the increase in global temperature and its consequences.
In addition, it is important to report that the complexity of the indicators, with just under 8 years to go before the agreements should be put into effect, is still a hindrance in the process of putting initiatives into operation. Silveira et al. (2021) developed a survey involving five prestigious institutions: the Global Burden of Disease Study (GBD), the Pan American Health Organization, the Sustainable Development Solutions Network, the World Bank and the World Health Organization (WHO), and analyzed their convergences and divergences regarding the health-related SDG indicators. Of the 104 indicators listed by these 5 institutions, only 60 of them were consistent with official Inter-agency and Expert Group SDG indicators. Besides that, out of these 60 indicators, only 22 are included in the lists of the five institutions. This perception demonstrates that there are significant inconsistencies, which certainly delay obtaining decisive information both for decision-making and for monitoring by governance and society of potential advances or setbacks in goals. And, considering the context presented in the OH approach, these variations make the process of integration and interdisciplinarity work, which seem to be the most suitable for carrying out the SDGs, more difficult (Queenan et al. 2017).
In Brazil, the prospects are huge. Brazil occupies prominence in the international scenario due to its large territory of continental dimensions, high population, and leading role in the production of various goods and commodities. Despite that, Brazil is still a very heterogeneous country in terms of economic development and key environmental variables in its regions (Swart and Brinkmann 2020). Considering that, previous studies demonstrate major weaknesses that signal the non-achievement of targets within the stipulated period. Reports from different surveys indicate that more than 50,000 people die in Brazil annually due to air pollution (Custódio et al. 2022); management of decisions related to climate changes impacts and solutions still belong to few groups which control both the production of knowledge and the responses given in crisis events (Lemos et al. 2020); Brazilian cities and their managers are more interested in positioning themselves as smart and technological cities than as sustainable cities (Machado Junior et al. 2018) and that, according to a group of 884 experts, Brazil’s chances of completing some of the 17 SDGs is low, and the prioritization of SDG 4 (Quality Education) and SDG 1 (End Poverty) are mandatory tasks to achieve goals aimed at improving health and quality of life (Moreira et al. 2019), since several basic principles shared by health promotion and sustainable development, such as equity, intersectoral methods, and sustainability, help to optimize their influence across traditional sectoral lines.
Considering the established scenario, the 2030 Agenda is an important tool in the search for sustainable and integral development, but the variety of its approaches makes the use of its indicators complex. Therefore, in this work, we selected several bibliographies in order to draw attention to issues concerning air pollution and climate change, based on the way in which these themes are covered by the SDGs, adapted to the Brazilian scenario. For this, there is a division into three main sections: the first presents aspects related to air pollution, including the course and status of local public policies established for its evaluation, as well as studies concerning the theme and its already proved consequences, including first some insights from Latin America and then, Brazil. In the second, a similar approach is given to climate change, building its parallel in relation to air pollution. The third section presents a table assembled with data about the current state of SDGs in Brazil, as well as discussing hotspots of action and perspectives for them. This discussion is intended, then, as a subsidy to foster reflections and raise awareness on the interconnections between human and environmental health in order to better address the gaps that are still found in sustainable development actions.
Air pollution
Chronology and legal aspects
The first studies addressing air pollution in Latin America date back to the 1950s, when universities and bodies linked to the Ministries of Health in various regions began measuring air pollutants, and the establishment of the Pan American Network for Standardized Sampling of Air Contamination — REDPANAIRE, in 1967 was a milestone in this process, as 7 years later, monitoring stations would be installed in 14 countries and would later be incorporated into the Global Air Quality Monitoring Program — UNEP/WHO (Colman Lerner et al. 2018). Comparatively, in the study developed by Gómez-Peláez et al. (2020) in cities in South America, although seven decades have passed since the beginning of these actions in the region, more than 100 million people are still directly exposed to increased levels of air pollution, and even though in the period 2010 to 2017 some cities such as São Paulo and Bogotá have registered a decrease in the levels of pollutants such as PM2.5, this is definitely not a regional trend, with continuous surpassing of the rates recommended both by local agencies and bodies and by the WHO itself.
The Brazilian scenario was not less complex. Duarte (2015) brings a very important historical account when describing the attitudes of the then Minister of Planning, João Paulo dos Reis Velloso, who in January 1972 showed a position clearly contrary to any environmental concern through his speeches that considered that the greater pollution in Brazil was actually poverty and that there were still many areas to be polluted, signaling the interest in receiving foreign capital from already developed countries, such as Japan, which sought to continue expanding their productive networks, but found themselves legally limited due to environmental impacts, already provoked in their own territories.
There was, at that moment, a great dilemma between the governmental interests in the period of Military Dictatorship in Brazil (1964–1985), which aimed for a format of progress and development at any cost (in a supposed attempt to promote jobs and improve income and life quality of the population), and those of the population itself, which suffered from the unbridled increase in environmental pollution, especially atmospheric, since the smoke from factories was considered a synonym of success (Duarte 2015). Although in a very inconsistent way, in 1967, Decree-Law 3030/1967 was enacted, which can be established as a founding framework for environmental concerns in Brazil, following trends and strong national and international media pressures, which would later legislate so that any substance that was emitted into the atmosphere could not leave it polluted. Given the lack of means to comply with this decree, it would be revoked shortly afterwards by the National Sanitation Policy, still in force, established by Law 5318/1967 (Arantes 2018).
With direct relation to air quality, it was only between the 1980s and 1990s that Brazil developed clear devices for the quantification of pollutants through the creation of the National Environmental Council — CONAMA (article 6 of the National Environmental Policy of Law 6938/1981) later converted into a consultative and deliberative body by Law 8028/1990, and assumed the role of elaborating norms and criteria for environmental quality standards in the country, through inspection resources (Valadão et al. 2022). CONAMA established in 1989 the National Air Quality Control Program — PRONAR, with the purpose of setting emission limits by sources of pollutants in order to ensure that socioeconomic development was possible, however, in an environmentally safe way. Resolution no. 03, of 1990, defined the levels of national air quality standards (National Air Quality Standards—NAQS), bringing an important contribution to the process of evaluation and control of pollution levels, but due to population, industrial and vehicular growth rapidly became outdated, and only in 2018 Brazil adjusted its concentrations to the standards established by the WHO back in 2005, showing an important delay in comprising the goals (Siciliano et al. 2020).
Scientific evidences
Along this path, scientific production has directly collaborated to prove the real impacts of air quality on the health of populations. In recent years, with increasing awareness of the scarcity of resources and the irreversible impacts of anthropogenic action, some studies can be listed that support the need for immediate actions to help mitigate these processes.
Latin America and Brazil: human exposure to air pollution
Starting with an overview of the American continent and especially Latin America and the Caribbean countries, Korc and Hauchman (2021) made an important warning about the large number of people in several countries, such as the Dominican Republic, Paraguay, Venezuela, Haiti, and Belize, that do not have clean primary sources to cook in their homes, needing to resort to the use of wood and charcoal and producing high levels of pollution, in the middle of 2018. These authors also showed that among the 35 American countries studied, only Canada and the USA had no annual records of PM2.5 concentration above WHO recommendations in 2016, a very worrying scenario. At the same time, another study carried out with PM2.5 levels in 366 Latin American cities with more than 100,000 inhabitants using satellite data showed that 58% of the population under study (more than 170 million people) live in areas with exposure to air pollution levels above the WHO averages, this increase is directly linked to cities with higher GDP, higher motorization rates, traffic jams, and larger size and inversely proportional to the presence of green areas in the municipalities (Gouveia et al. 2021). Husaini et al. (2022) also demonstrated that Latin America and Caribbean countries still lack studies to explore the regional impacts of air pollution in order to sensitize public gestors and reduce health impacts.
In Brazilian territory, a crucial issue is related to changes in land use, since several agricultural and extractive practices occur without any concern for sustainability. In a broad study involving all 26 Brazilian states and the Federal District in a 20-year historical series (1995–2014) to estimate the different types of territorial changes arising from crops, pastures, and forestry and crossing these data with the associated CO2 emissions, it was noticed that both the highest emissions occurred in the surroundings of the Amazon Biome, as well as the productive models of territorial use that expanded the most in the region, are the ones that most contribute to this type of pollution (generation of greenhouse gases) (Novaes et al. 2017). These data are in agreement with a literature review developed by Urrutia-Pereira et al. (2021) who sought to establish the relationship between exposure to smoke caused by the burning of biomass in the Brazilian Amazon Forest and the implications for human health faced by the population of the surrounding region. Working with a list of publications between the years 2005 and 2021, these authors demonstrated that despite great dissemination in the media, few studies were dedicated to evaluating this theme in the mentioned region, pointing to the urgent need for actions that provide an improvement in the behavior of the exposed population both in terms of preventing fires and in protective measures to reduce health damage.
Air pollution sources
In Latin America, the rapid increase in urbanization and the emergence of megacities contributed drastically to the accumulation of various pollutants in the atmosphere, especially those produced from the activities of industrial complexes and vehicle fleets (La Colla et al. 2021). As the region is mainly formed by developing countries, the mechanisms for monitoring the sources of pollution are often deficient or absent, contributing to poor air quality management (Riojas-Rodríguez et al. 2016) and, in addition, the accelerated population increase contributes to more anthropogenic polluting activities.
In Brazil, as an extension, wildfires also play a very important role in the generation of pollutants that directly affect the health of populations. Caumo et al. (2022) collected evidence from 27 papers published between 2000 and 2021 to conclude that the most vulnerable populations always present exacerbated clinical conditions (cardiorespiratory, mainly) in episodes immediately before, during, and after fires due to an increase of pollutants, such as particulate matter, which directly agrees with the findings of Ye et al. (2021), albeit in a more restricted period (2000–2015).
Sousa et al. (2020) went even further, exposing that in addition to the Western Amazon region, the territories that extend between the north of the state of Mato Grosso and the southeast of the state of Pará, called “Arco do Desmatamento”, and also Pantanal, in addition to being constantly ravaged by fire, rising temperatures and intense droughts, also have populations exposed to low and lacking hospital infrastructure, especially highly complex ones, not being able to provide effective and fast care. This condition may be associated with what was found in the investigation by Nawaz and Henze (2020) who highlighted that the burning of biomass that has been occurring mainly in the Amazon region, emitting aerosols with large amounts of particulate matter that spreads throughout the Brazilian territory, often causes illness and increase in premature deaths in areas far from the main fires, as reinforced by the study by Bainy et al. (2021).
Health impacts and costs
Floss and Barros (2019) used the report produced by the Lancet Countdown for the year 2019 to prepare a policy brief on key points that should be developed in Brazil in order to address recommendations nos. 2, 3, and 4, of the report that deal with: suppressing energy production from burning coal, reducing illegal deforestation to zero by 2030 (as well as carrying out reforestation practices and reducing the burning of biomass) and developing a personalized Brazilian version of air quality index, with online messages that alert the population to the increased risk of pollutants in certain scenarios, respectively. This last recommendation also comes with a direct mention of reducing the burden of diseases related to air pollution, especially in the most vulnerable populations, attesting to the imminent need for clear initiatives in this regard. An example of this is the study by Carneiro et al. (2021) who worked with secondary data from SUS regarding outpatient care for respiratory diseases in children under 5 years of age in Brazil and observed that most pathologies have stationary or ascending rates, and only asthma cases decreased. In addition, that same study showed rising disease rates in the Southeast region of Brazil, while in the others the levels tended to a stationary state.
Lima et al. (2021), in their turn, when analyzing numbers of hospitalizations for respiratory diseases between 1998 and 2020 in the city of Manaus — AM and the data on atmospheric pollutants obtained in the same period, denoted a strong correlation between them, in addition to obtaining an annual calculation average of more than BRL 19,000.00 (approximately US$3900.00 in May/2022 quotation) per hospitalization by the Brazilian Unified Health System (SUS), evidencing a high cost per patient admitted.
The Southeast region, individually, also contributes in a very significant way to pollution, although in a different way from the Amazon axis, and for this reason, it has been the most widely studied over the years, in the verified health impacts, the quality of the monitoring data provided and the pollution control programs implemented. An important study in the city of São Paulo focused on the impacts of air pollution showed that the increase in the atmospheric concentration of particulate matter was highly correlated with the increase in hospitalizations for respiratory diseases in the period from 2008 to 2017, with 302,000 hospitalizations representing a health cost of 111 million dollars (Santana et al. 2020). These results are in line with the research by Abe and Miraglia (2016), who evaluated São Paulo city air pollution using the Health Impact Assessment approach, and pointed out that if São Paulo reached the levels of PM2.5 recommended by the WHO (10 μm/m3, at that time) more than 5000 thousand premature deaths would be avoided, as well as guaranteed savings of more than 15 billion dollars.
Gouveia et al. (2017) investigated the same outcomes in the metropolitan region of São Paulo (including 10 municipalities in the state). These authors also observed a correlation between the levels of pollution found and hospitalizations, in this specific case, correlating PM10 levels with cardiovascular involvement. This perspective was also reinforced by Pamplona et al. (2020), who correlated air pollution in the city of São Paulo with congestive heart failure. The recent study by Leirião et al. (2022) also showed that the levels of pollution found in São Paulo probably contributed to the increase in deaths due to the COVID-19 pandemic, emphasizing that reducing pollution levels is also essential from the perspective of coping and improving the chances of death survival in future respiratory disease pandemics.
Other noteworthy studies in the city/state of São Paulo were Bravo et al. (2016) who, in addition to relating hospital deaths to air pollution, also observed that the cardiovascular effects of PM10 were more significant in population groups with less schooling (indicating the “non-democratization” of pollution); Pérez-Martínez et al. (2017) who observed that policies related to transport/traffic can have a significant impact on reducing pollutants based on their study on the restriction of heavy diesel vehicles; Nakada and Urban (2020), Rudke et al. (2021), and Cirqueira et al. (2022) who studied the effects of the COVID-19 pandemic (lockdowns and mobility restrictions) on pollution levels and noticed very heterogeneous results, concluding that the economic, health and vehicular traffic particularities of each city or region in the state of São Paulo should be taken into account in the search for emission mitigation strategies.
Mitigation strategies perceptions and challenges
Another major review developed by Andrade et al. (2017) used studies involving ozone (O3) emissions and the Metropolitan region of São Paulo — SP, over three decades (1980s-2010s), and demonstrated that challenges still remain for the Companhia de Tecnologia de Saneamento Ambiental (CETESB, Environmental Protection Agency) to the control of pollutants of secondary origin such as O3 and particulate matter, especially by vehicular sources and emissions. This finding is quite concerning since the state of São Paulo has the best service for monitoring and mitigating atmospheric pollution in Brazil. Studies also show frustrated alternatives that have already tried to reduce the emission of vehicular pollutants in the region, such as the one by Araujo and Araujo (2020) who analyzed the impact of the Vehicle Inspection Program on public health in the city of São Paulo. This measurement, instituted with the use of public funds, was in force between January 2010 and January 2014, with the purpose of minimizing the emission of pollutants by vehicles registered in the municipality, even so, neither its introduction nor its interruption had any correlation with the decrease in pollutant concentrations and, consequently, with lower rates of health outcomes (hospitalizations and deaths from various pathologies such as infarction, stroke, chronic obstructive pulmonary disease, and neoplasms), which attests to its null influence. Sá et al. (2017), however, points out that actions to change the direction of development towards more sustainable alternatives are still welcome. Regarding the absence of evidence from the Vehicle Inspection Program, Sá et al. (2017) mentioned that more in-depth evaluations are needed to solidify this hasty perception, and that there is no consistent data to attest to the lack of correlation in low- and middle-income regions, reinforcing that these particularities could completely change the results found. This counterpoint demonstrates the need for new assessments on the subject for proper decision-making.
Similar to what occurs in the Amazon region, Santana et al. (2020) verified the correlation between the emission of atmospheric pollutants in São Paulo and the increase in costs and hospitalizations for respiratory diseases between the years 2008 and 2017, realizing that the particulate matter increased year by year in the evaluated period and was highly correlated to the hospitalization rates and the increase in costs, which went from a total of US$ 111 million for 302 thousand hospitalizations. What is evident is the need for more rigid alternatives to recover from this scenario that has been generalized. Cubatão — SP, a notorious city for having already been considered by the UN as the one with the most polluted atmosphere in the world, in a recent study (Sarra and Mülfarth 2021) that evaluated the historical series 2010–2020, showed, mainly in the years 2015 to 2017, a 62% reduction in the number of exceeding the Air Quality Standard for PM10, which reflected, for example, a 30% drop in the infant mortality rate, a 95% drop in hospitalizations for acute bronchitis and bronchiolitis in children under 4 years of age and a 60% reduction in deaths of individuals over 60 years of age from diseases of the respiratory system, which allows us to conclude the positive impacts of the recovery and sustainable measures that have been effectively adopted and carried out in this municipality.
The importance of green areas in reducing pollutant levels was also attested by the study by Martins et al. (2021a, b) who, studying tree barks collected in parks in the city of São Paulo, realized that forest fragments help to contain particulate matter and various heavy metals such as copper and cobalt, even serving as biological monitors that allow tracking of anthropogenic pollution.
Climate change considerations
Brief legal and historical aspects
Similar to concerns about air pollution, attention to climate change, given the great affinity between the topics, has intensified in the last four decades. However, if the scientific demand for solutions to the problems caused by the human action in the environment has instigated several researchers today, it has been part of human knowledge for a long time that we could change the climate. According to Mahony and Endfield (2018), there is a connection that goes back to the period of imperial colonialism perpetrated by European countries, which considered tropical regions, given the variety and abundance of their resources, as inhabited by depraved humans, inferior to the European people. In addition, these authors emphasize that people could already perceive environmental changes, such as deforestation, would alter the rainfall regime, and this became a strategy of domination, even though there was no understanding of atmospheric pollution or global warming.
Following the historical line of important points directly related to the understanding of climate change, as illustrated by Sheehan (2019), in 1824, Fourier described the Earth’s natural greenhouse effect and, in 1861, Tyndall proved in the laboratory that water vapor in combination with other gases was capable of producing the greenhouse effect. Later, in 1896, Arrenhius built the first climate model demonstrating the atmospheric influence of carbon dioxide (CO2), which was confirmed in 1900 when Angstrom established that CO2 is able to absorb infrared radiation, producing heating, even in slight concentrations. Nevertheless, even with these scientific advances having already been observed in the transition from the 19th to the twentieth century, it was only in 1972 that the United Nations held the Stockholm Conference, the first to raise the issue of global warming and seek to establish principles of environmental protection worldwide, that would culminate in events such as Rio 92, the establishment of the Kyoto Protocol and much more recently, in 2016, the Paris Agreement (Sheehan 2019).
Brazil has been identified as a key country when it comes to global climate change (Lahsen and Ribot 2022), but the organization of climate services in the country is diffused, and this seems to be a major national challenge facing the 2030 Agenda (Escada et al. 2021). The country, which has one of the largest emerging economies in the world, is paradoxically a power in terms of biodiversity and the potential for the use of renewable energy sources, and at the same time, a major polluter due to forest fires, deforestation, livestock, and the use of fossil fuels (La Rovere 2020). Brazil ranks seventh among the countries with the highest emission of greenhouse gases (GHG) and although it has reduced GHGs by 54% between 2005 and 2012, the abandonment of deforestation control policies and the encouragement of predatory agricultural practices will certainly be obstacles to achieving goals directly or indirectly related to climate change (Rochedo et al. 2018).
The consequences of climate change in Brazil and other Latin American countries throughout the twenty-first century may compromise some important goals of the 2030 Agenda, especially food insecurity; floods and landslides; water shortage; vector-borne disease epidemics; displacement of the Amazon Forest biome; coral bleaching; risks of sea level rise in coastal regions, storms, and erosion, and systemic failure due to cascading impacts of hazards and epidemics (Hagen et al. 2022). The authors of this study also pointed out that the impacts of the risks will be heterogeneous in the region and that the groups most affected will be the populations of rural communities, indigenous peoples, Afro-Latin Americans, women, people with disabilities, and migrants.
Spatially, a study displayed the Brazilian hot-spots sensitive to climate change, based on the regional climate change index (RCCI) and the socioclimatic vulnerability index (SCVI) (Torres et al. 2012). The first index is directly related to meteorological variables, while the second incorporates regional and social factors, including the availability of water resources and agricultural vulnerability. The RCCI showed climatic hotspots in central Brazil and in the Amazon region. On the other hand, the SCVI revealed the main socio-climatic hotspots in the northeast region (the poorest region in the country) and several hotspots located in the main Brazilian metropolitan regions, such as Manaus, Belo Horizonte, Brasília, Salvador, Rio de Janeiro, and São Paulo.
In addition to the heterogeneity of vulnerability associated with climate change, policies related to its risks, at the level of cities and states, are diffuse and supported by non-governmental stakeholders, organizations of civil society, the private sector, universities, and research institutions. Only 14 of the 27 federative units and 6 cities have climate change policies. The study by Barbi and Da Costa Ferreira (2017) evaluated these policies based on five main points of analysis: (1) mitigation goals and intentions; (2) adaptation actions; (3) stakeholder participation; (4) policy implementation; (5) participation in transnational climate change networks. In general, points 1 and 5 are more covered in municipal policies, while points 2, 3, and 4 are better addressed in state policies. The authors also comment that the establishment of climate policies is an important step, but that law enforcement mechanisms are fundamental to ensure that mitigation and adaptation actions are taken.
Returning to the national sphere, two important elements can (and should) be used as a basis for expanding health care in a scenario of a changing climate: Law 12,187/2009, which establishes the National Policy on Climate Change (Brazil-NCCP), and the country’s national adaptation plan (Brazil-NAP). The Brazil-NAP comprises a general strategy and eleven sectoral strategies, one of which specifically concerns health (Brazil-H-NAP). Still, the absence of explicit references to the right to health shows that the country has considerable room to improve its engagement with the human rights framework, particularly through the establishment of mechanisms to promote transparency, monitoring, and participation of marginalized groups, aiming to increase access and reduce inequalities (Viveros-Uehara 2021).
Impacts of climate change
The increase in average temperature over the last few decades is already well reported in different parts of Brazil (Medeiros et al. 2018; Marengo et al. 2021; Monteiro et al. 2021), and the country has been identified as one of the places with the highest rates of mortality from heat waves attributed to human-induced climate change (Vicedo-Cabrera et al. 2021). A study that evaluated the association between hot waves and hospitalizations in Brazil during the years 2000–2015 showed a higher risk of hospitalizations for hot waves characterized by high daily temperatures and for long durations throughout Brazil, with the exception of the North region (hotter region). After controlling the temperature effect, the association remained for severe heat waves in the south and southeast (cooler regions). Hospitalizations among children aged 0 to 9 years, elderly > 70 years, and hospitalizations for perinatal conditions were most strongly associated with hot waves. In a temporal context, the strength of the heat wave-hospitalization association decreased substantially in the south, while an apparent increase was observed in the southeast (Zhao et al. 2019).
Another study conducted in macro-urban areas with data for the years 2000 to 2019 evaluated the association between extreme drought events and mortality and in general, the data showed an association between drought and general mortality, circulatory mortality, and respiratory mortality. A more robust positive association was found with some population groups, including women and the elderly. There was also great heterogeneity between the areas studied (Salvador et al. 2022). In addition to respiratory and circulatory diseases, studies have detailed the relationship between infectious diseases and changes in the climate, including dengue, malaria, and arboviruses. The increase in temperature and precipitation are the main climatic factors predicting this relationship (Sousa et al. 2018).
After exposing these scenarios, a very strong and important interrelationship between air pollution and temperature rise in Brazil is evident (as in other regions of the world) directly impacting human health, but also jeopardizing the balance of ecosystems, food production, and resource extraction. Discussing such aspects, and seeking to visualize the perspectives of action for making decisions that change this trajectory is fundamental work since one of the trends that have been observed is a Brazilian population remodeling, which will intensify in the future, as an escape from extreme environmental conditions, further exacerbating perceived regional inequalities (Oliveira and Pereda 2020).
Discussion
Table 1 presents the global goals related to the mitigation of impacts directly or indirectly related to air pollution and climate change, adapted for Brazil, and was prepared with information obtained from the website < https://odsbrasil.gov.br/ > , maintained and updated by the Brazilian Federal Government, in order to allow public monitoring of the goals of the 2030 Agenda.Table 1 2030 Agenda goals, targets and indicators, and their current status in Brazil. (1) The 2030 Agenda has 17 SDGs, of which six (1, 2, 3, 11, 12, and 13) were selected regarding the theme of the present discussion. Within each SDG there are targets, and each target has its own indicators. (2) This table was structured by first indicating one or more targets within each chosen SDG. For each target, its indicators classified as directly or indirectly linked to the target based on their specificity were listed. Next, the situation of the target in Brazil was displayed, as well as the current status of each of the indicators belonging to each target in 2022. (3) The colors selected for the lines of the SGDs seek to symbolize the same tones chosen by the UN. (4) The colors regarding Brazil’s data completion status on indicators of each target represent their level of concern — green: data is available (actions are being taken); yellow: need of attention (the status is still under construction); red: major concerns (there is no information available about the status of the indicator)
Of the 23 indicators selected from the six SGDs under study, 13 are in the “elaborated” status (green color status), and only one (Indicator 13.a.1) is not applicable to the Brazilian territory, therefore not having status of completeness. Regarding the indicators with “elaborated” status, both a positive and a negative perception can be traced. On the one hand, as more than half of the indicators selected to discuss the topic of this work already have collected data, this fact allows decision makers, public managers and society as a whole to work on practical strategies to contain damage and achieve better chances of success of the initiatives. Some of them even bring positive perspectives, such as indicator 3.9.2 (although not directly linked to the topics under discussion) or indicator 13.2.2, which denotes a reduction of more than 1/3 of greenhouse gas emissions (GHG) across Brazil between 1990 and 2016.
On the other hand, there is still a long way to go. For instance, the indicator “Number of deaths, missing persons and persons affected by disaster per 100,000 people”, in a time series from 2015 to 2021, had a national increase of more than 200%. This is certainly cause for concern, as studies show that there is an intimate relationship between air pollution, climate change, and natural disasters, whether in Brazil (Marengo et al. 2021; Perez et al. 2020; Matias Ribeiro et al. 2021; Pivello et al. 2021) or in other parts of the world (Chandrappa and Chandra Kulshrestha 2015; Kumar 2021). In addition, indicator 1.5.4, which is complementary to the previous one, demonstrates that less than 40% of Brazilian cities have defined strategies for disaster risk reduction in line with national strategies, denoting that a large part of the national territory is still vulnerable to ongoing environmental impacts and disasters.
It can also be observed that indicators 1.5.2 (SDG 1), 3.9.1 (SDG 3), and 11.6.1 (SDG 11), are under construction (the first two being more directly linked to issues of the climate — air pollution axis) which means that sufficient information has not yet been collected in Brazil to define the status of completeness. Of these goals, we cannot understand what condition they are in: whether they have advanced since the agreement made in 2015, or not.
Starting with the first indicator “Direct disaster economic loss in relation to global gross domestic product (GDP)”, the study by Kuhla et al. (2021) points out that the increase in heat stress will cause profound impacts both economically and socially. Through mathematical modeling, the authors point out that productivity at work will fall, favoring price increases and scarcity of resources, severely reducing the purchasing power of individuals, especially in countries such as Brazil, India, and Indonesia. Nevertheless, the study by Giannini et al. (2017) evaluated the impacts of climate change on 95 species of pollinators in 13 different types of crops in Brazil, and in the projections (considering the worst scenarios until the end of the twenty-first century), about 88% of Brazilian municipalities will face loss in the number of pollinating species, which can reach 100% of the species for some crops, such as sunflower. This scenario clearly contributes to the increase in food insecurity, with the municipalities with the lowest GDP being the most affected, putting more than 6 million people at risk.
This is not an isolated perception. Santos et al. (2022), working with projections of temperature increase and its impacts on agriculture and the economy of different Brazilian regions, also pointed out that climate change has the potential to cause a significant retraction of GDP, and even deepen existing social inequalities, for impacting mainly the poorest families or those directly dependent on agriculture. Leal Filho et al. (2018) and Costa et al. (2019) also demonstrate the climatic factors contributing to financial losses caused by the increase and distribution of vector-borne diseases and accidents with venomous animals (snake bites), respectively.
Actions that contribute to the reduction of atmospheric pollution can, on the other hand, positively affect the climate and quality of life of a population. An example of this was the study Martins et al. (2021a, b), who noted that in BRICS countries (Brazil, Russia, India, China and South Africa), the number of vehicles in use is linearly correlated with GDP progress. For these countries, the adoption of electric cars, for example, is not only a strategy to mitigate environmental impacts, but represents a real possibility for economic growth, as in highly developed nations such as Iceland and the Netherlands, where demand for clean energy grows continuously. And, as also demonstrated by Asere and Blumberga (2020), the level of energy efficiency and quality of a country is directly linked to the progress of its GDP. During the COVID-19 pandemic, ESG (environmental, government, and social) measures proved to be of great importance in dealing with the political, social, and health crisis. According to Jesus and Nascimento (2021), EMBRAPA Soils (a unit of EMBRAPA – Brazilian Agriculture Research Corporation) as a public company, implemented actions with multiple focus, developing a social, governmental and environmental role, with the provision of online courses, production of educational lives, donation of funds for COVID-19 detection tests and support for the development of public policies on environmental issues. This type of action can easily be adapted to the particularities of companies in the public and private sectors, creating a network of contributions that combine efforts (integrity, diversity, human rights, efficiency, prevention of corruption, natural resources protection) to reach the different SDGs established.
The second indicator, “Mortality rate attributed to household and ambient air pollution”, is a major concern. Rosário Filho et al. (2021) showed that the household use of “dirty” fuels like coal and biomass represents a serious health risk in developing countries, especially because people spend long periods in their homes and more vulnerable groups such as children, end up being the most affected, especially for respiratory pathologies. Fernandes et al. (2018), in a study with 996 individuals with moderate or severe asthma, exposed to scenarios of smoking, household pollution, or the two exposures combined, observed that individuals exposed to household pollution or with double exposure were those who presented the most severe cases of asthma and worsening of general health status. It is noteworthy that the use of rudimentary stoves, the main sources of household pollution related to the burning of “dirty” fuels, is particularly important in rural and less developed regions in Brazil. A study developed with secondary data on the Brazilian population pointed out that few studies have been dedicated to addressing the issue and that more than 30 million people still use firewood for cooking, especially due to the high price of liquefied petroleum gas (LPG), aggravating its risks of illness in the short and long term (Gioda et al. 2019).
The last indicator under construction is “Proportion of urban solid waste regularly collected and with adequate final discharge out of total urban solid waste generated, by cities”. Despite this information gap, investigations already carried out show that Brazil still faces major problems in the collection and especially in the final disposal of waste, and according to Alfaia et al. (2017), less than 60% of the collected waste has an adequate destination in Brazilian municipalities and, especially in small municipalities, there are important difficulties in adapting to the Brazilian National Policy on Solid Waste (NPSW) (Pereira and Fernandino 2019). Morita et al. (2021), in their review on the subject in Brazil, drew attention to the fact that inadequate management of solid waste is directly linked to the contamination of all environmental compartments (especially soil and water) and that, on a national scale, many of these impacts have gone unnoticed. The need for more efficient alternatives both from a legal and political framework, as well as sustainable technologies, is urgent for those authors.
In an even more complex sphere are indicators 2.4.1 (SDG2), 11.6.2 (SDG 11), 12.4.2 (SDG 12), 13.3.1, 13.3.2, and 13.b.1 (SDG 13), displayed on Table 1, for which no information is available. Given the importance of these indicators for a better understanding of the dimension in which the two problems listed are faced, an important temporal gap in data on the part of Brazilian governments is evident, as well as the difficulty encountered by different social sectors in monitoring the work that needs to be done to achieve the goals. Indicator 2.4.1 raises an extremely complex issue to be addressed in Brazil, which is the expansion of its agricultural frontiers in a sustainable way. There is great lobbying both by sectors that ignore the pressures caused by agribusiness on ecosystems, as well as by initiatives that establish a conflict between small producers, large-scale producers, universities, and research centers, instead of realizing that everyone efforts should be on the same side of the discussion (Lahsen et al. 2020). Guida et al. (2018) demonstrated that pesticides currently used in Brazil for the cultivation of different plants are capable of contaminating the atmosphere, even in more distant regions such as mountains, whereas Sun et al. (2019) pointed out that increasing pollution will eventually self-limit the growth of crops, since the temperature increase triggered (in a model of 1.5 to 2 °C) by the end of the twenty-first century will affect more than 95% of countries, with India and Brazil being the first two in the ranking.
As for indicators 11.6.2 and 12.4.2, the first stands out in this discussion because it is directly related to the quantification of particulate matter, in the case PM10 and PM2.5, in relation to the annual averages by the population size of Brazilian cities. Certainly, the study developed by Vormittag et al. (2021) reflects the great lack of coverage in Brazilian territory of services for monitoring and evaluating air quality in real time and with easy access and understanding by health managers and the population in general. This non-monitoring is a chronic problem, caused by the disorganization of responsibility between the public sector as to who is responsible for the process, and regions such as the Amazon and Cerrado, often subject to forest fires and heat waves, do not have this adequate follow-up (Silva and Vieira 2017). The indicators related to SDG13, on the other hand, are mainly about the need to improve policies, initiatives to prevent climate change and the introduction of environmental education content in the training of teachers, students and in the construction of national curriculum matrices. The absence of data in this sense corroborates the view presented by Frizzo and Carvalho (2018) who emphasized that environmental education in Brazil is silenced, extremely summarized (in the context of the National Education Plan and the National Common Curricular Base) to mentions about concepts of the global environmental discourse, in an extremely general approach and alien to the local reality. De Simoni et al. (2021) in their dossier on air quality in Brazil, reiterate that the country is the largest emitter of O3 precursor gases in Latin America and, therefore, has an extremely relevant role in the emission of short-lived climate pollutants, directly related to the process of global warming. This group of authors also emphasizes that, although Brazil has a certain political framework for the introduction of more restrictive measures to guarantee air quality, the lack of a timetable and legal certainty in the application of sanctions to deviations does not provide effectiveness of actions.
Regarding the advancement of public policies in relation to environmental health, Brazil has not shown conclusive steps for some years. Silva et al. (2019) draw attention to the fact that recently, although many of the problems identified in Brazil are still reversible, Brazilian environmental policy has been going backward in its achievements, including an increase in flexibility for Brazilian and international companies in the face of issues on which no more space our time could be wasted. The urban–rural-industrial axis has complex characteristics, in which highly polluting activities do not receive specific inspection and legal punishment. If, on the one hand, the increased space in public policies for the discussion of environmental risk from the perspective of the SUS represents an important advance in the last three decades, there is still a difficulty in identifying and solving issues worldwide that actually start on a community/local scale. Government positions, especially since 2016, represent steps backward in several areas of environmental health (Freitas et al. 2018), which need collaborative, multidisciplinary, and political-economic work to be overcome (Pettan-Brewer et al. 2021). According to the document presented by the Organization for Economic Co-operation and Development –OECD (2021), the need to eliminate gaps in responsibility between institutions and government parties is critical so that Brazil can consolidate its development without completely compromising its biodiversity and the health of its population.
Therefore, it can be said that the empty spaces detected in this survey are extremely important for the advancement of the Brazilian sustainability program and the absence of this information places Brazil in a delicate situation. These gaps, often associated with political disinterest, make many research and technology initiatives find a path of infra-legality (Hochstetler 2021) to develop their work, turning them fruitless, even though authors such as Mesquita and Bursztyn (2016) have already denounced that the weak interaction between sectors, favors the advancement of environmental changes that widen social inequality and increase vulnerability and the risk of poverty. The alert proposed by this discussion is added to existing initiatives that wish to emphasize the urgency of improving the air quality of the Brazilian population, not only because of its influence on a global scale, but also because of its fundamental connection to the difficulty of achieving sustainable progress, financially and ecologically.
Concluding remarks
Given the above, some conclusions can be drawn. Firstly, the variety of topics covered by the 2030 Agenda represent a challenge for developing countries, such as Brazil, in which several actions still need to be taken on in their practical aspects. Secondly, the development of research that delve into multidisciplinary alternatives to address the challenges already identified is crucial. In this sense, broad social sectors are called upon to contribute to the achievement of better panoramas in several of the indicators presented in this discussion. The numerous regional differences that make these initiatives difficult can find in environmental education an important ally in the training of well-prepared personnel with a realistic view of particular problems and how to circumvent them in order to achieve a model of sustainable development. The planning of new research and government decision-making must be parallel and convergent processes, which consider the need to prevent and reduce risks to health and the environment and give priority to alternatives that minimize the socioeconomic inequalities that are still so marked in the Brazilian territory.
Acknowledgements
The authors thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Universidade Federal do Rio Grande – FURG.
Author contribution
FRM and FMRSJ were major contributors to information collection and writing the manuscript. They read and approved the final manuscript.
Funding
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001, Conselho Nacional de Desenvolvimento Científico e Tecnológico—Research Productivity Fellowship, Grant 310856/2020–5 (FMRSJ) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Grant 21/2551–0001981-6.
Data availability
The datasets used and/or analyzed during the current discussion are available and from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Abe KC Miraglia SG Health impact assessment of air pollution in São Paulo, Brazil Int J Environ Res Public Health 2016 13 7 694 10.3390/ijerph13070694 27409629
Alfaia RGSM Costa AM Campos JC Municipal solid waste in Brazil: a review Waste Manag Res 2017 35 12 1195 1209 10.1177/0734242X17735375 29090660
Andrade MF Kumar P Freitas ED Ynoue RY Martins J Martins LD Nogueira T Perez-Martinez P Miranda RM Albuquerque T Gonçalves FLT Oyama B Zhang Y Air quality in the megacity of Sao Paulo: evolution over the last 30 years and future perspectives Atmos Environ 2017 159 66 82 10.1016/j.atmosenv.2017.03.051
Arantes MRL A legislação ambiental brasileira do império ao terceiro milênio: premissas técnicas Caminhos De Geografia 2018 19 66 325 344
Araujo OR Araujo MC O impacto nulo do Programa de Inspeção Veicular na saúde pública em São Paulo, SP Rev Saude Publica 2020 54 84 10.11606/s1518-8787.2020054001856 32844984
Asere L Blumberga A Does energy efficiency-indoor air quality dilemma have an impact on the gross domestic product? J Environ Manage 2020 262 110270 10.1016/j.jenvman.2020.110270 32094106
Atkinson QD Jacquet J Challenging the idea that humans are not designed to solve climate change Perspect Psychol Sci 2022 17 3 619 630 10.1177/17456916211018454 34738846
Bainy BK Paschoal IA Avila AMH Santos HO Avaliação da qualidade do ar no Sudeste do Brasil durante a pandemia da COVID-19 e do confinamento: relato de aumento da poluição atmosférica Cad Saude Publica 2021 37 9 e00242320 10.1590/0102-311x00242320 34669775
Barbi F Da Costa Ferreira L Governing climate change risks: subnational climate policies in Brazil Chin Political Sci Rev 2017 2 2 237 252 10.1007/s41111-017-0061-3
Benton GS Carbon dioxide and its role in climate change Proc Natl Acad Sci USA 1970 67 2 898 899 10.1073/pnas.67.2.898 5289026
Bravo M Son J de Freitas CU Gouveia N Bell ML Air pollution and mortality in São Paulo, Brazil: effects of multiple pollutants and analysis of susceptible populations J Expo Sci Environ Epidemiol 2016 26 150 161 10.1038/jes.2014.90 25586330
Carneiro VSM Vila VCDS Vieira MADS Trends in pediatric hospitalizations for ambulatory care sensitive respiratory diseases in Brazil Public Health Nurs 2021 38 1 106 114 10.1111/phn.12818 33043515
Caumo SE Gioda A Carreira R Jacobson LSV Hacon S Human health impacts caused by exposure to forest fires: the evidence obtained in the last two decades Rev Bras Climatol 2022 30 184 218
Chandrappa R Chandra Kulshrestha U Chandrappa R Chandra Kulshrestha U Air pollution and disasters Sustainable Air Pollution Management 2015 1 Cham Springer 325 343
Cirqueira SSR Rodrigues PF Branco P Vormittag E Nunes R Anastacio AVB Veras M Sousa S Saldiva PHN Heterogeneous impacts of mobility restrictions on air quality in the State of Sao Paulo during the COVID-19 pandemic Environ Pollut 2022 300 118984 10.1016/j.envpol.2022.118984 35151813
Colman Lerner JE, Mellado D, Sanchez EY (2018) Contaminantes atmosféricos. In: Porta A, Sanchez EY, Colman Lerner E (coords) Calidad del aire: Monitoreo y modelado de contaminantes atmosféricos. Efectos en la salud pública, 1st edn. EDULP, La Plata, pp 35–98
Costa MKBD Fonseca CSD Navoni JA Freire EMX Snakebite accidents in Rio Grande do Norte state, Brazil: epidemiology, health management and influence of the environmental scenario Trop Med Int Health 2019 24 4 432 441 10.1111/tmi.13207 30659709
Custódio P, Telles CPF, Azevedo Barros N (2022) Methodology for assessing the impact of environmental determinants on human health: case study of atmospheric industrial pollution in urban communities – Manaus/Amazonas/Brazil. In: Leal Filho W, Vidal DG, Dinis MAP, Dias RC (eds) Sustainable Policies and Practices in Energy, Environment and Health Research. World Sustainability Series. Springer, Cham, pp 349–369
De Simoni WF, Sant’Anna A, Alencar A, Pinheiro B, Araújo C, Vormittag E, Wincher H, Borges K, Faria M, Andrade MF, Porto P, Artaxo P, Rocha R, Esturba T (2021) O estado da qualidade do ar no Brasil. WRI Brasil, Woking Paper, 1–31
Destoumieux-Garzón D Mavingui P Boetsch G Boissier J Darriet F Duboz P Fritsch C Giraudoux P Le Roux F Morand S Paillard C Pontier D Sueur C Voituron Y The One Health concept: 10 years old and a long road ahead Front Vet Sci 2018 5 14 10.3389/fvets.2018.00014 29484301
Drakvik E, Kogevinas M, Bergman Å, Devouge A, Barouki R, on behalf of the HERA (Health and Environment Research Agenda) Consortium (2022) Priorities for research on environment, climate and health, a European perspective. Environ Health 21:37
Duarte RH “Turn to pollute”: air pollution and development model during the Brazilian “miracle” (1967–1973) Tempo 2015 21 37 64 87 10.1590/tem-1980-542x2015v213710
Dye C One Health as a catalyst for sustainable development Nat Microbiol 2022 7 467 468 10.1038/s41564-022-01076-1 35210574
Escada P Coelho CA Taddei R Dessai S Cavalcanti IF Donato R Kayano MT Martins ESPR Miguel JCH Monteiro M Moscati MC Climate services in Brazil: past, present and future perspectives Climate Services 2021 24 100276 10.1016/j.cliser.2021.100276
Espeschit IF Santana CM Moreira MAS Public policies and One Health in Brazil: the challenge of the disarticulation Front Public Health 2021 9 644748 10.3389/fpubh.2021.644748 34150698
Fernandes AGO de Souza-Machado C Pinheiro GP de Oliva ST Mota RCL de Lima VB Cruz CS Chatkin JM Cruz ÁA Dual exposure to smoking and household air pollution is associated with an increased risk of severe asthma in adults in Brazil Clin Transl Allergy 2018 8 48 10.1186/s13601-018-0235-6 30555680
Floss M Barros E Lancet Countdown: briefing para políticas de saúde no Brasil Rev Bras Med Fam Comunidade 2019 14 41 2286 10.5712/rbmfc14(41)2286
Freitas CM Rocha V Silva ELE Alpino TMA Silva MAD Mazoto ML Environmental health risk reduction in Brazil: conquests, limits and obstacles Cien Saude Colet 2018 23 6 1981 1996 10.1590/1413-81232018236.04702018 29972505
Frizzo TCE Carvalho ICM Políticas públicas atuais no Brasil: O silêncio da educação ambiental Rev Eletrônica Mestr Educ Ambient 2018 1 115 127
Giannini TC Costa WF Cordeiro GD Imperatriz-Fonseca VL Saraiva AM Biesmeijer J Garibaldi LA Projected climate change threatens pollinators and crop production in Brazil PLoS ONE 2017 12 8 e0182274 10.1371/journal.pone.0182274 28792956
Gioda A Tonietto GB Leon AP Exposure to the use of firewood for cooking in Brazil and its relation with the health problems of the population Cienc Saude Coletiva 2019 24 8 3079 3088 10.1590/1413-81232018248.23492017
Gómez-Peláez LM Santos JM Albuquerque TTA Reis Junior NC Andreão W Andrade MF Air quality status and trends over large cities in South America Environ Sci Policy 2020 114 422 435 10.1016/j.envsci.2020.09.009
Gouveia N Corrallo FP Leon ACP Junger W Freitas CU Air pollution and hospitalizations in the largest Brazilian metropolis Rev Saude Publica 2017 51 117 10.11606/S1518-8787.2017051000223 29211200
Gouveia N Kephart JL Dronova I McClure L Granados JT Betancourt RM O’Ryan AC Texcalac-Sangrador JL Martinez-Folgar K Rodriguez D Diez-Roux AV Ambient fine particulate matter in Latin American cities: levels, population exposure, and associated urban factors Sci Total Environ 2021 772 145035 10.1016/j.scitotenv.2021.145035 33581538
Guida YS Meire RO Torres JPM Malm O Air contamination by legacy and current-use pesticides in Brazilian mountains: an overview of national regulations by monitoring pollutant presence in pristine areas Environ Pollut 2018 242 Pt A 19 30 10.1016/j.envpol.2018.06.061 29957542
Hagen I Hugge C Ramajo L Chacón N Ometto JP Postigo JC Castellanos EJ Climate change-related risks and adaptation potential in Central and South America during the 21st century Environ Res Lett 2022 17 3 033002 10.1088/1748-9326/ac5271
Haq A Modibbo UM Ahmed A Ali I Mathematical modeling of sustainable development goals of India agenda 2030: a Neutrosophic programming approach Environ Dev Sustain 2021 1 1 28
Hochstetler K Climate institutions in Brazil: three decades of building and dismantling climate capacity Env Polit 2021 30 1 49 70 10.1080/09644016.2021.1957614
Husaini DC Reneau K Balam D Air pollution and public health in Latin America and the Caribbean (LAC): a systematic review with meta-analysis Beni Suef Univ J Basic Appl Sci 2022 11 1 122 10.1186/s43088-022-00305-0 36196224
Jesus IRD Nascimento PP ESG strategies to deal with COVID-19 in a Brazilian public research company Braz J Oper Prod Manag 2021 18 2 e20211153 10.14488/BJOPM.2021.028
Korc M Hauchman F Advancing environmental public health in Latin America and the Caribbean Rev Panam Salud Publica 2021 45 e118 10.26633/RPSP.2021.118 34539765
Kuhla K Willner SN Otto C Wenz L Levermann A Future heat stress to reduce people’s purchasing power PLoS ONE 2021 16 6 e0251210 10.1371/journal.pone.0251210 34111129
Kumar P Climate change and cities: challenges ahead Front Sustain Cities 2021 3 645613 10.3389/frsc.2021.645613
La Colla NS Botté SE Marcovecchio JE Atmospheric particulate pollution in South American megacities Environ Rev 2021 29 415 429 10.1139/er-2020-0105
La Rovere EL (2020) The potential contribution of emerging economies to stop dangerous climate change. The case of Brazil. Wiley Interdiscip Rev Clim Change 11(1):e614
Lahsen M Ribot J Politics of attributing extreme events and disasters to climate change Wiley Interdiscip Rev Clim Change 2022 13 1 e750 10.1002/wcc.750
Lahsen M Couto GA Lorenzoni I When climate change is not blamed: the politics of disaster attribution in international perspective Clim Change 2020 158 213 233 10.1007/s10584-019-02642-z
Laumann F von Kügelgen J Kanashiro Uehara TH Barahona M Complex interlinkages, key objectives, and nexuses among the sustainable development goals and climate change: a network analysis Lancet Planet Health 2022 6 5 e422 e430 10.1016/S2542-5196(22)00070-5 35550081
Leal Filho W Bonecke J Spielmann H Azeiteiro UM Alves F De Carvalho ML Nagy GJ Climate change and health: an analysis of causal relations on the spread of vector-borne diseases in Brazil J Clean Prod 2018 177 10 589 596 10.1016/j.jclepro.2017.12.144
Leirião LFL Debone D Miraglia SGEK Does air pollution explain COVID-19 fatality and mortality rates? A multi-city study in São Paulo state, Brazil Environ Monit Assess 2022 194 4 275 10.1007/s10661-022-09924-7 35286482
Lemos MC Puga BP Formiga-Johnsson RM Seigerman CK Building on adaptive capacity to extreme events in Brazil: water reform, participation, and climate information across four river basins Reg Environ Change 2020 20 53 10.1007/s10113-020-01636-3
Lima FTS, Lima AA, Cordeiro LS, Nascimento RR, Menezes M (2021) Hospital morbidity and its relationship to climate variables in the City of Manaus: cases and economic cost. Res Soc Dev 10(14): e98101421841
Machado Junior C Ribeiro DMNM Pereira RS Bazanini R Do Brazilian cities want to become smart or sustainable? J Clean Prod 2018 199 214 221 10.1016/j.jclepro.2018.07.072
Mahony M Endfield G Climate and colonialism Wiley Interdiscip Rev Clim Change 2018 9 1 e510
Marengo JA Cunha AP Cuartas LA Deusdará Leal KR Broedel E Seluchi ME Michelin CM De Praga Baião CF Chuchón Angulo E Almeida EK Kazmierczak ML Mateus NPA Silva RC Bender F Extreme drought in the Brazilian Pantanal in 2019–2020: characterization, causes, and impacts Front Water 2021 3 639204 10.3389/frwa.2021.639204
Martins LS Guimarães LF Junior ABB Tenório JAS Espinosa DCR Electric car battery: an overview on global demand, recycling and future approaches towards sustainability J Environ Manage 2021 295 113091 10.1016/j.jenvman.2021.113091 34171777
Martins APG Ribeiro AP Ferreira ML Martins MAG Negri EM Scapin MA Oliveira A Saiki M Saldiva PHN Lafortezza R Infraestrutura verde para monitorar e minimizar os impactos da poluição atmosférica Estud Avançados 2021 35 102 31 57 10.1590/s0103-4014.2021.35102.003
Matias Ribeiro MS Andrade LMB Spyrides MHC Lima KC Silva PE Batista DT Lara IAR Environmental disasters in Northeast Brazil: hydrometeorological, social, and sanitary factors Weather Clim Soc 2021 13 3 541 554
Medeiros RM Kozmhinsky M Holanda RM Silva VP Variability and thermal sensation of the period 1962–2015 in the great metropolis Recife-PE, Brazil) Rev Bras Geog Fis 2018 11 1 16 27
Mesquita PS Bursztyn M Integration of social protection and climate change adaptation in Brazil Br Food J 2016 118 12 3030 3043 10.1108/BFJ-02-2016-0082
Monteiro FF Gonçalves WA Andrade LMB Villavicencio LMM Silva CMS Assessment of urban heat islands in Brazil based on MODIS remote sensing data Urban Climate 2021 35 100726 10.1016/j.uclim.2020.100726
Moreira MR Kastrup E Ribeiro JM Carvalho AI Braga AP Brazil in 2030? Brazilian health specialists’ perceptions of the country’s potential to comply with the Brazil heading to 2030 SDGs Saúde Debate 2019 43 7 22 35 10.1590/0103-11042019s702
Morita AKM Ibelli-Bianco C Anache JAA Coutinho JV Pelinson NS Nobrega J Rosalem LMP Leite CMC Niviadonski LM Manastella C Wendland E Pollution threat to water and soil quality by dumpsites and non-sanitary landfills in Brazil: a review Waste Manag 2021 131 163 176 10.1016/j.wasman.2021.06.004 34146955
Nakada LYK Urban RC COVID-19 pandemic: impacts on the air quality during the partial lockdown in São Paulo state, Brazil Sci Total Environ 2020 730 139087 10.1016/j.scitotenv.2020.139087 32380370
Nawaz MO, Henze DK (2020) Premature deaths in Brazil associated with long-term exposure to PM2.5 from Amazon fires between 2016 and 2019. GeoHealth 4:e2020GH000268
Novaes RML Pazianotto RAA Brandão M Alves BJR May A Folegatti-Matsuura MIS Estimating 20-year land-use change and derived CO2 emissions associated with crops, pasture and forestry in Brazil and each of its 27 states Glob Chang Biol 2017 23 9 3716 3728 10.1111/gcb.13708 28370797
Oliveira J Pereda P The impact of climate change on internal migration in Brazil J Environ Econ Manag 2020 103 4 102340 10.1016/j.jeem.2020.102340
Organization for Economic Co-operation and Development – OECD (2021) Evaluating Brazil’s progress in implementing environmental performance review recommendations and promoting its alignment with OECD core acquis on the environment. OECD. https://www.oecd.org/environment/country-reviews/Brazils-progress-in-implementing-Environmental-Performance-Review-recommendations-and-alignment-with-OECD-environment-acquis.pdf. Accessed 12 Sept 2022
Pamplona YAP Arbex MA Braga ALF Pereira LAA Martins LC Relationship between air pollution and hospitalizations for congestive heart failure in elderly people in the city of São Paulo Environ Sci Pollut Res Int 2020 27 15 18208 18220 10.1007/s11356-020-08216-2 32172424
Pereira TS Fernandino G Evaluation of solid waste management sustainability of a coastal municipality from northeastern Brazil Ocean Coast Manag 2019 179 104839 10.1016/j.ocecoaman.2019.104839
Perez LP Rodrigues-Filho S Marengo JA Santos DV Mikosz L Climate change and disasters: analysis of the Brazilian regional inequality Sustainability in Debate 2020 11 3 260 296 10.18472/SustDeb.v11n3.2020.33813
Pérez-Martínez PJ, Andrade MF, Miranda RM (2017) Heavy truck restrictions and air quality implications in São Paulo, Brazil. J Environ Manage 202(Part 1):55–68
Pettan-Brewer C Martins AF de Abreu DPB Brandão APD Barbosa DS Figueroa DP Cediel N Kahn LH Brandespim DF Velásquez JCC Carvalho AAB Takayanagui AMM Galhardo JA Maia-Filho LFA Pimpão CT Vicente CR Biondo AW From the approach to the concept: One Health in Latin America-experiences and perspectives in Brazil, Chile, and Colombia Front Public Health 2021 9 687110 10.3389/fpubh.2021.687110 34631640
Pivello VR Vieira I Christianini AV Ribeiro DB Menezes LS Berlinck CN Melo FPL Marengo JA Tornquist CG Tomas WM Overbeck GE Understanding Brazil’s catastrophic fires: causes, consequences and policy needed to prevent future tragedies Perspect Ecol Conserv 2021 19 3 233 255
Queenan K Garnier J Nielsen LR Buttigieg S de Meneghi D Holmberg M Zinsstag J Ruegg S Hasler B Kock R Roadmap to a One Health agenda 2030 CAB Rev 2017 12 14
Ribeiro CS van de Burgwal LHM Regeer BJ Overcoming challenges for designing and implementing the One Health approach: a systematic review of the literature One Health 2019 7 100085 10.1016/j.onehlt.2019.100085 31016220
Riojas-Rodríguez H Silva AS Texcalac-Sangrador JL Moreno-Banda GL Air pollution management and control in Latin America and the Caribbean: implications for climate change Rev Panam Salud Publica 2016 40 3 150 159 27991972
Rocha DG Alexandre Weiss VP The convergences between the sustainable development goals and national agendas: the Brazilian case Health Promot Int 2019 34 Supplement 1 i46 i55 10.1093/heapro/daz010 30900731
Rochedo PR Soares-Filho B Schaeffer R Viola E Szklo A Lucena AFP Koberle A Davis JL Rajão R Rathmann R The threat of political bargaining to climate mitigation in Brazil Nat Clim Change 2018 8 8 695 698 10.1038/s41558-018-0213-y
Rosário Filho NA Urrutia-Pereira M D’Amato G Cecchi L Ansotegui IJ Galán C Pomés A Murrieta-Aguttes M Caraballo L Rouadi P Chong-Neto HJ Peden DB Air pollution and indoor settings World Allergy Organ J 2021 14 1 100499 10.1016/j.waojou.2020.100499 33510831
Rudke AP Martins JA Almeida DS Martins LD Beal A Hallak R Freitas ED Andrade MF Foroutan H Baek BH Albuquerque TTA How mobility restrictions policy and atmospheric conditions impacted air quality in the State of São Paulo during the COVID-19 outbreak Environ Res 2021 198 111255 10.1016/j.envres.2021.111255 33971134
Sá TH Tainio M Goodman A Edwards P Haines A Gouveia N Monteiro C Woodcock J Health impact modelling of different travel patterns on physical activity, air pollution and road injuries for São Paulo, Brazil Environ Int 2017 108 22 31 10.1016/j.envint.2017.07.009 28780491
Salvador C, Vicedo-Cabrera AM, Libonati R, Russo A, Garcia BN, Belem LBC, Gimeno L, Nieto R (2022) Effects of drought on mortality in macro urban areas of Brazil between 2000 and 2019. GeoHealth 6(3):e2021GH000534
Santana JCC Miranda AC Yamamura CLK Silva Filho SC Tambourgi EB Ho LL Berssaneti FT Effects of air pollution on human health and costs: current situation in São Paulo, Brazil Sustainability 2020 12 12 1 20 10.3390/su12124875 35136666
Santos CV Oliveira AF Ferreira Filho JBS Potential impacts of climate change on agriculture and the economy in different regions of Brazil Rev Econ Sociol Rural 2022 60 1 1 24 10.1590/1806-9479.2021.220611
Sarra SR Mülfarth RKC Atmospheric pollution and population health in the city of Cubatão between 2010 and 2020 Braz J Dev 2021 7 7 73509 73531 10.34117/bjdv7n7-499
Sheehan K (2019) Decades of Distraction: how the United States ignores climate change. Senior Honors Projects Paper 709
Siciliano B Dantas G Silva CM Arbilla G The updated Brazilian National Air Quality Standards: a critical review J Braz Chem Soc 2020 31 3 523 535
Silva AF Vieira CA Aspects of air pollution: a reflection about air quality in Brazilian cities Ciência e Sustentabilidade 2017 3 1 166 189
Silva LMB Silva JP Borges MAL Do global ao contexto nacional: evolução da política ambiental brasileira Rev Bras Gest Amb Sustent 2019 6 14 593 608 10.21438/rbgas.061401
Silveira F Martins AL Gadelha P Paes-Sousa R Quantifying convergence on health-related indicators of the 2030 agenda for sustainable development Bull World Health Organ 2021 99 3 228 235 10.2471/BLT.19.245811 33716345
Sousa TCMD Amancio F HaconSDS BC Doenças sensíveis ao clima no Brasil e no mundo: revisão sistemática Rev Panam Salud Publica 2018 42 e85 10.26633/RPSP.2018.85 31093113
Sousa TCM Barcellos CB Gracie R Hacon S Covid-19 e queimadas na Amazônia Legal e no Pantanal: aspectos cumulativos e vulnerabilidades Freitas CM, Barcellos C, Villela DAM (org) Covid-19 no Brasil: cenários epidemiológicos e vigilância em saúde 2020 1 Rio de Janeiro Editora Fiocruz 159 169
Sun Q Miao C Hanel M Borthwick AGL Duan Q Ji D Li H Global heat stress on health, wildfires, and agricultural crops under different levels of climate warming Environ Int 2019 128 125 136 10.1016/j.envint.2019.04.025 31048130
Swart J, Brinkmann L (2020) Economic complexity and the environment: evidence from Brazil. In: Leal Filho W, Tortato U, Frankenberger F (eds) Universities and Sustainable Communities: Meeting the Goals of the Agenda 2030. World Sustainability Series. Springer, Cham, pp 3–45
Torres RR Lapola DM Marengo JA Lombardo MA Socio-climatic hotspots in Brazil Clim Change 2012 115 3 597 609 10.1007/s10584-012-0461-1
Urrutia-Pereira M Rizzo LV Chong-Neto HJ Solé D Impacto da exposição à fumaça da queima de biomassa na Floresta Amazônica na saúde humana J Bras Pneumol 2021 47 5 e20210219 34669837
Valadão MBX Ribeiro FP Rodrigues MI Gatto A National environment policy instruments: how are they doing after 40 years of promulgation? Res Soc Dev 2022 11 3 e15711326262 10.33448/rsd-v11i3.26262
Vicedo-Cabrera AM Scovronick N Sera F The burden of heat-related mortality attributable to recent human-induced climate change Nat Clim Change 2021 11 6 492 500 10.1038/s41558-021-01058-x
Viveros-Uehara T Health care in a changing climate: a review of climate change laws and national adaptation plans in Latin America Health Hum Rights 2021 23 2 139 34966231
Vormittag EMPAA Cirqueira SSR Neto HW Saldiva PHN Análise do monitoramento da qualidade do ar no Brasil Estud Av 2021 35 102 7 30 10.1590/s0103-4014.2021.35102.002
Ye T Guo Y Chen G Yue X Xu R Coêlho MSZS Saldiva PHN Zhao Q Li S Risk and burden of hospital admissions associated with wildfire-related PM2·5 in Brazil, 2000–15: a nationwide time-series study Lancet Planet Health 2021 5 9 e599 e607 10.1016/S2542-5196(21)00173-X 34508681
Zhao Q Li S Coelho MS Saldiva PH Hu K Huxley RR Abramson MJ Guo Y The association between heatwaves and risk of hospitalization in Brazil: a nationwide time series study between 2000 and 2015 PLoS Med 2019 16 2 e1002753 10.1371/journal.pmed.1002753 30794537
| 36481854 | PMC9734578 | NO-CC CODE | 2022-12-14 23:28:29 | no | Environ Sci Pollut Res Int. 2022 Dec 9;:1-15 | utf-8 | Environ Sci Pollut Res Int | 2,022 | 10.1007/s11356-022-24601-5 | oa_other |
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Ann Surg Oncol
Ann Surg Oncol
Annals of Surgical Oncology
1068-9265
1534-4681
Springer International Publishing Cham
36484903
12849
10.1245/s10434-022-12849-7
Aso Research Letter
Impact of Surgical Delays During the Initial Surge of the COVID-19 Pandemic on Patients with Breast Disease
Nicholson K. MD 1
Kuchta K. MS 2
Pesce C. MD 13
Kopkash K. MD 13
Chichura A. MD 1
Yao Katharine MD [email protected]
13
1 grid.170205.1 0000 0004 1936 7822 Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL USA
2 grid.240372.0 0000 0004 0400 4439 Biostatistical Core, NorthShore University Health System Research Institute, Evanston, IL USA
3 grid.240372.0 0000 0004 0400 4439 Department of Surgery, NorthShore University Health System, Evanston, IL USA
9 12 2022
13
29 7 2022
12 11 2022
© Society of Surgical Oncology 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
==== Body
pmcOn 13 March 2020, the American College of Surgeons (ACS) issued a guideline that requested that all hospitals delay elective surgeries to conserve resources for patients infected with SARS CoV-2 virus.1 The objective of this study was to examine short-term pathologic outcomes of patients with breast cancer who experienced delays during this time period.
Patients and Methods
This was a retrospective single-institution chart review of patients who were scheduled for a surgical procedure between 16 March and 30 April 2020, but then were delayed because of the ACS guideline statement. Patients assigned to neoadjuvant therapy during this time period were excluded. Surgical delay was defined as date of diagnosis to date of surgery scheduled. We compared clinical and pathologic tumor characteristics for invasive and noninvasive cancers by comparing the largest size that was found on ultrasound, mammogram, or MRI and using methodology from our previous publication.2
Results
There was a total of 83 patients, of whom 57 (68.7%) had invasive cancer and 26 (31.3%) had ductal carcinoma in situ (DCIS). The median delay for all patients was 94 ± 49 days. Of 54 patients with hormone receptor positive (HR+) and Her2neu-negative disease, 46 (80.7%) received neoadjuvant endocrine therapy (NET) prior to surgery (Table 1). None of our patients with DCIS received NET. There were no significant differences in clinical and pathologic tumor size or grade for invasive or DCIS lesions (Table 2). Over 70% of patients for both invasive and DCIS lesions had the same clinical and pathologic tumor grade. Over 80% of patients with invasive disease had a final pathologic tumor size that was concordant with the clinical tumor size at presentation, and only three (5.5%) had a final pathologic tumor size that was greater than the clinical tumor size at presentation. Only 14 (60.9%) of DCIS lesions had a final pathologic tumor size that was concordant with the clinical tumor size at presentation, and 3 (13.0%) had a final pathologic tumor size that was greater than the clinical tumor size at presentation. Nine (34.6%) of DCIS lesions were upstaged to invasive cancer at surgical resection; all were American Joint Committee on Cancer (AJCC) T1N0 cancers.Table 1 Patient and tumor characteristics (n = 112) prior to surgical resection
Invasive cancer (n = 57) DCIS (n = 26)
Age, years 68 ± 12 64 ± 12
Race
White 37 (64.9%) 15 (57.7%)
Black 3 (5.3%) 2 (7.7%)
Hispanic 2 (3.5%) 0 (0%)
API 1 (1.8%) 4 (15.4%)
Other 14 (24.6%) 5 (19.2%)
Mean delay in surgery in days 85 ± 45 83 ± 33
Clinical tumor stage (anatomic) T1N0 35 (61.4%) TisN0 15 (100%)
T1N1 4 (7.0%)
T2N0 3 (5.3%)
T2N1 6 (10.5%)
T2N3 1 (1.8%)
T3N0 1 (1.8%)
T3N1 1 (1.8%)
T3N2 1 (1.8%)
T3N3 1 (1.8%)
T4NX 1 (1.8%)
Receptor status
HR+HER2neu− 52 (91.2%) NA
HR+ HER2neu+ 1 (1.8%) NA
HR−HER2neu+ 0 (0%) NA
HR−HER2neu− 2 (3.5%) NA
HR+ HER2neu not assessed 2 (3.5%) 16 (80%)
HR− HER2neu not assessed 0 (0%) 4 (20%)
Neoadjuvant therapy
Hormonal therapy 46 patients (out of 54 HR+ patients, 80.7%) 4 (15.4%)
Chemotherapy 2 patients (3.5%)* 0 (0%)
High risk lesion pathology NA NA
*Patients had received neoadjuvant therapy several months prior to March 2020
API Asian/Pacific Islander, HR Hormone receptor, DCIS Ductal carcinoma in situ
Table 2 Pathologic outcomes at surgical resection
Invasive disease (n = 57) DCIS (n = 26)
Tumor size
Clinical size 2.1 ± 2.1 1.6 ± 1.3
Pathologic size 1.9 ± 1.9 1.4 ± 1.2
Size the same on final pathology 46 (83.6%) 14 (60.9%)
Size smaller on final pathology 6 (10.9%) 6 (26.1%)
Size larger on final pathology 3 (5.5%) 3 (13.0%)
Tumor grade*
Grade stayed the same 40 (70.1%) 19 (73.0%)
Grade I to II or III 2 (3.5%) 0 (0%)
Grade II to III 0 (0%) 0 (0%)
Grade II to I 9 (15.8%) 1 (3.8%)
Grade III to II or I 2 (3.5%) 3 (11.5%)
Nodal status
Final node status same as clinical node status 30 (73%) 6 (100%)
Clinical node status N1, pathologic N0 0 (0%) 0 (0%)
Clinical node status N0, pathologic N1 11 (26.8%) 0 (0%)
Tumor upgrade
DCIS NA NA
Invasive disease NA 9 (34.6%) (all T1N0)
*Clinical tumor size on imaging compared to pathologic tumor size
DCIS Ductal carcinoma in situ
Discussion
Time from diagnosis to first surgery at our institution ranges from 30 to 35 days, but during the time of this study it was approximately 85 days. Nonetheless, our findings show little impact for short-term outcomes of tumor size or grade. Nodal status was within expected numbers given the fact that clinical examination of the axillary nodes can miss nodal metastases. Historically, it has been known that there are differences between tumor size on imaging and final pathology. Our previous study showed that there was concordance between imaging tumor size and pathologic size approximately 49–55% of the time.2 In this study, we show concordance rates of 80% between imaging and pathologic tumor size, and the imaging tumor size was larger than pathologic size only 5% of the time. The lack of tumor progression for tumor size and tumor grade for patients with invasive disease can likely be attributed to the fact that 80% of patients with HR+ disease were placed on NET. Older randomized trials have shown no survival difference between those elderly patients on hormonal therapy who underwent surgery versus those that did not undergo surgery, but progression-free survival was worse in those who did not have surgery.3 However, progression of disease was not observed right away; in one trial the median time interval to progression of disease was 1.69 years.3 Clinical trials examining NET have shown low rates of tumor progression. In one study, only 8% of patients on tamoxifen and 1% on an aromatase inhibitor at 168 days (24 weeks) experienced progression of disease.4 One retrospective study showed that 1 year of treatment with letrozole resulted in significant regression and < 10% of progression of disease.5 This study demonstrates the safety and efficacy of a NET approach to patients with HR+ disease whose surgeries were delayed.
On the other hand, our patients with DCIS had higher tumor upstage rates than those reported in literature, and approximately 60% were concordant on imaging, although this size discrepancy is more common with DCIS than invasive cancers.6 We did not routinely place patients with DCIS on NET, though the guidelines at the time stated that hormonal therapy for DCIS cases could “be considered.”7 A retrospective study showed that 14% of patients with DCIS with a delay of 91–120 days were upstaged to invasive cancer.6 Our median delay was 83 days, but approximately a third of the patients were upstaged to invasive cancer. Future studies are needed to further evaluate disease progression during the pandemic.
Our numbers are small, and larger, multi-institutional studies are needed to validate our findings. However, these findings can provide some reassuring data that surgical delays for patients with HR+ disease did not result in significantly larger tumors.
Disclosures
None.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Online March 13, 2020. (2020). Covid-19: recommendations for management of elective surgical procedures. American College of Surgeons. Retrieved October 8, 2021, from https://www.facs.org/covid-19/clinical-guidance/elective-surgery.
2. Tseng J Kyrillos A Liederbach E Clinical accuracy of preoperative breast MRI for breast cancer J Surg Oncol. 2017 115 8 924 931 10.1002/jso.24616 28409837
3. Fennessy M Bates T MacRae K Riley D Houghton J Baum M Late follow-up of a randomized trial of surgery plus tamoxifen versus tamoxifen alone in women aged over 70 years with operable breast cancer Br J Surg. 2004 91 6 699 704 10.1002/bjs.4603 15164437
4. Masuda N Sagara Y Kinoshita T Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial Lancet Oncol. 2012 13 4 345 352 10.1016/S1470-2045(11)70373-4 22265697
5. Rusz O Vörös A Varga Z One-year neoadjuvant endocrine therapy in breast cancer Pathol Oncol Res. 2015 21 4 977 984 10.1007/s12253-015-9911-1 25753983
6. Ward WH DeMora L Handorf E Preoperative delays in the treatment of DCIS and the associated incidence of invasive breast cancer Ann Surg Oncol 2020 27 386 396 10.1245/s10434-019-07844-4 31562602
7. Dietz JR Moran M Isakoff S Kurtzman S Willey S Burstein H Bleicher R Lyons J Sarantou T Baron P Stevens R Boobol S Anderson B Shulman L Gradishar W Monticciolo D Plecha D Nelson H Yao K Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic The COVID-19 pandemic breast cancer consortium Breast Cancer Res Treat. 2020 181 3 487 97 10.1007/s10549-020-05644-z 32333293
| 36484903 | PMC9734579 | NO-CC CODE | 2022-12-14 23:28:29 | no | Ann Surg Oncol. 2022 Dec 9;:1-3 | utf-8 | Ann Surg Oncol | 2,022 | 10.1245/s10434-022-12849-7 | oa_other |
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Syst Parasitol
Syst Parasitol
Systematic Parasitology
0165-5752
1573-5192
Springer Netherlands Dordrecht
36471195
10076
10.1007/s11230-022-10076-y
Article
Two new species of Acusicola Cressey, 1970 (Copepoda:Cyclopoida: Ergasilidae) parasitic on the gills of two estuarine actinopterygians off Brazil
http://orcid.org/0000-0003-2797-617X
Couto João Victor 1
http://orcid.org/0000-0002-6639-7544
de Nazaré Pereira Aldenice 2
http://orcid.org/0000-0003-3515-1127
Luque José Luis 3
http://orcid.org/0000-0002-8810-5549
Paschoal Fabiano 4
http://orcid.org/0000-0002-7921-5965
Pereira Felipe Bisaggio [email protected]
5
1 grid.8430.f 0000 0001 2181 4888 Programa de Pós-Graduação em Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901 Brazil
2 grid.472927.d 0000 0004 0370 488X Instituto Federal do Pará, Campus Abaetetuba, Avenida Rio de Janeiro, 3322, Francilândia, Abaetetuba, PA 68440-000 Brazil
3 grid.412391.c 0000 0001 1523 2582 Departamento de Parasitologia Animal, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ 23897-000 Brazil
4 grid.411204.2 0000 0001 2165 7632 Programa de Pós-Graduação em Biodiversidade e Conservação, Departamento de Oceanografia e Limnologia, Universidade Federal do Maranhão, Av. dos Portugueses, 1966, Bacanga, São Luís, MA 65080-805 Brazil
5 grid.8430.f 0000 0001 2181 4888 Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Bloco L4 sala 252, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901 Brazil
5 12 2022
116
29 9 2022
11 11 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Two new species of copepods assigned to the genus Acusicola Cressey, 1970 (Cyclopoida: Ergasilidae) are proposed based on post-metamorphic adult females, parasitizing the gills of two actinopterygian fish off Brazil namely, the Tripletail Lobotes surinamensis (Bloch) (Lobotidae), collected in the coastal zone of the State of Pará, near Curuçá Municipallity, and the Swordspine snook Centropomus ensiferus Poey (Centropomidae) collected in Sepetiba Bay, State of Rio de Janeiro, Brazil. Acusicola iamarinoi n. sp. parasite of L. surinamensis, differs from its closet congeners based on the first segment of the antennule armed with 10 setae, the presence of a maxillule armed with four elements and a pair of blunt processes dorsally on the fourth pedigerous somite. Acusicola pasternakae n. sp., collected from C. ensiferus, can be distinguished from its closest congeners based on the membranous sheath of the first endopodal segment of antenna with horizontal marks, the first segment of the antennule armed with 11 setae and a spine on the last exopodal segment of leg 2. This is the first report of representatives of Acusicola parasitizing fish of the families Lobotidae and Centropomidae as well as new geographical records of the genus in the coast of State of Pará and in Sepetiba Bay, Brazil.
Supplementary Information
The online version contains supplementary material available at 10.1007/s11230-022-10076-y.
Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnologico do Brasil (CNPq)http://dx.doi.org/10.13039/501100003758 Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão 84516/2022 Paschoal Fabiano
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pmcIntroduction
Members of the family Ergasilidae Burmeister, 1835 represent one of the richest groups of crustacean parasites, currently including 265 species from 30 genera, distributed worldwide (Oliveira et al., 2021; Walter & Boxshall, 2022). Most of these copepods are found infesting the gills of freshwater actinopterygians, but some species may be attached to nostrils, tegument and urinary bladder and, less frequently, parasitizes brackish and marine fish, as well as mollusks (Boxshall & Halsey, 2004; Rosim et al., 2013; Taborda et al., 2016). Ergasilidae is the richest family of parasitic copepods found on fish from Brazil, on which 74 species from 18 genera have been reported (Narciso et al., 2019; Narciso & Da Silva, 2020; Narciso et al., 2020; Narciso et al. 2021a, 2021b; Oliveira et al., 2021). However, some authors affirm that such diversity is still underestimated, since only a small fraction of the Brazilian ichthyofauna has been studied for parasitic copepods (Luque et al., 2013; Taborda et al., 2016; Narciso & Da Silva, 2020; Paschoal et al., 2022).
The genus Acusicola Cressey, 1970 is currently known to comprise 15 species, eight of which have been reported in Brazil, especially in the Amazon basin (Amado & Rocha, 1996; Santacruz et al., 2020; Walter & Boxshall, 2022). These ergasilid copepods, together with Miracetyma Malta, 1993 and Amplexibranchius Thatcher & Paredes, 1985, belong to a group of genera that has peculiar attachment mechanisms, which is composed by a pair of antennae with short terminal claw that latches into a groove on the second endopodal segment of the opposite pair, enabling the completely involvement of the gill filament. However, species of Acusicola presents a 2-segmented endopod on the first pair of legs armed with at least six elements; a feature that is not found in the other two genera of the group (Malta, 1993; Thatcher & Paredes, 1985; Boxshall & Halsey, 2004). This genus was originally proposed to accommodate Acusicola tenax (Roberts, 1965), firstly assigned to Ergasilus von Nordmann, 1832, infesting gill filaments of Pomoxis annularis Rafinesque (Centrarchidae) in Garza-Little Elm Lake, Texas, USA (Roberts, 1965; Cressey & Collette, 1970). Subsequently, other species of Acusicola have been reported in the American continent, from the gills of different teleost families, especially Belonidae, Engraulidae, and Mugilidae, as well as from plankton samples (Santacruz et al., 2020). Recently, Santacruz et al. (2020) proposed a new species of Acusicola parasitizing the gills of Amphilophus citrinellus (Günther) (Cichlidae) in Nicaragua, using for the first time in Acusicola an integrative taxonomic approach.
During a parasitological survey of estuarine fish off Brazil, two species of parasitic copepods belonging to the genus Acusicola were found on the gills of two teleost hosts: Lobotes surinamensis (Bloch) (Lobotidae), from the coastal zone of the State of Pará, and Centropomus ensiferus Poey (Centropomidae) from Sepetiba Bay, State of Rio de Janeiro, Brazil. Detailed morphological study of these specimens revealed that they represent two unknown species, which are fully described herein.
Materials and Methods
Fish were bought from local fisherman in two different localities: eight specimens of L. surinamenis obtained in January 2021 in the coastal zone of the State of Pará (0°33′42″S, 47°51′00″W), Northern Brazil; and four specimens of C. ensiferus obtained between January 2020 to March 2020 in Sepetiba Bay (22°57′18″S, 43°54′44″W), State of Rio de Janeiro, Southeastern Brazil. Hosts were analyzed mostly fresh, but some specimens were kept frozen at -20°C, prior to parasitological examination. Copepods were collected from the gills, by careful washing of gill filaments in flowing water or delicate detaching using a thin needle, fixed and preserved in 70% ethanol. For microscopical observations, parasite specimens were cleared in 85% lactic acid and the appendages were dissected and examined using the wooden slide procedure described by Humes and Gooding (1964). Drawings were made with the aid of a Zeiss Standard 20 microscope (Carl Zeiss Foundation, Germany), equipped with a drawing tube. Measurements, all in micrometers unless otherwise stated, were made using an ocular micrometer and are given by range followed by the mean and standard deviation in parentheses. The descriptive terminology and classification of copepods follow Boxshall and Halsey (2004). Prevalence and intensity are used according to Bush et al. (1997). Host identification was based on the key by Menezes and Figueiredo (1980) and Figueiredo and Menezes (1980); their nomenclature and classification were updated according to FishBase (Froese and Pauly, 2022). Type specimens were deposited in the collection of the Museu de Zoologia da Universidade de São Paulo (acronym MZUSP), Brazil.
Systematics
Order Cyclopoida Burmeister, 1834
Family Ergasilidae Burmeister, 1835
Genus Acusicola
Cressey, 1970
Type-species: Acusicola cunula Cressey, 1970 by original designation.
Acusicola iamarinoi n. sp.
Type host: The Tripletail Lobotes surinamensis (Bloch) (Acanthuriformes: Lobotidae).
Prevalence: 100% (eight infested fish out of eight examined).
Mean intensity: mean of 11.1 copepods per infected fish (range 4–21).
Site of infection: Gills.
Type locality: Coastal zone of the State of Pará, near Curuçá Municipality, Brazil (0°33'42"S, 47°51'00"W).
Specimens deposited: Holotype female (MZUSP-43421) and 9 paratypes female (MZUSP-43422).
ZooBank registration: urn:lsid:zoobank.org:act:5F71F3A0-7693-4890-9EF1-8872A4BB13C1.
Etymology: The new species is named in honor of Dr. Átila Iamarino from Brazil, for his contribution to science communication, especially during the COVID-19 pandemic.
Description
Adult female [based on 10 specimens; Figs. 1–3]. Body length from anterior margin of prosome to posterior margin of caudal rami 560–720 (654 ± 51.6). Body comprising prosome and urosome (Figs. 1A, B); prosome consisting of cephalosome, with antennule visible only in dorsal view and 4 pedigerous somites. Cephalosome and first pedigerous somite not fused (Figs. 1A, B). Cephalosome (Fig. 1A) longer than wide, 200–250 (220 ± 17.3) × 140–210 (181 ± 22.7), not inflated and slightly constricted, representing more than one third of body length; dorsal surface of cephalosome with inverted T-shaped mark (Fig. 1A). Depression between cephalosome and first pedigerous somite, with posterior margin of cephalosome distinct in both lateral and dorsal views (Figs. 1A, B). Fourth pedigerous somite ornate with pair of blunt processes on dorsal part of anterior margin (Figs. 1A, B). Urosome consisting of fifth pedigerous somite, genital double-somite, and 3 free abdominal somites; third abdominal somite (= anal somite) bipartite. Fifth pedigerous somite (Fig. 1C) short, with row of spinules on medio-ventral surface. Genital double-somite (Fig. 1C) longer than wide, 60–80 (69 ± 6.9) × 55–75 (66 ± 4.8), with ventral surface ornate with 2 plates of spinules on medio-ventral surface and row of spinules along posteroventral margin. Free abdominal somites (Fig. 1C) wider than long; first and second nearly equal in length; third somite smaller than previous two. Posteroventral and posterolateral margins of abdominal somites ornamented by row of spinules each; third somite with additional row of spinules on inner lateral margin.Fig. 1 Acusicola iamarinoi n. sp. (adult female). A, habitus, dorsal, ts = T-shaped mark; B, habitus, lateral, a1 = antennule, a2 = antenna, p1 = leg 1, p2 = leg 2, p3 = leg 3, p4 = leg 4, p5 = leg 5, pp = prosomal process; C, fifth pedigerous somite, abdomen and caudal rami, ventral; D, antennule, ventral, ae = aesthetascs. Scale bars: A–B = 200 µm; C = 50 µm; D = 25 µm
Caudal rami (Fig. 1C) longer than third abdominal somite; with row of spinules on ventral surface extending near posterior and medial margins; each ramus armed with 2 large medial setae, 1 minor medial seta and 1 seta at outer corner. Two egg-sacs (Fig. 2D), much longer than wide, each composed by 2–4 rows of eggs.Fig. 2 Acusicola iamarinoi n. sp. (adult female). A, antenna, ventral, fo = fossae, th = vestigial third endopodal segment, gr = groove; B, mouthparts, ventral, cp = chitinous process, mb = mandible, me = maxillule, sy = syncoxa, pr = protrusion; C, interpodal plates of legs 1 to 4, ventral; D, egg sac, dorsal; E, leg 5, lateral. Scale bars: A = 100 µm; B = 50 µm; C = 30 µm; D = 200 µm; E = 20 µm
Antennule 5-segmented (Fig. 1D), tapering distally, aesthetascs present on fourth and fifth segments; setal formula as follows: 10: 4: 4: 2 + ae: 5 + ae: all setae naked. Antenna (Fig. 2A) comprising coxobasis and 3-segmented endopod with terminal claw; coxobasis, first endopodal segment and the first half of second endopodal segment enclosed by membranous sheath. Coxobasis short, proximally longer, armed with modified peg seta on inner distal surface; membrane between coxobasis and first endopodal segment not inflated. First endopodal segment longest, nearly 2.4× longer than coxobasis, armed with 2 spiniform elements, 1 proximal on outer margin and 1 distal on medial margin, with hyaline processes along inner margin;outer margin of membranous sheath ornamented by small setules; second endopodal segment longer than wide, about 1.4× shorter than coxobasis, groove on the anterior margin, near half of segment; third endopodal segment vestigial, bearing short, curved claw with fossae on inner margin, near tip.
Mouthparts (Fig. 2B) include mandible, maxillule and maxilla; maxilliped absent. Mandible unsegmented, with anterior chitinous process, bearing palp and mid and posterior blades, anterior blade not observed; palp small and naked; mid blade with long spines in outer margin; posterior blade with smooth teeth along posterior margin. Maxillule small, bearing 3 unequal outer setae and 1 inner spiniform element. Maxilla comprising large syncoxa with 1 seta near basis and protrusion in the posterior margin near teeth; second segment (basis) bearing long and sharp anterior teeth with long spinules along anterior and apical margins.
Swimming legs 1–4 biramous (Figs. 3A–D), each with 2-segmented protopod comprising coxa and basis; interpodal plates (Fig. 2C) with row of spinules (legs 2 and 3) or smooth (legs 1 and 4). Armature of legs (spines, Roman numerals; setae, Arabic numerals) as follows:Fig. 3 Acusicola iamarinoi n. sp. (adult female). A, leg 1, ventral; B, leg 2, ventral, pr = protrusion; C, leg 3, ventral, pr = protrusion; D, leg 4, ventral, pr = protrusion. Scale bars: A = 20 µm; B–D = 25 µm
Coxa Basis Exopod Endopod
Leg 1 0-0 0-1 I-0; 0-1; II-5 0-1; II-4
Leg 2 0-0 0-1 I-0; 0-1; I-6 0-1; 0-2; I-4
Leg 3 0-0 0-1 I-0; 0-1; 0-6 0-1; 0-2; I-4
Leg 4 0-0 0-1 0-0; 0-5 0-1; 0-2; I-3
Leg 1 (Fig. 3A) coxa unarmed. Basis with outer naked seta. Exopod 3-segmented, with rows of spinules on outer margin of all segments; first segment with small outer spine; second segment with inner plumose seta; third segment with small subapical spine, long apical spine and 5 plumose setae. Endopod 2-segmented, both segments with rows of spinules on outer margin; first segment about 1.3× longer than exopodal ramus, with plumose inner seta; second segment with 4 plumose setae, 1 falciform subapical spine with hook near basis and 1 pectinate apical spine.
Leg 2 (Fig. 3B) coxa unarmed, with small protrusion on posterior margin. Basis with outer naked seta. Exopod 3-segmented, lacking spinules; first segment longest, with small outer spine; second segment with inner plumose seta; third segment shortest, with 6 apical plumose setae and 1 small outer spine. Endopod 3-segmented, with row of spinules on outer margin of second and third segments; first segment longest, with plumose inner seta; second segment with 2 plumose inner setae; third segment with subapical curved spine, and 4 plumose setae.
Leg 3 (Fig. 3C) similar to Leg 2, except for absence of outer spine on last exopodal segment and spinules on anterior outer margin of second endopodal segment.
Leg 4 (Fig. 3D) coxa unarmed with small protrusion on posterior margin. Basis with outer naked seta. Exopod 2-segmented, lacking spinules; first segment longest, unarmed; second segment with 5 long plumose apical setae. Endopod 3-segmented; first segment with patch of spinules on posteroventral and outer margins and 1 inner plumose seta; second segment with small patch of spinules on medioventral margin and 2 inner plumose setae; third segment with row of spinules on anterior ventral margin, 3 plumose setae and 1 long spine, about 1.4× shorter than endopodal ramus.
Leg 5 (Fig. 2E) represented by 2 naked setae, ventral seta longest; each carried on separate papilla.
Remarks
The new species differs from all congeners by its possession of a maxillule armed with four elements (i.e., three regular setae and one spiniform element), since the maxillule of the other known species has two (as in A. cunula Cressey, 1970, A. lycengraulidis Thatcher & Boeger, 1983a, 1983b, A. paracunula Amado & Rocha, 1996, A. pellonidis Thatcher & Boeger, 1983a, 1983b, A. rogeri Amado & Rocha, 1996, A. rotunda Amado & Rocha C.E.F., 1996, A. spinulosa Amado & Rocha C.E.F., 1996, A. tenax (Roberts, 1965) and A. tucunarense Thatcher, 1984) or three elements (as in A. braziliensis Amado & Rocha C.E.F., 1996, A. joturicola El-Rashidy & Boxshall, 1999, A. margulisae Santacruz, Morales-Serna, Leal-Cardín, Barluenga & de León, 2020, A. mazatlanensis El-Rashidy & Boxshall, 1999, A. minuta Araújo & Boxshall, 2001, A. spinuloderma El-Rashidy & Boxshall, 1999) (Cressey & Collette, 1970; Thatcher & Boeger, 1983a; Thatcher & Boeger, 1983b; Thatcher, 1984; Amado & Rocha, 1996; El-Rashidy & Boxshall, 1999; Araújo & Boxshall, 2001; Santacruz et al. 2020). Acusicola iamarinoi n. sp. has the following feature that may be considered an autapomorphy among species of Acusicola: a pair of dorsal blunt processes on the anterior margin of the fourth pedigerous somite. Therefore, the new species is easily diagnosed based on this autapomorphy and, consequently, clearly differs from the congeners.
Acusicola margulisae, a parasite of A. citrinellus from Nicaragua, shares with A. iamarinoi n. sp. a long first endopodal segment in leg 1, about 1.3× longer than the exopodal ramus. The new species differs from A. margulisae because its cephalosome is clearly separated from the first pedigerous somite (vs fused in the latter), its first antennulary segment is armed with 10 setae (vs 12 seta in the latter), the second endopodal segments of legs 1 and 2 lacking processes (vs present in the latter) and by the caudal rami with two long setae (vs one seta in the latter) (Santacruz et al., 2020).
Acusicola iamarinoi n. sp. resembles A. brasiliensis, A. minuta A. spinuloderma and A. tenax by sharing the presence of a long spine on the terminal segment of the endopod of leg 4. However, the new species differs from these congeners because it has the first antennulary segment armed with 10 setae (vs 11 in A. brasiliensis, 12 in A. minuta and A. spinuloderma, and 13 in A. tenax). Moreover, it differs from A. brasiliensis and A. spinuloderma in the absence of a spine on the last exopodal segment of leg 3 (vs presence in the latter two). Acusicola iamarinoi n. sp. also differs from A. minuta by the antenna lacking two membranous expansions on the inner margin of the second endopodal segment (vs presence in the latter); from A. spinuloderma by having the cephalosome clearly separated from the first pedigerous somite (vs fused in the latter); and from A. tenax by the presence of a spine on the first exopodal segment of leg 1 (vs absence in the latter) (Roberts, 1965; Amado & Rocha, 1996; El-Rashidy & Boxshall, 1999; Araújo & Boxshall, 2001).
Acusicola pasternakae. n. sp
Type host: The Swordspine snook Centropomus ensiferus Poey (Carangaria: Centropomidae).
Prevalence: 50% (two infested fish out of four examined).
Mean intensity: mean of 4 copepods per infected fish (range 2–6).
Site of infection: Gills.
Type locality: Sepetiba Bay, State of Rio de Janeiro, Brazil (22°57'18"S, 43°54'44"W).
Specimens deposited: Holotype female (MZUSP-43423) and 4 paratypes female (MZUSP-43424).
ZooBank registration: urn:lsid:zoobank.org:act:81615CB6-A754-457E-BBF0-33B54052AA1D
Etymology: The new species is named in honor of Dr. Natalia Pasternak Taschner from Brazil, for her contribution to science communication, especially during the COVID-19 pandemic.
Description
Adult female [based on 6 specimens; Figs. 4–6]. Body length from anterior margin of prosome to posterior margin of caudal rami 800–1000 (908 ± 82.6). Body comprising prosome and urosome (Figs. 4A, B); prosome consisting of cephalosome, with antennule visible only in dorsal view and 4 pedigerous somites. Cephalosome and first pedigerous somite not fused (Figs. 4A, B). Cephalosome (Fig. 4A) longer than wide, 250–340 (307 ± 31.4) × 200–255 (226 ± 22), not inflated and slightly constricted, representing more than one third of body length; dorsal surface of cephalosome with nauplius eye near anterior margin, inverted T-shaped mark and pair of sensilla (Figs. 4A). Depression between cephalosome and first pedigerous somite, with posterior margin of cephalosome distinct in both lateral and dorsal views (Figs. 4A, B). Second and third pedigerous somites ornate with 1 medial sensillum each (Figs. 4A, B). Urosome consisting of fifth pedigerous somite, genital double-somite, and 3 free abdominal somites; third abdominal somite (= anal somite) bipartite. Fifth pedigerous somite (Fig. 4C) short. Genital double-somite (Fig. 4C) longer than wide, 90–100 (97.2 ± 4.5) × 84–95 (89 ± 4), with row of spinules on medio-ventral surface and row of spinules along posteroventral margin. Free abdominal somites (Fig. 4C) wider than long; first somite longer than second; third somite smaller than previous two. First abdominal somite with row of spinules on posteroventral margin; second abdominal somite with 2 patches of spinules on anterior and posterolateral margins of ventral surface and 1 row of spinules on posteroventral margin; third somite with patch of spinules on medio-lateral margin.Fig. 4 Acusicola pasternakae n. sp. (adult female). A, habitus, dorsal, ts= T-shaped mark; B, habitus, lateral, ne = nauplius eye, a1 = antennule, a2 = antenna, se = sensillum, p1 = prosome 1, p2 = leg 2, p3 = leg 3, p4 = leg 4, p5 = leg 5; C, fifth pedigerous somite, abdomen and caudal rami, ventral; D, antennule, ventral, ae = aesthetascs. Scale bars: A–B = 300 µm; C = 100 µm; D = 50 µm
Caudal rami (Fig. 4C) longer than third abdominal somite; each ramus armed with 1 large medial seta, 2 unequal ventral setae and 1 seta at outer corner. Two egg-sacs (Fig. 5D), much longer than wide, each composed by 2–4 rows of eggs.Fig. 5 Acusicola pasternakae n. sp. (adult female). A, antenna, ventral, fo = fossae, th = vestigial third endopodal segment, gr = groove; B, mouthparts, ventral, mb = mandible, me = maxillule, sy = syncoxa; C, interpodal plates of legs 1 to 4, ventral; D, egg sac, dorsal; E, leg 5, lateral. Scale bars: A = 200 µm; B = 50 µm; C = 30 µm; D = 400 µm; E = 15 µm
Antennule 5-segmented (Fig. 4D), tapering distally, aesthetascs present on fourth and fifth segments; setal formula as follows: 11: 3: 4: 2 + ae: 6 + ae: all setae naked. Antenna (Fig. 5A) comprising coxobasis and 3-segmented endopod with terminal claw; coxobasis, first endopodal segment and the first half of the second endopodal segment enclosed by membranous sheath. Coxobasis short, proximally longer, armed with modified peg seta on inner distal surface; membrane between coxobasis and first endopodal segment not inflated. First endopodal segment longest, nearly 2.6× longer than coxobasis, armed with anterior spiniform element and posterior blunt element with thick spine at base, with hyaline processes along inner margin; membranous inner margin of membranous sheath ornamented with horizontal marks. Second endopodal segment longer than wide, about 1.2× longer than coxobasis, groove on the anterior margin, near half of segment. Third endopodal segment vestigial, bearing short, curved claw with fossae on inner margin near tip.
Mouthparts (Fig. 5B) include mandible, maxillule and maxilla; maxilliped absent. Mandible unsegmented, bearing palp and mid and posterior blades; palp small and naked, anterior blade not observed; mid blade with long spines in posterior margin; posterior blade with smooth teeth along posterior margin. Maxillule small, bearing 2 setae similar in size. Maxilla comprising large syncoxa with 2 setae, 1 on posterior margin and 1 near basis; second segment (basis), bearing long, sharp anterior teeth with long spinules along anterior and apical margins.
Swimming legs 1–4 biramous (Figs. 6A–D), each with 2-segmented protopod comprising coxa and basis; interpodal plates (Fig. 5C) with row of spinules (legs 1, 2 and 3) or smooth (leg 4). Armature of legs (spines, Roman numerals; setae, Arabic numerals) as follows:Fig. 6 Acusicola pasternakae n. sp. (adult female). A, leg 1, ventral, pr= protrusion; B, leg 2, ventral, pr = protrusion; C, leg 3, ventral, pr = protrusion; D, leg 4, ventral. Scale bars: A–D = 30 µm
Coxa Basis Exopod Endopod
Leg 1 0-0 0-1 I-0; 0-1; II-5 0-1; II-4
Leg 2 0-0 0-1 I-0; 0-1; I-6 0-1; 0-2; I-4
Leg 3 0-0 0-1 I-0; 0-1; 0-6 0-1; 0-2; I-4
Leg 4 0-0 0-1 0-0; 0-4 0-1; 0-2; I-3
Leg 1 (Fig. 6A) coxa unarmed with small protrusion on posterior margin. Basis with outer naked seta. Exopod 3-segmented, with rows of spinules on outer margin of all segments, reaching ventral surface on last segment; first segment with small outer spine; second segment with inner plumose seta; third segment with 2 apical spines of equal size and 5 plumose setae. Endopod 2-segmented, both segments with rows of spinules on outer margin; first segment about 1.3× shorter as exopodal ramus, with plumose inner seta; second segment with 4 plumose setae, 1 falciform subapical spine with a hook near basis and 1 pectinate apical spine, both with spinules on outer margin.
Leg 2 (Fig. 6B) coxa unarmed with small protrusion on posterior margin. Basis with outer naked seta. Exopod 3-segmented, lacking spinules; first segment longest, with small outer spine; second segment with inner plumose seta; third segment shortest, with 6 apical plumose setae and 1 small outer spine. Endopod 3-segmented, lacking spinules; first segment longest, with plumose inner seta; second segment with 2 plumose inner setae; third segment with subapical spine and 4 plumose setae.
Leg 3 (Fig. 6C) similar to Leg 2, except for absence of outer spine on last exopodal segment.
Leg 4 (Fig. 6D) coxa unarmed. Basis with outer naked seta and patch of spinules on posterior margin, near endopod attachment site. Exopod 2-segmented, lacking spinules; first segment longest, unarmed; second segment with 4 long, plumose apical setae. Endopod 3-segmented; first segment lacking spinules, with 1 inner plumose seta; second segment with row of spinules on posteroventral margin and 2 inner plumose setae; third segment with row of spinules on outer margin, patch of spinules on posteroventral surface, armed with 3 lateral plumose setae and 1 long apical spine about 2.1× shorter than endopodal ramus.
Leg 5 (Fig. 5E) represented by 2 naked setae, ventral seta longest; each inserted on separate papilla.
Remarks
Of the 15 nominal species assigned to Acusicola, only three have the last exopodal segment of leg 4 armed with four setae as in A. pasternakae n. sp. namely, A. rogeri, A. spinulosa and A. tenax. However, the new species differs from these closely species because in its antennule the first segment is armed with 11 setae (vs eight setae in A. rogeri and A. spinulosa and 13 setae in A. tenax) and its membranous sheath of the first endopodal segment of antennae has horizontal markings (vs absence of it in the last three species) (Roberts, 1965; Cressey & Collette, 1970; Amado & Rocha, 1996; Santacruz et al., 2020). The new species also differs from A. rogeri and A. spínulosa by the presence of a spine on the last exopodal segment of legs 2 and 3 (vs absence in the latter) (Cressey & Collette, 1970; Amado & Rocha, 1996).
In addition, Acusicola pasternakae n. sp. differs from A. tenax by having a spine on the first exopodal segment of leg 1 (vs absence in the latter). Moreover, A. pasternakae n. sp. differs from A. spinulosa because its cephalossome is separated from the first pedigerous somite (vs not separated in the latter), last endopodal segment of leg 1 with four setae and two spines (vs three reduced spines in the latter), last endopodal segment of leg 4 with three setae (vs four setae in the latter) and leg 5 reduced to two setae (vs leg 5 reduced to a single seta in the latter) (Roberts, 1965; Amado & Rocha, 1996).
Discussion
The two new species proposed in the present study were assigned to Acusicola based on the following features present in the parasitic females: a 5-segmented antennule, antennae with short curved apical claw that latches into a groove on the second endopodal segment of the opposite antenna, and a 2-segmented endopod with at least six elements on leg 1 (Cressey & Collette, 1970, Boxshall & Halsey, 2004). According to Santacruz et al. (2020), species of Acusicola parasitize a wide range of actinopterygian hosts, especially members of the families Belonidae, Engraulidae and Mugilidae, but some species are present in fish of the families Atherinopsidae, Cichlidae, Clupeidae, Poeciliidae, Pristigasteridae, and Centrarchidae. Currently, only one representative of Ergasilidae has been reported infesting species belonging to Lobotidae, i.e., Ergasilus monodi Brian, 1927 on L. surinamensis from Cameroon. In contrast, there are three reports of ergasilids infesting Centropomidae fish: Ergasilus sp. on Centropomus undecimalis (Bloch) from Brazil, Ergasilus davidi Suárez-Morales & Santana-Piñeros, 2008 and Therodamas mexicanus Suárez-Morales, Santana-Piñeros & González-Solís, 2008 on Centropomus robalito Jordan & Gilbert from Mexico (Brian, 1927; Tavares & Luque, 2004; González-Solís et al., 2008; Suárez-Morales & Santana-Piñeros, 2008). Consequently, the present results, represent the first report of the genus Acusicola infesting fish of the families Lobotidae and Centropomidae in the world, suggesting that these two families include potential hosts for ergasilid copepods.
Tavares and Luque (2004) examined 79 specimens of C. undecimalis from the same locality as the one of the present study (Sepetiba Bay, State of Rio de Janeiro), reporting Ergasilus sp. on the gills. In order to confirm the identity of these specimens, the vouchers deposited in the Coleção Carcinológica do Museu Nacional do Rio de Janeiro (accession number MNRJ-15426) were requested for analysis. Unfortunately, the curator of MNRJ informed that the material was lost during a fire that committed the museum in September 2018. Since C. undecimalis and C. ensiferus are sympatric in Sepetiba Bay, it is possible that the Ergasilus sp. reported by Tavares and Luque (2004) is conspecific to A. pasternakae n. sp.; however, in order to confirm such hypothesis, new collections of ergasilid copepods from the gills of C. undecimalis in Sepetiba Bay are necessary.
Since the erection of Acusicola species have been mostly reported from freshwater environment, but some infest catadromous hosts (Santacruz et al., 2020). Acusicola brasiliensis, for example, has been reported infesting Lile piquitinga (Schreiner & Miranda Ribeiro), a clupeid fish that occurs inshore, on muddy bottoms, as well as in brackish or moderately saline coastal lagoons. This ergasilid can be found on different types of habitats similar to its host, being reported from freshwater habitats in Alegre, State of Pará, brackish and marine conditions in Cambori Beach, State of Espírito Santo, Itaparica Island, State of Bahia, and São Cristovão Beach, State of Sergipe, all in Brazil (Amado & Rocha, 1996; Froese & Pauly, 2022). The Tripletail L. surinamensis has similar biology as L. piquitinga, in which adults inhabit bays, muddy estuaries and lower reaches of large rivers. Similarly, the Swordspine snook C. ensiferus, can be found in coastal waters, estuaries and lagoons, migrating to freshwater, usually preferring habitats with low salinity (Froese & Pauly, 2022). Although the two new species of copepods described in the present study were originally found from brackish waters, their habitat might be similar to that of the hosts, i.e., extending from freshwater to brackish and even more saline habitats.
Ergasilids represent the second most reported group of parasitic copepods infesting marine and brackish farmed fish, frequently causing tissue damage and economic losses (Thatcher, 1998; Johnson et al., 2004; Pádua et al., 2015). Within the Neotropical Region, Brazil has the greatest species richness of parasitic crustaceans, most of which are ergasilid copepods (Luque et al., 2013). Despite the frequent occurrence and impact in aquaculture, the knowledge pertaining to the diversity and distribution of these parasites is still underestimated, since less than 10% of the local ichthyofauna has been studied for parasitic copepods (Luque et al., 2013; Couto & Paschoal, 2021; Paschoal et al., 2022; Narciso et al., 2022). Such gapped knowledge is concerning, since aquiculture has been expressively expanding during the last years (see FAO, 2021), which also highlights the need for further investigations on Ergasilidade, as well as on other groups of parasitic copepods from fish in Brazil.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 417 kb)
Authors would like to thank the students of biology Nagylla de Fátima da Silva Sena and Julie Costa Rodrigues from Instituto Federal do Pará, as well as Larissa Maia from the Laboratory of Paleoparasitology, Instituto Oswaldo Cruz (acronym FIOCRUZ), Brazil, for collecting the parasite samples.
Author contributions
ANP, JLL and FP performed field collection and parasitological survey. JVC, FP and FBP analyzed the copepods, prepared the illustrations and wrote the first draft of the manuscript. All reviewed the manuscript and approved the final version. FBP and FP supervised the study.
Funding
JVC was supported by Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES), Brazil. JLL was supported by Conselho Nacional de Desenvolvimento Científico e Tecnologico do Brasil (CNPq), Brazil. FP was supported by Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA, process no. 84516/2022), Brazil.
Declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All applicable institutional, national and international guidelines for the care and use of animals were followed.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Amado, M. A. P. M., & Rocha, C. E. F. (1996). New species of parasitic copepods of the Genus Acusicola (Poecilostomatoida: Ergasilidae) from gill filaments of coastal and freshwater Brazilian fishes, and proposition of Acusicola rogeri n. sp. for A. tenax sensu Cressey & Collette (1970). Hydrobiologia¸ 324(3), 183–193. 10.1007/bf00016390
Araújo HMP Boxshall GA A new species of Acusicola Cressey (Copepoda: Ergasilidae) from northeastern Brazil Systematic Parasitology 2001 49 2 149 157 10.1023/a:1010624822047 11389336
Boxshall, G. A., & Halsey, S. H. (2004). An introduction to copepod diversity. The Ray Society.
Brian, A. (1927). Crustacea II. Copepoda parasitica. In: Monod, T. (Ed.), Contribution a I'etude de la faune du Cameroun (1th ed., pp. 570-587). Éditeur Scientifique.
Bush JO Lafferty KD Lotz JM Shostak AW Parasitology meets ecology on its own terms: Margolis et al. revisited Journal of Parasitology 1997 83 4 575 583 10.2307/2F3284227 9267395
Cressey R Collette B Copepods and needlefishes: A study in host-parasite relationships Fishery Bulletin 1970 68 347 432
Couto JV Paschoal F Two new species of Colobomatus Hesse, 1873 (Crustacea: Philichthyidae) parasitic in the interorbital canals of Holocentrus spp. (Holocentriformes: Holocentridae) in the South Atlantic Ocean Systematic Parasitology 2021 98 5–6 753 764 10.1007/s11230-021-10009-1 34708335
El-Rashidy RH Boxshall GA Ergasilid copepods (Poecilostomatoida) from the gills of primitive Mugilidae (grey mullets) Systematic Parasitology 1999 42 161 186 10.1023/a:1006075223683 10613535
Food and Agriculture Organization of the United Nations. (2021). Yearbook of Fishery and Aquaculture Statistics.
Figueiredo, J. L., & Menezes, N. A. (1980). Manual de Peixes Marinhos do Sudeste do Brasil. III. Teleostei (2). Museu de Zoologia da Universidade de São Paulo.
Froese, R., & Pauly, D. (2022). FishBase. World Wide Web electronic publication. http://www.fishbase.org, version 02/2022. Accessed on 2022-09-20.
González-Solís D Suárez-Morales E Santana-Piñeros A A new species and host range of Therodamas (Copepoda, Ergasilidae) from the Eastern Tropical Pacific Crustaceana 2008 81 9 1107 1117 10.1163/156854008X360842
Humes A Gooding R A method for studying the external anatomy of copepods Crustaceana 1964 6 3 238 240 10.1163/156854064x00650
Johnson SC Treasurer JW Bravo S Nagasawa K Kabata Z A Review of the Impact of Parasitic Copepods on Marine Aquaculture Zoological Studies 2004 43 2 229 243
Luque JL Vieira FM Takemoto RM Pavanelli GC Eiras JC Checklist of Crustacea parasitizing fishes from Brazil Check List 2013 9 6 1449 1470 10.15560/9.6.1449
Malta JCO Miracetyma etimaruya gen. et sp. N. (Copepoda, Poecilostomatoida, Ergasilidae) From Freshwater Fishes Of The Brazilian Amazon Acta Amazonica 1993 23 1 49 57 10.1590/1809-43921993231057
Menezes, N. A., & Figueiredo, J. L. (1980). Manual de Peixes Marinhos do Sudeste do Brasil. IV. Teleostei (3). Museu de Zoologia da Universidade de São Paulo.
Narciso RB Brandão H Perbiche-Neves G A New Genus of Ergasilidae (Copepoda: Cyclopoida) from the Gills of Astyanax fasciatus (Cuvier, 1819) (Actinopterygii: Characidae) Acta Parasitologica 2019 64 4 850 865 10.2478/s11686-019-00108-x 31432390
Narciso RB Da Silva RJ Two Gamispatulus Thatcher & Boger, 1984 (Cyclopoida: Ergasilidae) from Schizodon intermedius Garavello & Britski (Actinopterygii: Anostomidae), with description of a new species Zootaxa 2020 4803 3 463 482 10.11646/zootaxa.4803.3.3
Narciso RB Perbiche-Neves G Silva RJ A new species of Pseudovaigamus Amado, Ho & Rocha, 1984 (Cyclopoida: Ergasilidae) from the teleost Pimelodus maculatus Lacepède, 1803 Zootaxa 2020 4881 2 349 360 10.11646/zootaxa.4881.2.8
Narciso RB Brandão H Perbiche-Neves G Silva RJ A New Species of Rhinergasilus Boeger et Thatcher, 1988 (Copepoda: Ergasilidae) from Gills of Astyanax fasciatus (Cuvier, 1819) (Actinopterygii: Characidae) Acta Parasitologica 2021 65 2 327 334 10.2478/s11686-020-00168-4
Narciso RB Perbiche-Neves G Da Silva RJ Rhinergasilus unguilongus n. sp. (Copepoda: Ergasilidae): A Gill Parasite of the Freshwater Fish Prochilodus lineatus (Valenciennes, 1837) (Actinopterygii: Prochilodontidae) from the Neotropical Region, Brazil Acta Parasitologica 2021 66 1 155 162 10.1007/s11686-020-00270-7 32839924
Narciso RB Vieira DHMD da Silva RJ A new species of Tiddergasilus Marques & Boeger, 2018 (Copepoda: Ergasilidae) from the gills of Astyanax lacustris (Lütken) (Osteichthyes: Characidae) in Brazil Systematic Parasitology (available online) 2022 10.1007/s11230-022-10055-3
Oliveira MSB Corrêa LL Adriano EA Tavares-Dias M Integrative taxonomy of a new species of Therodamas (Ergasilidae) infecting the Amazonian freshwater fish Leporinus fasciatus (Anostomidae) Parasitology Research 2021 120 9 3137 3147 10.1007/s00436-021-07256-y 34374850
Pádua SB Jerônimo GT Menezes-Filho RN Taboga SR Martins ML Belo MAA Pathological assessment of farmed yellowtail tetra Astyanax altiparanae infested by Acusicola sp. (Ergasilidae) Aquaculture Reports 2015 2 63 66 10.1016/j.aqrep.2015.08.003
Paschoal F Couto JV Pereira FB Luque JL A New Species of Hatschekiid Copepod (Crustacea: Hatschekiidae) Parasitic on the Porkfish Anisotremus virginicus (Linnaeus, 1758) (Actinopterygii: Haemulidae), with Notes on Previously Known Species of Hatschekia Poche, 1902 Collected from Actinopterygians off Brazil Acta Parasitologica 2022 67 3 1126 1135 10.1007/s11686-022-00551-3 35476261
Roberts LS Ergasilus tenax sp. N. (Copepoda: Cyclopoida) from the White Crappie, Pomoxis annularis Rafinesque The Journal of Parasitology 1965 51 6 987 989 10.2307/3275889 5848834
Rosim DF Boxshall GA Ceccarelli PS A novel micro-habitat for parasitic copepods: a new genus of Ergasilidae (Copepoda: Cyclopoida) from the urinary bladder of a freshwater fish Parasitology International 2013 62 4 347 354 10.1016/j.parint.2013.03.003 23523989
Santacruz A Morales-Serna FN Leal-Cardín M Barluenga M Léon GP Acusicola margulisae n. sp. (Copepoda: Ergasilidae) from freshwater fishes in a Nicaraguan crater lake based on morphological and molecular evidence Systematic Parasitology 2020 97 2 165 177 10.1007/s11230-020-09906-8 32065374
Suárez-Morales E Santana-Piñeros AM A new species of Ergasilus (Copepoda: Cyclopoida: Ergasilidae) from coastal fishes of the Mexican Pacific Folia Parasitologica 2008 55 3 224 230 10.14411/fp.2008.030 19202681
Taborda N Paschoal F Luque JL A new species of Ergasilus (Copepoda: Ergasilidae) from Geophagus altifrons and G. argyrostictus (Perciformes: Cichlidae) in the Brazilian Amazon Acta Parasitologica 2016 61 3 549 555 10.1515/ap-2016-0073 27447219
Tavares LER Luque JL Community ecology of metazoan parasites of the later juvenile common snook Centropomus undecimalis (Osteichthyes: Centropomidae) from the coastal zone of the state of Rio de Janeiro, Brazil Brazilian Journal of Biology 2004 64 3 523 529 10.1590/S1519-69842004000300015
Thatcher V Copepods and fishes in the Brazilian Amazon Journal of Marine Systems 1998 15 1–4 97 112 10.1016/s0924-7963(97)00043-2
Thatcher V Boeger W The Parasitic Crustaceans of Fishes from the Brazilian Amazon, 8, Acusicola lycengraulidis n. sp. (Copepoda: Cyclopidea) from Lycengraulis grossidens Cuvier Acta Amazonica 1983 13 5–6 943 951 10.1590/1809-43921983a1356943
Thatcher V Boeger W The Parasitic Crustaceans of Fishes from the Brazilian Amazon, 10, Acusicola pellonidis n. sp. (Copepoda: Cyclopidea) from Pellona castelnaeana (Valenciennes) Amazoniana 1983 8 2 273 279
Thatcher V Paredes V A Parasitic Copepod, Amplexibranchius bryconis gen. et sp. Nov. (Ergasilidae: Acusicolinae), from an Amazonian Fish and Remarks on the Importance of Leg Morphology in this Subfamily Amazoniana 1985 9 2 205 214
Walter, T. C., & Boxshall, G. (2022). World of Copepods Database. Ergasilidae Burmeister, 1835. WoRMS. https://www.marinespecies.org/copepoda/aphia.php?p=taxdetails&id=128571. Accessed on 2022-09-20
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pmcWarm greetings to all our readers!!! We hope this year brings relief and progress to humanity. BJIT remains committed to delivering on its challenge of consistently showcasing and disseminating novel researches pertaining to computing applications and capable of altering the quality of human life. It is a matter of great privilege for me to unveil before you the forty fifth issue i.e. Volume 14 Number 07 of the “International Journal of Information Technology” [An official Journal of Bharati Vidyapeeth’s Institute of Computer Applications and Management (BVICAM), New Delhi] with acronym BJIT. The issue is live on the Springer content platform SpringerLink and available to the prospective readers through Springer CS package globally.
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The manuscript, “Intrusion detection system using soft labeling and stacking ensemble”, Hadi Nazari Abdoli emulates a convolution neural network-based intrusion detection system. The next manuscript “Grey wolf-based feature reduction for intrusion detection in WSN using LSTM”, S. Karthic et. al. simulates an enhanced intrusion detection system for digital devices. The manuscript “CNN-based device-free health monitoring and prediction system using WiFi signals”, Amit Kumar et. al. suggests a novel deep learning based device-free way to monitor breathing rate and heart rate in different human positions. The next manuscript “Implementation of an integrated classification approach of adaptive extreme learning machine and correlation based feature selection for odia complex characters”, Sradhanjali Nayak et. al. evaluates a handwritten character recognition mechanism for Odia complex characters. The manuscript “Leveraging genre classification with RNN for Book recommendation”, Mala Saraswat M et. al. elaborates a Recurrent Neural Networks (RNN) based deep learning approach to classify books plots and reviews. The manuscript “ Mental healthcare chatbot based on natural language processing and deep learning approaches: Ted the therapist”, Sumit Pandey et. al. evaluates an AI-web based chatbot to evaluate people with mental health-related issues. Conflicts in evidence can be addressed through several mechanisms. The manuscript “A new association coefficient measure for the conflict management and its application in medical diagnosis”, Palash Dutta et. al. explores a novel measure for conflict management in medical diagnosis. The next manuscript “Performance analysis of static hand gesture recognition approaches using artificial neural network, support vector machine and two stream based transfer learning approach”, Anjali R. Patil et. al. outlays an efficient machine learning based algorithm for hand gesture recognition. The manuscript “Questions clustering using canopy-K-means and hierarchical-K-means clustering”, Marwah Alian et. al. analyzes and corrects the question datasets by removing duplicates. The manuscript “Deep-learning with context sensitive quantization and interpolation for underwater image compression and quality image restoration”, Rashmi Nair et. al. evaluates the performance and reliability of a compression framework for underwater image compression. The manuscript “Fungi affected fruit leaf disease classification using deep CNN architecture”, Sukanya Gaikwad et.al. extends convolutional neural networks for classification of fruit-leaf disease pairs. The last manuscript “Exponential Rider-Henry Gas Solubility optimization-based deep learning for rice plant disease detection”, T. Daniya et. al. details an deep learning framework for plant disease detection.
I am sure the contributions in this issue, which is an amalgamation of novel applications of artificial intelligence and machine learning, shall pave way to improve our life and sustainability in the present environment. The manuscripts of the issue will not only enrich our readers’ knowledgebase but will also motivate many of the potential researchers to take up these challenging application areas and contribute effectively for the overall prosperity of the mankind.
As a matter of policy, all the manuscripts received and considered for the Journal, are double blind peer reviewed by at-least two independent referees. Our panel of expert referees’ posses a sound academic background and have a rich publication record in various prestigious journals representing Universities, Research Laboratories and other Institutions of repute, globally. Finalizing the constitution of the panel of referees, for double blind peer review(s) of the considered manuscripts, was a painstaking process, but it helped us to ensure that only the best, interesting and novel of the considered manuscripts are showcased and that too after undergoing multiple cycles of review, as required.
I wish to express my sincere gratitude to the Guest Editors of this Special Issue; namely Prof. P. Suganthan, Prof. P. Panigrahi and Prof. Swagatam Ghosh to have found time from their busy schedules and contributed in reviewing and selecting the best manuscripts for this Special Issue. I also thank the entire editorial board, members of the resident editorial team and our panel of experts in steering the considered manuscripts through multiple cycles of review and bringing out the best from the contributing authors. I thank my esteemed authors for having shown confidence in BJIT and considering it a platform to showcase and share their original research work. I would also wish to thank the authors whose papers could not have been published in this issue of the Journal, probably because of the minor shortcomings. However, I would like to encourage them to actively contribute for the forthcoming issues.
I will fail in my duty, if I do not thank the members of the team from the Springer, particularly Ms. Suvira Srivastav, Ms. Jeyapradha Saravanan, Ms. Bhuvaneswari Rangaswamy, Ms. Teena Bedi and Ms. Nidhi Chandok for their constant support in realizing the issue and presenting it before you.
The undertaken Quality Assurance Process involved a series of well-defined activities that, I trust, went a long way in ensuring the quality of the publication. Still, there is always a scope for improvement, and so, I request the contributors and readers to kindly mail us their criticism, suggestions and feedback at [email protected], which will certainly be of immense value addition in further enhancing the quality of forthcoming issues.
M. N. Hoda
Editor-in-Chief
International Journal of Information Technology (BJIT)
| 0 | PMC9734583 | NO-CC CODE | 2022-12-14 23:45:33 | no | Int J Inf Technol. 2022 Dec 5; 14(7):3287-3290 | utf-8 | Int J Inf Technol | 2,022 | 10.1007/s41870-022-01134-1 | oa_other |
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J Int Bus Stud
J Int Bus Stud
Journal of International Business Studies
0047-2506
1478-6990
Palgrave Macmillan UK London
581
10.1057/s41267-022-00581-z
Point
Africa rising: Opportunities for advancing theory on people, institutions, and the nation state in international business
Nachum Lilac [email protected]
1Lilac Nachum
is Professor of International Business at City University New York and an AIB Fellow. She was a Fulbright Scholar to Africa in 2021–2022 and is a visiting professor at Strathmore Business School. Her current research interests include global supply chains and value creation in a global world, emerging market MNEs, and the relationship between firms, society, and governments as they shape the international strategies of firms, with a focus on Africa.
Stevens Charles E. [email protected]
2Charles E. Stevens
is Associate Professor of Management and Global Business at Rutgers Business School. His research focuses on how institutions and social judgments such as reputation and legitimacy affect multinational firms’ strategy and performance. He is especially interested in these issues in the context of emerging markets such as Africa and China.
Newenham-Kahindi Aloysius [email protected]
3Aloysius Newenham-Kahindi
is a Canadian Research Chair in International Sustainable Development and Associate Professor of International Business at the University of Victoria, Canada. His research focuses on understanding how formal and informal institutions interact with and affect firms in emerging economies. He seeks to improve our understanding of why governance under informal institutions functions; and how firms (e.g., MNEs) can adjust to and honor these informal institutions; and how they fail when they do not honor and adjust to constraints imposed by informal institutions in Africa.
Lundan Sarianna [email protected]
45Sarianna Lundan
holds the Chair in International Management and Governance at the University of Bremen and she is the Editor-in-Chief of the Journal of International Business Policy. She is also a Visiting Distinguished Professor at Aalto University. Her research focuses on the impact of MNEs on home and host countries and the co-evolution of firms and institutions. She is a Fellow of AIB and EIBA.
Rose Elizabeth L. [email protected]
6Elizabeth L. Rose
is Research Chair Professor of Business Policy and Strategy at the Indian Institute of Management Udaipur. Her research examines various aspects of how firms internationalize, with a particular focus on smaller firms and those starting from an emerging-market base. She is a Fellow of the Academy of International Business and has served on the organization’s Executive Board.
Wantchekon Leonard [email protected]
7Leonard Wantchekon
is James Madison Professor of Political Economy and Professor of Politics and International Affairs at Princeton University. He has made substantive and methodological contributions to Political Economy, Economic History, and Development Economics, with a strong focus on Africa. He is a Fellow of the American Academy of Arts and Sciences, the Econometric Society, and a member of the Executive Committee of the International Economic Association.
1 grid.212340.6 0000000122985718 Baruch College, CUNY, New York, NY 10010 USA
2 grid.430387.b 0000 0004 1936 8796 Department of Management and Global Business, Rutgers Business School, Rutgers University, Newark, NJ 07102 USA
3 grid.143640.4 0000 0004 1936 9465 Gustavson Business School, University of Victoria, Victoria, BC V8W 2Y2 Canada
4 grid.7704.4 0000 0001 2297 4381 Faculty of Business Studies and Economics, University of Bremen, 28359 Bremen, Germany
5 grid.5373.2 0000000108389418 Department of Management Studies, School of Business, Aalto University, 02150 Espoo, Finland
6 grid.512270.3 0000 0004 1780 0928 Indian Institute of Management Udaipur, Balicha Campus, Udaipur, Rajasthan 313001 India
7 grid.16750.35 0000 0001 2097 5006 Department of Politics, Princeton University, 321 Bendheim Hall, Princeton, NJ 08544 USA
6 12 2022
118
23 9 2021
29 7 2022
28 9 2022
© Academy of International Business 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Africa is rising, but IB scholars have largely failed to take notice. We argue that this is a missed opportunity. Not only is Africa a dynamic and distinctive region, but its rise presents a number of puzzles for international business (IB) research, with phenomena that seem to challenge fundamental assumptions underlying IB theories. In order to unravel these puzzles and better explain business dynamics on the continent, we contend that there is a need for IB theorizing to place greater emphasis on the role of people, to balance IB’s traditional emphasis on institutions, location-specific assets, and other macro-level attributes. We explore how this conceptual shift presents new avenues for inquiry into issues that are of importance for IB but have received limited attention to date. Such issues include entrepreneurial human capital, social networks, institutional co-evolution, and the informal economy. As such, we argue that, while extant theories in IB inform explanations and predictions regarding business activity across the continent, Africa’s diverse and distinctive characteristics offer the potential to serve as a context for testing and developing generalizable, cutting-edge IB theory.
Supplementary Information
The online version contains supplementary material available at 10.1057/s41267-022-00581-z.
Résumé
L'Afrique est en plein essor, mais les chercheurs en affaires internationales (International Business—IB) n'ont pas réussi à en tenir compte. Nous argumentons qu'il s'agit là d'une occasion manquée. Non seulement l'Afrique est une région dynamique et distincte, mais son essor présente un certain nombre d'énigmes pour la recherche en IB, avec des phénomènes susceptibles de remettre en question les postulats fondamentaux sous-tendant les théories de l’IB. Afin d'élucider ces énigmes et de mieux expliquer la dynamique des affaires sur le continent, nous soutenons qu'il est nécessaire que la conception théorique en IB mette davantage l'accent sur le rôle de l’homme, pour contrebalancer l'importance traditionnelle accordée par l'IB aux institutions, aux actifs spécifiques localisés et à d'autres attributs au niveau macro. Nous explorons comment cette mutation conceptuelle ouvre de nouvelles voies d'investigation sur des questions qui ont de l’importance pour l'IB, mais n'ont pourtant reçu qu'une attention limitée jusqu'à présent. Ces questions comportent le capital humain entrepreneurial, les réseaux sociaux, la co-évolution institutionnelle et l'économie informelle. À ce titre, nous argumentons que, si les théories existantes de l'IB permettent d'expliquer et de prédire les affaires des entreprises sur le continent, les caractéristiques diverses et distinctives de l'Afrique offrent la possibilité d’utiliser celles-ci en tant que contexte pour tester et développer une théorie de l'IB généralisable et avant-gardiste.
Resumen
África está en ascenso, pero los académicos de negocios internacionales no se han dado por enterados. Nosotros sostenemos que se trata de una oportunidad perdida. África no sólo es una región dinámica y distintiva, sino que su auge presenta una serie de rompecabezas para la investigación de los negocios internacionales, con fenómenos que parecen desafiar los supuestos fundamentales en los que se basan las teorías de los negocios internacionales. Para desentrañar estos rompecabezas y explicar mejor la dinámica empresarial en el continente, sostenemos que es necesario que la teoría de los negocios internacionales haga más hincapié en el papel de las personas, para equilibrar el énfasis tradicional de los negocios internacionales en las instituciones, los activos específicos de la ubicación y otros atributos a nivel macro. Exploramos cómo este cambio conceptual presenta nuevas vías de investigación sobre cuestiones que son importantes para negocios internacionales pero que han recibido poca atención hasta la fecha. Entre estas cuestiones se encuentran el capital humano empresarial, las redes sociales, la coevolución institucional y la economía informal. En este sentido, sostenemos que, si bien las teorías existentes de negocios internacionales informan sobre las explicaciones y predicciones relativas a la actividad empresarial en todo el continente, las características diversas y distintivas de África ofrecen el potencial de servir como contexto para poner a prueba y desarrollar una teoría de negocios internacionales generalizable y de vanguardia.
Resumo
A África está crescendo, mas estudiosos de IB majoritariamente não perceberam. Argumentamos que esta é uma oportunidade perdida. A África não é apenas uma região dinâmica e distinta, mas sua ascensão apresenta uma série de enigmas para a pesquisa em negócios internacionais (IB), com fenômenos que parecem desafiar pressupostos fundamentais subjacentes a teorias de IB. A fim de desvendar esses enigmas e explicar melhor a dinâmica dos negócios no continente, afirmamos que é necessário que a teorização em IB dedique maior ênfase no papel de pessoas para equilibrar a ênfase tradicional de IB em instituições, ativos de localização específica e outros atributos de nível macro. Exploramos como essa mudança conceitual apresenta novos caminhos para a investigação de questões relevantes para IB, mas que receberam atenção limitada até o momento. Tais questões incluem capital humano empreendedor, redes sociais, coevolução institucional e economia informal. De tal forma, argumentamos que, embora teorias existentes em IB forneçam explicações e previsões sobre a atividade empresarial em todo o continente, características diversas e distintas da África ofereçam o potencial para servir como um contexto para testar e desenvolver teorias generalizáveis e de ponta em IB.
非洲正在崛起, 但 IB 学者在很大程度上没有注意到这一点。我们认为这是错失机会。非洲不仅是一个充满活力和独特的地区, 而且它的崛起给国际商务 (IB) 研究带来了许多谜题, 一些现象似乎挑战了 IB 理论的基本假设。为了解开这些谜题并更好地解释非洲大陆的商业动态, 我们认为 IB 理论需要更加强调人的作用, 以平衡 IB 对制度、特定位置资产以及其它宏观层面属性的传统强调。我们探讨了这种概念转变如何为探究对 IB 重要但迄今为止受到有限关注的问题提供新途径。这些问题包括创业人力资本、社会网络、制度共同演化和非正规经济。因此, 我们认为, 尽管现存的IB理论为整个非洲大陆的商业活动提供了解释和预测, 非洲的多样化和独特的特征提供了作为测试和发展可普遍化的、前沿的 IB 理论情境的潜力。
Keywords
international business theory
Africa
human capital
entrepreneurship
network relations theory
diaspora
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pmcINTRODUCTION
The phrase, ‘Africa Rising’, has emerged to describe the promising prospects of Africa and the opportunities it represents for business.1 It speaks to a continent that is home to some of the world’s fastest-growing economies, many of which are rapidly improving their regulatory environments and political institutions. Investment on the continent is coming from an increasing variety of sources – not only Western nations but also the ‘Global South’, including China, India, and African countries themselves, led by South Africa (George, Corbishley, Khayesi, Haas, & Tihanyi, 2016; Mol, Stadler, & Ariño, 2017). While Africa’s foreign direct investment (FDI) stock is still dominated by the extractive sector, the composition of investment is diversifying, with more recent FDI flows focusing on higher-skill manufacturing and services (UNCTAD, 2019b: 10; UNCTAD, 2021: 10; EY, 2021). Through programs such as the G7 countries’ Build Back Better World (B3W), China’s Belt and Road Initiative (BRI), and the EU-Africa Business Forum (EABF), governments around the world are increasingly paying attention to Africa, not just as a recipient of aid, but as a strategic target for billions of dollars of investment in economic and business activities (Stevens & Newenham-Kahindi, 2021). While Africa’s rise is neither uniform across the continent nor inevitable – the global pandemic, in particular, has hit many African economies hard – it is difficult to deny that Africa has ‘risen’ over recent decades, and that firms and governments have begun to take notice.
Academic interest in Africa is booming in diverse fields, including economics, finance, and health (Canen & Wantchekon, 2022; Henn & Robinson, 2021; McMillan & Zeufack, 2022). However, international business (IB) scholarship on Africa lags (Barnard, 2020). ‘Silence’ is the word that Mol et al. (2017: 3) use to characterize the state of IB research on Africa. Of the 6241 articles published in leading IB journals from 1995 through mid-2021, only 124 (2%) focused on Africa.2 This is dwarfed by the 1617 articles on Asia, 812 of which focused on China. Among these journals, JIBS has lagged, with fewer than 1% of its articles published during this timeframe focusing on Africa. We contend that this is a missed opportunity for IB scholarship. Not only is Africa a complex and dynamic research context but it also presents numerous puzzles that seem to challenge key theoretical assumptions on issues including FDI patterns and the role of institutions.
The purpose of this paper is to stimulate IB scholars’ interest in Africa. We argue that Africa represents a fertile context for the development of novel theoretical thinking and for redefining the boundaries of existing IB theories (Bamberger & Pratt, 2010; Banerjee, 2022; Barnard, 2020; Mellahi & Mol, 2015). Attempting to understand Africa from the perspective of country-level institutions and other macro attributes alone often leads to a focus on ‘voids’ and what Africa lacks to the neglect of the opportunities it offers (George et al., 2016). In addition, focusing on national-level institutions ignores the substantial variation in conditions – regional and local – that contributes to the dynamism of economies on the continent. Instead, we contend that shifting the perspective to focus on what Africa possesses necessarily leads to an increased emphasis on the role of people-centric dynamics, such as entrepreneurial human capital, relational assets (including personal networks; diaspora communities; and ethnic, familial, and religious ties), and the interplay between formal and informal institutions and the actors embedded in them, in order to understand business and economic activity on the continent (Anosike, 2019; Gennaioli, La Porta, Lopez-de-Silanes, & Shleifer, 2013; Marks, Dawa, & Kanyemba, 2020; Michalopoulos & Papaioannou, 2015; Moscona, Nunn, & Robinson, 2020; Yenkey, 2015).
We develop this theoretical perspective with reference to Africa as a whole, while acknowledging that Africa is a complex continent comprised of diverse countries and sub- and cross-national regions. The people-centric issues on which we focus are not categorically unique to Africa, but they are particularly salient on the continent. We posit that acknowledging and exploring such issues will help IB researchers to both better explain and predict business activities in Africa specifically, and to leverage Africa’s potential as the origin for generalizable, cutting-edge IB research.
We begin by discussing the complexity and distinctiveness of the African context with respect to attributes such as language, ethnicity, and political economy. These are critical for understanding Africa but have not been central to IB scholarship. We show the impact of Africa’s distinctive qualities on IB-related phenomena and point to puzzling inconsistencies between the realities of the African context and the predictions of IB theories. Next, we discuss the central importance of individuals in Africa’s economic and business activities, and argue that a greater focus on people, with associated modifications to the conceptualization of institutions and the role of the state, may help to explain many of the inconsistencies and provide a basis for extending IB theoretical frameworks. We suggest that Africa offers a particularly suitable context for exploring the micro-foundations of IB theories and deepening our understanding of their nuances and conclude by discussing directions for future research.
THE AFRICAN CONTEXT: DYNAMIC, DIVERSE, AND DISTINCT
Were it a single country, Africa would be fourth in PPP-adjusted GDP (behind China, the U.S., and India) and the third-largest by population (behind China and India). The United Nations projects that, by 2100, Africa will be the birthplace of 40% of the world’s population. Africa accounts for 20% of the earth’s land mass – equivalent to China, India, the U.S., and most of Europe, combined – with a vast reservoir of natural resources. The continent is also home to some of the world’s most rapidly expanding economies, according to the IMF. In 2019, prior to the global pandemic, four of the six fastest-growing economies, in terms of real GDP growth, were in Africa: Libya, Rwanda, Ethiopia, and Uganda. During 2010–2019, 16 African countries experienced average annual real GDP growth over 5%, led by Ethiopia (9.6%), Rwanda (7.2%), Tanzania (6.7%), and Ghana (6.7%). Moreover, Africa is becoming increasingly important in geopolitical terms, with prominent diplomatic and military ties with both the West and the Global South.
While the statistics provide evidence that Africa as a whole is trending positively on many dimensions, not all African countries are ‘rising’ – many continue to face macroeconomic volatility, high unemployment, and other substantial challenges and ‘extreme conditions’ (Hällgren, Rouleau, & de Rond, 2018). Comparisons with other continents show Africa is still catching up to its potential on several dimensions (Table 1). Africa is the world’s least globally integrated continent, with respect to trade and FDI flows, accounting for 2.9% of global FDI stock in 2019, compared with 25% for Asia and 8% for Latin America (UNCTAD, 2021). Similarly, Africa’s share of world trade is 2.6%. It has the lowest GDP per capita and labor productivity (GDP per person employed), and its countries generally fare poorly on the World Bank’s Ease of Doing Business index.3 The World Bank’s classification of national economies, based on per capita gross national income identifies most African countries as low- or lower-middle income.Table 1 Africa in a comparative perspective
Africa East Asia & Pacific South Asia Latin America Europe & Central Asiaa European Union (EU) North America
Diversity
Ethnic diversity 0.63 0.37 0.52 0.39 0.40 0.20 0.60
Religious diversity 0.45 0.40 0.31 0.42 0.44 0.35 0.76
Linguistic diversity 0.58 0.44 0.57 0.18 0.36 0.23 0.41
Global integration
Trade (% GDP) 75.35 44.01 38.99 51.4 62.85 92.18 29.65
FDI, net inflows (% GDP) 2.80 1.51 1.58 3.00 2.21 1.14 1.51
FDI, net outflows (% GDP) 0.13 0.95 0.37 0.70 0.86 1.24 0.86
Remittances, received (% GDP) 4.45 0.57 3.89 2.00 2.00 0.78 0.04
Labor market and human development
Informality (% GDP) **** 34.40 23.10 28.18 34.33 35.54 16.36 11.25
Total population (in millions) 1273 2103 1836 589 419 447 365
Population growth (annual %) 2.20 0.57 1.18 1.00 0.45 0.06 0.55
Population under 15 years old, % total 39.02 20.36 28.01 24.30 21.16 15.13 18.27
Population in urban areas (% population) 47.31 56.59 34.43 80.20 67.18 74.74 82.36
Literacy rate (% population > age 15)*** 69.08 96.03 72.95 94.20 99.04 n.a. n.a.
School enrollment, tertiary (% gross) 13.81 45.79 25.30 51.40 74.83 73.07 86.71
Individuals using Internet (% population) 31.20 62.04 35.33 68.00 77.05 83.84 90.15
Mobile subscriptions (per 100 people) 87 126 86 103 131 122 106
Economic development
GDP, PPP (millions $) * 5464 30,145 11,462 9130 9260 19,850 22,417
GDP per capita, PPP (thousands $)* 6020 14,330 6244 16,034 22,114 44,388 61,251
GDP per-capita growth (annual %) 0.95 5.17 2.83 − 0.30 1.86 1.75 1.57
GDP per person employed (thousands $)* 18,508 27,259 18,289 35,091 51,951 97,693 124,636
Manufacturing, value added (% GDP) 10.55 25.70 13.67 13.00 14.66 14.92 10.85
Market cap, domestic companies (% GDP)*** 34.3 49.4 77.5 44.4 26.4 51.5 144.9
Institutional quality and governance
Quality of governance (WGI)** 29.16 57.86 35.07 53.39 66.62 87.60 85.96
Ease of doing business score** 52.83 60.33 58.17 60.00 73.55 76.22 81.82
External debt stocks (% GNI) 47.83 18.00 22.30 40.80 46.60 n.a. n.a.
General government expenditure (% GDP) 16.2 15.9 10.8 16.2 16.7 20.6 14.4
Inflation, GDP deflator (annual %) 12.50 1.69 4.01 3.20 3.95 2.20 1.79
Total reserves (% total external debt) 73.17 126.30 67.70 41.50 55.70 n.a. n.a.
Regional averages or total, 2019 (unless otherwise indicated); growth rates: 5-year averages.
Source: World Bank Development Indicators, UNCTAD FDI database, Alesina et al., 2003 (groupings based on World Bank classification).
Legend: *International PPP adjusted $ at constant 2017 prices. **Higher scores reflect higher quality. ***As of 2018. ****As of 2017, Dynamic Macroeconomic General Equilibrium model.
Excluding high-income countries.
Of course, Africa is a continent – not a country. In this paper, we develop our theoretical perspective with reference to Africa as a whole, allowing us to embrace the continent’s diversity across its 54 countries. As one example of this diversity, Africa has an incredible variety of indigenous languages – by some estimates, over 2000 spoken languages or dialects, accounting for about one-third of the world’s total (Heine & Nurse, 2000). In addition to these, Arabic, colonial languages such as English, French, and Portuguese, and creoles such as Afrikaans (derived from Dutch) are widely spoken (Table 1). Africa’s languages also change over time. For instance, Rwanda shifted from its historical colonial language (French) to English, for more effective global engagement; it also joined the Commonwealth in 2009, despite having no colonial ties to the UK.4 Swahili’s symbolic and practical importance has grown considerably over time, from a regional language spoken primarily in East Africa, to one that is gaining increasing adoption throughout the continent as a ‘home-grown’ pan-African lingua franca (BBC, 2022).5 In parallel, there has also been a continuous spread of colonial languages in some other countries, post-independence, crowding out indigenous languages. For instance, many more Angolans have now shifted to speaking Portuguese, compared to when the country gained independence in 1975 (Soares de Oliveira, 2015). Language also reflects cultural concepts that are important for understanding Africa (and doing business on the continent), including ubuntu, indaba, and ujamaa (Selmier, Newenham-Kahindi, & Oh, 2015).6
Africa has remarkable ethnic fragmentation (Alesina, Devleeschauwer, Easterly, Kurlat, & Wacziarg, 2003); its 800+ ethnic groups influence many of the continent’s social, economic, and political relationships (Alesina & La Ferrara, 2005; Eifert, Miguel, & Posner, 2010; Udogu, 2018). Colonial powers drew Africa’s national borders with little regard to ethnic groups, driven by the desire to increase control rather than creating national unity (Alesina, Easterly, & Matuszeski, 2011). These yielded nation states characterized by large numbers of very diverse ethnic groups, as well as ethnic groups whose historical homelands span multiple countries (Table 1). For instance, the Maasai are spread between Tanzania and Kenya; the San across southern African countries; the Batwa in Democratic Republic of the Congo, Rwanda, and Burundi; the Fulan, Hausa, and Tuareg across western African countries; the Somali, who are scattered across five countries in the Horn of Africa; and the Berbers in northwestern Africa. Elsewhere, political borders grouped several ethnic groups with different languages, religions, and traditions together into single countries, such as Nigeria’s Yoruba, Igbo, and Hausa (Thomson, 2016). In some African countries, diverse ethnic groups co-exist peacefully. In others, the legacy of colonial and post-colonial policies has resulted in ethnic fragmentation, leading to intense conflict within and across nations, with strong economic, political, and social implications (Kirk-Greene, 1980).7
Africa’s political economy, and its mix of political systems, offers another example of its inherent institutional diversity (Abrahamsen, 2016; Henn & Robinson, 2021; Musila, 2017). Mauritius and Rwanda – both among Africa’s fastest-growing economies – have achieved this outcome with very different political systems. Likewise, alongside countries characterized by ineffective and/or corrupt governments, others (e.g., Botswana, Mauritius, and Rwanda) have achieved notable governance standards. The Transparency International’s Corruption Perceptions scores of several African countries exceed those of some European nations. Rwanda was 38th in the 2020 Ease of Doing Business ranking, just two spots behind Switzerland (and ahead of The Netherlands); this is especially noteworthy considering the differential between Rwanda’s GDP per capita (PPP) of US $2322 and Switzerland’s US $73,114.
While Africa’s diversity is not, on face value, completely surprising, given the continent’s size, these variations introduce subtleties, belie generalizations, and require the acknowledgement of nuances and distinctions in order to explain phenomena of interest to IB scholars. Moreover, the complicated colonial history has resulted in a remarkable degree of both within-country variation and cross-country similarities in Africa’s sub-regional blocs. This variation occurs across many different facets, but often concerns how individuals communicate, identify with, and interact with each other – including issues of language, ethnicity, politics, and technology. As such, the African context gives rise to a number of theoretical puzzles for IB scholars. We argue that these people-related issues are key to understanding the African context, and how it can contribute to theoretical development in IB.
AFRICA AS A SOURCE OF THEORETICAL PUZZLES FOR IB
Africa’s rise presents a number of puzzles for IB research: growth happening where extant theory would suggest that the fundamentals are not conducive to economic expansion, investment going to (or staying in) surprising places, and variation within and across countries that defies many theoretical explanations (Canen & Wantchekon, 2022; Darendeli & Hill, 2016; EY, 2021; Pilling, 2018; Stevens & Newenham-Kahindi, 2021; The Economist, 2017). Why have Ethiopia and Côte d’Ivoire experienced rapid economic growth despite continuous conflict and strife? How has Rwanda – which experienced horrific ethnic-related genocide in the recent past – become a model of peace and institutional stability? Why has Kenya outperformed neighboring Tanzania, to emerge as a regional economic and technological hub, despite greater corruption, more ethnic division, and weaker institutions? Why did investors not decamp from countries such as Morocco and Algeria in the upheaval of the ‘Arab Spring’? How has Lagos – a city of over 15 million people that is “as dynamic as many of the booming cities of Asia” (Pilling, 2018) – thrived despite its location in a country notorious for weak governance and substantial linguistic and ethnic fragmentation? Why, despite having the lowest rate of Internet penetration, has Africa emerged as the world’s second-largest mobile banking market? How and why has the massive informal economy served as a catalyst, rather than an obstacle, for innovation, entrepreneurship, and growth? While conventional IB explanations for trade and investment (availability of natural resources, institutions, etc.) provide some insights, they do not seem to tell the whole story (Barnard, Cuervo-Cazurra, & Manning, 2018; Canen & Wantchekon, 2022; George et al., 2016).
Research about Africa is replete with findings that call conventional IB wisdom into question; examples include the role of institutions and their impact on local and foreign actors, and the determinants of both FDI patterns in Africa and Africa’s regional and global integration. For instance, Ofori-Dankwa and Scott (2013) find that the expected relationship between environmental dynamism and capital structure is reversed in Africa. Similar inconsistencies are found with respect to the institutional determinants of foreign venture capital (Hearn, Oxelheim, & Randøy, 2018). Nachum and Ogbechie (2019, 2023) demonstrate competitive dynamics between foreign and local banks in Nigeria that are inconsistent with the notion of the liability of foreignness. Researchers have identified puzzling theoretical inconsistencies in MNEs’ non-market strategies for dealing with corruption, political risk, CSR, and crony capitalism in Africa (e.g., Darendeli & Hill, 2016; Parente, Rong, Geleilate, & Misati, 2019 Stevens & Newenham-Kahindi, 2017, 2021).
Empirical findings regarding the patterns of FDI within Africa likewise deviate from the assumptions of IB location models. Rolfe, Perri, and Woodward (2015) observe no relationship between African firms’ location choices within Africa and the quality of the regulatory environment, corruption, or political stability, while White, Kitimbo, and Rees (2019) note that the quality of formal institutions does not affect the location choices of South African firms in the region. Dike and Rose (2019) find that African telecommunications firms’ FDI location decisions are not well captured by existing theoretical frameworks. In part, these inconsistencies may arise because regional investors evaluate location-specific assets differently from the Western MNEs that have been the basis of most of the theoretical development in IB. However, findings inconsistent with extant theory have also emerged in relation to Chinese firms investing in Africa, e.g., regarding the impact of political risk on location choice (Lu, Huang, & Muchiri, 2017). The choice of many African countries as hosts for inward FDI often appears inconsistent with their locational attractiveness, based on conventional IB measures (Asiedu, 2002).
Africa’s low level of intra-regional integration also defies established IB predictions.8 Intra-regional shares of total FDI and trade in Africa are 10 and 16%, respectively, compared with 48 and 58% in Asia (Ngouhouo, Nchofoung, & Kengdo, 2021; UNCTAD, 2019a). Notable inconsistencies relate to geographic proximity (Head, & Mayer, 2014) and the predominance of the ‘home region’ that explains many FDI patterns elsewhere (Casanova, 2009; Rugman, 2005; Rugman & Verbeke, 2004). Firm-level studies of African firms’ decisions regarding where, how, and why to internationalize highlight the complex and distinctive dynamics underlying these deviations from traditional IB expectations (Adomako, Amankwah-Amoah, Tarba, & Khan, 2021; Dike & Rose, 2019).9
AFRICA AS AN OPPORTUNITY FOR ADVANCING IB SCHOLARSHIP
The puzzles raised by Africa’s rise represent an opportunity for IB researchers. The small, albeit rapidly growing, body of IB research on Africa is diverse, both theoretically and methodologically.10 Theoretical perspectives include institutional theory, transaction cost economics, stakeholder theory, the eclectic paradigm, the resource-based view, and micro-level theories related to leadership and justice. Researchers have used a variety of methodological approaches: quantitative and qualitative, utilizing primary and secondary data. A key theme underlying much of the extant research is the importance placed on the role of people, to better explain business dynamics on the continent (Horwitz & Ronnie, 2021; Newenham-Kahindi, Kamoche, Chizema, & Mellahi, 2013; Parente et al., 2019). We argue that this suggests the need to consider not only the role of institutions themselves, but to focus on the economic, political, and social actors that inhabit the institutions and the incentive structures they face, in order to unravel the puzzling deviations from theoretical predictions presented by Africa.
In this way, studying the African context offers the potential to extend and deepen our understanding of key theories used in IB. As the ‘puzzles’ imply, there is a need to investigate how IB frameworks perform in conditions that differ from the contexts in which they have been developed and traditionally applied. Leveraging important and distinctive attributes of the African context should enable the development of a more nuanced approach to IB research. In some cases, this may warrant the development of new theories and frameworks; mainly, though, we expect that it will require a shift in emphasis, to balance IB’s traditional emphasis on institutions, location-specific assets, and other macro-level attributes with an increased consideration of people and the micro-foundations of IB theory (Boddewyn, 2016; Dunning & Lundan, 2008).
We argue that this shift in emphasis creates opportunities for providing novel answers to traditional IB questions, as well as asking new ones. It also allows for the development of deeper insights into areas of importance to IB such as human capital, entrepreneurship, social networks, and the informal economy by observing them from the distinctive perspective of Africa. We highlight some particularly promising areas for Africa-based theory development below; these are summarized in Table 2.Table 2 Key attributes of Africa and their implications for theory development in IB
Topical issue Attributes of Africa Implications for theory
Demographics Africa’s population is young and growing rapidly The young, tech-savvy population has implications for theories relating to learning and innovation (e.g., technology leapfrogging) and FDI strategy (e.g., Africa is experiencing a shift from asset-seeking extractive FDI to market-seeking service-sector FDI)
Economic growth While some countries have been left behind, others are experiencing rapid growth It remains unclear whether African countries’ development path will resemble other countries’ (e.g., emerging economies in East, Southeast, and South Asia) or whether they will follow distinct pathways, with implications for trade and FDI (inward and outward)
Global connectivity While rising, Africa’s share of global FDI and trade lags those of other regions This has implications for theory related to learning, governance, and global value chains (GVCs), especially with respect to breaking into existing relationships
Intra-regional linkages Despite its geographic fragmentation, regional blocs (EAC, ECOWAS, etc.) and continent-wide pacts (African Union, African Continental Free Trade Area) are developing Increased integration has implications for spillovers of information, people, and trade; these are salient for theories pertaining to, among others entrepreneurship, stakeholder management, FDI, and trade
Language Africa has thousands of indigenous languages in addition to those brought by colonial and other outside forces Language is an important issue for theories of FDI location choice and trade patterns, along with stakeholder management, legitimacy, and social license to operate
Ethnic fragmentation Many nations have diversity of ethnic groups, and many ethnic groups span national borders Ethnicity affects a wide range of IB issues, including social networks, subsidiary management, non-market strategy, political risk, and corruption
Governance Many countries have enacted substantial improvements in governance quality and the rule of law. In addition to formal institutions, policymakers, political will, and policy enforcement play an important role There are implications for the role of agency in institutional theory (e.g., the question of whether institutions shape firm behavior, or whether/how MNEs shape institutions through institutional entrepreneurship, non-market strategies, and state capture). Within- and cross-country variation allows researchers to address the question of which institutions matter for IB
Human capital Human capital, especially entrepreneurial human capital, has played a large role in Africa’s ‘rise’ Human capital has limited location-boundedness and is only loosely tied to a country’s average level of formal education This has implications for the OLI paradigm, theories of locational and ownership advantage, and foreign entry strategy (including location choice, entry mode, and partner selection). Forms of firm-specific assets related to entrepreneurship in an IB context remain under-researched: resilience, adaptability under conditions of volatility, comfort with the informal economy, the role of social networks and diaspora linkages
Diaspora Africa has a large and important diaspora, along with an under-examined ‘inverse diaspora’ population There are implications for theories of human and social capital, and constructs including cultural and psychic distance. Migrant and diaspora communities are underappreciated factors in national and sub-national location choice, venture financing, and immigrant entrepreneurship.
Informal economy Much of Africa’s growth has been catalyzed, rather than hindered, by the informal sector The informal economy has been understudied by IB scholars; however, MNEs are increasingly leveraging it in their supply chains and in how they relate to stakeholders
Africa is rising, but IB scholars have largely failed to take notice. We argue that this is a missed opportunity. Not only is Africa a dynamic and distinctive region, but its rise presents a number of puzzles for international business (IB) research, with phenomena that seem to challenge fundamental assumptions underlying IB theories. In order to unravel these puzzles and better explain business dynamics on the continent, we contend that there is a need for IB theorizing to place greater emphasis on the role of people, to balance IB’s traditional emphasis on institutions, location-specific assets, and other macro-level attributes. We explore how this conceptual shift presents new avenues for inquiry into issues that are of importance for IB but have received limited attention to date. Such issues include entrepreneurial human capital, social networks, institutional co-evolution, and the informal economy. As such, we argue that, while extant theories in IB inform explanations and predictions regarding business activity across the continent, Africa’s diverse and distinctive characteristics offer the potential to serve as a context for testing and developing generalizable, cutting-edge IB theory.
Entrepreneurial Human Capital
A stronger focus on people may better explain Africa’s grassroots rise of entrepreneurship and the bottom-up development of the private sector, both of which defy the expectation that ‘extreme conditions’ should not be conducive to the strong entrepreneurial culture and comfort with risk-taking that permeate the continent.11 Olopade (2014: 20) uses the Yoruba word kanju to refer to “the specific creativity born from African difficulty”, giving the example of how Nigeria’s ‘Nollywood’ film industry sprang into being from the ingenuity of an electronics dealer who needed to offload surplus blank VHS tapes. Today, Nollywood is a multi-billion-dollar film industry, and the world’s second largest in terms of output, ahead of Hollywood and behind only India’s Bollywood (Akinwotu, 2021). Similarly, Adomako, Amankwah-Amoah, Dankwah, Danso, and Donbesuur (2019) find that, far from being impediments, institutional voids serve to enable new venture internationalization in Ghana; entrepreneurs in Africa are often able to do considerably more with a lot less (König, Schmidt, Kindermann, Schmidt, & Flatten, 2022).
To help explain this phenomenon, we highlight the notion of entrepreneurial human capital. This construct pertains to characteristics of nations’ domestic entrepreneurial culture, with a focus on businesspeople who have the business acumen, education, language skills, and international orientation to engage with foreign firms that seek local partners in Africa. Recognition of the critical importance of entrepreneurial human capital in facilitating economic development has led some to suggest that it might sometimes be a more important driver of economic development than institutions (Canen & Wantchekon, 2022; Gennaioli et al., 2013; Zallé, 2019). Proponents further reason that a focus on human capital offers a promising path to economic development; developing human capital from the ‘bottom up’ can be enacted rather quickly, compared to the time needed to develop institutions and close institutional gaps from the ‘top down’. This debate between the relative importance of institutions and human capital has salience for IB, given the prominence of theoretical perspectives such as institutional theory and institutional economics in the field (Aguilera & Grøgaard, 2019).
Viewing entrepreneurial human capital as a type of location-specific advantage raises a number of questions and avenues for future IB research. How do foreign firms tap into this reservoir of in-country knowledge and expertise, which is often housed in individuals and small firms? Conversely, how do African entrepreneurs and entrepreneurial firms gain market access and internationalize, given the headwinds that they face? There is considerable variation, both within and across nations, in entrepreneurial human capital. While many African countries’ average level of formal education is relatively low, this belies the fact that almost all countries have a class of highly educated, cosmopolitan entrepreneurs and business elites. What are the implications for MNEs’ strategies, ranging from location choice to staffing approaches?
Considering entrepreneurial human capital has implications for theoretical frameworks pertaining to FDI and foreign entry strategy, as it implies the need to reconsider the role of domestic business partners and the local business elite for firms’ strategies related to entry mode, location choice, and partner selection. This matters for the springboard theory (Luo & Tung, 2018), and other frameworks attempting to explain the outward internationalization of emerging market MNEs. A firm’s home-country environment might be rich in entrepreneurial human capital that enables outward expansion, even if it lacks the other forms of capital and resources that are generally associated with internationalization. As intra-African investment remains rather low, but is an increasing priority, this offers the opportunity to observe the development of international activity with respect to business to and from emerging and developing markets.
Networks, Linkages, and Diaspora
Given the global mobility of individuals and social networks, entrepreneurial human capital is not strictly location bound. This has implications for theoretical frameworks such as the OLI paradigm, as key ‘national’ assets may be located outside of either the home or host country. A primary example is the role of the diaspora with respect to cross-border business activity related to Africa (Mohan & Zack-Williams, 2002). The African Union views the diaspora ‘as an important part of our continent’, officially recognizing it as ‘Africa’s Sixth Region’ (Kamei, 2011). Africa’s historical diaspora is large – on the order of 160 million people, according to African Union estimates – and has grown substantially since the late 20th century.12 Much of the cosmopolitan African entrepreneurial class may not actually be resident in their home countries. Alternatively, they may be returnees after many years abroad for work or education, or descendants of immigrants from African countries returning to their ancestral homelands (Akyeampong, 2000; Kaba, 2011; Lituchy, 2019). Such nuances have considerable importance for human and social capital, for both individuals and firms, and complicate the interpretation of common IB constructs such as cultural and psychic distance.13
Empirical studies provide evidence that the diaspora is beneficial to the economic development of African countries (Gnimassoun & Anyanwu, 2019). Remittances (some US $45 billion in 2021, according to World Bank data) are the most tangible manifestation of this impact. However, the diaspora’s contributions extend well beyond remittances, ranging from increased trade and FDI links, better access to foreign capital markets, and substantial infusion of human capital, skills, and technology (Clemens, 2011). Africa’s diaspora has been instrumental in the dissemination of social and institutional norms conducive to development and has had important ramifications for local cultures and social dynamics (Gnimassoun & Anyanwu, 2019). Just as the African Union officially encourages the participation of the diaspora in African economies, individual African governments actively factor the diaspora into their domestic development programs (Lituchy, 2019; Plaza & Ratha, 2011).
There is also another important diaspora where Africa is concerned: the ‘inverse diaspora’ of non-Africans (including individuals of Indian, Chinese, Arab, and Lebanese descent) who become embedded in Africa and the local business environment. For instance, there are approximately 3 million individuals of Indian ethnicity living in east and southern Africa. While small in terms of the overall population, they have had an outsized economic and political influence, both domestically and in building ties between Africa and India, as well as with the broader Indian diaspora in the UK and North America. China’s rapidly growing presence on the continent has been catalyzed by the presence of approximately 1 million people moving from China to Africa during the last two decades (Barnard et al., 2018). French (2019) notes that most of these Chinese citizens have moved under their own initiative, seeking entrepreneurial opportunities and enhancing ties between China and Africa along the way.
Without accounting for such phenomena, it is very difficult to grasp the nature of investment patterns, both into and out of Africa. For example, it would be impossible to understand why the Somali multinational Dahabshiil (Africa’s largest money transfer company) located physical operations in Minneapolis and Columbus, Ohio, without knowing that these cities are home to the U.S.’s largest Somali and Somali-American populations (let alone why a firm from Somalia – which would seem to face formidable liabilities of foreignness – would have a locational advantage in the U.S.). Ethiopia’s bond market and investment schemes in Washington D.C., which are based entirely on activities of the diaspora, offer another example of the global reach of Africa’s flexible locational assets. Africans abroad help to overcome information asymmetries between Africa and non-African investors and offer an understanding of how to combine western and African approaches, facilitating investment in both directions (Galeto, 2011; Leblang, 2011). In addition, the African diaspora, which forms a substantial part of the continent’s entrepreneurial class, is a major source of inward investment, playing a pivotal role in the formation of trans-local networks to pursue business opportunities on the continent (Griffin-El & Olabisi, 2018).
These influences have a strong impact on the patterns of FDI flows to Africa, at times overriding the traditional location advantages considered in IB, creating economic relationships that are driven by the connections of the diaspora and may not be consistent with the predictions of IB models. Research on Africa notes the outsized role that social networks, local communities, and stakeholder relations play in shaping firms’ strategy and performance (Acquaah, 2007; Ado, Su, & Wanjiru, 2017; Manning, Kannothra, & Wissman-Weber, 2017). The IB literature has been criticized for not taking social networks into account (Cuypers, Ertug, Cantwell, Zaheer, & Kilduff, 2020). Africa presents an ideal context for deeper examination of social network theory in the IB context.
Moreover, the impact of the diaspora on economic outcomes is complicated, and sometimes counterintuitive, calling for additional work in this area (Barnard, Deeds, Mudambi, & Vaaler, 2019). For instance, Barnard and Pendock (2013) note that complex – and sometimes negative – emotions (such as guilt and a sense of loss) of South African diaspora can sometimes impede ongoing, beneficial engagement by cross-border economic activity and knowledge sharing. Mayer, Harima, and Freiling (2015) note the challenges faced by returnees and members of the Ghanaian diaspora in creating effective linkages between Ghana and their countries of residence. The size and breadth of its diaspora makes Africa a prime setting for theoretical development in this area.
Institutions
Placing an emphasis on people does not negate the well-established IB focus on the importance of institutions (Aguilera & Grøgaard, 2019). However, careful consideration of the African context may allow us to develop clearer insights into which aspects of the institutional environment are particularly salient, and how firms manage institutional complexity (Verbeke, van Tulder, Rose, & Wei, 2021). In some cases, institutions are effective at predicting investment flows and economic growth in Africa. Ghana, for instance, has a strong history of democratic institutions and relatively low levels of corruption, making clear its attractiveness for FDI. Twitter provides a recent example; the 2021 decision to locate its Africa headquarters in Ghana, instead of regional economic and technology powerhouse Nigeria, while a surprise to many observers, is consistent with the institutional perspective (Ndukwe, 2021). As a counterexample, however, Kenya tends to score poorly on measures of institutional quality and corruption – factors that should deter both foreign and domestic investment – but the country has done surprisingly well at attracting FDI. Part of this puzzle can be explained by recognizing that while some of Kenya’s institutions are weak and underdeveloped, policymakers have recently created new institutions that have fostered a booming information technology sector (Canen & Wantchekon, 2022).
Institutions in Africa are complex, multifaceted, and constantly evolving.14 In their recent Attractiveness Report on Africa, EY (2021) found little connection between African countries’ ‘ease of doing business’ and FDI activity, contrary to what traditional IB theoretical frameworks would predict. What was identified, instead, was a stronger relationship between improvements in ease of doing business scores and foreign investment. Apparently, MNEs are focusing on trends rather than levels, and making investment decisions based on perceptions of where Africa’s institutions may be headed in the future, rather than their current states or historical legacies (EY, 2021). Understanding Africa’s institutions requires consideration of the people who shape them, starting with policymakers; specific policies and issues relating to political will are often more meaningful than macro-level indicators of institutional quality (Canen & Wantchekon, 2022). It is also necessary to unpack a country’s institutions, as both the quality and enforcement of specific institutions often varies quite widely, even within a single nation.
Rather than being a largely exogenous force that ‘happens’ to MNEs, the business–government interface in Africa is often dynamic and malleable. Foreign actors (MNEs, governments, NGOs, and multilateral organizations) tend to have more agency with respect to shaping their host environment than is typically assumed in the IB literature, assisting them in navigating challenging terrain (Cantwell, Dunning, & Lundan, 2010). With this flexibility, though, come attendant concerns regarding state capture;15 questions about MNEs’ net impact on issues including governance, sustainability, and social issues; and the constant need for firms to manage how they are viewed in the eyes of multiple stakeholders under rapidly evolving circumstances (Darendeli & Hill, 2016; Obi, 2010; Stevens & Newenham-Kahindi, 2021). Scholars need to better understand how foreign MNEs navigate such complexity and gain (or lose) legitimacy, reputation, and the social license to operate in developing countries, such as those in Africa (Newburry, Deephouse, & Gardberg, 2019; Newenham-Kahindi & Stevens, 2018).16
Considering not just institutions, but the actors that inhabit and shape them, implies an opportunity to develop and deploy theorical frameworks that remain underutilized in IB, such as evolutionary theory (Cantwell et al., 2010), institutional logics and institutional entrepreneurship (Newenham-Kahindi & Stevens, 2018), and organizational learning theory (Pedersen, Larsen, & Dasi, 2020), all of which are particularly well suited for the dynamic African context. This also suggests a need for more IB research to take a longitudinal, process-oriented approach that places a stronger emphasis on the challenging, multilevel process of subsidiary management (Meyer, Li, & Schotter, 2020). Future theorizing would, thus, benefit from paying attention to people-oriented factors (individual- and family-level ties, diaspora communities, individual- and firm-level experiences and strategies) that influence foreign investment decisions, as well as the post-entry strategies, policies, and relationships that might entice a firm to stay, even when faced with changing conditions. These are areas in which Africa offers considerable scope for theory development in areas of interest to IB scholars.
Informality and Innovation
In much of Africa, the informal economy is the economy. Africa has, arguably, the world’s largest informal economy. While estimates vary, the United Nations suggests that the informal economy accounts for more than 80% of employment across the continent (UNDP, 2022). The informal economy encompasses all sectors, even education; Olopade (2014) reports that up to 25% of the schools in South Africa are unregistered. Importantly for IB and global value chains, activity in the informal economy often crosses borders, from informal trans-border shipping and transport to the ubiquitous street vendors who sell foreign-produced handicrafts and use the revenues to purchase local goods. Despite expectations that informality would decline as African countries developed, it continues to grow (McMillan & Zeufack, 2022; Medina, Jonelis, & Cangul, 2017), altering many notions of business ecosystems as discussed at macro levels of analysis (Abrahamsen, 2016).
Some IB research has considered the role of the informal economy in emerging regions such as Africa. Yakovleva and Vazquez-Brust (2018) find that foreign MNEs in Ghana, unfamiliar with the robust informal economy, struggled with how to deal with it. Over time, firms switched from a conflictual approach to a more cooperative strategy, resulting in improved legitimacy and performance, with positive outcomes pertaining to social challenges such as poverty, inequality, and sustainability. Newenham-Kahindi and Stevens (2018) use an institutional logics perspective to explore MNEs’ novel approaches to leveraging the informal economy – which they had initially shunned – allowing them to build legitimacy and overcome liabilities of foreignness in East and Central Africa. Such findings run counter to the literature’s standard expectation of the informal economy as an illegitimate phenomenon that firms should combat or avoid (Webb, Tihanyi, Ireland, & Sirmon, 2009).
While informal enterprises often operate at a basic subsistence level, representing a survival strategy of last resort, the informal economy also gives rise to entrepreneurial opportunities and the potential for radical innovation, especially regarding technology. That Africa is home to more than 600 technology hubs (Shapshak, 2019) is counterintuitive at first glance, as access to the Internet is relatively low; the proportion of the population using the Internet as of 2020 ranged from 79% in Seychelles to just 6.5% in South Sudan (World Bank, 2022). However, Internet penetration is growing rapidly, via access through mobile phones. African demographics skew toward the young and tech-savvy, and the lack of older incumbent technologies and business models has facilitated disruption and technology leapfrogging in Africa – albeit still with inherent challenges (Amankwah-Amoah, 2015).
Fintech is an area with strong potential to benefit from this nexus of the informal economy and radical innovation, and M-Pesa is a prime example. Created in Kenya, M-Pesa is world-leading in its utilization of mobile technology to facilitate payments outside of the traditional banking system. It increases financial inclusion by being accessible to more of the population – an important issue, as a large proportion of people in Africa lack bank accounts. M-Pesa is just one example of mobile-related technological leapfrogging in Africa. The embrace of mobile telephony across the continent, as a solution to infrastructure-challenged land-line systems, has had far-reaching consequences for mobile banking, health, education, and trade (Olopade, 2014), and offers global research and policy implications, as Africa leads many developed countries in this regard (Piper, 2020).17 The rise of new technologies, including fintech and blockchains, brings new opportunities and optimism for African SMEs’ growth and internationalization (Business Insider Africa, 2022). Many of these technology-related innovations address pressing social issues as well, creating promising avenues for linking IB theory with research streams on social entrepreneurship, sustainability, language, and stakeholder engagement strategies (Garrone, Piscitello, & D’Amelio, 2019; Parente et al., 2019; Selmier et al., 2015). Africa is, thus, an ideal context in which to study the intersection of technology, institutions, and societal grand challenges from an IB perspective.
DISCUSSION AND CONCLUSIONS
The field of IB lags with respect to studying Africa (Barnard et al., 2018; Mol et al., 2017; Zoogah, Peng, & Woldu, 2015). This is a missed opportunity, for both Africa and IB scholars. IB’s traditional theoretical focus has been on macro-economic dynamics, considering institutions as created by nation states and business relationships managed via formal regulations and the rule of law (Boddewyn, 2016; Dunning & Lundan, 2008). As such, the nation state and MNEs have been the primary units of analysis. A key argument of our paper is the need to balance such macro-level factors with social ties, human capital, and other less-appreciated issues related to individuals in order to delve into the mechanisms of how international business takes place in the African context. However, while a people-centric focus is particularly salient in Africa, it is not idiosyncratic to the continent, or even to emerging markets. As such, while extant theories in IB can inform our ability to explain and predict business activity across the continent, Africa has great potential to inform and influence generalizable IB theory.
The African context – precisely because it differs from the contexts in which IB theories have been developed – represents an ideal laboratory for testing existing theoretical frameworks, investigating their boundary conditions, and revisiting their underlying assumptions (Hernandez & Guillén, 2018; Nkomo, 2017). Recent theoretical developments have paid attention to micro-level dynamics and begun to articulate the micro foundations of some of the theoretical frameworks that are used in IB research (Felin, Foss, & Ployhart, 2015; Foss & Pedersen, 2019; Kano & Verbeke, 2019). These studies suggest that focusing on the micro- and meso-levels of analysis is essential for the development of managerially relevant theory, for understanding the strategic choices made by internationalizing firms, and for taking a co-evolutionary perspective on institutions that incorporates dynamism and change into IB theories (Buckley, Chen, Clegg, & Voss, 2016; di Giovanni, Levchenko, & Mejean, 2018). From a policy perspective, this approach also facilitates the design of micro-level institutional reforms aimed at promoting entrepreneurship and foreign direct investment.
We believe that the foundations developed in this paper offer real potential for future research that extends existing theories and develops new ones. For instance, our conceptualization of the centrality of people in the African business context provides a novel, and potentially fruitful, lens through which to extend entrepreneurship-related theory, with its focus on the individual – or small groups of individuals – collaborating to create value (Keupp & Gassmann, 2009). It could be employed to develop the notion of resource bricolage and doing more with less (Baker & Nelson, 2005).18 Entrepreneurship and gender also intersect in interesting and unexpected ways in Africa. In 2021, Uganda (38.5%), Botswana (38.4%), and Ghana (37.2%) had the highest percentage of female business owners, followed by the US (35.6%). Oluwole (2022) notes that “woman entrepreneurs in Africa are resilient and adaptable, particularly those in low and middle-income economies, often surpassing men in terms of entrepreneurial activity”, which suggests promising avenues for research and theory building pertaining to international entrepreneurship.
Another direction for research that would benefit from the African environment is an extended consideration of relational modes of governance. The importance of relationships and social ties across Africa, which has roots in the extended family and small local communities, offers a valuable context for theory development (Cao & Lumineau, 2015). Such research could draw attention to types of social connections that exist in many parts of the world, especially emerging and developing markets, but their ubiquity in Africa makes it an excellent context in which to study this phenomenon. One area for which Africa-based research appears to be particularly promising is the relationship between firms in the formal economy and those operating as informal entities. Africa’s vast informal economy, which is intricately interwoven with the formal economy, offers fertile ground for extending our understanding of these complex dynamics (Acquaah, 2007; De Soto, 1989, 2000; Godfrey, 2011; McGahan, 2012).
Additional scholarship is needed to deepen our understanding of Africa’s diversity and the search for underlying logic(s) that might explain the associated patterns and offer a basis for classifying African countries and sub-regions. This research could build on what IB scholars know regarding location theory and location advantages to find a middle ground between ‘Africa’ as a homogenous unit, and Africa as a collection of uniquely heterogeneous countries. The important role of sub-regional blocs in Africa (such as the East African Community, Arab Maghreb Union, and Economic Community of West African States) points to the need for IB researchers to consider cross-country flows of investment, people, and information that might otherwise be overlooked from a purely country- or continent-level approach.19 The African context also offers the potential to consider new types of locational advantages.
Lastly, the shift of focus toward a more people-centric perspective needs to be accompanied by methodological developments. Many of the commonly employed methods in IB research, often based on analyses of large databases of country-level data, are not always suitable for capturing the phenomena and dynamics that matter in Africa and other emerging regions (Bob-Milliar, 2020). Some of Africa’s distinctive characteristics – such as diversity, fragmentation, informality, and ethnicity – challenge existing methods and data collection practices (Groskopf, 2016; Jerven, 2013). Macroeconomic data rarely take the informal economy into account (The Economist, 2018). Likewise, the widely used operationalization of key constructs may not reflect the conceptual foundations needed to understand Africa’s business logic. For instance, culture is generally operationalized at the country level (e.g., Hofstede, GLOBE), but Africa’s cultural diversity often has little relation with national borders (Luiz, 2015). Africa’s vast diversity along cultural, institutional, and other dimensions undermines the very meaning of country averages and suggests the need for greater nuance, conceptually and empirically, regarding commonly used IB concepts such as ‘distance’. These empirical issues are not unique to Africa (Rose, 2021), but they are especially pronounced on the continent, and hence more vividly observable (Barnard, 2020). However, as the extant body of IB research on Africa shows, the task is not insurmountable, and learning more about effective approaches to undertaking research on the continent presents an opportunity for IB researchers, more broadly, to enhance our strategies and practices related to data collection, operationalization of key constructs, and methodological issues.
Studying Africa offers the potential to develop rich insights into key IB issues applicable to a much broader collection of contexts – emerging and developed markets alike. To date, IB research on emerging markets has been dominated by investigations of firms that are internationalizing to and from China. While this research provides important insights, China’s institutional environment is quite specific. At the same time, the people-centric approach that we advocate for research in Africa is appropriate for other contexts, at any level of development, and creates the potential for insights that are new to IB research. Issues of networks, entrepreneurial human capital, and disruptive innovation are just as appropriate for a discussion of Silicon Valley as they are for understanding Nairobi's ‘Silicon Savannah’. Africa’s rise, while a tenuous but dynamic work-in-progress, has been a boon to its people and its countries. It is our belief that IB scholarship is primed for its own ‘Africa rising’ moment that positions the African continent squarely at the forefront of cutting-edge IB theory building and research.
Notes
As one example, ‘Africa rising’ appeared on the cover of The Economist in 2011, a decade after the magazine had declared Africa ‘the hopeless continent’.
This is based on a Social Sciences Citation Index search of the title, abstract, and keywords of articles published in Global Strategy Journal, International Business Review, Journal of International Business Studies, Journal of International Management, Journal of World Business (Columbia Journal of World Business), and Management International Review (not indexed on Scopus for 1995–2004). Additional information can be found in the online appendix, Table A1.
This index has been the subject of substantial criticism for being based on Western standards and evaluating business practices in ways that are not sensitive to local dynamics (e.g., Broome, Homolar, & Kranke, 2018; Doshi, Kelley, & Simmons, 2019; Krever, 2013).
As further evidence that colonial ties are not destiny, fellow non-anglophone nations Mozambique (in 1995), and Gabon and Togo (both in 2022), also joined the Commonwealth, due to the perceived benefits of doing so (Lundan & Jones, 2001).
Swahili, while indigenous to Africa, has always been inherently global. It arose as a trading language to facilitate communication with merchants from the Middle East along the East African coast, and roughly a fifth of Swahili vocabulary consists of Arabic loanwords, including the language’s name (sawahili, meaning ‘of coasts’).
Ubuntu (‘humanity toward others’) and indaba (‘discussion of issues’) come from the Zulu and Xhosa languages, and ujamaa (‘extended family’) from Swahili; English translations are only approximate.
Ethnic diversity and the impact of ethnic leaders, known as chiefs, on political life also varies considerably. In Tanzania, chiefship was formally abolished after independence; in Uganda and Ghana, it is officially recognized as having legal and political power. The Constitution of South Africa makes special provision for chiefs, formally outlining their legal and political roles in their communities (Section 12 of the Constitution).
The legacy of slavery and colonization, and the marks that they have left on Africa’s contemporary economic relationships, also contributed to these patterns. For instance, in East Africa, as well as Angola, most transport routes are aligned from east to west along old slave trading routes, making north–south trade challenging. The recently established African Continental Free Trade Area (AfCFTA) and increased integration within Africa’s sub-regions (East Africa, West Africa, etc.) aims to improve this situation. We thank an anonymous referee for these insightful comments.
For instance, Barnard and Luiz (2018) discuss how societal instability at home incentivized the use of ‘escape FDI’ by South African MNEs. While much of South Africa’s ‘escape FDI’ has been to Europe and Australia, some South African MNEs (such as SAB-Miller and MTel) have been quite willing to invest in riskier contexts.
Additional information can be found in online appendix Table A2.
Respondents in sub-Saharan Africa had the highest risk appetite in the Global Preference Survey, more than double that of respondents from Middle East & North Africa (#2) and North America (#3) (Falk, Becker, Dohmen, Enke, Huffman, & Sunde, 2018).
The International Organization for Migration estimates that, during 1965–2021, nearly half a million people emigrated from Africa annually. A Gallup survey shows that Sub-Saharan Africa has the world’s highest share of people wishing to migrate, if they had the means to do so – more than double the world’s average (Esipova, Ray, & Pugliese, 2017).
Of course, extensive diasporas, whether forced or voluntary, are not unique to Africa (e.g., Indians in Southeast Asia), and outward migration has implications for ‘brain drain’.
Political borders, as they are understood in Western societies, were historically rare in Africa (Michalopoulos & Papaioannou, 2020). State formation and power were challenged by Africa’s vast land and terrain geography, which raised the costs of exercising political authority and posed obstacles for consolidation (Herbst, 2015). These challenges were accentuated by the artificial borders (Alesina et al., 2011) drawn by the European colonial powers, which were often inconsistent with local realities (Depetris-Chauvin, Durante, & Campante, 2020; Thomson, 2016). The newly elected governments, post-independence, established weak and often dysfunctional political and economic institutions, which further weakened the states’ legitimacy and challenged their effectiveness (Acemoglu & Robinson, 2010).
A major institutional roadblock to investment and innovation is “state capture”, whereby connected domestic and international firms receive favorable regulation, contracts, or enforcement in exchange for campaign contributions and other forms of political support. A salient and well documented case is that of the Gupta brothers’ capture of the South African state under the former President Zuma. The bold response to this political distortion was rather exemplary: first a public disclosure of the crime by a “truth commission”, followed by the arrest of President Zuma and more recently the Gupta brothers (Cheng, 2022)
Note that ‘foreign MNEs’ are a diverse group, and how MNEs navigate such challenges – and opportunities – likely varies depending on whether they are Western, Chinese, African, etc. (Mazé & Chailan, 2021).
Other examples include off-grid electricity and energy systems that have revolutionized life across Africa, particularly in rural areas that never had fully functioning traditional systems. Solar-based investments have been particularly successful in bypassing the need for traditional on-grid infrastructure. Numerous African entrepreneurial firms (e.g., Mobisol in Tanzania, and M-Kopa and d.light in Kenya) have emerged recently, offering clean energy and power generation capacity based on alternative energy.
The global COVID-19 pandemic has highlighted the importance of learning how to ‘do more with less’ for small entrepreneurial firms as well as global MNEs. This capability assumes added urgency in the context of countries with fragile security, public health, and infrastructure conditions.
For instance, integration among countries in the East African Community influences firms’ location choices, non-market strategies, and political risk within the region, resulting in patterns that would not be anticipated based on traditional IB theories (Stevens & Newenham-Kahindi, 2017, 2021).
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 38 KB)
Acknowledgements
We thank Alain Verbeke and the three anonymous reviewers for their helpful comments and suggestions. We acknowledge, with gratitude, the illuminating discussions during Fellows Cafés at the 2021 AIB-UKI Chapter and AIB conferences.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Accepted by Alain Verbeke, Editor-in-Chief, 17 October 2022. This article was single-blind reviewed.
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REFERENCES
Abrahamsen R Africa and international relations: Assembling Africa, studying the world African Affairs 2016 116 462 125 139 10.1093/afraf/adw071
Acemoglu D Robinson JA Why is Africa poor? Economic History of Developing Regions 2010 25 1 21 50 10.1080/20780389.2010.505010
Acquaah M Managerial social capital, strategic orientation, and performance Strategic Management Journal 2007 28 12 1235 1255 10.1002/smj.632
Ado A Su Z Wanjiru R Learning and knowledge transfer in Africa-China JVs: Interplay between informalities, culture, and social capital Journal of International Management 2017 23 166 179 10.1016/j.intman.2016.11.003
Adomako S Amankwah-Amoah J Dankwah GO Danso A Donbesuur F Institutional voids, international learning effort and internationalization of emerging market new ventures Journal of International Management 2019 25 4 100666 10.1016/j.intman.2019.04.001
Adomako S Amankwah-Amoah J Tarba SY Khan Z Perceived corruption, business process digitization, and SMEs’ degree of internationalization in sub-Saharan Africa Journal of Business Research 2021 123 196 207 10.1016/j.jbusres.2020.09.065
Aguilera R Grøgaard B The dubious role of institutions in international business: A road forward Journal of International Business Studies 2019 50 1 20 35 10.1057/s41267-018-0201-5
Akinwotu, E. 2021. Nollywood moment: African film industries ‘could create 20m jobs’. The Guardian. https://www.theguardian.com/global-development/2021/oct/05/nollywood-booming-while-african-film-industries-could-create-20m-jobs-report.
Akyeampong, E. 2000. Africans in the diaspora: The diaspora and Africa. African Affairs, 99(395): 183-215. Centenary Issue: A Hundred Years of Africa.
Alesina A Devleeschauwer A Easterly W Kurlat S Wacziarg R Fractionalization Journal of Economic Growth 2003 8 2 155 194 10.1023/A:1024471506938
Alesina A La Ferrara E Ethnic diversity and economic performance Journal of Economic Literature 2005 43 3 762 800 10.1257/002205105774431243
Alesina A Easterly W Matuszeski J Artificial states Journal of the European Economic Association 2011 9 246 277 10.1111/j.1542-4774.2010.01009.x
Amankwah-Amoah J Solar energy in sub-Saharan Africa: The challenges and opportunities of technological leapfrogging Thunderbird International Business Review 2015 57 1 15 31 10.1002/tie.21677
Anosike P Entrepreneurship education as human capital: Implications for youth self-employment and conflict mitigation in Sub-Saharan Africa Industry and Higher Education 2019 33 1 42 54 10.1177/0950422218812631
Asiedu E On the determinants of FDI to developing countries: Is Africa different? World Development 2002 30 1 107 119 10.1016/S0305-750X(01)00100-0
Baker T Nelson RE Creating something from nothing: Resource construction through entrepreneurial bricolage Administrative Science Quarterly 2005 50 3 329 366 10.2189/asqu.2005.50.3.329
Bamberger PA Pratt MG Moving forward by looking back: Reclaiming unconventional research contexts and samples in organizational scholarship Academy of Management Journal 2010 53 665 671 10.5465/amj.2010.52814357
Banerjee, B. 2022. Decolonizing management theory: A critical perspective. Journal of Management Studies, Forthcoming.
Barnard H The Africa we want and the Africa we see: How scholarship from Africa stands to enrich global scholarship Africa Journal of Management 2020 6 2 132 143 10.1080/23322373.2020.1753493
Barnard H Cuervo-Cazurra A Manning S Africa business research as a laboratory for theory-building: Extreme conditions, new phenomena, and alternative paradigms of social relationships Management and Organization Review 2018 13 3 467 495 10.1017/mor.2017.34
Barnard H Deeds D Mudambi R Vaaler P Migrants, migration policies, and international business research: Current trends and new directions Journal of International Business Policy 2019 2 275 288 10.1057/s42214-019-00045-6
Barnard H Luiz JM Escape FDI and the dynamics of a cumulative process of institutional misalignment and contestation: Stress, strain and failure Journal of World Business 2018 53 605 619 10.1016/j.jwb.2018.03.010
Barnard H Pendock C To share or not to share: The role of affect in knowledge sharing by individuals in a diaspora Journal of International Management 2013 19 1 47 65 10.1016/j.intman.2012.11.003
BBC. 2022. https://www.bbc.com/news/world-africa-60333796. Accessed July 21, 2022.
Bob-Milliar GM Introduction: Methodologies for researching Africa African Affairs 2020 10.1093/afraf/adaa011
Boddewyn JJ International business–government relations research 1945–2015: Concepts, typologies, theories and methodologies Journal of World Business 2016 51 1 10 22 10.1016/j.jwb.2015.08.009
Broome A Homolar A Kranke M Bad science: International organizations and the indirect power of global benchmarking European Journal of International Relations 2018 24 3 514 539 10.1177/1354066117719320 30111983
Buckley PJ Chen L Clegg LJ Voss H Experience and FDI risk-taking: A microfoundational reconceptualization Journal of International Management 2016 22 2 131 146 10.1016/j.intman.2016.02.001
Business Insider Africa. 2022. Why Africa is the fintech market of tomorrow. https://africa.businessinsider.com/local/markets/why-africa-is-the-fintech-market-of-tomorrow/4v984l8 (January 28).
Canen N Wantchekon L Political distortions, state capture, and economic development in Africa Journal of Economic Perspectives 2022 36 1 101 124 10.1257/jep.36.1.101
Cantwell J Dunning J Lundan S An evolutionary approach to understanding international business acidity: The co-evolution of MNEs and the institutional environment Journal of International Business Studies 2010 41 567 586 10.1057/jibs.2009.95
Cao Z Lumineau F Revisiting the interplay between contractual and relational governance: A qualitative and meta-analytic investigation Journal of Operations Management 2015 33–34 15 42 10.1016/j.jom.2014.09.009
Casanova L Global Latinas: Latin America's emerging multinationals 2009 London Palgrave McMillan
Cheng, A. 2022. Who are the Gupta brothers, the family accused of looting South Africa? Washington Post. https://www.washingtonpost.com/world/2022/06/09/gupta-brothers-south-africa-arrested-dubai-extradition/ (June 9)
Clemens MA Plaza S Ratha D The financial consequences of high-skill emigration: Lessons from African doctors abroad Diaspora for development in Africa 2011 Washington DC World Bank 165 182
Cuypers I Ertug G Cantwell J Zaheer A Kilduff M Making connections: Social networks in international business Journal of International Business Studies 2020 51 714 736 10.1057/s41267-020-00319-9
Darendeli IS Hill TL Uncovering the complex relationships between political risk and MNE firm legitimacy: Insights from Libya Journal of International Business Studies 2016 47 1 68 92 10.1057/jibs.2015.27
De Soto H The other path: The invisible revolution in the third world 1989 New York Harper & Row
De Soto H The mystery of capital 2000 New York Basic Books
Depetris-Chauvin E Durante R Campante FR Building nations through shared experiences: Evidence from African football American Economic Review 2020 110 5 1572 1602 10.1257/aer.20180805
di Giovanni J Levchenko AA Mejean I The micro origins of international business-cycle comovement American Economic Review 2018 108 1 82 108 10.1257/aer.20160091
Dike M Rose EL Cross-border expansion and competitive interactions of indigenous mobile network operators in sub-Saharan Africa Thunderbird International Business Review 2019 61 1 29 42 10.1002/tie.21971
Doshi R Kelley JG Simmons BA The power of ranking: The ease of doing business indicator and global regulatory behavior International Organization 2019 73 3 611 643 10.1017/S0020818319000158
Dunning JH Lundan S Multinational enterprises and the global economy 2008 Cheltenham Edward Elgar
Eifert B Miguel E Posner DN Political Competition and Ethnic Identification in Africa American Journal of Political Science 2010 54 2 4940 5510 10.1111/j.1540-5907.2010.00443.x
Esipova, N., Ray, J., & Pugliese, A. 2017. Number of potential migrants worldwide tops 700 million. Gallup survey, June 8th.
EY. 2021. Reset for growth: Fast forward. EY Attractiveness Report—Africa. November.
Falk A Becker A Dohmen T Enke B Huffman D Sunde U Global evidence on economic preferences Quarterly Journal of Economics 2018 133 4 1645 1692 10.1093/qje/qjy013
Felin T Foss NJ Ployhart RE The microfoundations movement in strategy and organization theory Academy of Management Annals 2015 9 1 575 632 10.5465/19416520.2015.1007651
Foss NJ Pedersen T Microfoundations in international management research: The case of knowledge sharing in multinational corporations Journal of International Business Studies 2019 50 9 1594 1621 10.1057/s41267-019-00270-4
French, H. 2019. Why 1 million Chinese migrants are building a new empire in Africa. Quartz. https://qz.com/217597/how-a-million-chinese-migrants-are-building-a-new-empire-in-africa/.
Galeto V Plaza S Ratha D Migration and productive investment: A conceptual framework Diaspora for development in Africa 2011 Washington DC World Bank 283 302
Garrone P Piscitello L D’Amelio M Multinational enterprises and the provision of collective goods in developing countries under formal and informal institutional void: The case of electricity in sub-Saharan Africa Journal of International Management 2019 25 100650 10.1016/j.intman.2018.09.002
Gennaioli N La Porta R Lopez-de-Silanes F Shleifer A Human capital and regional development The Quarterly Journal of Economics 2013 1 105 164 10.1093/qje/qjs050
George G Corbishley C Khayesi JNO Haas MR Tihanyi L Bringing Africa in: Promising directions for management research Academy of Management Journal 2016 59 377 393 10.5465/amj.2016.4002
Gnimassoun B Anyanwu JC The diaspora and economic development in Africa Review of World Economy 2019 155 785 817 10.1007/s10290-019-00344-3
Godfrey PC Toward a theory of the informal economy Academy of Management Annals 2011 5 1 231 277 10.5465/19416520.2011.585818
Griffin-El EW Olabisi J Diasporic synergies: Conceptualizing African entrepreneurship based upon trans-local networks Journal of African Business 2018 20 4 1 17
Groskopf, C. 2016. Why is Central Africa missing from so many maps? Quartz Africa, February 4th.
Hällgren M Rouleau L de Rond M A matter of life or death: How extreme context research matters for management and organization studies Academy of Management Annals 2018 12 111 153 10.5465/annals.2016.0017
Head K Mayer T Gopinath G Helpman E Rogoff K Gravity equations: Workhorse, toolkit, and cookbook Handbook of International Economics 2014 Amsterdam Elsevier 131 195
Hearn B Oxelheim L Randøy T The institutional determinants of private equity involvement in business groups - the case of Africa Journal of World Business 2018 53 118 133 10.1016/j.jwb.2016.02.002
Heine B Nurse D African languages: An introduction 2000 Cambridge, UK Cambridge University Press
Henn, S. & Robinson J. A. 2021. Africa’s latent assets. Centre for Economic Policy Research, Discussion Paper 15963, London.
Herbst J States and power in Africa: Comparative lessons in authority and control 2015 2 Princeton, NJ Princeton University Press
Hernandez E Guillén MF What’s theoretically novel about emerging-market multinationals? Journal of International Business Studies 2018 49 24 33 10.1057/s41267-017-0131-7
Horwitz, F.M., & Ronnie, L. 2021. Human resource management in the African context. In E. Parry, M.J. Morley, & C. Brewster (Eds.), The Oxford Handbook of Contextual Approaches to Human Resource Management.
Jerven M Poor numbers: How we are misled by African development statistics and what to do about it 2013 Ithaca, NY Cornell University Press
Kaba JA The status of Africa’s emigration brain drain in the 21st century Western Journal of Black Studies 2011 35 187 207
Kamei S Diaspora as the ‘Sixth Region of Africa’: An assessment of the African Union initiative Diaspora Studies 2011 4 1 59 76 10.1163/09763457-00401004
Kano L Verbeke A Theories of the multinational firm: A microfoundational perspective Global Strategy Journal 2019 9 117 147 10.1002/gsj.1332
Keupp MM Gassmann O The past and the future of international entrepreneurship: A review and suggestions for developing the field Journal of Management 2009 35 3 600 633 10.1177/0149206308330558
Kirk-Greene AH ‘Damnosa Hereditas’: Ethnic ranking and the martial races imperative in Africa Ethnic and Racial Studies 1980 3 4 393 414 10.1080/01419870.1980.9993313
König AKP Schmidt CVH Kindermann B Schmidt MAP Flatten TC How individuals learn to do more with less: The role of informal learning and the effects of higher-level education and unemployment in Ghana Africa Journal of Management 2022 8 2 194 217 10.1080/23322373.2022.2039051
Krever T Quantifying law: Legal indicator projects and the reproduction of neoliberal common sense Third World Quarterly 2013 34 1 131 150 10.1080/01436597.2012.755014
Leblang D Plaza S Ratha D Another link in the chain: Migrant networks and international investment Diaspora for development in Africa 2011 Washington DC World Bank 79 102
Lituchy TR Special Issue on the Diaspora Journal of African Business 2019 20 1 1 5 10.1080/15228916.2019.1578938
Luo Y Tung RL A general theory of springboard MNEs Journal of International Business Studies 2018 49 129 152 10.1057/s41267-017-0114-8
Lu JW Huang X Muchiri M Political risk and Chinese outward foreign direct investment to Africa Africa Journal of Management 2017 3 1 82 98 10.1080/23322373.2016.1275941
Luiz JM The impact of ethno-linguistic fractionalization on cultural measures: Dynamics, endogeneity, and modernization Journal of International Business Studies 2015 46 1080 1098 10.1057/jibs.2015.6
Lundan S Jones G The ‘Commonwealth effect’ and the process of internationalization World Economy 2001 24 1 99 118 10.1111/1467-9701.00345
Manning S Kannothra C Wissman-Weber N The strategic potential of community-based hybrid models: The case of global business-services in Africa Global Strategy Journal 2017 7 125 149 10.1002/gsj.1147
Marks J Dawa S Kanyemba S Transnational entrepreneurship in Sub-Saharan Africa: An absorptive capacity theory of knowledge spillover entrepreneurship perspective Journal of Entrepreneurship and Innovation in Emerging Economies 2020 6 1 114 139 10.1177/2393957519895851
Mayer SD Harima A Freiling J Network benefits for Ghanaian diaspora and returnee entrepreneurs Entrepreneurial Business and Economics Review 2015 3 3 95 122 10.15678/EBER.2015.030306
Mazé D Chailan C A South-South perspective on emerging economy companies and institutional coevolution: An empirical study of Chinese multinationals in Africa International Business Review 2021 30 4 101704 10.1016/j.ibusrev.2020.101704
McGahan AM Challenges of the informal economy for the field of management Academy of Management Perspectives 2012 26 3 12 21 10.5465/amp.2012.0104
McMillan MS Zeufack A Labor productivity growth and industrialization in Africa Journal of Economic Perspectives 2022 36 1 3 32 10.1257/jep.36.1.3
Medina, L., Jonelis, A., & Cangul, M. 2017. The informal economy in Sub-Saharan Africa: Size and determinants. IMF Working Paper WP/17/156.
Mellahi K Mol M Africa is just like every other place, in that it is unlike any other place Africa Journal of Management 2015 1 2 201 209 10.1080/23322373.2015.1026761
Meyer KE Li C Schotter APJ Managing the MNE subsidiary: Advancing a multi-level and dynamic research agenda Journal of International Business Studies 2020 51 4 538 576 10.1057/s41267-020-00318-w
Michalopoulos S Papaioannou E On the ethnic origins of African development: Chiefs and precolonial political centralization Academy of Management Perspectives 2015 29 1 32 71 10.5465/amp.2012.0162 27011760
Michalopoulos S Papaioannou E Historical legacies and African development Journal of Economic Literature 2020 58 1 53 128 10.1257/jel.20181447
Mohan G Zack-Williams AB Globalisation from below: Conceptualising the role of the African diasporas in Africa’s development Review of African Political Economy 2002 29 92 211 236 10.1080/03056240208704610
Mol M Stadler C Ariño A Africa: The new frontier for global strategy scholars Global Strategy Journal 2017 7 3 9 10.1002/gsj.1146
Moscona J Nunn N Robinson JA Segmentary lineage organization and conflict in Sub-Saharan Africa Econometrica 2020 88 5 1999 2036 10.3982/ECTA16327
Musila G Navigating epistemic disarticulations African Affairs 2017 116 692 704 10.1093/afraf/adx031
Nachum L Ogbechie C Where have foreign banks in Nigeria gone? Market structure, competitive intensity and the capabilities of Nigeria banks Africa Journal of Management 2019 5 3 5 21 10.1080/23322373.2019.1648999
Nachum L Ogbechie C Are environmental conditions in the eyes of the beholder? Competitive dynamics between local and foreign firms in Africa Forthcoming, Africa Journal of Management 2023 9 1 1
Ndukwe, I. 2021. Ghana basks in Twitter’s surprise choice as Africa HQ. BBC Business. https://www.bbc.com/news/world-africa-56860658.
Newburry W Deephouse DL Gardberg NA Newburry W Deephouse DL Gardberg NA Global aspects of reputation and strategic management Global aspects of reputation and strategic management 2019 Bingley, UK Emerald Publishing Limited 1 20
Newenham-Kahindi A Kamoche K Chizema A Mellahi K Effective people management in Africa 2013 London Palgrave Macmillan
Newenham-Kahindi A Stevens C An institutional logics approach to liability of foreignness: The case of mining MNEs in sub-Saharan Africa Journal of International Business Studies 2018 49 881 901 10.1057/s41267-017-0111-y
Ngouhouo I Nchofoung T Kengdo NAA Determinants of trade openness in Sub-Saharan Africa: Do institutions matter? International Economic Journal 2021 35 1 96 119 10.1080/10168737.2020.1858323
Nkomo SM Time to look in the mirror: Producing management theory and knowledge for Africa Africa Journal of Management 2017 3 1 7 16 10.1080/23322373.2017.1304629
Obi C Oil as the ‘curse’ of conflict in Africa: Peering through the smoke and mirrors Review of African Political Economy 2010 37 126 483 495 10.1080/03056244.2010.530947
Ofori-Dankwa J Scott DJ Dynamism, capital structure and performance in a sub-Saharan economy: Extending the institutional difference hypothesis Organization Science 2013 24 5 1422 1438 10.1287/orsc.1120.0789
Olopade D The bright continent 2014 New York Houghton Mifflin Harcourt Publishing
Oluwole, V. 2022. Uganda, Botswana and Ghana are the world’s top economies with the most female entrepreneurs. Business Insider Africa. https://africa.businessinsider.com/local/lifestyle/uganda-botswana-and-ghana-are-the-worlds-top-3-economies-with-the-most-female/0kfjp0j (July 18)
Parente R Rong K Geleilate JMG Misati E Adapting and sustaining operations in weak institutional environments: A business ecosystem assessment of a Chinese MNE in Central Africa Journal of International Business Studies 2019 50 275 291 10.1057/s41267-018-0179-z
Pedersen T Larsen M Dasi A Searching locally and globally: Applying Daniel Levinthal’s scholarship to international business Journal of International Business Studies 2020 51 9 1532 1546 10.1057/s41267-020-00315-z
Pilling, D. 2018. Nigerian economy: Why Lagos works. Financial Times. https://www.ft.com/content/ff0595e4-26de-11e8-b27e-cc62a39d57a0 . March 15.
Piper, K. 2020. What Kenya can teach its neighbors—and the US—about improving the lives of the “unbanked”. Vox. https://www.vox.com/future-perfect/21420357/kenya-mobile-banking-unbanked-cellphone-money.
Plaza S Ratha R Diaspora for development in Africa 2011 Washington DC World Bank Publication
Rolfe R Perri A Woodward D Adeleye I Ibeh K Kinoti A White L Patterns and determinants of intra-African foreign direct investment The changing dynamics of international business in Africa 2015 London Palgrave Macmillan, London 101 122
Rose EL The decline of US manufacturing: Issues of measurement Management and Organization Review 2021 17 1 24 28 10.1017/mor.2020.82
Rugman A The regional multinationals: MNEs and ‘global’ strategic management 2005 Cambridge, UK Cambridge University Press
Rugman A Verbeke A A perspective on regional and global strategies of multinational enterprises Journal of International Business Studies 2004 35 3 18 10.1057/palgrave.jibs.8400073
Selmier WT Newenham-Kahindi A Oh CH “Understanding the words of relationships”: Language as an essential tool to manage CSR in communities of place Journal of International Business Studies 2015 46 153 179 10.1057/jibs.2014.58
Shapshak, T. 2019. Africa now has 643 tech hubs which play “pivotal” role for business. Forbes, October 30.
Soares de Oliveira, R., 2015. Magnificent and beggar land: Angola since the civil war. Oxford University Press.
Stevens CE Newenham-Kahindi A Legitimacy spillovers and political risk: The case of FDI in the East African Community Global Strategy Journal 2017 7 10 35 10.1002/gsj.1151
Stevens CE Newenham-Kahindi A Avoid, acquiesce … or engage? New insights from sub-Saharan Africa on MNE strategies for managing corruption Strategic Management Journal 2021 42 273 301 10.1002/smj.3228
The Economist. 2017. Why Africa’s development model puzzles economists. August 19.
The Economist. 2018. Informal trade is ubiquitous in Africa, but too often ignored. Sep 1.
Thomson A An introduction to African politics 2016 4 London and New York Routledge
Udogu EI The issue of political ethnicity in Africa 2018 New York and London Routledge
UNCTAD Key statistics and trends in regional trade in Africa 2019 Geneva UNCTAD
UNCTAD World investment report: Special economic zones 2019 Geneva UNCTAD
UNCTAD World investment report: Investing in sustainable recovery 2021 Geneva UNCTAD
UNDP. 2022. https://www.undp.org/africa/events/informal-economy-africa-which-way-forward. Accessed July 16, 2022.
Verbeke, A., van Tulder, R., Rose, E.L., Wei, Y. 2021. The multiple dimensions of institutional complexity in international business research. Emerald Publishing.
Webb JW Tihanyi L Ireland RD Sirmon DG You say illegal, I say legitimate: Entrepreneurship in the informal economy Academy of Management Review 2009 34 3 492 510 10.5465/amr.2009.40632826
White L Kitimbo A Rees L Institutions and the location strategies of South African firms in Africa Thunderbird International Business Review 2019 61 61 73 10.1002/tie.21965
World Bank. 2022. https://data.worldbank.org/indicator/IT.NET.USER.ZS, accessed July 17, 2022.
Yakovleva N Vazquez-Brust DA Multinational mining enterprises and artisanal small-scale miners: From confrontation to cooperation Journal of World Business 2018 53 52 62 10.1016/j.jwb.2017.08.004
Yenkey CB Mobilizing a market: Ethnic segmentation and investor recruitment into the Nairobi Securities Exchange Administrative Science Quarterly 2015 60 4 561 595 10.1177/0001839215597269
Zallé O Natural resources and economic growth in Africa: The role of institutional quality and human capital Resources Policy 2019 62 616 624 10.1016/j.resourpol.2018.11.009
Zoogah DB Peng MW Woldu H Institutions, resources, and organizational effectiveness in Africa Academy of Management Perspectives 2015 29 1 7 31 10.5465/amp.2012.0033
| 0 | PMC9734589 | NO-CC CODE | 2022-12-14 23:28:29 | no | J Int Bus Stud. 2022 Dec 6;:1-18 | utf-8 | J Int Bus Stud | 2,022 | 10.1057/s41267-022-00581-z | oa_other |
==== Front
J Technol Transf
J Technol Transf
The Journal of Technology Transfer
0892-9912
1573-7047
Springer US New York
9984
10.1007/s10961-022-09984-4
Article
Does the intensity of use of social media influence the economic sustainability of the university?
http://orcid.org/0000-0001-5951-6392
Gelashvili Vera [email protected]
1
http://orcid.org/0000-0002-6836-6573
Martínez-Navalón Juan Gabriel [email protected]
1
http://orcid.org/0000-0002-9788-8629
Gómez-Borja Miguel Ángel [email protected]
2
1 grid.28479.30 0000 0001 2206 5938 Department of Business Economics, Faculty of Legal and Social Sciences, King Juan Carlos University, Paseo de los Artilleros S/N. 28032, Madrid, Spain
2 grid.8048.4 0000 0001 2194 2329 Department of Business Administration, Faculty of Economics and Business Administration, University of Castilla-La Mancha, Plaza de la Universidad, 1, 02071 Albacete, Spain
8 12 2022
125
18 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
In the last decades the term sustainability has become indispensable for society, governments and companies. Its correct implementation is of utmost importance, and therefore public institutions continuously promote the actions of sustainable development. During the pandemic, universities adapted to online teaching, using different platforms or even social media. The intensity of social media use has had positive and negative impacts. Several studies have linked the use of social media to sustainable development. Therefore, this study analyses the intensity of social media use in public universities and the relationship between the three dimensions of sustainability. To achieve the objectives set out, a sample of 447 users was used, and the data was analysed based on PLS-SEM (Partial Least Squares Structural Equation Modeling). Variance-based SEM is a methodological option to carry out analyses that measure the simultaneous behaviour of dependence relationships. The results have shown that the intensity of the use of social media and the economic sustainability of universities is weak, even if it is positive. Furthermore, there is a strong and positive relationship between the three dimensions of sustainability at the university level. This study contributes to the academic literature on the subject and highlights the critical role of higher education institutions in promoting sustainability.
Keywords
Social media
Intensity of use
Economic sustainability
Social sustainability
Environmental sustainability
JEL Classification
Q01
Q50
L82
I20
I23
==== Body
pmcIntroduction
Sustainability is becoming increasingly important as it is seen as an essential part of our lives (Segovia-Vargas et al., 2021). The three dimensions of sustainability (i.e. social, environmental and economic) play an essential role in the development of sustainable actions (Hansmann et al., 2012; Purvis et al., 2019), which is why more and more reports produced by companies emphasise the relationship between their activities and sustainability (Cunha & Moneva, 2018; Ruhnke & Gabriel, 2013; Sellami et al., 2019). A study by Hornuf et al. (2021) on sustainability-oriented crowd investors has concluded that these investors are concerned about the non-financial effects on the company of a default in their portfolios. This indicates that sustainability-oriented actions have more than just a monetary effect. Therefore, every company/business should be oriented towards having its actions have an effect on some dimension of sustainability or sustainable development in general. Among the different categories of business, the relevance of public enterprises as active agents in sustainable development is growing substantially in recent times (Gelderman et al., 2017; Hamid et al., 2017; Lăzăroiu et al., 2020). Among public businesses, we can highlight public universities as organizations that have an important impact on society as educational and research ecosystems involved with the different dimensions of sustainability (Hamid et al., 2017).
During the Covid-19 pandemic, both public and private universities and other educational institutions were forced to adapt their face-to-face activities to an online environment (Adedoyin & Soykan, 2020). Interaction between students and professors was developed on the basis of institutional platforms, although in many cases social media were also used to communicate, advertise or express opinions in the academic field (Jogezai et al., 2021). All of this has considerably increased the intensity of social media use (Ali Taha et al., 2021; Najah et al., 2021). The use of social media has had both positive and negative impacts. Negative aspects include the possibility of not controlling the time spent using social media and even becoming addicted for users (Latif et al., 2019). On the positive side, the possibility of communication, exchange of information, knowledge or the possibility of influencing users on sustainable actions (Barrot, 2021; Hamid et al., 2017; Saura et al., 2019). This indicates that the intensity of use of social media has an effect on the sustainability actions taken by users. In particular, the intensity of use of the social media Facebook was identified as one of the variables affecting environmental sustainability (Hamid et al., 2017).
The use of social media during the pandemic was not only used for communication, but also for online shopping, online work, online education, online care, etc. (Baert et al., 2020; Lucini et al., 2020; Sharma et al., 2020), which has increased the intensity of social media use (Najah et al., 2021). This in turn affected the different pillars of sustainability. In the case of economic sustainability, many unneeded resources were not purchased by users because they were afraid of unnecessary expenses, i.e. the pandemic contributed to people reflecting on their priorities (Fumero & Martín, 2020). In the case of environmental sustainability, the biggest impact has been on pollution mitigation (Coccia, 2021; Mishra, 2022). In short, we can say that the pandemic has had an impact on the intensity of use of social media and on the dimensions of sustainability, which in many cases have been studied together assuming the positive relationship between them (Purvis et al., 2019).
Taking all of this into account, the main objective of this study is to analyse the relationship between the three dimensions of sustainability and whether the intensity of use of social media is related to the economic sustainability of the universities in Spain. First, the direct relationship between intensity of use and economic sustainability is studied. Then the relationship between economic sustainability and two other dimensions of sustainability is analysed. This is because economic sustainability is considered as part of social and environmental sustainability (Purvis et al., 2019; Ranjbari et al., 2021). One of the gaps we found when conducting this study was that there were no quantitative studies on the direct relationship between social and environmental sustainability. And the qualitative studies indicated a lack of academic literature on this important relationship (Murphy, 2012), especially in the context of universities, which to the best of our knowledge is not any. Therefore, the last hypothesis analyses the relationship between social and environmental sustainability.
In order to carry out the study, data was collected using a self-administered questionnaire. The first part of the methodology was a descriptive analysis of the sample and the answers received. Then the methodology of data analysis based on PLS-SEM (Partial Least Squares Structural Equation Modeling) was used. The analysis of the study was divided into two parts. The first part was the validation of the measurement scale and in the second part the relationship between the proposed model and its predictive ability was analysed.
Results have shown that the intensity of the use of social media and the economic sustainability of universities is weak, although positive. Furthermore, there is a strong and positive relationship between the three dimensions of sustainability at the university level.
Finally, the originality of this study is the proposed model on the relationships between the intensity of social media use and different dimensions of sustainability that have not previously been studied in the context of universities. The results obtained fill the gap in the scare academic literature on sustainability actions carried out in public universities. Moreover, it promotes and highlights the importance of sustainable development, one of the cross-cutting ideas throughout the United Nations Sustainable Development Goals proposal.
Literature background and hypothesis development
Social media and its intensity of use
In recent decades, technological advances have changed people’s habits (Adesote & Fatoki, 2013; Saura et al., 2022c), making knowledge transfer mostly based on electronic resources or even through social media (Barrot, 2021; Hamadi et al., 2021). Since the first appearance of social media, they have been successful worldwide as there are different social media for people of all ages, interests and backgrounds (Martínez-Navalón et al., 2019). Hence, more and more social media are being developed for different purposes (Troise & Camilleri, 2021). Among the most famous social media, we can highlight Facebook, YouTube, Instagram, TikTok, LinkedIn, Twitter or Snapchat (Permana & Meinarni, 2021; Rajeh et al., 2021; Troise & Camilleri, 2021). People use these social media to interact with each other, for entertainment, exchange opinions, learn more about topics of interest, promote social or non-social causes, etc. In addition to this, social media are the main means for companies to promote their products and services, announce new product launches or design specific products for their customers based on opinions and suggestions received. It is therefore normal for people to spend a lot of time browsing social media and sharing content or thoughts about products and services. The study elaborated by INE (2021) has shown that almost 65% of the Spanish population aged 16 to 74 years has used social media during the last three months (such as Instagram, Facebook, Twitter, YouTube, etc.). This percentage is 6.1 points higher than in 2019. In addition, teenagers under the age of 16, who were not the subjects of the previous study, use social media regularly (Dennen et al., 2020).
According to different studies (Martínez-Navalón et al., 2019; Saura et al., 2019), people use social media first of all for entertainment but also to transfer knowledge, and information about culture, sport, weather, business or, in many cases, it is used as a work tool as well. There are, therefore, many advantages to be gained from using social media.
A study carried out by Barrot (2021) has analysed the use of social media in 2008–2019 in the area of education, in particular the impact of social media in the language learning environment. The results showed a positive effect of social media as a tool for language learning and the teaching environment. Another study (Hamadi et al., 2021) in education has concluded that the use of social networking in higher education has a positive impact on cooperative learning, and students have expressed their intention to use social media as a learning tool. According to Latif et al. (2019), social media are powerful tools in education and learning. The study results have shown that the majority of the surveyed students used social media for communication, learning, opinions, ideas or feedback.
Apart from education, social media are used for different purposes. A study based on Italian companies has concluded that social media such as Facebook, LinkedIn and YouTube are used by companies to reach out to their consumers, communicate commercial information about products and services and promote their business (Troise & Camilleri, 2021). In addition to this, the social media Instagram and Twitter are used to let company stakeholders know about CSR (Corporate Social Responsibility) actions and initiatives.
Among the consequences of COVID-19 is the rapid adoption of new technologies and digital platforms by businesses (Saura et al., 2021c). For this reason during the pandemic, the use of social media has been increased (Valdez et al., 2020; Zhong et al., 2020). That has allowed people to stay informed, stay in touch with other people, or keep working. Although, the use of social media has not only been positive, but also negative (González-Padilla & Tortolero-Blanco, 2020; Obi-Ani et al., 2020; Venegas-Vera et al., 2020). Among the positive outcomes, Venegas-Vera et al. (2020) considered the possibility of sharing critical data rapidly across geographical boundaries, social interaction between medical and non-medical specialists to see the progress and discuss the results or better management of the crisis by taking advantage of social media tools. The same study has identified the negative points of using social media in health care, which include much low-quality information, a tendency of data depending on users’ core beliefs or panic transmission.
Another study (González-Padilla & Tortolero-Blanco, 2020) on the influence of social media on people during the pandemic concluded that the worst disadvantage of using social media platforms during the Covid-19 was that it often spread erroneous, alarmist and exaggerated information. All this is a cause of depression, stress or anxiety, and diseases considered among the most common in the 21st century. Disadvantages of using social media can also include addiction, distraction and privacy problems (Latif et al., 2019). But it should not be forgotten that the use of social media has had significant advantages both for individuals to interact with family members or other people, as well as for companies that have used social media to develop their work better during the pandemic (Dubbelink et al., 2021; Hashim et al., 2020; Pennington, 2021). Another advantage of social media platforms during the Covid-19 pandemic has been the possibility of arranging collaborative research projects, surveys, and multi-centre studies (González-Padilla & Tortolero-Blanco, 2020).
Therefore, all these essential aspects have considerably increased the intensity of the use of social media (Pennington, 2021). The power of social media use is a variable that has been extensively analysed in the academic literature (Boer et al., 2021; Charoensukmongkol, 2016; Mieczkowski et al., 2020; Roberts & David, 2022). The intensity of social media use is measured through a scale that considers the frequency of social media use, length of time people spend on different social platforms, or taking into account people’s subjective experiences on social media (Mieczkowski et al., 2020). Therefore, the intensity of social media use shows the degree of social media integration in people’s daily lives and not the symptoms of addiction to social media use. Addiction to social media use is directly related to anxiety, depression, attention-deficit/hyperactivity disorder symptoms, and obsessive–compulsive disorder (Andreassen et al., 2016). The age variable is also important when discussing the intensity of social media use or addiction to social media use (Andreassen et al., 2016; Boer et al., 2021; Silmi et al., 2020). Excessive use of social media and phone use, in general, in teenagers has been shown to have an impact on reduced sleep time (Royant-Parola et al., 2017). It also affects negatively young people’s daily school performance and mood.
In Spain, the latest data provided by the INE (2021), in 2020, the frequency of use of information and communication technologies (ICT) by the population was 91.3% connecting at least once a week (3.6 points more than in 2019), 83.1% daily (5.5 points more) and 81.0% several times a day (6.1 points more). If we concentrate further, 93.8% of students and young people aged 16 to 24 (93.0%) are the most active on the social media. By sex, the activity of women (66.4%) is higher than that of men (62.9%). From here, we can see that in the Spanish population, the intensity of use of social media is relatively high.
Sustainability: evolution and key data
Sustainability is an important concept, first appearing in the Brundtland Report in 1987 in the United Nations General Assembly Report of the World Commission on Environment and Development. This report defines sustainability as the development that meets the needs of the present without compromising the ability of future generations to meet their own needs. Although there have been more general definitions of sustainability, this is the most commonly used definition in the academic literature. Sustainability has been studied in different sectors (Al Hawaj & Buallay, 2022; Qorri et al., 2018; Sardianou et al., 2021), where studies have primarily focused on the importance and meaning of sustainable development for both individuals and companies or governmental institutions. In the last decades, the concept of sustainability has been introduced into every person’s life. Governments and official institutions are continuously trying to promote sustainability actions and new sustainability regulations (Flores, 2006; Howes et al., 2017; Liao et al., 2020; Plumed Lasarte et al., 2018). Sustainability reporting is not mandatory for large companies, although IFRS (International Financial Reporting Standards)1 is studying the possibility of implementing the need for this report in the coming years. The information would inform stakeholders about companies’ sustainability actions carried out. Although it is not a binding document, a voluntary one, there are many large companies nowadays that prepare it (Borga et al., 2009; Ruhnke & Gabriel, 2013; Sellami et al., 2019), thus gaining the trust of internal and external users and a good image of their company in the business world. Several studies have concluded that corporate sustainability is related to good performance and growth, and competitive advantage in the market (Alshehhi et al., 2018; Malesios et al., 2018; Ojo et al., 2015). Although there are studies that point out that sustainability is a business strategy for many companies, knowing that they can gain more consumers or the trust of existing consumers (Ajmal et al., 2018; Haseeb et al., 2019). Another purpose of the sustainability reports for the companies is to provide transparent and legitimate information about their activities (Cunha & Moneva, 2018). Taking all this into account, it can be confirmed that sustainable development plays a crucial role in the life of companies.
There are three pillars (models) of sustainability: economic sustainability, social sustainability, and environmental sustainability (Hansmann et al., 2012; Purvis et al., 2019). Over the years, the three sustainability models have been studied extensively in the academic literature and implemented in practice (Alshehhi et al., 2018; Kuhlman & Farrington, 2010; Purvis et al., 2019; Sardianou et al., 2021). All three together make up sustainable development for the business and society. Generally, sustainable development is understood as the development that meets the needs of the present without compromising the ability of future generations to meet their own needs.2
Social sustainability is related to reducing social poverty and achieving a more balanced world for everybody (Atanda, 2019; Basiago, 1998; Eizenberg & Jabareen, 2017). According to a study elaborated by Polèse and Stren (2000, p.15), social sustainability refers to the development that is compatible with harmonious evolution of civil society, fostering an environment conductive to the compatible cohabitation of culturally and socially diverse groups while at the same time encouraging social integration, with improvements in the quality of life for all segments of the population. i.e. the search for a balance in social welfare to achieve social goals with a particular focus on the most vulnerable people. Therefore, companies practising social sustainability must prioritise social equity, health, wellness and well-being (Amrutha & Geetha, 2020). The great importance of this issue calls for more academic studies to give visibility and promote social sustainability actions (Eizenberg & Jabareen, 2017).
One of the definitions of environmental sustainability in the academic literature is set out by Goodland (1998), who refers to it as the maintenance of natural capital that includes the use of renewable and nonrenewable resources on the source side and pollution and waste assimilation on the sink side. In other words, the main objective of environmental sustainability is protecting the natural balance of the planet while limiting the impact of human activities on the earth, i.e. caring for the vitality of ecosystems and environmental health. Apart from this definition, some researchers have defined environmental sustainability and has been studied more extensively than the other sustainability models (Howes et al., 2017; Moldan et al., 2012; Morelli, 2011). According to several studies (Centobelli et al., 2020; Koul et al., 2022; Naidoo & Gasparatos, 2018), companies in different sectors are obliged or advised to follow environmental sustainability policies and strategies. Although the study by Howes et al. (2017) has pointed out that environmental sustainability strategies have not been met over the last decades due to their complex implementation.
Looking at economic sustainability separately, it refers to maintaining and protecting scarce natural resources, taking into account and ensuring positive social and environmental outcomes (Cadil et al., 2018). If economic sustainability is carried out in the right way, it will guarantee a responsible return on resources in the long term (Segovia-Vargas et al., 2021). Therefore, economic sustainability must have a circular effect that will strengthen the economy and society; that is why companies must focus on renewable, reusable and recyclable actions and practices, among others (Rai et al., 2021). Considering all this, we can see that economic sustainability is directly related to social and environmental sustainability.
One of the main objectives of this study is to analyse the relationship between the intensity of use of social media and economic sustainability in Spanish universities. Therefore, the following table (Table 1) analyses the evolution of the relationship between these two variables in the academic literature.Table 1 Analysis of the relevant literature in the context of intensity of social media use and economic sustainability
Author(s) Year Objectives Methods employed Findings/Implications
Hamid et al 2017 Analyse the role of social media (in particular Facebook) in attracting student interest related to environmental sustainability issues Systematic literature review Social media plays an important role in enhancing the vision of environmental sustainability at the university
Environmental sustainability actions carried out by universities have a positive effect on students where social media serve to convey information and policies about it
Pouri and Hilty 2018 Analysing the relationship between ICTs and the Enabled Sharing Economy and Environmental Sustainability Systematic literature review Online platforms can encourage a type of consumption in which available resources are shared and consumed collaboratively between people
The sharing economy has an effect on sustainability by reducing the number of goods or services to be produced
Latif et al 2019 Analysing the growing trend to social media intensity use for teaching and learning Systematic literature review Social media is identified as a powerful tool for social interactions and academic activities as well as for teaching and learning
Ur Rahman et al 2020 Analysing the role of social media use in SMEs’ financial sustainability Survey of 383 owners /managers. Consistent Partial Least Square method Social media use as a communication platform reduces the costs of internal operations of SMEs, which implies the possibility of improving the financial sustainability of these companies
Nchofoung and Asongu 2022 Study the relevance of ICT for sustainable development Data provided from140 countries
Cuantitative analysis (different statistical methods)
ICTs have a positive effect on sustainable development, in particular this relationship is modulated by trade openness and foreign direct investment
Source own elaboration
The literature review has not shown papers that directly analyse the relationship between the intensity of use of social media and economic sustainability, but there is literature that points to the relationship of these two variables indirectly. For example, the study by Pouri and Hilty (2018) studies the effect of ICTs on the sharing economy and environmental sustainability. The results of the work show that ICTs have an effect on both variables studied. Therefore, if ICTs affect positively to the sharing economy, it will affect economic sustainability too. Since the latter aims to conserve and maintain resources for future generations (Cadil et al., 2018) what is the goal of the sharing economy too—sharing resources and services to avoid unnecessary use of them. Another international study (Nchofoung & Asongu, 2022) has shown the positive relationship between the use of ICTs in sustainable development, which in addition to economic sustainability also includes environmental and social sustainability.
Hypothesis development
As seen in the literature review, the use of social media in times of pandemic has been intense, having both positive and negative impacts on users and companies and governmental organisations. In addition to this, the Covid-19 pandemic has changed people’s habits (Favale et al., 2020; Izzo et al., 2021; Sibley et al., 2020). People prefer to do most of their activities online for fear of becoming infected, such as taking yoga classes online or other physical or mental activities, shopping, meeting online instead of meeting in person, etc. (Bhatti et al., 2020; Lucini et al., 2020; Sharma et al., 2020). Companies, in turn, had to adapt to online work (Baert et al., 2020; Belzunegui-Eraso & Erro-Garcés, 2020), so all communication between employees or customers was done via telephone or social media. All this has considerably increased the intensity of social media use (Ali Taha et al., 2021; Najah et al., 2021). In addition, face-to-face classes have been transformed into online courses in universities, so students and university staff had to adapt to the new normal. This, of course increased the use of social media for higher education students.
But what is the relationship between the intensity of social media use by the university students and economic sustainability? According to the study by Segovia-Vargas et al. (2021), economic sustainability ensures economic balance and guarantees long-term income for all. Therefore, if the intensity of social media use is done for work or to generate profits and not for addiction, as in some cases (Latif et al., 2019), there may be a positive relationship between these two variables. Ur Rahman et al. (2020) has concluded that the use of social media in SMEs positively affects the financial sustainability of SMEs by helping to reduce costs. The positive relationship between ICTs and sustainable development is also proven (Nchofoung & Asongu, 2022). Another study elaborated by Hamid et al. (2017) has pointed out that social media sites, particularly Facebook, among higher education students, can influence students’ environmental sustainability actions.
On this basis, the following hypothesis is formulated:
Hypothesis H1
The intensity of use has a direct and positive impact on Economic sustainability.
The three pillars or dimensions of sustainability are interrelated to achieve sustainable development (Gelashvili et al., 2021a, 2021b; Kuhlman & Farrington, 2010; Purvis et al., 2019). According to Purvis et al. (2019), economic sustainability is part of environmental and social sustainability (see Fig. 1). Based on a study elaborated by Albareda-Tiana et al. (2017), the academic literature has focused on sustainability in higher education on environmental management, ecological footprint and greening campuses, where work has mainly been done on the economic and environmental dimensions of sustainability. Still, less progress has been made on the social dimension of sustainability.Fig. 1 Interaction of the three pillars of sustainability.
Source: own elaboration based on Purvis et al. (2019)
It is essential to underline the role of higher education institutions in the proper development of the sustainability pillars (Parrado Castañeda & Trujillo Quintero, 2015). Sustainable universities are defined (Velazquez et al., 2006) as those institutions that direct, involve, and promote the minimisation of environmental, economic and social impacts at regional and global levels. Likewise, paying attention to the effects generated on human health by using resources in teaching, research, and administration to help society transition to sustainable lifestyles. Thus, universities have an important impact on sustainability as future generations are educated there. Furthermore, universities should promote sustainable actions (Pappas, 2012) and be examples for other entities or society to achieve sustainable development and transmit it to students (Amaral et al., 2020; Parrado Castañeda & Trujillo Quintero, 2015).
Taking all this into account, the following hypotheses are intended to analyse whether there is a positive relationship between economic sustainability and social and environmental sustainability in higher education.
Therefore, the following hypotheses are raised:
Hypothesis H2
Economic sustainability has a direct and positive impact on social sustainability.
Hypothesis H3
Economic sustainability has a direct and positive impact on environmental sustainability.
Finally, the relationship between social sustainability and environmental sustainability in higher education is studied. A study elaborated by Murphy (2012) has highlighted the lack of academic studies on the relationship between social sustainability and environmental sustainability. Although, it is worth noting the abundant literature on sustainability in general (Alshehhi et al., 2018; Liao et al., 2020; Sardianou et al., 2021), where the importance of sustainability for private or public institutions for the proper development of a country or individuals is studied (Amaral et al., 2020; Qorri et al., 2018; Sardianou et al., 2021; Segovia-Vargas et al., 2021). According to Purvis et al. (2019), three different possible relationships can be between social and environmental sustainability. In the first one, it can be assumed that the three dimensions of sustainability are related. In the second, economic sustainability is understood as part of environmental sustainability, and finally, there is no relationship between the three dimensions of sustainability. If we consider the first possibility, we can say that there is a positive relationship between social and environmental sustainability.
Taking this into account the following hypothesis on the relationship between social sustainability and environmental sustainability in universities, the following hypothesis is proposed:
Hypothesis H4
Social sustainability has a direct and positive impact on environmental sustainability.
According to theoretical studies consulted, acceptance is expected for the four hypotheses proposed. Therefore, the following research model is proposed (Fig. 2):Fig. 2 Research model.
Source: own elaboration
Methodology
Data
Data collection was carried out using a self-administered questionnaire to carry out the study. This questionnaire was elaborated using the measurement scales analysed in the bibliographical analysis shown above.
The questionnaire was disseminated online through students’ social media and email databases in the Spanish public universities. The social media used for the study were Instagram, LinkedIn and Facebook. Both dissemination methods were chosen for the safety of data collection during the pandemic.
In terms of the questionnaire structure, it should be noted that it is divided into three parts. The first part is for the classification of the individuals in the sample. The second part is to analyse whether individuals have sufficient knowledge about what sustainability is and its three dimensions. Finally, the relevant questionnaire has been carried out to carry out the analysis of the proposed model.
The type of questionnaire chosen is a Likert scale questionnaire. This scale ranges from strongly agree “5” to strongly disagree “0”. The reason for choosing this type of questionnaire is that it is the most widely used and reliable type of scale found in the area of social sciences as it can pick up the level of feeling of the individual comma, which helps to make a more accurate analysis of their thoughts (Alismail & Zhang, 2020).
The number of completed questionnaires was 480 individuals, but after analysing the respondents’ sustainability knowledge, 33 questionnaires were eliminated as they did not meet the minimum levels of basic sustainability knowledge.
Table 2 shows the classification of the individuals analysed. It can be seen that the majority of individuals (58.84%) are women compared to 47.74% of men. In terms of hours of use of social media, it can be seen that most individuals use social media between one and two hours a day. They are followed by users who use social media between 2 and 3 h per day. It is also worth noting the extremes of the sample in terms of daily hours of social media use 4.35% of the sample use social media less than 30 min compared to 16.23% of the sample who use social media more than 4 h a day. Between 1 and 2 h is the most predominant range of social media use per day with 23.87%. Regarding the number of social media used by the individuals in the sample, 24.6% have more than five social media, followed by individuals who have three social media with 23.77%, and only 5.22% of the individuals surveyed have only one social media.Table 2 Sample Characteristics (n = 347)
Classification variable Variable Frequency Percentage
Gender Female 203 58.84%
Male 144 47.74%
Daily networking < 30 min 15 4.35%
30 min/1 h 39 11.30%
1/2 h 96 27.83%
2/3 h 80 23.19%
3/4 h 61 17.68%
> 4 h 56 16.23%
Number of social media used 1 18 5.22%
2 49 14.20%
3 82 23.77%
4 69 20.00%
5 44 12.75%
> 5 83 24.06%
Source own elaboration
Method of data analysis
The methodology applied in this study for the validation of the measurement scale and its subsequent measurement analysis is the method of Partial Least Squares Structural Equation Modeling (PLS-SEM). This method of structural equations based on variances makes it possible to obtain the estimation of the measurement model proposed, taking into account the dependent and independent variables that form it (Hilkenmeier et al., 2021). It also allows the possibility of obtaining the size of the indirect and direct effects that exist in the relationship between variables (Del-Castillo-Feito et al., 2020). Its use is also common when conducting analyses of composite models, allowing the estimation of latent variables and the measurement of the structural model (Hair et al., 2018). Such models can be composed of both reflective and formative variables since PLS-SEM is able to analyse with both in the same model (Gelashvili et al., 2021a, 2021b), as well as decide whether or not to impose the direction and sign of the hypotheses stated in the model (Hair et al., 2011).
This methodology is an excellent option for conducting analyses in social science studies (Cachón-Rodríguez et al., 2021) and is supported by published studies in the areas of economics, sociology, business and others (Schnelbächer and Heidenreich, 2020). This is not only evidence of the exponential increase in the use of PLS-SEM in research articles, but also of the introduction of PLS-SEM as one of the main methods of analysis in statistical analysis books (Cepeda-Carrión et al., 2022). In the case of novel studies, Hair et al. (2019) advise using PLS-SEM, since its analysis allows a more sensitive study of these experimental relationships. As for Sarstedt et al. (2020), they indicate that the requirements of PLS-SEM analysis are currently increasing in complexity and stringency, confirming the critical importance of the analysis methods of this methodology and further demonstrating its robustness.
For the analysis of this study, the SmartPLS software has been used, whose reliability is proven and which is highly applied in most studies using the PLS-SEM methodology (Stolze & Sailer, 2022).
Analysis of the results
Measurement model
In the analysis of the study results, it should be noted that the research is divided into two parts. In the first part of this study, the analysis of the validation of the measurement scale is carried out. Checking that the items used in the questionnaire are valid, the scale of measurement is acceptable for analysis. Once the measurement scale has been validated, the second part of the analysis is carried out. In this second part, the study of the relationships of the proposed model and its predictive capacity is carried out.
To carry out the first part of the analysis, it must be considered that all variables are reflective in nature. This indicates that a series of studies must be applied to validate it. The calculations used are Individual reliability, composite reliability, convergent validity and discriminant validity. The results obtained in these analyses can be seen in Tables 3 and 4.Table 3 Measurement items
Constructs Items Correlation loading CA rho_A CR AVE
Intensity of use (ITU-1) Social networking is part of my daily activity 0.776*** 0.72 0.777 0.807 0.586
(ITU-2) I am proud when I say to people that I use social media 0.881***
(ITU-3) I would have a hard time if social media disappeared 0.617**
Economic sustainability (SUSEC-1) My university tries to maximise its profit to ensure its continuity 0.636*** 0.867 0.880 0.905 0.658
(SUSEC-2) My university tries to build long-term relationships with its iter groups to ensure its long-term success 0.843***
(SUSEC-3) My university is continuously trying to improve the quality of the services it offers 0.866***
(SUSEC-4) My university tries to have a competitive pricing policy 0.805***
(SUSEC-5) My university tries to do everything possible to be more productive 0.881***
Social sustainability (SUSS-1) My university supports and sponsors public health programmes 0.749*** 0.91 0.913 0.928 0.650
(SUSS-2) My university sponsors social and cultural events (music, sport, etc.) 0.728***
(SUSS-3) My university is involved in and financially supports social causes 0.857***
(SUSS-4) My university helps to improve the quality of life of the local community 0.831***
(SUSS-5) My university treats employees fairly (no discrimination or abuse, regardless of gender, race, origin or religion) 0.821***
(SUSS-6) My university provides training and promotion opportunities for employees 0.819***
(SUSS-7) My university helps to solve social problems 0.828***
Evironmental sustainability (SUSE-1) My university has a recycling policy 0.873*** 0.94 0.94 0.952 0.768
(SUSE-2) My university promotes positive environmental ethics among stakeholders 0.879***
(SUSE-3) My university values and protects the environment 0.902***
(SUSE-4) My university has pollution awareness campaigns 0.853***
(SUSE-5) My university defends the diversity of nature, encouraging it to be valued and protected 0.881***
(SUSE-6) My university tries to use only the necessary natural resources 0.870***
CA = Cronbach’s alpha; CR = Composite Reliability; AVE = Average Variance Extracted
*p-valor < 0,05, **p-valor < 0,01, ***p-valor < 0,001
Source: own elaboration
Table 4 Measurement discriminant validity
Constructs Fornell-Lakert Heterotrait-Monotrait ratio (HTMT)
Intensity of use Environmental sustainability Economic sustainability Social Sustainability Intensity of use Environmental sustainability Economic sustainability Social Sustainability
Intensity of use 0.766
Environmental sustainability 0.108 0.876 0.134
Economic sustainability 0.133 0.687 0.811 0.158 0.757
Social sustainability 0.157 0.714 0.798 0.806 0.184 0.772 0.893
Source: own elaboration
First, we carried out the analysis of individual reliability. The research is applied by taking into account the loadings (λ) of the items. The criterion chosen for this study sets the threshold at 0.707 (Carmines & Zeller, 1979; Del-Castillo-Feito et al., 2020); the threshold was exceeded for all the items in this study. The same applies to the study of composite reliability, where Cronbach’s Alpha is analysed using the criterion of Nunnally and Bernstein (1994). The level of reliability of this study is high. To increase the robustness of the study, we have also carried out the analysis of Dijkstra and Henseler (2015) by setting a cut-off ratio (rho_A) of 0.7 (Gelashvili et al., 2021a, 2021b), which also outperformed by all the variables in the study.
As for the convergent validity analysis, the average variance extracted (AVE) is analysed and measured using the criterion of Fornell and Larcker (1981). This criterion states that the AVE must obtain at least a 50% explanation of the underlying constructs, with a cut-off point of 0.5 (Hair et al., 2018). After analysing the convergent validity, all the study constructs exceed the cut-off score.
To satisfactorily complete the analysis of the measuring instrument, it is necessary to carry out the last analysis criterion. The study of discriminant validity analyses the amount of variance that a construct obtains from its indicators (AVE) and whose contribution must be more significant than that which it can share with other constructs in the model (Cachón-Rodríguez et al., 2021; Del-Castillo-Feito et al., 2020).
Two criteria are used for this analysis, the Fornell-Lakers criterion (1981), which analyses the amount of variance of a variable captured from its indicators. This must be greater than what it shares with other variables (Del-Castillo-Feito et al., 2019). The second criterion is the Heterotrait-monotrait ratio (HTMT) criterion. This criterion is more current and more rigorous than the analysis of (Hair et al., 2019). This analysis fixes that the confidence intervals should not exceed 0.9. This would indicate that the variables in the model analysed would be empirically different from (Dijkstra & Henseler, 2015). All items pass the Fornell-Lakert criterion, but not the Heterotrait-monotrait ratio (HTMT) criterion, where item ITU-4 had to be removed for the criterion to be met (Cachón Rodríguez et al., 2019).
Once all the analyses carried out have been satisfactory, it can be said that the scale of measurement proposed has been validated. This statement indicates that the items are valid to measure the relationships proposed in the model of this study.
Structural model analysis
Once the measurement scale has been studied, the structural model is studied. For this purpose, a bootstrapping of 50,000 samples is carried out, which allows us to obtain the t-statistics and the standard errors. Hair et al. (2019) state that for studies with experimental relationships, a bootstrapping of 10,000 samples can be used, but in this case, to make the study more robust, it was decided to bootstrap 50,000 samples.
Obtaining t-statistics and standard errors allow the possibility of measuring the relationships in the structural model and analysing the model’s predictive capacity. Before starting, a study should be carried out to show no multicollinearity in such a model. The criterion used is the VIF criterion, which measures whether there is multicollinearity in the model. The maximum level of VIF indicators of the endogenous variables is five points (Gelashvili et al., 2021a, 2021b).
Applying this analysis, scores of less than 2.74 have been obtained so that the structural model is considered to show no symptoms of multicollinearity. Therefore, the PLS analysis is carried out to measure the relationship between the different variables analysed.
The model analysis shows that all hypotheses are validated (Table 5 and Fig. 3) and accepted. The hypothesis “H.1” Intensity of use → Economic Sustainability has a low significance while the other three hypotheses; “H.2” Economic Sustainability → Social Sustainability, (H.3) Economic Sustainability → Environmental Sustainability and “H.4” Social Sustainability → Environmental Sustainability have a high significance. Similarly, the t-statistics and confidence intervals also indicate the acceptance of all hypotheses stated in the model.Table 5 Analysis of the hypotheses in the structural model proposed
Path coeff (β) Statistics t (β/STDEV) f2 Confidence interval
5.0% 95.0%
H1. Intensity of use Economic Sustainability 0.133* 1.78 0.11 0.042 0.249
H2. Economic Sustainability Social Sustainability 0.798*** 33.422 1.748 0.758 0.837
H3. Economic Sustainability Environmental Sustainability 0.324*** 3.972 0.15 0.188 0.459
H4. Social Sustainability Environmental Sustainability 0.456*** 5.347 0.167 0.312 0.596
R2: Environmental Sustainability = 0.548; Economic Sustainability = 0.18; Social Sustainability = 0.636
Q2: Environmental Sustainability = 0.416; Economic Sustainability = 0.10; Social Sustainability = 0.407
For n = 50,000 subsamples. Students in single queue *p < 0.05; **p < 0.01 ***p < 0.001
Source: own elaboration
Fig. 3 Proposed research model (results).
Source: own elaboration
Similarly, the t-statistics and confidence intervals also indicate the acceptance of all hypotheses stated in the model (Aldás-Manzano, 2014). If we look at the explained variance of the constructs “Economic Sustainability” and “Social Sustainability”, they have a medium but close to high or substantial predictive power. In the case of the predictive power of the construct “Economic Sustainability,” it has a weak predictive power (Chin, 1998).
Finally, effect size analysis studies how an exogenous variable contributes to explaining an endogenous variable. It can be seen that hypotheses “H.1” and “H.3” have a negligible effect, while hypotheses “H.2” and “H.4” have a moderate explanatory effect (Cohen, 1988). As for the predictive relevance of the model (Q2) obtained by blindfolding, we can see that the model has predictive validity (Hair et al., 2019).
Discussion
As we can see in Fig. 3, four hypotheses have been analysed in this study to see the direct relationship between the intensity of use of social media and economic sustainability in relation to Spanish public universities. This relationship has been established as academic literature (Purvis et al., 2019; Ranjbari et al., 2021) considers economic sustainability as part of social and environmental sustainability (see Fig. 1). The measurement of these relationships using PLS-SEM with reflective and formative variables and the analysis of the sign of the hypothesis, significance, path coefficient and t-statistics has provided important insights into the field of sustainability. The analyses carried out show us through data analysis reliable results for practical analysis (Saura et al., 2022a). The results have shown that the relationship between intensity of use and economic sustainability is significant. Therefore, based on the result, hypothesis 1 is accepted although the relationship between the two variables is not very strong. Studies by (Hair, et al., 2019) consider that the results obtained between intensity of use and economic sustainability are valid for acceptance.
Other hypotheses make reference to the relationship between the three dimensions of sustainability at the university level. According to Purvis et al. (2019) the largest dimension of sustainability is environmental sustainability, which includes social sustainability and within social sustainability we can find economic sustainability. On this basis we can assume that economic sustainability is part of social and environmental sustainability. Therefore, hypotheses 2 and 3 have been proposed, which study the relationship between economic sustainability and social and environmental sustainability. PLS-SEM has again been used to measure the proposed relationships and the results have shown that there is a direct and positive relationship between the proposed relationships. Hypotheses 2 and 3 are therefore accepted. According to the results obtained, both hypotheses have been accepted with a high significance and a strong relationship.
Finally, the relationship between the social and environmental dimensions has been studied. The relationship established between these two variables is direct and positive with a high level of significance. The assessment has also been done with PLS-SEM and has fulfilled the hypothesis sign, significance, path coefficient and t-statistics.
Summarising the analysis of the study where the relationship between intensity of use and the dimensions of sustainability is studied, it is important to analyse these relationships because as demonstrated in the study their relationship exists both theoretically and practically.
Conclusions and implications
This study aimed to determine whether the intensity of use of social media in public universities in Spain impacted economic sustainability. Also, to check whether there was a relationship between social, economic and environmental sustainability at the university level. It is considered essential to analyse this aspect because the pandemic caused by Covid-19 has led universities to change their face-to-face teaching style to online teaching, which has increased the use of social media. In order to achieve the objectives set out in the study, we have used the methodology of PLS-SEM and through this we have verified the relationship between the study variables, which were intensity of use of social media, economic sustainability, social sustainability and environmental sustainability in the Spanish public universities. A sample of 447 students from the university was used for this purpose.
The first hypothesis that studied the relationship between the intensity of social media use and economic sustainability in higher education has shown that there is a positive and direct relationship between them, although the relationship is rather weak. There are no previous studies that have studied this relationship before so it is not possible to compare and see if this result is in line or not with other academic literature. In all ways we can conclude that the intensity of social media use by university students has a positive effect on economic sustainability. This relationship could be caused by cost savings related to the intensive use of ICTs during the pandemic. Other hypotheses of the study focused on the relationship between the three dimensions of sustainability at university level. The results obtained have confirmed a strong and positive relationship between economic sustainability and social and environmental sustainability. The relationship between social sustainability and environmental sustainability has also been established. These results align with some of the literature (Purvis et al., 2019; Ranjbari et al., 2021), where it was confirmed that the three dimensions of sustainability work together and each of them is positively related to the others. Therefore, we can affirm that the three pillars of sustainability have a positive and strong relationship at the university level. This implies that if the actions of only one dimension of sustainability are carried out by the university, this will automatically positively affect the other two dimensions of sustainability, allowing to work as a set of dimensions. Theoretical and practical implications derived from the results of this work are proposed below.
Theoretical Implications
This study has theoretical implications for the academic literature. The review of the academic literature has shown many studies on the three dimensions of sustainability but very few that analyse these dimensions together, measuring the impact they have on each other (Murphy, 2012). Furthermore, most of the studies are theoretical, without being able to use quantitative data. In addition to this, it has been seen that the use of social media has increased considerably in the last two years, which has its advantages and disadvantages for both companies and users. With that in mind (i) This study contributes to the literature on the excessive use of social media that during the pandemics had to be used as teaching tools. Future literature should focus on the importance of this variable because apart from the advantages, it has disadvantages that are extremely dangerous (Latif et al., 2019) in the long term; (ii) This study contributes to the academic literature on the relationship between the three dimensions of sustainability, which is not much, and most of the studies are theoretical; (iii) More focus should be on the relationship between social media use and economic sustainability, since the result is weak. If other studies confirm this result, it may be interesting in the future to promote its practical implementation in higher education institutions.
Practical implications
From a practical point of view, this study contributes to and underlines the importance of implementing sustainable actions in higher education institutions. Universities are bridges to promote sustainable activities that will be developed in the future by students who are the future generations. Therefore, much attention must be paid to the correct implementation of each of the three pillars of sustainability at the university level. One of the main implication of the study is that universities should promote and lead to creation of sustainable knowledge, as a study by the Saura et al., (2022a, 2022b, 2022c) has concluded that the creation of sustainable knowledge is an important factor in driving sustainability and the circular economy. These practices can be generalised to public or private companies too. Therefore, it should be noted that an increase in the intensity of the organisation’s social media use will lead to better economic sustainability. Investments in social network management will be necessary. And in turn, this improvement in economic sustainability will lead to an improvement in social and environmental sustainability.
Limitations and future research
This study is not free of limitations. The first limitation is the sample analysed, the low number of responses and analysing only some universities, not all Spanish public universities may influence the results. Having a complete sample is important because several studies have indicated that location can be an important factor in Spain as it is a country with several autonomous communities and a lot of difference between them in terms of economic and social level. Another limitation is the non-existence of another robustness test of the methodology. Therefore, future lines of research will focus on improving these aspects, firstly to try to get a larger and more generalised sample and secondly to use another type of methodology and compare the results in order to have more robust results.
Acknowledgements
This research paper was presented at the BENI Conference 2022—Business, Entrepreneurship & Innovation. We would like to express our sincere gratitude to the organizers of this Conference and our session chair for valuable comments and suggestions.
Funding
This research received no external funding.
Declarations
Conflicts of Interest
The authors declare no conflict of interest.
1 https://assets.ey.com/content/dam/ey-sites/ey-com/en_gl/topics/sustainability/ey-the-future-of-sustainability-reporting-standards-june-2021.pdf
2 https://en.unesco.org/themes/education-sustainable-development/what-is-esd/sd
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References
Adedoyin OB Soykan E Covid-19 pandemic and online learning: The challenges and opportunities Interactive Learning Environments 2020 10.1080/10494820.2020.1813180
Adesote SA Fatoki OR The role of ICT in the teaching and learning of history in the 21st century Educational Research and Reviews 2013 8 21 2155 2159 10.5897/ERR2013.1617
Ajmal MM Khan M Hussain M Helo P Conceptualizing and incorporating social sustainability in the business world International Journal of Sustainable Development & World Ecology 2018 25 4 327 339 10.1080/13504509.2017.1408714
Al Hawaj AY Buallay AM A worldwide sectorial analysis of sustainability reporting and its impact on firm performance Journal of Sustainable Finance & Investment 2022 12 1 62 86 10.1080/20430795.2021.1903792
Albareda-Tiana S Fernández Morilla M Mallarach Carrera JM Vidal Raméntol S Barreras para la sostenibilidad integral en la Universidad Revista Iberoamericana De Educación 2017 73 253 272 10.35362/rie730301
Aldás-Manzano MJ Moutinho AK Bigné L Manrai E Confirmatory Tetrad Analysis as a tool to decide between the formative/reflective nature of constructs in marketing and management research The Routledge Companion to the Future of Marketing 2014 Routledge 348 378
Ali Taha V Pencarelli T Škerháková V Fedorko R Košíková M The use of social media and its impact on shopping behavior of Slovak and Italian consumers during COVID-19 pandemic Sustainability 2021 13 4 1710 10.3390/su13041710
Alismail S Zhang H Exploring and understanding participants’ perceptions of facial emoji Likert scales in online surveys: A qualitative study ACM Transactions on Social Computing 2020 3 2 1 12 10.1145/3382505
Alshehhi A Nobanee H Khare N The impact of sustainability practices on corporate financial performance: Literature trends and future research potential Sustainability 2018 10 2 494 10.3390/su10020494
Amaral AR Rodrigues E Gaspar AR Gomes Á A review of empirical data of sustainability initiatives in university campus operations Journal of Cleaner Production 2020 250 119558 10.1016/j.jclepro.2019.119558
Amrutha VN Geetha SN A systematic review on green human resource management: Implications for social sustainability Journal of Cleaner Production 2020 247 119131 10.1016/j.jclepro.2019.119131
Andreassen CS Billieux J Griffiths MD Kuss DJ Demetrovics Z Mazzoni E Pallesen S The relationship between addictive use of social media and video games and symptoms of psychiatric disorders: A large-scale cross-sectional study Psychology of Addictive Behaviors 2016 30 2 252 10.1037/adb0000160 26999354
Atanda JO Developing a social sustainability assessment framework Sustainable Cities and Society 2019 44 237 252 10.1016/j.scs.2018.09.023
Baert S Lippens L Moens E Weytjens J Sterkens P The COVID-19 crisis and telework: A research survey on experiences, expectations and hopes SSRN Electronic Journal 2020 10.2139/ssrn.3596696
Barrot JS Social media as a language learning environment: A systematic review of the literature (2008–2019) Computer Assisted Language Learning 2021 10.1080/09588221.2021.1883673
Basiago AD Economic, social, and environmental sustainability in development theory and urban planning practice The Environmentalist 1998 19 2 145 161 10.1023/A:1006697118620
Belzunegui-Eraso A Erro-Garcés A Teleworking in the Context of the Covid-19 Crisis Sustainability 2020 12 9 3662 10.3390/su12093662
Bhatti A Akram H Basit HM Khan AU Raza SM Naqvi MB E-commerce trends during COVID-19 Pandemic International Journal of Future Generation Communication and Networking 2020 13 2 1449 1452
Boer M Stevens GW Finkenauer C de Looze ME van den Eijnden RJ Social media use intensity, social media use problems, and mental health among adolescents: Investigating directionality and mediating processes Computers in Human Behavior 2021 116 106645 10.1016/j.chb.2020.106645
Borga F Citterio A Noci G Pizzurno E Sustainability report in small enterprises: Case studies in Italian furniture companies Business Strategy and the Environment 2009 18 3 162 176 10.1002/bse.561
Cachón Rodríguez G Prado Román C Zúñiga-Vicente JÁ The relationship between identification and loyalty in a public university: Are there differences between (the perceptions) professors and graduates? European Research on Management and Business Economics 2019 25 3 122 128 10.1016/J.IEDEEN.2019.04.005
Cachón-Rodríguez G Blanco-González A Prado-Román C Diez-Martin F Sustainability actions, employee loyalty, and the awareness: The mediating effect of organization legitimacy Managerial and Decision Economics 2021 10.1002/mde.3340
Cadil J Mirosnik K Petkovova L Mirvald M Public support of private R&D–effects on economic sustainability Sustainability 2018 10 12 4612 10.3390/su10124612
Carmines E Zeller R Reliability and validity assessment 1979 SAGE Publications, Inc.
Centobelli P Cerchione R Esposito E Evaluating environmental sustainability strategies in freight transport and logistics industry Business Strategy and the Environment 2020 29 3 1563 1574 10.1002/bse.2453
Cepeda-Carrión G Hair JF Ringle CM Roldán JL García-Fernández J Guest editorial: Sports management research using partial least squares structural equation modeling (PLS-SEM) International Journal of Sports Marketing and Sponsorship 2022 23 2 229 240 10.1108/IJSMS-05-2022-242
Charoensukmongkol P Mindful Facebooking: The moderating role of mindfulness on the relationship between social media use intensity at work and burnout Journal of Health Psychology 2016 21 9 1966 1980 10.1177/1359105315569096 25680915
Chin WW Marcoulides GA The partial least squares approach to structural equation modeling Modern methods for business research 1998 Lawrence E 295 336
Coccia M High health expenditures and low exposure of population to air pollution as critical factors that can reduce fatality rate in COVID-19 pandemic crisis: A global analysis Environmental Research 2021 199 111339 10.1016/j.envres.2021.111339 34029545
Cohen J Statistical power analysis for the behavioral sciences 1988 Routledge
Cunha DR Moneva JM The elaboration process of the sustainability report: A case study Revista Brasileira De Gestão De Negócios 2018 20 533 549 10.7819/rbgn.v0i0.3948
Del-Castillo-Feito C Blanco-González A González-Vázquez E The relationship between image and reputation in the Spanish public university European Research on Management and Business Economics 2019 25 2 87 92 10.1016/j.iedeen.2019.01.001
Del-Castillo-Feito C Cachón-Rodríguez G Paz-Gil I Political disaffection, sociodemographic, and psychographic variables as state legitimacy determinants in the European Union American Behavioral Scientist 2020 10.1177/0002764220981116
Dennen VP Choi H Word K Social media, teenagers, and the school context: A scoping review of research in education and related fields Educational Technology Research and Development 2020 68 4 1635 1658 10.1007/s11423-020-09796-z
Dijkstra TK Henseler J Consistent partial least squares path modeling MIS Quarterly 2015 39 2 297 316 10.25300/MISQ/2015/39.2.02
Dubbelink SI Herrando C Constantinides E Social media marketing as a branding strategy in extraordinary times: Lessons from the COVID-19 pandemic Sustainability 2021 13 18 10310 10.3390/su131810310
Eizenberg E Jabareen Y Social sustainability: A new conceptual framework Sustainability 2017 9 1 68 10.3390/su9010068
Favale T Soro F Trevisan M Drago I Mellia M Campus traffic and e-Learning during COVID-19 pandemic Computer Networks 2020 176 107290 10.1016/j.comnet.2020.107290
Flores RM La Agenda 21 impulsora del desarrollo sostenible y de la protección del medio ambiente en Europa y en España Boletín Económico De Ice 2006 2899 31 46
Fornell C Larcker DF Structure equation models: LISREL and PLS applied to customer exist-voice theory Journal of Marketing Research 1981 18 2 39 50 10.2307/3151718
Fumero, N. P., & Martín, R. H. (2020). Reflexiones sobre sostenibilidad turística durante la pandemia: una agenda para el sector frente a los ODS. Turismo pos-COVID-19. Cátedra de Turismo CajaCanarias-Ashotel de la Universidad.
Gelashvili V Martínez-Navalón JG Enríquez GH How stress and anxiety when using mobile restaurant reservation Apps influence users’ satisfaction and trust Journal of Indian Business Research 2021 13 3 395 412 10.1108/JIBR-08-2020-0276
Gelashvili V Martínez-Navalón JG Saura JR Using partial least squares structural equation modeling to measure the moderating effect of gender: An empirical study Mathematics 2021 9 24 3150 10.3390/math9243150
Gelderman CJ Semeijn J Vluggen R Development of sustainability in public sector procurement Public Money & Management 2017 37 6 435 442 10.1080/09540962.2017.1344027
González-Padilla DA Tortolero-Blanco L Social media influence in the COVID-19 pandemic International Braz j Urol 2020 46 120 124 10.1590/S1677-5538.IBJU.2020.S121 32550706
Goodland R The urgent need for ecosystem integrity and ethics to support environmental sustainability Global Bioethics 1998 11 1–4 29 46 10.1080/11287462.1998.10800729
Hair JF Ringle CM Sarstedt M PLS-SEM: Indeed a silver bullet Journal of Marketing Theory and Practice 2011 19 2 139 152 10.2753/MTP1069-6679190202
Hair JF Risher JJ Sarstedt M Ringle CM When to use and how to report the results of PLS-SEM European Bussines Review 2019 31 1 2 24 10.1108/EBR-11-2018-0203
Hair JF Sarstedt M Ringle CM Gudergan SP Advance issues in partial least squares structural equation modeling 2018 Sage Publishing
Hamadi M El-Den J Azam S Sriratanaviriyakul N Integrating social media as cooperative learning tool in higher education classrooms: An empirical study Journal of King Saud University-Computer and Information Sciences 2021 34 6 3722 3731 10.1016/j.jksuci.2020.12.007
Hamid S Ijab MT Sulaiman H Anwar RM Norman AA Social media for environmental sustainability awareness in higher education International Journal of Sustainability in Higher Education 2017 18 4 474 491 10.1108/IJSHE-01-2015-0010
Hansmann R Mieg HA Frischknecht P Principal sustainability components: Empirical analysis of synergies between the three pillars of sustainability International Journal of Sustainable Development & World Ecology 2012 19 5 451 459 10.1080/13504509.2012.696220
Haseeb M Hussain HI Kot S Androniceanu A Jermsittiparsert K Role of social and technological challenges in achieving a sustainable competitive advantage and sustainable business performance Sustainability 2019 11 14 3811 10.3390/su11143811
Hashim S Masek A Abdullah NS Paimin AN Muda WHNW Students’ intention to share information via social media: A case study of COVID-19 pandemic Indonesian Journal of Science and Technology 2020 10.17509/ijost.v5i2.24586
Hilkenmeier F Fechtelpeter C Decius J How to foster innovation in SMEs: Evidence of the effectiveness of a project-based technology transfer approach The Journal of Technology Transfer 2021 10.1007/s10961-021-09913-x
Hornuf L Stenzhorn E Vintis T Are sustainability-oriented investors different? Evidence from equity crowdfunding The Journal of Technology Transfer 2021 10.1007/s10961-021-09896-9
Howes M Wortley L Potts R Dedekorkut-Howes A Serrao-Neumann S Davidson J Nunn P Environmental sustainability: A case of policy implementation failure? Sustainability 2017 9 2 165 10.3390/su9020165
Izzo L Santonastaso A Cotticelli G Federico A Pacifico S Castaldo L Ritieni A An Italian survey on dietary habits and changes during the COVID-19 lockdown Nutrients 2021 13 4 1197 10.3390/nu13041197 33916384
Jogezai NA Baloch FA Jaffar M Shah T Khilji GK Bashir S Teachers’ attitudes towards social media (SM) use in online learning amid the COVID-19 pandemic: The effects of SM use by teachers and religious scholars during physical distancing Heliyon 2021 7 4 e06781 10.1016/j.heliyon.2021.e06781 33948511
Koul B Yakoob M Shah MP Agricultural waste management strategies for environmental sustainability Environmental Research 2022 206 112285 10.1016/j.envres.2021.112285 34710442
Kuhlman T Farrington J What is sustainability? Sustainability 2010 2 11 3436 3448 10.3390/su2113436
Lasarte MP Bruna DG Duque CM Planificación turística, promoción y sostenibilidad ambiental: el caso de España Retos 2018 8 15 7 17 10.17163/ret.n15.2018.01
Latif MZ Hussain I Saeed R Qureshi MA Maqsood U Use of smart phones and social media in medical education: Trends, advantages, challenges and barriers Acta Informatica Medica 2019 27 2 133 10.5455/aim.2019.27.133-138 31452573
Lăzăroiu G Ionescu L Uță C Hurloiu I Andronie M Dijmărescu I Environmentally responsible behavior and sustainability policy adoption in green public procurement Sustainability 2020 12 5 2110 10.3390/su12052110
Liao L Warner ME Homsy GC When do plans matter? Tracking changes in local government sustainability actions from 2010 to 2015 Journal of the American Planning Association 2020 86 1 60 74 10.1080/01944363.2019.1667262
Lucini D Gandolfi CE Antonucci C Cavagna A Valzano E Botta E Biganzoli E # StayHomeStayFit: UNIMI’s approach to online healthy lifestyle promotion during the COVID-19 pandemic Acta Bio Medica: Atenei Parmensis 2020 91 3 e2020037 10.23750/abm.v91i3.10375
Malesios C Skouloudis A Dey PK Abdelaziz FB Kantartzis A Evangelinos K Impact of small-and medium-sized enterprises sustainability practices and performance on economic growth from a managerial perspective: Modeling considerations and empirical analysis results Business Strategy and the Environment 2018 27 7 960 972 10.1002/bse.2045
Martínez-Navalón JG Gelashvili V Debasa F The impact of restaurant social media on environmental sustainability: An empirical study Sustainability 2019 11 21 6105 10.3390/su11216105
Mieczkowski H Lee AY Hancock JT Priming effects of social media use scales on well-being outcomes: the influence of intensity and addiction scales on self-reported depression Social Media + Society 2020 6 4 1 15 10.1177/2056305120961784
Mishra A Positive side effects of the Covid-19 pandemic on environmental sustainability: Evidence from the quadrilateral security dialogue countries Management of Environmental Quality: An International Journal 2022 33 3 674 691 10.1108/MEQ-09-2021-0214
Moldan B Janoušková S Hák T How to understand and measure environmental sustainability: Indicators and targets Ecological Indicators 2012 17 4 13 10.1016/j.ecolind.2011.04.033
Morelli J Environmental sustainability: A definition for environmental professionals Journal of Environmental Sustainability 2011 1 1 2 10.14448/jes.01.0002
Murphy K The social pillar of sustainable development: a literature review and framework for policy analysis Sustainability: Science, Practice and Policy 2012 8 1 15 29 10.1080/15487733.2012.11908081
Naidoo M Gasparatos A Corporate environmental sustainability in the retail sector: Drivers, strategies and performance measurement Journal of Cleaner Production 2018 203 125 142 10.1016/j.jclepro.2018.08.253
Najah FFL Nurazizah YS Mulyana AA The effect of social media use intensity on anxiety, depression and stress level during covid-19 pandemic outbreak International Journal of Nursing and Health Services (IJNHS) 2021 4 5 522 529 10.35654/ijnhs.v4i5.508
Nchofoung TN Asongu SA ICT for sustainable development: Global comparative evidence of globalisation thresholds Telecommunications Policy 2022 46 5 102296 10.1016/j.telpol.2021.102296
Nunnally, J. C., & Bernstein, I. H. (1994). Psychometric theory. (MCGraw-Hil). 3aed. Michigan.
Obi-Ani NA Anikwenze C Isiani MC Social media and the Covid-19 pandemic: Observations from Nigeria Cogent Arts & Humanities 2020 7 1 1799483 10.1080/23311983.2020.1799483
Ojo, E., Mbohwa, C., & Akinlabi, E. (2015). Sustainability-competitive advantage. In: Proceedings of the 2015 International Conference on Operations Excellence and Service Engineering, Florida. pp. 592–600.
Pappas E A new systems approach to sustainability: University responsibility for teaching sustainability in contexts Journal of Sustainability Education 2012 3 1 3 18
Parrado Castañeda ÁM Trujillo Quintero HF Universidad y sostenibilidad: Una aproximación teórica para su implementación AD-Minister 2015 26 149 163 10.17230/ad-minister.26.7
Pennington N Communication outside of the home through social media during COVID-19 Computers in Human Behavior Reports 2021 4 100118 10.1016/j.chbr.2021.100118 34568638
Permana IPH Meinarni NPS Ratio analysis on Tiktok (social media) for qualitative research using explorative methods Jurnal Ekonomi & Bisnis JAGADITHA 2021 8 1 30 38 10.22225/jj.8.1.2944.30-38
Pouri MJ Hilty LM Bungartz HJ Kranzlmüller D Weinberg V Weismüller J Wohlgemuth V ICT-enabled sharing economy and environmental sustainability—a resource-oriented approach Advances and new trends in environmental informatics: Managing disruption, big data and open science 2018 Cham Springer International Publishing 53 65
Purvis B Mao Y Robinson D Three pillars of sustainability: In search of conceptual origins Sustainability Science 2019 14 3 681 695 10.1007/s11625-018-0627-5
Qorri A Mujkić Z Kraslawski A A conceptual framework for measuring sustainability performance of supply chains Journal of Cleaner Production 2018 189 570 584 10.1016/j.jclepro.2018.04.073
Rai SS Rai S Singh NK Organizational resilience and social-economic sustainability: COVID-19 perspective Environment, Development and Sustainability 2021 23 8 12006 12023 10.1007/s10668-020-01154-6 33519297
Rajeh MT Sembawa SN Nassar AA Al Hebshi SA Aboalshamat KT Badri MK Social media as a learning tool: Dental students’ perspectives Journal of Dental Education 2021 85 4 513 520 10.1002/jdd.12478 33219515
Ranjbari M Esfandabadi ZS Zanetti MC Scagnelli SD Siebers PO Aghbashlo M Tabatabaei M Three pillars of sustainability in the wake of COVID-19: A systematic review and future research agenda for sustainable development Journal of Cleaner Production 2021 297 126660 10.1016/j.jclepro.2021.126660 34785869
Roberts JA David ME On the outside looking in: Social media intensity, social connection, and user well-being: The moderating role of passive social media use. Canadian Journal of Behavioural Science/Revue canadienne des sciences du comportement 2022 10.1037/cbs0000323
Royant-Parola S Londe V Tréhout S Hartley S The use of social media modifies teenagers’ sleep-related behavior L’encephale 2017 44 4 321 328 10.1016/j.encep.2017.03.009
Ruhnke K Gabriel A Determinants of voluntary assurance on sustainability reports: An empirical analysis Journal of Business Economics 2013 83 9 1063 1091 10.1007/s11573-013-0686-0
Sardianou E Stauropoulou A Evangelinos K Nikolaou I A materiality analysis framework to assess sustainable development goals of banking sector through sustainability reports Sustainable Production and Consumption 2021 27 1775 1793 10.1016/j.spc.2021.04.020
Sarstedt M Ringle CM Cheah JH Ting H Moisescu OI Radomir L Structural model robustness checks in PLS-SEM Tourism Economics 2020 26 4 531 554 10.1177/1354816618823921
Saura JR Herráez BR Reyes-Menendez A Comparing a traditional approach for financial Brand communication analysis with a big data analytics technique IEEE Access 2019 7 37100 37108 10.1109/ACCESS.2019.2905301
Saura JR Ribeiro-Soriano D Palacios-Marqués D Assessing behavioral data science privacy issues in government artificial intelligence deployment Government Information Quarterly 2022 10.1016/j.giq.2022.101679
Saura JR Ribeiro-Soriano D Palacios-Marqués D Adopting digital reservation systems to enable circular economy in entrepreneurship Management Decision 2022 10.1108/MD-02-2022b-0190
Saura JR Ribeiro-Soriano D Saldaña PZ Exploring the challenges of remote work on Twitter users’ sentiments: From digital technology development to a post-pandemic era Journal of Business Research 2022 142 242 254 10.1016/j.jbusres.2021.12.052
Schnellbächer B Heidenreich S The role of individual ambidexterity for organizational performance: Examining effects of ambidextrous knowledge seeking and offering The Journal of Technology Transfer 2020 45 5 1535 1561 10.1007/s10961-020-09781-x
Segovia-Vargas MJ Camacho-Miñano MDM Pedrosa Alberto FC Gelashvili V Sheltered employment centres: Sustainability and Social Value Sustainability 2021 13 14 7900 10.3390/su13147900
Sellami YM Hlima NDB Jarboui A An empirical investigation of determinants of sustainability report assurance in France Journal of Financial Reporting and Accounting 2019 17 2 320 342 10.1108/JFRA-02-2018-0019
Sharma K Anand A Kumar R The role of Yoga in working from home during the COVID-19 global lockdown Work 2020 66 4 731 737 10.3233/WOR-203219 32925134
Sibley CG Greaves LM Satherley N Wilson MS Overall NC Lee CH Houkamau CA Effects of the COVID-19 pandemic and nationwide lockdown on trust, attitudes toward government, and well-being American Psychologist 2020 75 5 618 630 10.1037/amp0000662 32496074
Silmi ZK Rachmawati WR Sugiarto A Hastuti TP Correlation of Intensity of Use of Social Media with The Level of Social Anxiety In Adolescents Midwifery and Nursing Research 2020 2 2 60 64 10.31983/manr.v2i2.5880
Stolze A Sailer K Advancing HEIs’ third-mission through dynamic capabilities: The role of leadership and agreement on vision and goals The Journal of Technology Transfer 2022 47 2 580 604 10.1007/s10961-021-09850-9 33840891
Troise C Camilleri MA Camilleri MA The use of digital media for marketing, CSR communication and stakeholder engagement Strategic corporate communication in the digital age 2021 Emerald Publishing Limited 161 174
Ur Rahman R Ali Shah SM El-Gohary H Abbas M Haider Khalil S Al Altheeb S Sultan F Social media adoption and financial sustainability: Learned lessons from developing countries Sustainability 2020 12 24 10616 10.3390/su122410616
Valdez D Ten Thij M Bathina K Rutter LA Bollen J Social media insights into US mental health during the COVID-19 pandemic: Longitudinal analysis of Twitter data Journal of Medical Internet Research 2020 22 12 e21418 10.2196/21418 33284783
Velazquez L Munguia N Platt A Taddei J Sustainable university: What can be the matter? Journal of Cleaner Production 2006 14 9–11 810 819 10.1016/j.jclepro.2005.12.008
Venegas-Vera AV Colbert GB Lerma EV Positive and negative impact of social media in the COVID-19 era Reviews in cardiovascular medicine 2020 21 4 561 10.31083/j.rcm.2020.04.195 33388000
Zhong B Jiang Z Xie W Qin X Association of social media use with mental health conditions of nonpatients during the COVID-19 outbreak: Insights from a national survey study Journal of Medical Internet Research 2020 22 12 e23696 10.2196/23696 33302256
| 0 | PMC9734591 | NO-CC CODE | 2022-12-14 23:28:29 | no | J Technol Transf. 2022 Dec 8;:1-25 | utf-8 | J Technol Transf | 2,022 | 10.1007/s10961-022-09984-4 | oa_other |
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Environ Sci Pollut Res Int
Environ Sci Pollut Res Int
Environmental Science and Pollution Research International
0944-1344
1614-7499
Springer Berlin Heidelberg Berlin/Heidelberg
36484938
24541
10.1007/s11356-022-24541-0
Research Article
Assessing financial factors for oil supply disruptions and its impact on oil supply security and transportation risks
Li Zhenxing [email protected]
1
http://orcid.org/0000-0002-0597-458X
Hasan Mohammad Maruf [email protected]
[email protected]
234
http://orcid.org/0000-0003-1363-2747
Lu Zheng [email protected]
3
1 grid.412720.2 0000 0004 1761 2943 School of Economics and Management, Southwest Forestry University, Yunnan Kunming, 650233 China
2 grid.13291.38 0000 0001 0807 1581 School of International Studies, Sichuan University, Chengdu, 610065 Sichuan China
3 grid.13291.38 0000 0001 0807 1581 School of Economics, Sichuan University, Chengdu, 610065 Sichuan China
4 grid.13291.38 0000 0001 0807 1581 Belt and Road Research Institute of Sichuan University, Chengdu, Sichuan China
Responsible Editor: Nicholas Apergis
9 12 2022
116
16 10 2022
25 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The evaluation of energy security offers a standard for policy research and highlights the problems of securing the energy supply. A composite index for analyzing the risk of Southeast Asian nations’ oil supply is developed in this study. Indicators used to calculate the index include the import-to-LGE ratio, GPR, market liquidity, gross domestic product, the import-to-consumption ratio, heterogeneity, oil price volatility, US$ volatility, and transportation risk. The index is based on these and other factors. According to the findings, Nepal and Sri Lanka are the most susceptible to oil supply interruptions. This indicates that India is more likely to shift its oil suppliers. At the same time, Maldives, Nepal, and Sri Lanka have the lowest supply risk scores, indicating that they are the most vulnerable to supply disruptions. Reduce the effect of oil supply risk by enacting policies such as the adoption of renewable technologies, nuclear power generation, diversification of exporting supplies, and reducing fossil fuel subsidies.
Keywords
Financial factors
Geopolitical rest
Market liquidity
Transportation risk
Supply risk
Southeast Asia
==== Body
pmcIntroduction
The influence of the local and international political and financial atmosphere on the economy, industries, and market behavior has become a focal point of study in the context of an increasingly interconnected globalized trade (Zameer et al. 2021). Recent events, such as the turbulence in global economic industries caused by the COVID-19 outbreak, Britain’s formal withdrawal from Asia, and the escalation of global trade frictions, have only served to heighten this sense of unpredictability (Yasmeen et al. 2020). As a result, scholars have begun to pay more attention to how political uncertainty or political risk can affect economic activities (Zameer et al. 2020b). Additionally, it has been emphasized that geopolitical risk has a role in shaping economic cycles and trends between nations that disrupt the otherwise calm and orderly development of global relations are all examples of geopolitical risks (Wang et al. 2019). Terrorist acts are only one kind of geopolitical risk, conflicts in important locations, political disputes over taxation and state spending, the continuous trade friction between Nepal and India, and so on. Studies of the relationship between conflicts and economies have been informed by actual observations of the impact that GPRs have on economies. Existing research has mainly examined the influences of economic growth on the environment, using both linear and non-linear estimation techniques, because environmental quality changes across the stages of the economy’s development. The EKC framework proposed by Grossman and Krueger has been widely used in the aforementioned studies, with the primary objective of examining the relationship between economic development and environmental quality (Shahbaz et al. 2020). This theory proposes that scale and composition effects contribute to environmental degradation at the outset of economic development in an underdeveloped economy (Zameer et al. 2020a). For instance, during this period of rapid development, industrialization often occurs, leading to a spike in demand for energy, especially fossil fuels, in the context of developing nations, which in turn has negative effects on the environment. However, once economic growth reaches a certain level, the technique effect kicks in, effectively canceling out the trade-off between economic expansion and environmental degradation through the medium of technological progress (Qu et al. 2022). The EKC hypothesis is a set of postulates that advocates for a connection between GDP growth and environmental quality in the form of an inverted U. Several other macroeconomic variables, such as natural resource consumption, technological innovation, globalization, human capital, and financial development, are hypothesized to influence environmental quality.
The treadmill theory of production, endogenous growth theory, and globalization theory of growth can all be used to make sense of the interconnections between technological progress, natural resource availability, international trade, and environmental quality. The treadmill theory of production postulates that using natural resources to make goods is the root cause of environmental degradation (Huang and Liu 2021). To promote economic growth, it is important to make use of natural resources (Han et al. 2022). However, overuse of certain natural resources, such as main fossil fuel sources, may have unfavorable ecological effects, as measured by an increase in ecological footprint. In contrast, limiting the expansion of ecological footprints via the use of natural resources that are easier on the planet may have a significant impact on environmental quality.
Such political news has global repercussions, reinforcing the view that political risk is a critical component in determining the direction of various asset markets. As a result, it is crucial to consider an investment’s ability to withstand geopolitical risks (Jin et al. 2022). According to a 2017 Gallup poll reflecting the opinions of over a thousand financial backers, a majority of respondents (75%) expressed concern about the global economy as a result of the many militaries and diplomatic crises taking place throughout the globe. Together with economic, macroeconomic, and economic strategy uncertainty, GPRs may have severe adverse impacts on asset price dynamics (Xu et al. 2022).
Proponents argue that economic restrictions are the primary obstacle to implementing sustainability in the energy industries; this is a problem that could be exacerbated by seeping geopolitical risks, which would in turn make it more difficult for the green transformation to accelerate its goal of sustainable development (Zhang et al. 2022). The growth of rich and emerging nations’ stock and credit markets are the best predictors of their economies’ overall financial progress. On the other hand, climatic and geopolitical threats make the equities and bond markets, including green bonds industries, very unstable (Hosseini et al. 2013). Given this setting, we want to calculate how green equities and green bonds will react to different global geopolitical threats. There are two ways in which green markets might be affected by geopolitical uncertainty.
To start, the price of hydrocarbons is a major indirect avenue via which geopolitical risk may affect green markets. A large body of recent empirical research shows that fluctuations in oil prices have a negative correlation with green stock and green bond values (Mohsin et al. 2019). Numerous studies show that the oil price is vulnerable to geopolitical concerns (Ikram et al. 2019). The crude oil industry is also impacted by geopolitical risk through the supply and demand channels, as stated. Rising oil costs, however, could boost green investments through the substitution effect since the research suggests that renewable or cleaner energy may replace dirty or carbon-content resources (Iqbal et al. 2019).
Studies of the relationship between conflicts and economies have been informed by actual observations of the impact that GPRs have on economies. Many researchers have tried to dissect the impact of various geopolitical events on financial markets, and such studies have received a lot of attention (Mohsin et al. 2020). Many countries in the present century have undergone civil war, international conflict, political instability, and terrorist attacks; in fact, one-third of all nations have been affected by civil wars alone. Changes in leadership, administration or the occurrence of political upheavals, civil unrest, or more violent incidents like terrorist attacks are all examples of events with the potential to disrupt economic performance and asset markets (Agyekum et al. 2021).
Traditional methods of aggregating indicators were employed in earlier research, which concentrated on particular elements of indicator selection. Furthermore, they failed to account for the relative weights of the various indicators, which makes the findings difficult to trust. A composite indicator technique for assessing oil supply risk has never been used in any prior research. The methodological approach for quantitative risk assessment in oil disruptions is the topic of this study. Many standards are developed, and the interrelationships among all indexes are evaluated and explored. These factors are then combined into (CI) using an integer programming strategy, with constraints on the weights assigned to each sub-indicator. In contrast to other studies, this one examines the oil supply risk in Southeast Asia holistically and adds significantly to the body of knowledge. In addition, we have included an empirical estimate of the interruption of oil supplies in our contribution. Although most models presume that local oil output is unaffected by supply interruption, our research reveals that this assumption has major consequences for oil supply interruption. While several indicators, such as “country-specific” regulations, critical gasoline resources, foreign currency reserves, and environmental exposures that potentially impact the sources of risk of oil supply, have not been studied because of data unavailability.
Literature review and hypothesis development
This section is further separated into two major sub-sections in which the previous one discusses the theoretical framework, while the concluding reviews the related empirical literature.
Theoretical underpinning
According to the endogenous growth hypothesis, emerging countries may improve their economic and environmental well-being via technological innovation that is realized (Iqbal et al. 2022). In addition, technical advancement might be seen as the impetus needed to alter the economic and industrial structure of emerging nations to make better use of natural energy. Energy-use-related emissions may be greatly reduced if technology advancements in the energy sector catalyze the shift from the use of dirty to clean energy sources. Therefore, it is widely understood that public investment in R&D for clean energy development improves environmental well-being (Asbahi et al. 2019). According to this theory, the expansion of the ecological footprints of emerging economies may be slowed by technical innovation via the medium of the clean energy transition.
Globalization, in its many forms, may be beneficial to a country’s economic development, but it also has a wide range of environmental impacts, as the globalization theory of growth acknowledges. For instance, as a result of trade liberalization, more nations are engaging in cross-border commerce to increase their value added. However, there are distinctions among trade partners in terms of environmental consequences (Xia et al. 2020). There is a common misconception that countries with stricter environmental restrictions may take advantage of those with laxer ones via international commerce. Additionally, nations that rely heavily on fossil fuels tend to excel in polluting production methods and eventually become net exporters of polluting products. As a result, it is reasonable to assume that globalization of commerce has unintended ecological implications in these nations (Shah et al. 2019). By contrast, nations that do not rely on fossil fuels for their economies should see good environmental consequences as a result of globalization, thanks to their ability to specialize in and export cleaner commodities.
Alternatively, it has been argued that improvements in human capital, particularly via the channels of investments in health and education, might affect environmental quality (Mohsin et al. 2020). Human capital development, for instance, may raise people’s environmental consciousness, which in turn motivates them to adopt eco-friendly purchasing habits that have a beneficial effect on the environment. Investment in education has been postulated to encourage energy consumers to utilize greener energy sources and switch to cleaner energy options, which would significantly reduce (Xiuzhen et al. 2022). Moreover, it might ultimately help in developing technical advances and employing defend qualities. A further tenet of endogenous growth theory is that investments in R&D and human capital go hand in hand. Therefore, it may be predicted once again that improving human capital can improve the environment by way of technical innovation. Finally, it is argued that an economy’s financial system has a significant impact on its environmental quality. An undeveloped financial system may be harmful to environmental quality, although it is expected to increase economic development. Pollution-heavy companies, for instance, may find it easier to get financing from the less-developed financial systems of developing nations, where the money borrowed may then be used to support practices that are harmful to the environment (Ullah et al. 2020). Green finance, which may give loans to businesses eager to invest in energy-efficient industrial processes, is one area where a sophisticated financial system might be advantageous (Agri et al. 2018). Economic growth may also have a significant influence on funding R&D programs that seek to advance environmental technology via innovation.
Empirical evidence
Below, we provide a historical overview of the empirical research that has examined the impacts of natural resource usage, technological innovation, globalization, economic growth, human capital, and financial development on the ecological footprint in the context of emerging nations.
Nexus between technological innovation and environment
Due to the small number of research examining the connection between technological innovation and ecological footprint in the setting of developing nations, the literature on the topic is scant. Most of these studies have emphasized the role that improved technology plays in reducing ecological footprint expansion by facilitating more effective resource management (Nhuong and Quang 2022). After analyzing 280 Chinese cities to determine the correlation between technological advancements and environmental impact, the results of this research show that technological progress enhances ecological quality by lowering the tally of environmental harm. Similar findings were reached by Ren et al. (2022) about the need for technology advancement in the mitigation of rising countries’ ecological impact. observed similar results for the BRICS nations. According to the authors, these developing countries’ ecological footprints might be reduced with the aid of emerging environmental technology. But, Darling et al. (2022) argued that technological progress harms the environment in the member states of the Asia–Pacific Economic Cooperation (APEC). The authors argued that APEC nations should embrace cutting-edge technology to speed up the process of industrialization; nevertheless, it has been shown that such developments in technology also have negative effects on the natural world. In conclusion, it is possible to state that a consensus has not yet been achieved in the literature about the effects of technological developments on the ecological footprint.
Nexus between globalization and environment
In summarizing the research on the relationship between globalization and developing countries’ ecological footprint, Ahmad et al. (2019) reviewed about 100 and above studies and concluded that development is a double-edged sword with uncertain environmental effects. According to Maithya et al. (2022), globalization promotes environmental deterioration by raising Turkey’s ecological footprint. reached a similar conclusion for the emerging countries of South Asia, arguing that the nations’ ecological footprints have become worse in tandem with the economy’s increasing involvement in globalization. Using yearly data from 1971 to 2014, however, concluded that globalization had a positive effect on Egypt’s ecological footprint. Diniz et al. (2022) drew parallels between the globalization process and the efforts of Belt and Road Initiative nations to lower their ecological impact over the long term. On the other hand, Ahmadian-Yazdi et al. (2022) looked into the link between financial globalization and ecological footprints and discovered that the former enhances environmental well-being by reducing long-term ecological footprint estimates in the context of developing countries. Relatedly, found that financial globalization may explain the discrepancies in the ecological footprint level of these nations, although economic and trade globalization cannot. This was based on an analysis of 14 MENA economies. made a similar point, arguing that developing nations see an increase in their ecological footprint as a result of financial globalization-induced FDI inflows since their environmental policies are ineffective.
Nexus between economic growth and environment
Since the groundbreaking work of Nassani et al. (2019), the EKC hypothesis has provided a theoretical framework for exploring the connection between real income growth and environmental deterioration. Most of the research that has backed up the EKC theory has noted that once an economy achieves a certain level of development, it can control the rise in the ecological footprint statistics, something it could not do when its economic growth was slower. Using ecological footprint as a surrogate for environmental quality, used the generalized method of moments (GMM) strategy and found support for the EKC hypothesis across an assemblage of developing countries over the long term, who conducted a similar analysis for five Southeast Asian countries and also found that economic growth increases ecological footprint figures monotonically; however, they concluded that the EKC hypothesis was correct because the predicted elasticity parameter for the squared term of economic growth was relatively smaller. However, the EKC hypothesis has been disputed by several earlier research, which have indicated that it does not apply to all economies. Therefore, this research indicated that it may not be able to lower the ecological footprint level even after attaining the level of economic development necessary to do so and that continued economic growth might lead to a larger ecological footprint level instead. According to Khan et al. (2020), the EKC theory for ecological footprint does not apply to Tunisia because of the U-shaped link between economic development and environmental deprivation in the country. However, discovered a U-shaped relationship between China’s and India’s economic growth and ecological footprint, suggesting that the EKC hypothesis’s veracity has yet to be shown for these emerging countries. Similarly, research in China rejected the EKC theory for the same reason.
Nexus between human capital and environment
Charnes et al. (1978) utilized annual data to estimate the connection within the context of developing nations. Based on the data, it seems that improvements in human capital only have a negligible effect on the national ecological footprint in the near term. To be more specific, the authors argued that investing in education to increase human capital can raise people’s consciousness about the dangers of environmental degradation, which in turn can lead to better resource management and preservation. Gilbertson et al. (2012) found that investing in human capital reduced South Africa’s and China’s respective long-term ecological footprint figures. Renault et al. (2017) looked at the situation in India, another growing country, and found similar evidence that increasing human capital led to a smaller ecological footprint. In addition, the authors determined that human capital had a direct and unambiguous impact on the estimated ecological footprint. However, found a negative in a survey of 13 MENA nations. Human capital growth, the authors observed, is linked to greater economic potential and social well-being, both of which are likely to increase ecological demand and the resulting footprint. Therefore, on the environment are unknown.
Nexus between financial development and environment
In the existing literature, particularly in the context of rising nations, it has been demonstrated that there are several natural elements associated with financial development. Financial expansion may raise the environmental footprints of industrialized nations, but it may reduce the footprints of less-developed countries over the long run (He et al. 2019). For this reason, the authors suggested that achieving ecological sustainability in underdeveloped countries is more reliably accomplished by bolstering the credibility of the banking sector than in affluent nations. The researchers hypothesized that the negative correlation between economic development and environmental cost in developing countries could be accounted for by the underdeveloped economic industries of these nations; consequently, they concluded that even moderate development in the economic industry does not lead to a corresponding increase in environmental footprints. In contrast, Fang et al. (2021) indicated that economic development is bad for Qatar’s environment since it increases the nation’s immediate and long-term environmental footprint. To examine the link between GDP development and environmental cost, a group of researchers from 11 developing nations utilized the augmented mean group (AMG) estimator (Bertoldi and Mosconi 2020). Singapore had a positive correlation between economic growth and environmental footprint, whereas China and Vietnam had a negative correlation, and India, Brazil, the Philippines, Mexico, South Korea, South Africa, Bangkok, and Istanbul had no important correlation at all. New evidence reveals, however, that the environmental costs of low-, middle-, and high-income nations are largely unaffected by financial expansion. Therefore, studies that have shown economic growth to be negative for the environment have typically concluded that it may lead to a larger demand for environmental reserves and that the use of these resources might impose higher chances of rising environmental footprint statistics.
Data and method
The GRA-SRA energy poverty index method
Because many indexes are used to measure energy poverty, there is no one standard to measure it, making a quantitative assessment of energy poverty even more critical. Thus, the authors have devised an all-encompassing index to measure energy crises and simultaneously incorporate the current situation when analyzing norms and indexes for assessing energy poverty. As a result, the multifunctional energy poverty complete index is a broad measure that depicts home energy consumption effectiveness and purity. China’s unique energy import, energy supply development, domestic energy spending, and the total quantity of cookery implements were all analyzed by Verhoef et al. (2015). As a result, this study employs both GRA and SRA methods to evaluate the power index.
The indicator indicates a nation’s actual performance throughout the evaluation phase. An approximation of the values of factors for multifunctional energy poverty is made when two parameters have a close link to each other. A higher percentage of weight is given to the indices that have the greatest number of significant correlations. The GRA method calculates connection levels when assigning weights, while SRA employs a balanced price strategy. After that, the indication weights and numbers are combined to produce an oil extent of poverty using a simple linear weighting technique. Because of this, the basic idea of GRA is to establish similarities between various indicators and reference indices to verify the tightness of a connection. When it comes to the gray interference pattern among the hands, geometrical (GRA) (Porter 1980).
When it comes to a gray interference pattern among the indicators, geometrical (GRA) Furthermore, the comparison series displays the effectiveness of signal k over n assessment phases (defined), while the comparison series reflects the efficacy of indication I over n assessment phases (denoted). The following approaches are used to determine the GRA level between the variables. GRA may be calculated using these steps. Calculating the mean image (or initial image) of X0 and Xi, i = 1, 2, …, m.
where1 Xi′=Xixi1=xi′1,xi′2,xi′3,⋯,xi′n;i=0,1,2,⋯,m
Calculating the difference sequences of i = 1, 2, …, m as2 Δjk=x0′k-xi′k,Δ=Δi1,Δi2,Δi3,⋯,Δin,i=1,2,⋯,m
Ascertaining the maximum and minimum variances3 M=maximaxkΔikm=miniminkΔik
Computing gray relational coefficients by4 Y0ik=m+ξMΔik+ξM;ξ∈0,1;k=1,2,3,⋯,n;i=1,2,3,⋯,m
where ξ is the differentiating coefficient, which is estimated to be 0.5 in the literature.
Computing the gray relational grade by5 Y0i=1n∑k=1nY0ik;i=1,2,⋯,m2′
where 1/n can be substituted by the weights wk, as in the following; if the effect of each factor is different, where ∑kn=16 Y0i=1n∑k=1nY0ik.wk;i=1,2,⋯,m
Therefore, 1/n means the criteria weights are equally distributed, and Wk implies that the consequences are unevenly distributed, which resembles a common actual life scenario. Further discussion is provided by the differentiation of the dual GRA equations. Because all of the input conditions had equal values, we conclude that Deng’s Greg Analyses is a perfect starting point (He et al. 2020). The dual directional absolute GRG is computed using the following procedure for the two variable sets Xi and Xj.Placing the set of data with associated mirrored sequencing together with normalization.
Making sure that the data numbers vary between 0 and 1 in each sequence.
Determining the specific set of zero-starting line pictures.
Calculating |si|, |sj|, and |sj–si|.
To determine pure GRG (), the following steps must be followed:7 εij=1+si+sj1+si+sj+sj-si
Calculating the dual directional absolute.
GRG (ε ±), as8 ε±=+maxεij,εijn;Δ=εij-εijn>0
9 ∈±=+maxεij,εijn;Δ=εij-εijn>0-maxεij,εijn;Δ=εij-εijn<0
“ − ” is the opposite correlation, and “ + ” is a clear correlation. A gray relation’s strength may be measured by assigning stages to such signals. Accordingly, JCL and the JGI scales explain the data, with probably 2 different links being described.
To indicate the variables of t and the rising outcome variable, Xtm is set. The high values from phase t to phase t − 1 and the lagged ordering of the increasing variable, q, are also shown. Frequency distribution-mixed frequencies regression has the following particular form:10 t=α+0tm+1t-mm+⋯+mt-1m+⋯+2mt-2m+⋯+qmt-qm+t
Abbreviated as follows: = α + (θ,)tm + tmtm=t-i/mm
The delayed operator L goes by the letter L. the classic regression model’s attributes and t = N (0, 2) are similar to the randomized perturbations period’s characteristics.
A vector autoregressive lagged-mixed statistics regression model is proposed by (2013) in mixed statistics (ADL-MIDAS model). Given that the model’s components are of the first order, we may write down the model as follows: t + 1L = α + γtL + (m,)H + tL.
According to this study, China’s petroleum safety ratings are Yt + 1L. Rising explaining variables are measured by XtH and reduced independent variable by m, with the latter denoting the quantity of data sample from t to t + 1. Here, monthly GPRs are (m,) = i = 1(i;)i − 1)m.
It is a phrase that represents a random error. Lagged operators are used in conjunction with a quadratic weighting factor for rising data to create the weight function W(L1m,θ) = ∑i = 1pxω(i;θ)L(i − 1)/m. The rising explanatory variable’s distributed lagged ordering is denoted by the symbol px.
In their paper, a wide range of MIDAS models and weights factors are presented by Nasim and Fatima (2020). Almon polynomials scale value, exponential Almon polynomials value component, beta weight function, etc., are some of the most commonly used weighted values. This study uses the beta function as a weighting factor because of its usefulness to techniques used to collect and the accessibility of its variables. The MIDAS model uses beta sources. List probability density. The beta distribution family has various forms that just 2 factors may represent. The overgrowth of parameters produced by combining data may be efficiently avoided. This study uses the beta functional as the weighting factor because of its evaluation and accessibility of variables. The MIDAS model uses beta sources. List probability density. The many variants of the beta distribution family may be represented using only two variables. When data is mixed together, the multiplication of parameters may be avoided. It may be described in terms of what it does: (8)ωi(θ) = ωi(θ1,θ2) = f(xi,θ1,θ2)∑i = 1imaxf(xi,θ1,θ2).
ωi(θ) = ωi(θ1,θ2) = f(xi,θ1,θ2)i = 1imaxf(xi,θ1,θ2), where i is the distribution lag order, Imax is the maximum lag order of the weight function. The variation range of i is i = 0, 1, …, Imax. In addition, xi = i/Imax, where i is the distribution lag order, and Imax is the maximum lag order of the weight function. The variation range of i is i = 0, 1, …, Imax. In addition, xi = i/imax, f(xi,θ1,θ2) = xiθ1 − 1(1 − xi)θ2 − 1Γ(θ1 + θ2)Γ(θ1)Γ(θ2), Γ(θ) = ∫0∞e – xxθ − 1dx.fxi,θ1,θ2=xiθ1-11-xiθ2-1Γθ1+θ2Γθ1Γθ2,Γθ=0∞e-xxθ-1dx.
Data
In this study, we use the GPR index introduced by Caldara and Hosseini et al. (2013) to quantify geopolitical unpredictability. Terrorist threats, nuclear tensions, war threats, and military battles between nations all have a role in this. Through a series of textual searches, have tallied the total number of times that references to geopolitical tensions have been made. Eleven domestic and foreign newspapers’ digital archives were combed, and the GPR of 19 areas was calculated (Gielen et al. 2019). Compared to other methods of assessment, GPR’s readings are quick and frequent. We analyzed the potential effects of global GPR, GPR BROAD from oil-exporting countries, GPR from oil-importing countries, and China’s GPR on China’s oil security. India, Nepal, Bhutan, Sri Lanka, Afghanistan, and Pakistan are among the nations that export oil to the extent that this information is currently available. Other than the aforementioned five nations, there are a total of 14 nations and areas that do not participate in oil exports.
This study covers the period from January 1999 to December 2017 since there is a dearth of incomplete data from the last few years. The National Bureau of Statistics provides the figures for reliance on oil imports. Both the CEIC financial database and the U.S. Energy Data Management are mined for the oil carbon intensity and the oil carbon dioxide emission percentage (EIA) (Lin and Zhu 2019). Brent crude oil price from the BP Statistical Review of World Energy is used as the international crude oil price and U.S. Energy Information Administration figures for China’s GDP and population. The author uses data from BP’s Statistical Review of World Energy to compile the rest of the measures (Ahmad et al. 2020). Some examples include the percentage of oil imported as a whole, the part of global oil manufacturing that China holds, the reserve manufacturing ratio, etc.
Results and discussion
Gold scarcity helps stimulate financial development in developing nations. The health of a corporation may be affected by gold in various ways. Money serves as a store of value and a medium of trade; hence it must be protected by money. Furthermore, it is a secure kind of finance, among other benefits. Gold’s value is set on the global market, where it is traded at a constant rate. Gold was a safe refuge for stockholders during the great depression (Bucelli et al. 2018). According to the economic model, when times are tough, share prices fall and gold prices go up. This is why gold is seen as a haven for investors concerned about inflation. The share market often experiences large-scale crashes. Much research has shown that bond prices drop and gold prices rise during times of crisis. The glue is high; therefore, it is a good time to sell gold and purchase stocks.
Political risk index score
Oil is a crucial part of today’s global economy and geopolitical risk (GRP). The development and improvement of transportation have contributed to a rise in oil usage (Dotan et al. 2022). Oil is essential to the running of many sectors, and even a little fluctuation in oil prices might affect share industry results. The economic and financial development systems of the nations that import and export oil determine the degree of this volatility. Table 1 demonstrates that oil price and gold price futures have the largest mean values for liquidities, indicating that these two futures are the least liquid. A large percentage of trading days with no training is a sign of illiquidity, and it is also the cause of the low median value for research estimations of stock price movements in sample share prices. It has been shown via study that size bias may be influenced by differences in mean and standard liquidity variations across product future industries (Xu et al. 2020). To account for any size bias in the liquidity assessments, this research normalized the data. Five common measures of liquidity are summarized statistically in Table 1. These results demonstrate that the scale effect has been mitigated in commodities’ future markets generally. Livestock futures have a low average value because of the frequent occurrence of trading days with no buyers or sellers (Tsujimoto et al. 2019).Table 1 Descriptive statistics
LGE LGB GPR GPR BROAD GPR NARROW GPR THREAT GRP ACT Oil
Mean 5.7768 4.9887 4.8665 4.6988 4.90898 4.9487 4.099 3.007
Median 5.2887 4.9087 4.8765 4.6687 4.85787 4.8897 4.0899 3.02543
Maximum 6.8698 5.0677 5.98876 5.6898 5.99687 6.0477 5.697 5.0321
Minimum 4.3487 4.8088 4.0398 4.1887 4.04588 4.0587 2.5299 2.5678
Std. dev 0.6077 0.0676 0.3498 0.2786 0.36287 0.3698 0.5198 0.8756
Skewness 0.9098 0.5687 0.4288 0.6198 0.39487 0.4198 − 0.1980 − 0.1660
Kurtosis 3.1398 2.5087 2.7187 3.2698 2.61676 2.5777 3.3898 2.8976
Jarque–Bera 254.6888 116.6198 61.0878 121.1879 59.9987 67.0098 18.4798 23.7654
Probability 0.2222 0.2222 0.2222 0.2222 0.222222 0.3345 0.4432 0.4321
Observations 1860 1860 1860 1860 1860 1860 1860 1860
Findings suggest that effects on futures market sizes may be moderate and that product future markets exhibit wide variation in standard deviations of liquidity indicators. To reduce the potential for size bias, we recalculated the liquidity indicators (Zhang et al. 2018). The size effect on product futures industries is reduced by looking at Table 1, which offers a statistical summary of five basic liquidity parameters (Table 1).
As stand-ins for the global oil price, we choose the price of crude oil, often known as petroleum, including GRP, LGE, LGB crude oil, Brent crude oil, gas oil, and heating oil. Modern economic systems see these crude oils as important production factors, which means they may have far-reaching consequences for several sectors of the international economy (Barrutia and Echebarria 2021). In addition, the prices of geopolitical risk (GRP) crude oil, Brent crude oil, gasoline, and heating oil are widely recognized as major worldwide benchmarks for petroleum prices. For example, GRP crude oil is produced and sold all over the globe as a reflection of the global supply and demand framework, as described by Cross and Todorov (2014). However, the relevance of studying crude oil’s directional predictability to share prices may be highlighted by the fact that its price has fluctuated widely over the last two decades owing to economic crises, political tensions, conflicts, global wars, etc.
The accessibility of information for the relevant factors dictates both the start and end points of the sample periods. DataStream provides information on oil prices and financial markets, whereas the website http://www.policyuncertainty.com/about.html is where you may get information about GPR and uncertainty. After that, we use the standard approach to compute daily returns by deducting the natural logarithm of prices on day t − 1 from prices on day t.
The GPR index is constructed by Kaklauskas et al. (2018).
The index is calculated by counting how many times key phrases associated with GPR appear in each of the selected newspapers every day starting in 1984. And last, they standardize the index to a value of 100 for the years 2005–2020.
Energy independence, energy-saving, carbon dioxide emission, technical advancements, and refinery systems analysis are vital topics of existing research into China’s refinery sector in China’s petroleum industry. Walls examined China’s oil refinery business in the context of the international economy using statistics since 2008 (Table 2) but was upbeat about refinery capacity increase in the upcoming (Ranjan et al. 2021) from the standpoint of energy supplies. China’s oil industry chain was analyzed to see how stock market returns reacted to worldwide oil price changes. Impacts on oil production, need, demand, shocks, spillover effects, and cautious requirement shocks significantly impacted current and foreseeable oil availability. In their paper, Mitchell and Mitchell explained the structural crisis in the oil and gas sector throughout the globe. According to the study, the worldwide oil sector is shaped by the management and goals established by national oil firms like China. The country’s enormous oil companies and the authorities that control them must adapt to a new context that has decreased oil consumption. Still, domestic demand has grown excessively due to pricing mismatches between local and overseas markets.Table 2 Political risk index score
Country 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
Afghanistan 0.41 0.47 0.71 0.71 0.66 0.57 0.77 0.59 0.46 0.49 0.64 0.59 0.47 0.62 0.65 0.64
Bangladesh 0.47 0.38 0.46 0.52 0.58 0.61 0.67 0.69 0.57 0.41 0.69 0.76 0.55 0.54 0.66 0.56
Bhutan 0.59 0.68 0.77 0.76 0.68 0.67 0.65 0.69 0.71 0.69 0.77 0.77 0.71 0.84 0.85 0.65
India 0.57 0.64 0.46 0.48 0.51 0.53 0.49 0.47 0.48 0.36 0.45 0.34 0.37 0.39 0.43 0.53
Nepal 0.63 0.69 0.69 0.62 0.59 0.74 0.76 0.79 0.75 0.81 0.83 0.65 0.67 0.79 0.81 0.68
Pakistan 0.37 0.45 0.41 0.39 0.38 0.37 0.41 0.42 0.34 0.31 0.32 0.32 0.34 0.37 0.28 0.33
Sri Lanka 0.42 0.47 0.47 0.41 0.39 0.42 0.41 0.44 0.29 0.37 0.32 0.34 0.36 0.29 0.44 0.42
Maldives 0.64 0.84 0.63 0.61 0.59 0.72 0.73 0.76 0.75 0.81 0.79 0.67 0.68 0.75 0.61 0.59
Geopolitical risk index score
The Chinese government needed a solution to the issue and has endeavored to promote oil sector innovations. China’s energy supply networks were examined by Leung et al. When it comes to the security of the country’s electricity generation networks, China’s reliance on the refining oil products of the USA is highlighted. Montero et al. (2012) provided an overview of China’s petroleum company’s present growth stage from the perspectives of oil supply reliance and global commerce (Table 3). They reviewed the current dangers of energy flow, finances, and the climate using design options from supplier viewpoints. The threat of refiner equipment breakdown is a concern. Because of the large amount of Middle Eastern oil with a rising sulfur content and the rising need for reduced transportation fuel, many new refineries are needed to perform oil with rising sulfur content and start producing softer and smoother crude oil. According to the researcher, this would cause much more excessive (Table 3).Table 3 Physical oil supply risk
Country 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
Afghanistan 0.38 0.51 0.69 0.66 0.70 0.61 0.80 0.61 0.50 0.51 0.70 0.61 0.51 0.59 0.71 0.64
Bangladesh 0.51 0.41 0.50 0.48 0.61 0.59 0.71 0.71 0.61 0.39 0.71 0.80 0.61 0.60 0.70 0.56
Bhutan 0.61 0.70 0.80 0.80 0.70 0.71 0.71 0.71 0.66 0.71 0.80 0.80 0.69 0.90 0.91 0.65
India 0.61 0.70 0.50 0.50 0.49 0.49 0.51 0.51 0.50 0.41 0.51 0.40 0.41 0.41 0.50 0.53
Nepal 0.59 0.71 0.71 0.59 0.61 0.80 0.80 0.81 0.81 0.77 0.77 0.71 0.71 0.81 0.77 0.68
Pakistan 0.41 0.51 0.39 0.41 0.40 0.41 0.39 0.39 0.41 0.29 0.29 0.29 0.41 0.41 0.31 0.33
Sri Lanka 0.42 0.47 0.47 0.41 0.39 0.42 0.41 0.44 0.29 0.37 0.32 0.34 0.36 0.29 0.44 0.42
Maldives 0.64 0.84 0.63 0.61 0.59 0.72 0.73 0.76 0.75 0.81 0.79 0.67 0.68 0.75 0.61 0.59
In addition, several studies examine the refinery company’s fuel efficiency and emissions that impact the environment. There are several ways to reduce the amount of energy used in refinery and converter operations, and. assessed the potential for power in technology advancement. An examination of the reduction potential suggested by various technical advances was conducted by Gamage et al. (2021) to examine CO2 emission in Chinese chemical industrial processes.
Expensive-to-run fuel performance and system administration are some of the focus areas of several studies. Inter MPEC planning model developed by Mandema et al. (2005) was used to optimize the planning of the fueling gas line in refineries (see Table 3). The diesel fuel system of the refinery may benefit from the suggested method’s increased energy efficiency (Cockerill et al. 2004). Refinery sector heat recovery was the primary focus of. Modeling and simulating an ORC system to collect inter-wasted heating elements included considering thermal efficiency, platform simplicity, technical feasibility, and economic aspects. Installation growth is coupled with an issue with capacity. The conducting site between power businesses and grid firms was addressed, and optimum simulations were constructed. According to Martinez-Tejada et al. (2021), China suffers from a lack of traditional thinking. It was found that China’s power source was formed by resource scarcity and capability under-utilization. Below was driven by policies and long-term investment choices related to fuel rising prices ingraining. To summarize, the refinery company’s excess supply has been noted just a few times in the previous study. However, existing research suggests that China’s refining industry faces a severe but unsolved overcapacity problem because of the supply–demand conflict in the national oil sector, the processing facility electricity security concerns, and the immediate requirement for developed factories to fulfill tighter pollution rules.
Market liquidity is a significant factor in the oil vulnerability index as a whole. India, South Korea, and Japan have the worst situations, with values of 0.168, 0.175, 0.08, and 0.68, correspondingly. In contrast, a stronger indicator of market liquidity is the fact that Afghanistan, Bhutan, Nepal, and Bangladesh all have values of about 0.001. It is easier for nations like Afghanistan, Pakistan, Nepal, Bhutan, and Bangladesh to move between oil suppliers because of their lower market liquidity. China, the USA, India, South Korea, and Japan all have large impacts on market liquidity on total risk, whereas Afghanistan, Pakistan, Nepal, Bhutan, and Bangladesh all have small effects (Ma et al. 2021). Table 3 displays the totals for those nations most at risk due to their dependence on oil. Pakistan, Sri Lanka, Nepal, Bhutan, Bangladesh, and Afghanistan all had scores higher than 1, making them susceptible. Countries with scores below 1 but over 0.50 are less at risk.
Dependence risk
As a result of recent research, it has emerged that examining power issues from a supply chain viewpoint has several benefits than overanalyzing them from a more traditional approach. When it comes to brand distribution, the supply chain involves everything from purchasing raw materials to converting them into finished goods. Supply chain management strategy and optimization are the primary focus of current research on the supply chain.
The planning process, yearly review, and optimization of the oil production chain are the primary research areas. Iversen et al. (2002) have reviewed China’s oil production chain safety from a national viewpoint. According to them, the supplier is still in its adolescence in the oil business. Empirical research by Zhang et al. (2021) examined the UK’s adoption and effectiveness of sustainable oil and gas production chains. There are possible improvements for oil supply security focused on supply chain analysis, and a DEA-like model was constructed to assess oil supply security. A study by. examined the effects of several calculated decision options on inventories reducing defects to minimize inventories costs and maintain the same overall risk for stocks from supply chain management practices. According to Duan et al. (2010), a practical technique was used to study supply chain efficiency and cluster competitiveness. The oil production chain of a particular oil firm was modeled using linear models offered by Can and Canöz (2021) who used a disconnected and integrated approach and gave optimal planning for the company. Silva and Henriques (2021) used a Lagrangean decomposition technique for investment planning in the oil supply chain under uncertainty and risk concerns. Vos and Cattaneo (2021) used a scorecard to assess supply chain management’s success. Excess capacity in the supply network, on the other hand, is rarely discussed (see Table 4).Table 4 The results of the unit root test
Variable ADF test PP test
Trend and intercept Trend and intercept
LGE − 62.776*** − 85.7760***
LGB − 86.79987*** − 87.00982***
GPR − 58.3998** − 123.6974***
GPR BROAD − 23.0881*** − 93.1998***
GPR NARROW − 30.2798*** − 92.0499***
GPR THREAT − 17.2984*** − 95.9986***
GPR ACT − 8.8488*** − 100.6678***
OIL − 11.6875*** − 104.2998***
It is well known that most socioeconomic time series data suffer from the unit root issue. Before doing any kind of estimate (LGE, LGB, GPR), we checked to see whether our data had a unit root. Selecting the right time series model for our data is crucial for avoiding the estimate of false regression. We conducted (Ma et al. 2022) four-unit root tests as a result, including the two gold standards (the Augmented Dickey-Fuller (ADF) and Phillips-Perron (PP)) and two more advanced types (with structural breakdowns) (ADF and PP). The data is shown in Table 4. This proves that the variables in this study are stationary at the level of the data and the first difference. As a result, the autoregressive distributed lag (ARDL) model is the most appropriate for determining the parameters of our model.
Physical oil supply risk
A distribution network assessment investigates oil companies' excess capacity and electricity safety concerns. When it comes to supply chain analysis, it provides a holistic overview of the entire industry while also considering particular sectors and their interactions with their transmission and distribution sectors. In the refinery sector, operating capability and excess capacity are governed by supply from the transmission and distribution markets. It also relies on the hazards likely to be faced at a particular time. As a result, from a systemic viewpoint, supply chain analysis may highlight the driving causes behind the overcapacity issue. Supply-chain-related factors, such as refined national products, inventory control, and transportation ability, affect the oil industry’s ability to deal with disruptions in crude oil imports. As a result, distribution network analyses on power security challenges can present sector responses from dynamic response viewpoints (Table 5).Table 5 PCA: the correlation matrix between different geopolitical risk indicators
GPRI GTT UCR URT SAU VC
LGE 2 0.51886 0.84776 0.56777 0.6288 0.66423
LGB 2 0.72498 0.55098 0.36991 0.58849
GPR 2 0.20388 0.24668 0.48842
GPR BROAD 2 0.21882 0.6664
GPR NARROW 2 0.27699
GPR THREAT 2
Market risk index score
It has been frequently used in studies on capital investment mechanisms, improved performance, and policy studies in the energy sector. When it comes to China’s PV power advancement, for example, created a dynamic model that included financial and strategic factors. In their different scenarios of nontraditional oil production, used a system dynamic method. Chen et al. (2021) built a system dynamics simulation model to understand better Canada’s power supply and demand. This section introduces a simple foundation for a dynamic response modeling China’s oil production network. Supply chains are made up of upstream, midstream, and downstream. Drill stations, upgrade systems, and the main power plant are parts of the upstream industry. Refinery and chemical factories make up the midstream industry. The lower industries include transportation and petroleum.
Infrastructure risk
Petroleum is supplied by imports and domestically produced reserves. The term “nationwide petroleum products containers” relates to both government-owned corporate strategy batteries and advertising collections possessed by oil corporations. Then, oil is transferred to production sites following demand arrangements made by the oil corporations. Using a production schedule, petroleum is refined into oil products such as gasoline and diesel. Most of the time, supply and production plans are set at the start of the year and then tweaked each month to reflect market conditions. It is standard procedure to transport petroleum products to local storage and then distribute them to small shops. Purchasing and use of oil products follow. Crude oil is also imported and exported for local storing.
Each thirty period, the everyday processing of petroleum products and the output rates of fuel, gas, and petroleum are modified in our models. The production adjustment mechanism is a crucial refinery industry function. Suppose crude oil supply and refineries are adequate. In that case, our model predicts that the daily production of oil products will match or surpass the preceding 30 time-steps average daily consumption but will not exceed the limits of possible output. There is also a limit on the proportion of fuel in diesel and petrol engines between 2 and 4 (Yumei et al. 2021).
Gasoline and petroleum consumption services, on the other hand, are provided on a daily and monthly basis. The standard deviation for gasoline usage spans 15% compared (February 2008) to 13% (May 2003), and 93 percent of the prediction errors fall within 8 to 8%. More than 81% of the relative errors in kerosene consumption are within the limit of 15 percentage points to 15%, while kerosene demand has a close GPR, LGE, and LGB error range of 49.9 to 23.66%. Equations (1), (2), and (3) have fitting values shown in Table 1. The corresponding default values in Table 2 are offered in different colors, which is also reported in Table 6. The colors red and blue denote positive and negative mistakes, respectively. Using a dark blank indicates a higher absolute inaccuracy. In the first two years, 2008 and 2011, exports of oil products included significant mistakes.Table 6 Regression analysis of oil supply risk
Variables OLS-random effect OLS-fixed effect
LGE − 0.9691 3.4371
(− 0.4459) (− 1.199)
LGB − 0.7021* − 4.8561*
(− 2.81111) (− 3.6191)
GPR 7.1778* 1.0561*
(− 2.1551) (− 19.6041)
GPR BROAD 4.7114* 1.0241*
(− 2.1739) (− 39.4121)
GPR NARROW 0.0788 0.0151
GPR THRAT − 0.9691 3.4371
(− 0.4459) (− 1.199)
GPR ACT − 0.8891 2.5071
(− 0.4519) (− 1.219)
OIL − 0.9688 4.4411
(− 0.4461) (− 1.188)
Constant − 0.7021* − 4.8561*
(− 2.81111) (− 3.6191)
R2 7.1778* 1.0561*
(− 2.1551) (− 19.6041)
N 4.7114* 1.0241*
(− 2.1739) (− 39.4121)
Adj. R2 0.0788 0.0151
Predicted everyday petroleum, fuel, and kerosene consumption are fed into the model using IAEA’s World Energy Outlook 2013 scenario study findings (IEA). Choice functions inside the fuel supply system are activated by inputs from downstream to upstream industries, resulting in transport and distribution plan changes. Fuels such as petrol, diesel, and kerosene are made from crude oil at refineries. Upstream supplies, refineries, and lower needs influence the amount of processing crude oil. The division in the upstream side and only petroleum, diesel, and kerosene are transported since statistics on other oil products are missing.
Every moment in the system corresponds to a single day of actual time. Every month is divided into thirty similar days for ease of computation. Each step of the design mimics the usage, manufacturing, transportation, and storing of oil products.
Overall composite index score
Refining reserve is used for a short period before being transferred to local storing. Local stores handle imports, exports, and transmission to local downstream shops. The collection management strategy is the primary function in the accumulated sector. Shorter and higher limits are imposed to minimize supply problems or overstocks, as in the crude oil supply industry. Based on the average flow-ins and stream of the previous 365 periods, we change the top limit of local storing every 365 moments. A safety factor and the maximum level are assumed to be multiplied together to get the lower threshold of the range. Petrol components have different safety coefficients. If the actual capacity falls below the minimum limitation at any point in the modeling time, order indications will be transmitted upstream. The extra storage space will be transferred to lower-priority areas if demand surpasses the max limit.
Trump’s election as president of China in 2016 was widely anticipated, but his administration has introduced new levels of uncertainty to global geopolitical threats, notably those involving China. Therefore, the paper treats Trump’s election as president of China in 2016 as an exogenous event and treats it as the instrumental variable of China’s geopolitical risk (Barykin et al. 2020). Column (1) of Table 6 is the result of first-stage regression, which has a positive relationship with the geopolitical risk of China (GPR) at the 1 percentage significance level, which supports the nature of relevance for good instrument variable regression that is shown in columns (2) and (3). Consistent with H1, the data demonstrate that the geopolitical risk of China (GPR) is positively associated with both the. We performed a battery of experiments to confirm the usefulness of instrumental variables. The Anderson test has a p-value of 0.000, indicating that there is no under-identification problem; the, which is greater than the critical discriminant value of 16.380, indicating that there is no weak identification problem; and the Sargan test has a p-value of 0.000, indicating that the equation.
Meanwhile, prior work (Williams 2021) suggests that we may employ the geopolitical risk uncertainty of countries other than China as an instrumental variable (Yin et al. 2021). First-stage regression results shown in Table 6 show that it is positively related to China’s geopolitical risk (GPR) at the 1 percentage significance level,
Robustness analysis
Extraction and purification manufacturing excess supply in China is discussed by first defining the supply abilities of the oil production sequence as follows: The retrieval, optimization, transportation, collection, and structures differ of oil work together to match the last requirement and avert supply problems inside specific periods under certain levels of customers’ feedback. If any part of the oil production chain fails, it might lead to an oil production deficit. It is reasonable to anticipate that the oil production chain’s production and transportation processes will be unaffected for a while. Refinery and storing administration significantly impact the oil-supplied company’s capacity to meet demand. For this section, statistical data from 2013 is used. Oil production capabilities in coping with diverse demand fluctuations are studied, but the over degree of the refinery business is quantified based on these results.
providing support for the nature of relevance for a good equipment variable; in contrast, satisfying the nature of heterogeneity for a good instrument factor. The regression analysis is shown in columns (4) and (5). Consistent with H1, the findings indicate a positive relationship between China’s geopolitical risk (GPR). We conducted a battery of tests to confirm the usefulness of instrumental variables and found that the p-value of the Anderson test is 0.000, indicating that the IV2-Korea has no under-identification problem.
Discussions
The COVID-19 problem has had a far-reaching effect on energy consumption, and the steps used to slow it have not been seen for 70 years. The complete impact of the current scenario is yet unclear, but it will be determined by the length of the recovery pathways and lockdown measures adopted throughout the globe (Guisado Hernández et al. 2021). This unanticipated circumstance, together with the state stimulus packages that will be implemented over the following several years, will have far-reaching consequences for the energy sector and the clean energy and energy security transitions that are now underway. Across the value chains of the biomass energy business, the financial effect is felt, with most energy firms reporting (Jaisinghani and Kanjilal 2019) significant revenue losses. Less demand for their goods, such as gas, coal, oil, and power, and reduced pricing, hurt them. As a result of a lack of available storage space, oil prices fell dramatically on average, with geopolitical risk reaching historically low negative prices.
In the aftermath of the COVID-19 pandemic, the biomass sector may develop in quite different ways than in the past. Weak energy companies in any industry may be weakened by low demand and prices, which can put pressure on the company’s finances. Some company segments, such as those with renewable power projects in the strongest economic condition, will be buffered from market signals. These market shocks will be felt most keenly by privately held businesses with extensive price sensitivity. There will be a squeezing together of sellers and buyers.
Concerns concerning energy security have been raised because investments will be required even if it takes a considerable amount of time for global energy consumption to recover to its trend before the COVID-19 crisis. Keeping palm oil output at current levels, reinvesting in aging electricity networks, and replacing aging power generating capacity with a capital-intensive mix of flexible sources and renewables all contribute to maintaining the current levels of energy supply. Expenditure in such endeavors will not be bolstered even by a moderate economic recovery.
Due to worldwide supply chain disruptions, biomass renewable energy solutions are in limited supply. Therefore, the biomass sector needs to prioritize the domestic production of renewable energy technology. Because of this whole reliance on foreign sources for technological advancement, the danger is quite high. Therefore, various methods and procedures for enhancing production capacity should be investigated. Several factors have contributed to a slow decline in renewable energy generation in several countries’ uncertainty about renewable energy’s true capacity, a lack of a trained labor force and financial resources, and an absence of adequate R&D initiatives. As a consequence, in the epidemic condition that affects the unsustainable enterprises active in the off-grid energy sector, the poor facilitation of energy access is a direct result of the lack of local capabilities and disruption in the biomass energy technology supply chains. These factors need cutting-edge practices and efficient policies from biomass suppliers and other interested parties to sustain regional manufacturing capabilities. To achieve development goals related to the sustainability pillars, it is necessary to create and improve their energy technologies and to ease energy access (economic, social, and environmental).
Production sectors, renewable energy-based power generation, economic incentives for R&D projects, carbon trading/pricing, the adoption of Feed-in Tariffs, and other associated regulations might all play a role in fostering the production of biomass renewable energy technology (Muggeridge et al. 2014). It is obvious that a wide variety of incentives already exists; nonetheless, it is important to give top priority to those that might have a significant impact on the decentralization of biomass renewable energy technologies. Investments in research and development (R&D) may be eligible for tax breaks and subsidies, as well as repayment-free cash prizes from a variety of sources. Some additional steps should be considered as well, such as reducing the income tax for selling electricity generated by locally created renewable energy technology, providing economic (Vakulchuk et al. 2020) subsidies to power generated using locally made renewable energy and green technology innovation, etc.
Conclusion and policy implications
An empirical examination of Southeast Asian nations’ oil supply vulnerabilities was carried out in this research. Using a variety of variables, such as supply chain operations, infrastructural risk, market volatility, transportation risk, and dependency risk, a conceptual foundation that is rather thorough is constructed. These indications have been combined using a mathematical composite indicator. Each signal’s weight has been limited to provide a valid assessment. The evaluation has also included country risk for oil-importing and exporting nations. According to our research, the danger potential of these nations varies greatly. For example, financial, social, and geostrategic challenges are all possible in Bhutan and Afghanistan. Maldives, Nepal, and Sri Lanka have the lowest supply risk score, which indicates that they are more likely to shift their oil suppliers.
To attain international oil security, international and domestic energy policy must take into account gasoline consumption sustainably and oil supply. Because each nation has a unique risk profile owing to its signals, each country needs a unique policy instrument to lower its oil supply risk. To achieve the goal, national oil supply security policies should be given the highest priority. The following are the ramifications for public policy that we foresee. Switching to renewable, optimizing energy structure, conserving resources, using and expanding clean energy, and reducing oil consumption are all important first steps in reducing the danger of oil imports from outside. To lessen their dependency on imported oil, oil-importing nations should encourage FDI in local manufacturing and research. Foreign investment in less-developed nations should be protected to guarantee a steady rise in oil imports. Countries that rely on oil imports should work together with other oil importers to reduce their dependence on oil imports. To maintain a steady supply of oil, it is necessary to support a wide range of oil import sources. Exporting nations may shift their reliance on oil from high-risk areas like Africa and Latin America to politically stable ones like Russia, Canada, and South America. This would reduce and diversify their reliance on these regions. Lastly, governments need to maintain the safety and security of transportation by diversifying their transportation routes. The TAPI project, which would deliver Caspian Sea natural gas from Kyrgyzstan through Afghanistan and Pakistan to Delhi, should be pushed to reduce maritime dependence on oil importation. The scarcity of oil resources and the advancement of technologies should be done in order to minimize the effect of an oil supply disruption.
Author contribution
Zhenxing Li: Conceptualization, Software, and Data Creation, Revision of manuscript.
Mohammad Maruf Hasan: Conceptualization, Methodology, Software, Data Creation, Writing-original draft preparation and Revision of manuscript.
Zheng Lu: visualization, editing, proofreading, and Revision of manuscript.
Data availability
The data that support the findings of this study are openly available upon request.
Declarations
Ethical approval and consent to participate
The authors declared that they have no known competing financial interests or personal relationships, which seem to affect the work reported in this article. We declare that we have no human participants, human data or human issues.
Consent for publication
We do not have any individual person’s data in any form.
Competing interests
The authors declare no competing interests.
Preprint service
Our manuscript is not posted on a preprint server prior to submission.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Agri PJ Joyo M Ram N Magsi H Risk assessment of climate variability on rice productivity in Sindh province of Pakistan Agril Engg Vet Sci 2018 34 68 77
Agyekum EB Amjad F Mohsin M Ansah MNS A bird’s eye view of Ghana’s renewable energy sector environment: a multi-criteria decision-making approach Util Policy 2021 10.1016/j.jup.2021.101219
Ahmad M, Beddu S, binti Itam Z, Alanimi FBI (2019) State of the art compendium of macro and micro energies. Advances in Science and Technology Research Journal 13(1):88–109. 10.12913/22998624/103425
Ahmad M Li H Anser MK Are the intensity of energy use, land agglomeration, CO2 emissions, and economic progress dynamically interlinked across development levels? Energy Environ 2020 10.1177/0958305X20949471
Ahmadian-Yazdi F Mesgarani M Roudari S Natural resource rents and social capital interaction: new evidence on the role of financial development J Environ Assess Policy Manag 2022 24 2250021 10.1142/S1464333222500211
Asbahi AAMH Gang FZ Iqbal W Novel approach of principal component analysis method to assess the national energy performance via energy trilemma index Energy Rep 2019 10.1016/j.egyr.2019.06.009
Barrutia JM Echebarria C Effect of the COVID-19 pandemic on public managers’ attitudes toward digital transformation Technol Soc 2021 67 101776 10.1016/j.techsoc.2021.101776 34642513
Barykin SY Kapustina IV Kirillova TV Economics of digital ecosystems J Open Innov Technol Mark Complex 2020 6 124 10.3390/joitmc6040124
Bertoldi P, Mosconi R (2020) Do energy efficiency policies save energy? A new approach based on energy policy indicators (in the EU Member States). Energy Policy. 10.1016/j.enpol.2020.111320
Bucelli M Paltrinieri N Landucci G Integrated risk assessment for oil and gas installations in sensitive areas Ocean Eng 2018 150 377 390 10.1016/j.oceaneng.2017.12.035
Can CK, Canöz I (2021) Testing Minsky’s financial fragility hypothesis for Turkey’s public finances. Public Finan Q. 10.35551/PFQ_2020_4_4
Charnes A Cooper WW Rhodes E Measuring the efficiency of decision making units Eur J Oper Res 1978 10.1016/0377-2217(78)90138-8
Chen CF Li J Shuai J Linking social-psychological factors with policy expectation: using local voices to understand solar PV poverty alleviation in Wuhan, China Energy Policy 2021 151 112160 10.1016/j.enpol.2021.112160
Cockerill KA Iverson GM Jones DS Linnik MD Therapeutic potential of toleragens in the management of antiphospholipid syndrome BioDrugs 2004 18 297 305 10.2165/00063030-200418050-00002 15377172
Darling S, Harvey B, Hickey GM (2022) Advancing pluralism in impact assessment through research capacity: lessons from the Yukon Territory, Canada. J Environ Assess Policy Manag :2250026.10.1142/S1464333222500260
Diniz LL Machado PM Lima JS Coastal scenery quality: a management tool for sandy beaches J Environ Assess Policy Manag 2022 24 2250024 10.1142/S1464333222500247
Dotan A, David P, Arnheim D, Shoenfeld Y (2022) The autonomic aspects of the post-COVID19 syndrome. Autoimmun Rev 21(5):103071. 10.1016/j.autrev.2022.103071
Duan J Dixon SL Lowrie JF Sherman W Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods J Mol Graph Model 2010 29 157 170 10.1016/j.jmgm.2010.05.008 20579912
Fang J Gozgor G Mahalik MK The impact of economic complexity on energy demand in OECD countries Environ Sci Pollut Res 2021 28 33771 33780 10.1007/s11356-020-12089-w
Gamage PT, Dong P, Lee J et al (2021) Hemodynamic alternations following stent deployment and post-dilation in a heavily calcified coronary artery: in silico and ex-vivo approaches. Comput Biol Med 139. 10.1016/j.compbiomed.2021.104962
Gielen D Boshell F Saygin D The role of renewable energy in the global energy transformation Energy Strateg Rev 2019 24 38 50 10.1016/j.esr.2019.01.006
Gilbertson J Grimsley M Green G Psychosocial routes from housing investment to health: evidence from England’s home energy efficiency scheme Energy Policy 2012 10.1016/j.enpol.2012.01.053
Guisado Hernández P Blanco Lobo P Villaoslada I SARS-CoV-2 infection in a pediatrics STAT1 GOF patient under ruxolitinib therapy-a matter of balance? J Clin Immunol 2021 41 1502 1506 10.1007/s10875-021-01081-9 34109505
Han Y Tan S Zhu C Liu Y Research on the emission reduction effects of carbon trading mechanism on power industry: plant-level evidence from China Int J Clim Chang Strateg Manag 2022 10.1108/IJCCSM-06-2022-0074
He L Zhang L Zhong Z Green credit, renewable energy investment and green economy development: empirical analysis based on 150 listed companies of China J Clean Prod 2019 208 363 372 10.1016/j.jclepro.2018.10.119
He W Abbas Q Alharthi M Integration of renewable hydrogen in light-duty vehicle: nexus between energy security and low carbon emission resources Int J Hydrogen Energy 2020 10.1016/j.ijhydene.2020.06.177
Hosseini SE Andwari AM Wahid MA Bagheri G A review on green energy potentials in Iran Renew Sustain Energy Rev 2013 27 533 545 10.1016/j.rser.2013.07.015
Huang S Liu H Impact of COVID-19 on stock price crash risk: evidence from Chinese energy firms Energy Econ 2021 10.1016/j.eneco.2021.105431
Ikram M Mahmoudi A Shah SZA Mohsin M Forecasting number of ISO 14001 certifications of selected countries: application of even GM (1,1), DGM, and NDGM models Environ Sci Pollut Res 2019 10.1007/s11356-019-04534-2
Iqbal W Yumei H Abbas Q Assessment of wind energy potential for the production of renewable hydrogen in Sindh Province of Pakistan Processes 2019 10.3390/pr7040196
Iqbal N Tufail MS Mohsin M Sandhu MA Assessing social and financial efficiency: the evidence from microfinance institutions in Pakistan Pakistan J Soc Sci 2022 39 149 161
Iversen LF Møller KB Pedersen AK Structure determination of T cell protein-tyrosine phosphatase J Biol Chem 2002 277 19982 19990 10.1074/jbc.M200567200 11907034
Jaisinghani D Kanjilal K Marketing investments and firm performance in manufacturing sector: a panel threshold model for China J Asia Pacific Econ 2019 24 117 126 10.1080/13547860.2018.1554617
Jin C, Tsai FS, Gu Q, Wu B (2022) Does the porter hypothesis work well in the emission trading schema pilot? Exploring moderating effects of institutional settings. Res Int Bus Financ 62. 10.1016/j.ribaf.2022.101732
Kaklauskas A Zavadskas EK Radzeviciene A Quality of city life multiple criteria analysis Cities 2018 72 82 93 10.1016/j.cities.2017.08.002
Khan SAR Yu Z Sharif A Golpîra H Determinants of economic growth and environmental sustainability in South Asian Association for Regional Cooperation: evidence from panel ARDL Environ Sci Pollut Res 2020 27 45675 45687 10.1007/s11356-020-10410-1
Lin B Zhu J Determinants of renewable energy technological innovation in China under CO2 emissions constraint J Environ Manage 2019 247 662 671 10.1016/j.jenvman.2019.06.121 31279143
Ma J Mo Z Gal D The route to improve the effectiveness of negative PSAs J Bus Res 2021 123 669 682 10.1016/j.jbusres.2020.10.028 33536692
Ma Q Mentel G Zhao X Natural resources tax volatility and economic performance: evaluating the role of digital economy Resour Policy 2022 75 102510 10.1016/J.RESOURPOL.2021.102510
Maithya JK Ming’ate FLM Letema SC The impact of wetland utilisation on provisioning ecosystem services in Nyando Wetland, Kenya J Environ Assess Policy Manag 2022 24 2250023 10.1142/S1464333222500235
Mandema JW, Hermann D, Wang W et al (2005) Model-based development of gemcabene, a new lipid-altering agent. AAPS J 7. 10.1208/AAPSJ070352
Martinez-Tejada I, Czosnyka M, Czosnyka Z et al (2021) Causal relationship between slow waves of arterial, intracranial pressures and blood velocity in brain. Comput Biol Med 139. 10.1016/j.compbiomed.2021.104970
Mohsin M, Nurunnabi M, Zhang J et al (2020) The evaluation of efficiency and value addition of IFRS endorsement towards earnings timeliness disclosure. Int J Financ Econ. 10.1002/ijfe.1878
Mohsin M, Zaidi U, Abbas Q, Iqbal HMRN, Chaudhry IS (2019) Relationship between multi-factor pricing and equity price fragility: evidence from Pakistan. Int J Sci Technol Res 8:434-442
Montero AJ Diaz-Montero CM Deutsch YE Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer Breast Cancer Res Treat 2012 132 215 223 10.1007/S10549-011-1889-0 22138748
Muggeridge A Cockin A Webb K Recovery rates, enhanced oil recovery and technological limits Philos Trans R Soc A Math Phys Eng Sci 2014 372 20120320 10.1098/rsta.2012.0320
Nasim A, Fatima U (2020) Cost of electricity generation in Pakistan–comparison of coal plants with oil and natural gas based plants. Tech Rep. https://ideaspak.org/wp-content/files_mf/1595325363ElectricityGeneration2020.pdf
Nassani AA Aldakhil AM Abro MMQ The impact of tourism and finance on women empowerment J Policy Model 2019 41 234 254 10.1016/j.jpolmod.2018.12.001
Nhuong BH, Quang PT (2022) Are FDI inflows crucial for environmental protection in various Asian regions? J Environ Assess Policy Manag :2250028. 10.1142/S1464333222500284
Porter ME (1980) Competitive strategy: Techniques for analyzing industries and competitors. University Of Illinois At Urbana-Champaign’s, Academy For Entrepreneurial Leadership Historical Research Reference In Entrepreneurship, Available, pp 917–948
Qu M Liang T Hou J Laboratory study and field application of amphiphilic molybdenum disulfide nanosheets for enhanced oil recovery J Pet Sci Eng 2022 208 109695 10.1016/j.petrol.2021.109695
Ranjan R, Partl R, Erhart R et al (2021) The mathematics of erythema: development of machine learning models for artificial intelligence assisted measurement and severity scoring of radiation induced dermatitis. Comput Biol Med 139. 10.1016/j.compbiomed.2021.104952
Ren X, Qin J, Dong K (2022) How does climate policy uncertainty affect excessive corporate debt? The case of China. J Environ Assess Policy Manag 2250025. 10.1142/S1464333222500259
Renault E Sarisoy C Werker BJM Efficient estimation of integrated volatility and related processes Econom Theory 2017 33 439 478 10.1017/S0266466616000013
Shah SAA Zhou P Walasai GD Mohsin M Energy security and environmental sustainability index of South Asian countries: a composite index approach Ecol Indic 2019 106 105507 10.1016/j.ecolind.2019.105507
Shahbaz M Raghutla C Song M Public-private partnerships investment in energy as new determinant of CO2 emissions: the role of technological innovations in China Energy Econ 2020 86 104664 10.1016/j.eneco.2020.104664
Silva HE Henriques FMA The impact of tourism on the conservation and IAQ of cultural heritage: the case of the Monastery of Jerónimos (Portugal) Build Environ 2021 190 107536 10.1016/j.buildenv.2020.107536
Todorov TS Evaluating project and program management as factor for socio-economic development within EU Procedia Soc Behav Sci 2014 119 819 828 10.1016/j.sbspro.2014.03.092
Tsujimoto Y Rakotoson T Tanaka A Saito K Challenges and opportunities for improving N use efficiency for rice production in sub-Saharan Africa Plant Prod Sci 2019 22 413 427 10.1080/1343943X.2019.1617638
Ullah K Rashid I Afzal H SS7 vulnerabilities—a survey and implementation of machine learning vs rule based filtering for detection of SS7 network attacks IEEE Commun Surv Tutorials 2020 22 1337 1371 10.1109/COMST.2020.2971757
Vakulchuk R Overland I Scholten D Renewable energy and geopolitics: a review Renew Sustain Energy Rev 2020 122 109547 10.1016/j.rser.2019.109547
Verhoef PC Kannan PK Inman JJ From multi-channel retailing to omni-channel retailing J Retail 2015 91 174 181 10.1016/j.jretai.2015.02.005
Vos R Cattaneo A Poverty reduction through the development of inclusive food value chains J Integr Agric 2021 20 964 978 10.1016/S2095-3119(20)63398-6
Wang R Zameer H Feng Y Revisiting Chinese resource curse hypothesis based on spatial spillover effect: a fresh evidence Resour Policy 2019 64 101521 10.1016/j.resourpol.2019.101521
Williams LD Concepts of digital economy and industry 4.0 in intelligent and information systems Int J Intell Networks 2021 2 122 129 10.1016/J.IJIN.2021.09.002
Xia Z Abbas Q Mohsin M Song G Trilemma among energy, economic and environmental efficiency: can dilemma of EEE address simultaneously in era of COP 21? J Environ Manage 2020 10.1016/j.jenvman.2020.111322
Xiuzhen X Zheng W Umair M Testing the fluctuations of oil resource price volatility: a hurdle for economic recovery Resour Policy 2022 79 102982 10.1016/j.resourpol.2022.102982
Xu Y Chen Z Peng MYP Anser MK Enhancing consumer online purchase intention through gamification in China: perspective of cognitive evaluation theory Front Psychol 2020 10.3389/fpsyg.2020.581200
Xu X Lin Z Li X Multi-objective robust optimisation model for MDVRPLS in refined oil distribution Int J Prod Res 2022 60 6772 6792 10.1080/00207543.2021.1887534
Yasmeen H Tan Q Zameer H Exploring the impact of technological innovation, environmental regulations and urbanization on ecological efficiency of China in the context of COP21 J Environ Manage 2020 274 111210 10.1016/j.jenvman.2020.111210 32798843
Yin C Zhao W Cherubini F Pereira P Integrate ecosystem services into socio-economic development to enhance achievement of sustainable development goals in the post-pandemic era Geogr Sustain 2021 2 68 73 10.1016/j.geosus.2021.03.002
Yumei H Iqbal W Nurunnabi M Nexus between corporate social responsibility and firm’s perceived performance: evidence from SME sector of developing economies Environ Sci Pollut Res 2021 28 2132 2145 10.1007/s11356-020-10415-w
Zameer H Wang Y Yasmeen H Reinforcing green competitive advantage through green production, creativity and green brand image: implications for cleaner production in China J Clean Prod 2020 10.1016/j.jclepro.2019.119119
Zameer H, Yasmeen H, Wang R et al (2020b) An empirical investigation of the coordinated development of natural resources, financial development and ecological efficiency in China. Resour Policy 65. 10.1016/j.resourpol.2020b.101580
Zameer H, Wang Y, Vasbieva DG, Abbas Q (2021) Exploring a pathway to carbon neutrality via reinforcing environmental performance through green process innovation, environmental orientation and green competitive advantage. J Environ Manage 296. 10.1016/j.jenvman.2021.113383
Zhang ZEJ Deng Y Effects of fatty acid methyl esters proportion on combustion and emission characteristics of a biodiesel fueled marine diesel engine Energy Convers Manag 2018 10.1016/j.enconman.2017.12.098
Zhang K Wang Z Chen G Training effective deep reinforcement learning agents for real-time life-cycle production optimization J Pet Sci Eng 2022 208 109766 10.1016/j.petrol.2021.109766
Zhang P, Ma C, Sun Y et al (2021) Global hybrid multi-scale convolutional network for accurate and robust detection of atrial fibrillation using single-lead ECG recordings. Comput Biol Med 139. 10.1016/j.compbiomed.2021.104880
| 36484938 | PMC9734592 | NO-CC CODE | 2022-12-14 23:28:29 | no | Environ Sci Pollut Res Int. 2022 Dec 9;:1-16 | utf-8 | Environ Sci Pollut Res Int | 2,022 | 10.1007/s11356-022-24541-0 | oa_other |
==== Front
Mol Biotechnol
Mol Biotechnol
Molecular Biotechnology
1073-6085
1559-0305
Springer US New York
36463391
614
10.1007/s12033-022-00614-w
Original Paper
m6A ‘writer’ KIAA1429 regulates the proliferation and migration of endothelial cells in atherosclerosis
Rong Jian 1
Jie Yingxin 1
http://orcid.org/0000-0001-5767-8611
Zhao Hui [email protected]
2
1 grid.417028.8 0000 0004 1799 2608 Department of Emergency Medicine, Tianjin Hospital, No. 406, Jiefang South Road, Hexi District, Tianjin, 300211 China
2 grid.417028.8 0000 0004 1799 2608 Department of Cardiology, Tianjin Hospital, No. 406 Jiefang South Road, Hexi District, Tianjin, 300211 China
3 12 2022
19
13 9 2022
15 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Increasing evidences have illustrated the important role of N6-methyladenosine (m6A) in atherosclerosis (AS). However, the role of m6A modification in AS pathophysiological process is still unknown. Here, the present work tried to investigate the expression and function of m6A methyltransferase KIAA1429 in AS pathology and explored its undergoing m6A-dependent molecular mechanism. Results indicated that KIAA1429 remarkedly up-regulated in oxidative low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). KIAA1429 over-expression inhibited the proliferation/migration in ox-LDL-treated HUVECs, while, KIAA1429 knockdown up-regulated the proliferation and migration. Mechanistically, via m6A modification sites binding, ROCK2 mRNA was post-transcriptionally upregulated by KIAA1429 in response to Actinomycin D. Collectively, our study demonstrated the regulation of KIAA1429 on ox-LDL-induced HUVECs via m6A/ROCK2 pathway. These findings provide new insights for m6A-mediated epigenetics in AS.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12033-022-00614-w.
Keywords
N6-methyladenosine
KIAA1429
HUVECs
Endothelial cells
Atherosclerosis
==== Body
pmcIntroduction
Atherosclerosis (AS) acts as chronic inflammatory vascular disorders with increasing morbidity worldwide, which is a deposition of plaque accumulation and multifactorial inflammatory process in vascular walls [1, 2]. AS is responsible for occurrence of various clinical manifestation, e.g., coronary heart diseases, peripheral arterial disease and myocardial infarction and stroke [3, 4]. Low density lipoprotein (LDL) functions as a basic factor of AS. LDL enters into the vascular wall through vascular endothelium, and the retained LDL is modified into ox-LDL. Ox-LDL is phagocytosed by macrophages to form foam cells, which continuously increases and fuse to form the lipid core of AS plaque [5, 6]. Endothelial dysfunctions, especially endothelial cells damage, function as critical pathology for AS [7, 8].
N6-methyladenosine (m6A) acts as the most abundant posttranscriptional modification for mRNAs, which partially determines the fate of RNA, including RNA stabilization, splicing, and nuclear export [9, 10]. m6A methylations have been shown to regulate series of inflammatory processes, including the inflammatory vascular disorder of endothelial cells in AS [11]. For example, FTO-mediated m6A demethylations regulate the expression of lipid-related genes and regulates lipid metabolism to lead to occurrence of diabetic hyperlipidemia [12]. m6A methyltransferase methyltransferase-like 3 (METTL3) is highly expressed in ox-LDL-induced HUVECs and METTL3 knockdown inhibits HUVECs’ proliferation and tube formation in ox-LDL-treated HUVECs. Besides, METTL3 positively regulates JAK2/STAT3 pathway in m6A-dependent manner in HUVECs [13]. Therefore, the emerging findings indicate the critical roles of m6A in AS.
Given that the potential function of m6A in abnormal lipids metabolism-related AS pathology, we focused on the undergoing regulation of m6A in ox-LDL-induced HUVECs. In the initial screening, we detected several m6A key enzymes (i.e., KIAA1429, METTL3, WTAP) to discovery the up-regulated or down-regulated elements in ox-LDL-induced HUVECs. Results showed that the novel m6A writer KIAA1429 up-regulated upon ox-LDL administered. Finally, we focused on KIAA1429 and then explored its functions. Our cellular assays’ results showed that the expression of KIAA1429 (also known as VIRMA) increased upon ox-LDL administered and the response showed a dosage-dependent manner. KIAA1429 could regulate the proliferation and migration of HUVECs in ox-LDL administered. Moreover, KIAA1429 bound to the m6A modification sites of ROCK2 mRNA and then enhanced its mRNA stability. In conclusion, m6A writer KIAA1429 targeted m6A/ROCK2 axis to regulate the proliferation/migration of endothelial cells.
Materials and Methods
Cell Culture
HUVECs (Human umbilical vein endothelial cells) cell lines were provided by the Institute of the Chinese Academy of Sciences (Shanghai, China). Then, the cells were cultured in endothelial cell medium (Catalog #1001, ScienCell Research Laboratories, San Diego, CA, United States) supplemented with 10–12% fetal bovine serum (FBS, Catalog #0500, ScienCell Research Laboratories), 1% endothelial cell growth supplement (ECGS, Catalog #1052, ScienCell Research Laboratories), and 1% penicillin/streptomycin solution (Catalog #0513, ScienCell Research Laboratories). Passages 2–4 of cells were used for this project. All cells were cultured in humidified air in 37 °C at 5% CO2. ox-LDL (Yesen, Shanghai, China) was added to HUVECs (0–100 μg/mL concentration, 24 h) to construct endothelial cell injury. This study was approved by the ethics committee of Tianjin Hospital.
Transfection
For the silencing of KIAA1429 in vitro studies, the shRNA targeting KIAA1429 (sh-KIAA1429) and negative control siRNA (sh-NC) were synthesized (RiboBio, Guangzhou, China) based on the manufacturer’s suggestion. As regarding to overexpression of KIAA1429, pcDNA based overexpression plasmid specific to KIAA1429 or corresponding scrambled oligonucleotide sequences as a negative control were transfected.
Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)
Total RNA was extracted from HUVECs samples using modified TRIzol co-purification technique (Invitrogen, Hemel Hempstead, UK) as previously reported [14]. In brief, 500 μl of cell suspension was washed by 75–78% ethanol before solubilization using nuclease-free water (50 μl). To identify the level of KIAA1429 mRNA, RNA (1 μg) was reversely transcribed to cDNA by PrimeScript™ RT Reagent Kit (TaKaRa). Then, RT-qPCR was performed using One Step TB Green® PrimeScript™ PCR Kit (TaKaRa, Cat.#RR086B) as recommended by manufacturers’ protocols. The quantification of mRNA reference gene was calculated using the 2−ΔΔCt method. The primers used in PCR amplification were showed in Table S1.
Western Blot
Total proteins were collected using RIPA buffer (Thermo Scientific, CA, USA) and then quantified for protein quantification by using Pierce™ BCA Protein Quantification Kit (Thermo Scientific) [15]. Protein (20 μg) was used for electrophoresis loading SDS-PAGE and transferred onto PVDF membranes (Millipore, Billerica, MA, USA). The membranes were blocked with 5% skimmed milk and incubated with primary antibodies, including anti-KIAA1429 (Cell Signaling Technology, 1:1000, #88,358), anti-ROCK2 (Cell Signaling Technology, 1:1000, #47,012), and beta-actin (CWBio, Beijing, China). After incubation by primary antibodies or their corresponding secondary antibodies, blots were developed using SuperSignal West Dura Persistence Substrate (Thermo Scientific).
Proliferation CCK-8 Assay
For the proliferation of HUVECs, CCK-8 assay was performed. HUVECs cells were plated onto 96-well plates. 10μL CCK-8 reagent (Dojindo Japan) was added into each well at 24, 48, 72, and 96 h. Then, optical density (OD) value of wells was detected at 450 nm was recorded by automatic enzyme-mark reader (Multiskan FC, Thermo Fisher Scientific, Waltham, MA, USA) using a microplate reader.
Migration Assay
For the migration of HUVECs, wound healing assay was performed. In brief, 2 × 104 HUVECs about 90% confluence were plated 6-well plates. Medium was removed and then cell monolayers were manually wounded with 200 ul pipette tip. After twice washing with PBS, cells were incubated at 37 °C. The wound closure was evaluated with an inverted microscope. The migration rate was quantified according to distance. The migration rate was calculated: migration rate = migration distance/original distance.
m6A Quantification
The m6A quantification of global mRNA was measured by EpiQuik m6A RNA Methylation Quantification Kit (Colorimetric) (Epigentek) following the manufacturer’s protocol. 200 ng Poly-A-purified RNA was coated on assay wells and capture antibody solution was separately added to suitable concentration following the manufacturer’s instructions. The m6A level was colorimetrically quantified by absorbance at a wavelength of 450 nm.
RNA Immunoprecipitation (RIP) assay
The interaction within RNAs was identified by RIP-PCR. RIP assay was performed by Magna RIP-RNA-Binding Protein Immunoprecipitation Kit (Magna RIP Kit; Millipore, Bedford, MA, USA). Cell was lysed in lysis buffer with protease inhibitor/RNase inhibitor, and the cell extract was incubated with protein A/G agarose beads conjugated with antibody/IgG at 4 °C for 2 h. Magnetic dynabeads (Life Technologies, USA) were washed or incubated with Proteinase K. Finally, purified RNA was subjected for RT-PCR analysis.
m.6A-RNA Immunoprecipitation PCR (MeRIP-PCR)
To quantify the m6A-modified ROCK2 mRNA, MeRIP-PCR was performed. In brief, anti-m6A antibody (Millipore, cat. #ABE572) was conjugated to protein A/G magnetic beads in IP buffer (20 mM Tris pH 7.5, 1% NP-40, 140 mM NaCl, 2 mM EDTA). Total RNA was isolated from HUVECs and incubated with the antibody in IP buffer supplemented with RNase inhibitor and protease inhibitor. The precipitated RNA was eluted with elution buffer and detected using further qRT-PCR assay.
RNA Stability
To analyze the ROCK2 mRNA stability, HUVECs were administrated with actinomycin D (Act D, 2 μg/mL, Sigma) and then collected in different time-point (0 h, 3 h, 6 h). ROCK2 mRNAs were extracted using Trizol reagent. Finally, mRNA levels were detected by qRT-PCR and normalized to the values measured in the mock treatment group (the 0 h group) using the primers: forward, 5’- TCAGAGGTCTACAGATGAAGGC-3′, reverse, 5′- CCAGGGGCTATTGGCAAAGG-3′.
Statistical Analysis
Data was expressed as the mean ± standard deviation (SD) in independent replicate. Student’s t-test or variance (ANOVA) analysis was used to compare difference of independent groups. Assays were performed in triplicate. Data were exhibited as Mean ± Standard Deviation (SD). **p < 0.01, *p < 0.05 were considered a statistical difference.
Results
KIAA1429 up-Regulated in the ox-LDL-Induced HUVECs
To construct the cellular AS model, human endothelial cells (HUVECs) were administrated with ascending ox-LDL (0–100 μg/mL) concentration. With the ascending dosage of ox-LDL, m6A quantitative analysis was performed and results demonstrated that m6A modification level increased upon ox-LDL administered (Fig. 1A). Besides, the level of m6A writer KIAA1429 in the ox-LDL-induced HUVECs was detected and results indicated that KIAA1429 mRNA (Fig. 1B) and protein levels (Fig. 1C) were upregulated in ox-LDL treated HUVECs. Moreover, the proliferation of HUVECs was detected and results illustrated that proliferative ability of HUVECs was repressed in ox-LDL administered in dosage-dependent manner (Fig. 1D). In conclusion, these results and findings suggested that KIAA1429 upregulated in ox-LDL-induced HUVECs.Fig. 1 KIAA1429 up-regulated in the ox-LDL-induced HUVECs. A m6A quantitative analysis was performed to detect the m6A modification level in HUVECs with ox-LDL administered (0–100 μg/mL). B RT-PCR detected the level of KIAA1429 mRNA in HUVECs with ox-LDL administered (0–100 μg/mL). C Western blot was performed to show the KIAA1429 protein in HUVECs with ox-LDL administered (0–100 μg/mL). D The proliferation of HUVECs was detected using CCK-8 to illustrate the proliferative ability of HUVECs. Assays were performed in triplicate. Data were exhibited as Mean ± Standard Deviation (SD). **p < 0.01, *p < 0.05
KIAA1429 Inhibited the Proliferation/Migration for ox-LDL Administrated HUVECs
Given that KIAA1429 showed an overexpression in ox-LDL administrated human endothelial cells (HUVECs), we subsequently performed the bio-functional assays to confirm the role of KIAA1429 in AS. Firstly, KIAA1429 knockdown (Fig. 2A) and overexpression (Fig. 2B) transfection were respectively constructed in HUVECs. The proliferation of HUVECs was detected and results illustrated that proliferative ability of HUVECs was up-regulated in KIAA1429 knockdown, while KIAA1429 overexpression repressed proliferation (Fig. 2C). Wound healing assay was performed and results indicated that KIAA1429 knockdown promoted the migration of HUVECs, while KIAA1429 overexpression reduced it (Fig. 2D). In conclusion, these results and findings suggested that KIAA1429 inhibited the proliferation/migration for ox-LDL administrated HUVECs.Fig. 2 KIAA1429 repressed the proliferation/migration for ox-LDL administrated HUVECs. A, B RT-qPCR and western blot for (A) KIAA1429 knockdown and (B) KIAA1429 overexpression were performed to detect the efficient of transfection. C CCK-8 assay for the proliferation of HUVECs was performed to illustrate the proliferative ability of HUVECs upon KIAA1429 knockdown and KIAA1429 overexpression. D Wound healing assay indicated the migration of HUVECs upon KIAA1429 knockdown and KIAA1429 overexpression. Assays were performed in triplicate. Data were exhibited as Mean ± Standard Deviation (SD). **p < 0.01, *p < 0.05
ROCK2 Acted as the Target of KIAA1429
Using diverse screening methods, we carefully discovered the target of KIAA1429, e.g., bioinformatics predictive analysis and multiplex cell assays (RT-PCR, western blot et. al). Our pre-experiments data illustrated that ROCK2 (Rho associated coiled-coil containing protein kinase 2) had m6A modification sites in its 3’-UTR, which suggested that ROCK2 might act as the target of KIAA1429 (Fig. 3A). In the pathophysiology of AS, ROCK2 functions as an essential element in AS [16]. The m6A modification site on ROCK2 mRNA was ‘GGACU’ motif. In the ROCK2 gene, the m6A modification site distributed in 3’-UTR of ROCK2 (Fig. 3B). Using the SRAMP online tool (http://www.cuilab.cn/sramp), analysis demonstrated that there were m6A modification site on ROCK2 mRNA (Fig. 3C). In ox-LDL-treated HUVECs, m6A quantitative analysis indicated that KIAA1429 knockdown reduced the m6A modification level, while KIAA1429 overexpression up-regulated the m6A modification level (Fig. 3D). RIP-PCR analysis revealed that KIAA1429 remarkably interacted with ROCK2 mRNA in HUVECs (Fig. 3E). In conclusion, these results and findings suggested that ROCK2 acted as the target of KIAA1429.Fig. 3 ROCK2 acted as the target of KIAA1429. A The m6A modification site on ROCK2 (Rho associated coiled-coil containing protein kinase 2) mRNA was ‘GGACU’ motif. B In the ROCK2 gene, the m6A modification site distributed in 3’-UTR of ROCK2. C SRAMP online tool (http://www.cuilab.cn/sramp) demonstrated the m6A modification site on ROCK2 mRNA. D m6A quantitative analysis was performed to detect the role of KIAA1429 knockdown/overexpression on the ox-LDL-treated HUVECs. E RIP-qPCR analysis indicated interaction within KIAA1429 and ROCK2 mRNA in HUVECs. Assays were performed in triplicate. Data were exhibited as Mean ± Standard Deviation (SD). **p < 0.01, *p < 0.05
KIAA1429 Enhanced the Stability of ROCK2 mRNA
Moreover, we tried to explore the function of KIAA1429 on ROCK2. Firstly, MeRIP-PCR analysis was performed to detect the m6A modification level on ROCK2 mRNA. Results indicated that KIAA1429 knockdown reduced the m6A modification on ROCK2 mRNA (Fig. 4A), while KIAA1429 overexpression up-regulated the m6A modification level (Fig. 4B). In the ox-LDL-induced HUVECs, ROCK2 mRNA increased upon ox-LDL administered in dosage-dependent manner (Fig. 4C). RIP-qPCR analysis found that KIAA1429 knockdown reduced the precipitated ROCK2 mRNA enrichment, while KIAA1429 overexpression up-regulated the precipitated ROCK2 mRNA enrichment (Fig. 4D). RNA stability analysis revealed that KIAA1429 knockdown decreased the ROCK2 mRNA upon Act D treatment, while KIAA1429 overexpression up-regulated the ROCK2 mRNA upon Act D treatment (Fig. 4E). Moreover, KIAA1429 knockdown reduced the ROCK2 protein in ox-LDL-induced HUVECs, while KIAA1429 overexpression increased the ROCK2 protein (Fig. 4F). In conclusion, these results and findings suggested that KIAA1429 enhanced the stability of ROCK2 mRNA.Fig. 4 KIAA1429 enhanced the stability of ROCK2 mRNA. A MeRIP-PCR analysis was performed using the anti-m6A antibody to detect the m6A modification level on ROCK2 mRNA. Ox-LDL-induced HUVECs were transfected with KIAA1429 knockdown (sh-NC-IgG, sh-NC-m6A, sh-KIAA1429-IgG, sh-KIAA1429- m6A). B Ox-LDL-induced HUVECs were transfected with KIAA1429 overexpression (vector-IgG, vector-m6A, KIAA1429-IgG, KIAA1429- m6A). C RT-PCR was performed to detect the ROCK2 mRNA level in the ox-LDL-induced HUVECs. D RIP-qPCR analysis was performed using anti-m6A antibody. The precipitated ROCK2 mRNA enrichment was analyzed as compared to controls. E RNA stability analysis was performed to detect the ROCK2 mRNA upon Act D treatment in ox-LDL-induced HUVECs. F Western blot analysis was performed to detect the ROCK2 protein in ox-LDL-induced HUVECs. Assays were performed in triplicate. Data were exhibited as Mean ± Standard Deviation (SD). **p < 0.01, *p < 0.05
Discussion
In atherosclerosis (AS), the activity of vascular endothelial cells could reflect cells’ metabolism and proliferation [17–19]. AS is a life-threatening vascular disease, and m6A modification level is dysregulated in its pathophysiologic processes of AS [20, 21]. Here, we found that m6A writer KIAA1429 upregulated in ox-LDL-induced HUVECs. Moreover, the function and corresponding molecular mechanism in AS progression are of great value for precision targeted therapy.
Here, this research constructed cellular AS model using ox-LDL-induced HUVECs, and results revealed that m6A level increased upon ox-LDL administered. Because the deregulated m6A level in ox-LDL-induced HUVECs, we assumed that m6A regulators might participate in HUVECs’ pathophysiology.
In the initial screening, we detected several m6A key enzymes (i.e., KIAA1429, METTL3, WTAP) to discovery the up-regulated or down-regulated elements. Finally, we focused on the novel m6A writer KIAA1429 and then explored its functions. Our cellular assays’ results showed that the expression of KIAA1429 increased upon ox-LDL administered and the response showed a dosage-dependent manner.
Functional assays illustrated that KIAA1429 overexpression repressed proliferation and migration of HUVECs, while KIAA1429 knockdown recovered the repression on HUVECs’ proliferation and migration. As is known to all that the ability of proliferation/migration of vascular endothelial cell is very critical for the vascular bio-function. Thus, in these findings, KIAA1429 regulated the proliferation and migration of HUVECs, which significantly showed the roles of KIAA1429 on HUVECs.
Increasing evidence synergistically indicates the potential vital roles of m6A modification on AS [22]. For instance, ox-LDL remarkably stimulation promotes the m6A modification level of macrophages in AS and METTL3 knockdown inhibits the oxLDL-induced inflammatory response and m6A modification [23]. Besides, ALKBH5 low-expression significantly increases SPHK1 m6A mRNA methylation, in contrast, METTL3 overexpression reduces expression of SPHK1 mRNA [24]. In vascular endothelium of atherogenic inflammatory cascades, METTL3-mediated RNA hypermethylation up-regulates NLRP1 mRNA transcript and down-regulates KLF4 transcript via YTHDF1/YTHDF2 m6A reader proteins [25]. Thus, these findings suggest the vital functions of m6A on AS.
The online tool suggested that there were m6A modification sites on ROCK2 mRNA (Fig. 3C). Moreover, we performed RIP-PCR (Fig. 3E, 4D) and MeRIP-PCR (Fig. 4A, B) to identify the molecular interaction within KIAA1429 and ROCK2 mRNA. In the pathophysiology of AS, ROCK2 functions as an essential element in AS [16]. For instance, circCHMP5/ROCK2 axis regulates cell cycle, proliferation, angiogenesis and inflammation in ox-LDL-induced HUVECs [26]. CircUSP36/ROCK2 axis regulates cell apoptosis and inflammatory responses, and promotes cell migration and invasion in ox‑LDL‑induced injury for HUVECs [27]. Here, we found that ROCK2 up-regulated in the ox-LDL-induced HUVECs. KIAA1429 targeted the m6A modification site of ROCK2 mRNA and then up-regulated the mRNA stability of ROCK2. Therefore, in this results, KIAA1429/ROCK2 axis accelerated the proliferation and migration of HUVECs.
For the deficiencies and defects, we talk briefly about what we’ve found in this research. Firstly, being limited by the laboratory external conditions, in vivo assays were unable to proceed as we initially assumed. Moreover, clinical sample research was difficult to put into practice due to the COVID-19. Furthermore, our understanding of m6A is still in its infancy because of the absence of more research. With the great development of m6A and Epigenomics, it would be greatly help to the contribution of our work to the field of AS.
Conclusion
In conclusion, the present research found a novel manner in AS by which KIAA1429 negatively regulated the proliferation and migration of HUVECs. Mechanistically, KIAA1429 targeted the m6A modification site of ROCK2 mRNA to install m6A modification of ROCK2, thereby enhancing ROCK2 mRNA stability (Fig. 5). These new findings provide novel insight for vascular endothelial cells injury for AS.Fig. 5 KIAA1429/m6A/ROCK2 axis regulates the proliferation and migration of endothelial cells in atherosclerosis
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 kb)
Acknowledgements
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References
1. Keeter WC Ma S Stahr N Moriarty AK Galkina EV Atherosclerosis and multi-organ-associated pathologies Seminars in Immunopathology 2022 44 363 374 10.1007/s00281-022-00914-y 35238952
2. Kong P Cui ZY Huang XF Zhang DD Guo RJ Han M Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention Signal Transduction and Targeted Therapy 2022 7 131 10.1038/s41392-022-00955-7 35459215
3. Liu D Liu J Zhang D Yang W Advances in relationship between cell senescence and atherosclerosis Zhejiang da xue xue bao Yi xue ban = Journal of Zhejiang University Medical sciences. 2022 51 95 101 35576118
4. Tuvali O Sella G Haberman D Cuciuc V George J Colchicine in Atherosclerotic Vascular Disease: The Good, the Bad, and the Ugly The Israel Medical Association Journal : IMAJ 2022 24 191 197 35347935
5. Chan YH Ramji DP Atherosclerosis: pathogenesis and key cellular processes current and emerging therapies, key challenges, and future research directions Methods in Molecular Biology 2022 2419 3 19 10.1007/978-1-0716-1924-7_1 35237955
6. Kaiser Y Daghem M Tzolos E Meah MN Doris MK Moss AJ Kwiecinski J Kroon J Nurmohamed NS van der Harst P Adamson PD Williams MC Dey D Newby DE Stroes ESG Zheng KH Dweck MR Association of Lipoprotein(a) With Atherosclerotic Plaque Progression Journal of the American College of Cardiology 2022 79 223 233 10.1016/j.jacc.2021.10.044 35057907
7. Kłosiewicz-Latoszek L Cybulska B Stoś K Tyszko P Hypolipaemic nutraceutics: Red yeast rice and Armolipid, berberine and bergamot Annals of Agricultural and Environmental Medicine : AAEM 2021 28 81 88 33775071
8. Madeline Chee YM Lew PS Darryl Lim MJ True Idiopathic Radial Artery Aneurysm: A Case Report and Review of Current Literature EJVES Vascular Forum 2020 49 34 39 10.1016/j.ejvsvf.2020.11.003 33937898
9. Chang Y Yi M Wang J Cao Z Zhou T Ge W Muhammad Z Zhang Z Feng Y Yan Z Felici M Shen W Cao H Genetic regulation of N6-methyladenosine-RNA in mammalian gametogenesis and embryonic development Frontiers in Cell and Developmental Biology 2022 10 819044 10.3389/fcell.2022.819044 35359444
10. Li Y Meng L Zhao B The roles of N6-methyladenosine methylation in the regulation of bone development, bone remodeling and osteoporosis Pharmacology & Therapeutics 2022 238 108174 10.1016/j.pharmthera.2022.108174 35346729
11. Wu W Zhang F Zhao J He P Li Y The N6-methyladenosine:Mechanisms, diagnostic value, immunotherapy prospec-ts and challenges in gastric cancer Experimental cell Research 2022 415 113115 10.1016/j.yexcr.2022.113115 35341774
12. Yang Z Yu GL Zhu X Peng TH Lv YC Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders Genes & diseases 2022 9 51 61 10.1016/j.gendis.2021.01.005 35005107
13. Dong G Yu J Shan G Su L Yu N Yang S N6-methyladenosine methyltransferase METTL3 promotes angiogenesis and atherosclerosis by upregulating the JAK2/STAT3 pathway via m6A reader IGF2BP1 Frontiers in Cell and Developmental Biology 2021 9 731810 10.3389/fcell.2021.731810 34950654
14. Jia J Wang Y Huang R Du F Shen X Yang Q Li J Protein disulfide-isomerase A3 knockdown attenuates oxidized low-density lipoprotein-induced oxidative stress, inflammation and endothelial dysfunction in human umbilical vein endothelial cells by downregulating activating transcription factor 2 Bioengineered 2022 13 1436 1446 10.1080/21655979.2021.2018980 34983301
15. Xu L Xu C Lin X Lu H Cai Y Interference with lysophosphatidic acid receptor 5 ameliorates oxidized low-density lipoprotein-induced human umbilical vein endothelial cell injury by inactivating NOD-like receptor family, pyrin domain containing 3 inflammasome signaling Bioengineered 2021 12 8089 8099 10.1080/21655979.2021.1983975 34662522
16. Takeda Y Matoba K Kawanami D Nagai Y Akamine T Ishizawa S Kanazawa Y Yokota T Utsunomiya K ROCK2 Regulates Monocyte Migration and Cell to Cell Adhesion in Vascular Endothelial Cells International Journal of Molecular Sciences 2019 10.3390/ijms20061331 31752090
17. Zheng L Li M Wei J Chen S Xue C Zhan Y Duan Y Deng H Xiong W Li G Zhou M The emerging roles of the interaction between m6A modification and c-Myc in driving tumorigenesis and development Journal of Cellular Physiology 2022 10.1002/jcp.30733 35892164
18. Chang H Yang J Wang Q Zhao J Zhu R Role of N6-methyladenosine modification in pathogenesis of ischemic stroke Expert Review of Molecular Diagnostics 2022 10.1080/14737159.2022.2049246 35236212
19. Chen YS Ouyang XP Yu XH Novák P Zhou L He PP Yin K N6-Adenosine Methylation (m(6)A) RNA Modification: An emerging role in cardiovascular diseases Journal of Cardiovascular Translational Research 2021 14 857 872 10.1007/s12265-021-10108-w 33630241
20. Zhao W Li J Ma Q Cai J Li A Wu W Lv Y Cai M N6-methyladenosine modification participates in neoplastic immunoregulation and tumorigenesis Journal of Cellular Physiology 2022 10.1002/jcp.30730 36288570
21. Zhou M Liu W Zhang J Sun N RNA m(6)A modification in immunocytes and DNA Repair: The biological functions and prospects in clinical application Frontiers in Cell and Developmental Biology 2021 9 794754 10.3389/fcell.2021.794754 34988083
22. Fu J Cui X Zhang X Cheng M Li X Guo Z Cui X The role of m6A ribonucleic acid modification in the occurrence of atherosclerosis Frontiers in Genetics 2021 12 733871 10.3389/fgene.2021.733871 34603394
23. Li Z Xu Q Huangfu N Chen X Zhu J Mettl3 promotes oxLDL-mediated inflammation through activating STAT1 signaling Journal of Clinical Laboratory Analysis 2022 36 e24019 34825733
24. Kumari R Dutta R Ranjan P Suleiman ZG Goswami SK Li J Pal HC Verma SK ALKBH5 Regulates SPHK1-dependent endothelial cell angiogenesis following ischemic stress Frontiers in Cardiovascular Medicine 2021 8 817304 10.3389/fcvm.2021.817304 35127873
25. Chien CS Li JY Chien Y Wang ML Yarmishyn AA Tsai PH Juan CC Nguyen P Cheng HM Huo TI Chiou SH Chien S METTL3-dependent N(6)-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium Proceedings of the National Academy of Sciences of the United States of America 2021 10.1073/pnas.2025070118 34810252
26. Li X Kang X Di Y Sun S Yang L Wang B Ji Z CircCHMP5 Contributes to Ox-LDL-induced Endothelial Cell Injury Through the Regulation of MiR-532–5p/ROCK2 axis Cardiovascular Drugs and Therapy 2022 10.1007/s10557-022-07316-0 36459266
27. Miao J Wang B Shao R Wang Y CircUSP36 knockdown alleviates oxidized low-density lipoprotein-induced cell injury and inflammatory responses in human umbilical vein endothelial cells via the miR-20a-5p/ROCK2 axis International Journal of Molecular Medicine 2021 10.3892/ijmm.2021.4873 34751408
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J Therm Anal Calorim
J Therm Anal Calorim
Journal of Thermal Analysis and Calorimetry
1388-6150
1588-2926
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10.1007/s10973-022-11721-w
Article
Energy and exergy analysis of a modified three-stage auto-cascade refrigeration cycle using low-GWP refrigerants for sustainable development
http://orcid.org/0000-0002-8517-7205
Qin Yanbin [email protected]
1
Li Nanxi 2
Zhang Hua 1
Liu Baolin 1
1 grid.267139.8 0000 0000 9188 055X University of Shanghai for Science and Technology, Shanghai, 200093 People’s Republic of China
2 grid.458467.c 0000 0004 0632 3927 Chinese Academy of Science, Shanghai Institute of Technical Physics, Shanghai, 200083 People’s Republic of China
7 12 2022
114
29 7 2022
15 10 2022
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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
This study proposed a modified three-stage auto-cascade refrigeration cycle (MTARC) operating with environmentally benign zeotropic mixture of R1234yf/R170/R14 at the refrigeration temperature level of − 80 °C. Compared with the conventional three-stage auto-cascade refrigeration cycle (CTARC), MTARC incorporates an additional pressure regulator between the condenser and separator to realize phase separation at a lower pressure and temperature. A comprehensive evaluation of energy and exergy performance of the two cycles was conducted theoretically. Under a typical working condition, the cooling capacity, COP and exergy efficiency of the MTARC are improved by 15.85%, 11.69% and 7.65% in comparison with the CTARC, respectively. In addition, a lower evaporating temperature was also obtained by the MTARC under the same operating condition. When the intermediate pressure drops from 2 to 1 MPa, the cooling capacity, COP and exergy efficiency are improved by 35.43%, 25.25% and 16.74%, respectively, for the MTARC, meanwhile the compressor outlet temperature increases 19.93 °C from 92.27 to 112.20 °C. Therefore, the selection of the intermediate pressure should be comprehensively considered to ensure a desirable cycle performance and a proper working condition for the compressor. The proposed modified cycle offers new pathways for designing innovative cryogenic refrigeration systems, thereby potentially improving the energy economy in a myriad of modern energy applications for sustainability concerns.
Keywords
Energy
Exergy
Three-stage ARC
Thermodynamic
Intermediate pressure
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 51906151 Qin Yanbin http://dx.doi.org/10.13039/501100010031 Postdoctoral Research Foundation of China 2019M661572 Qin Yanbin
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pmcIntroduction
With the development of industry and society, the attainment of low temperatures below − 50 °C has drawn more and more attentions in many fields [1]. In recent years, in response to the current COVID-19 pandemic, the ultra-low temperature (UTL) around − 80 °C is increasingly demanded in biomedical areas such as the cryopreservation of new vaccines and cryosurgery. Economical refrigeration in the ULT range cannot be achieved with standard single-stage systems because of the required high compression ratio, which leads to a low efficiency and high discharge temperature [2]. Principally, temperatures below − 40 °C can be obtained by multi-stage compression refrigeration cycles, cascade refrigeration cycles and auto-cascade refrigeration cycles (ARC) [3]. Among these applications, the ARC systems have been extensively used because of their simple structure, high reliability, low cost and high thermodynamic efficiency [4]. In recent decades, energy shortage and environmental pollution have become progressively severe, calling for more utilizations of the ARC system which is higher in refrigeration efficiency and more environmentally friendly [5]. Thus, much effort has been made on improving the ARC systems, which mainly includes two aspects: to improve the structure of the existing ARC systems, and to look for mixed refrigerants that can meet the needs of environmental protection and exhibit high thermodynamic efficiency as well [6].
In terms of structural optimization of refrigeration systems, the ejector was found to be able to convert the pressure energy of the refrigerant into kinetic energy and then return to pressure energy, thereby recovering the throttling loss and improving the system efficiency [7–11]. Hao et al. [12] proposed a novel hybrid auto-cascade refrigeration system coupled with an ejector cycle. This hybrid cycle effectively saves high-grade electric energy or mechanical energy by the ejector driven by low-grade thermal energy such as waste heat and solar energy. It was found that the ejector can reduce the compressor input power by 50%. Yu et al. [13] studied the performance of an ejector-enhanced two-stage ARC and found that the modified system can effectively improve the coefficient of performance (COP). When using R23/R134a as the working fluid, the pressure ratio of compressor was reduced by 25.8% and the COP was improved by 19.1% over the conventional ARC. Similarly, Bai et al. [14, 15] also studied a two-stage ARC, and results show that by adding an ejector to the system can boost the exergy efficiency and COP by 25.1% and 9.6%, respectively. Rodríguez-Jara et al. [2] used an ejector as the expansion valve in ARC and found that the COP was increased by 12%. This study also indicates that the mixture of R1150/R600a is a suitable combination for ARC.
As for other aspects of system structure optimization, a double internal ARC system was introduced by Cheng et al. [16], and the authors concluded that the modified system can effectively increase the mass flow of the low boiling point component entering the evaporator, and further improve the system performance. Compared with the flash tank system, the proposed system shows a 9.6% higher heating capacity and a 6.1% higher COP. Chen et al. [17] used two separators in a modified ARC to achieve partial-condensation separation, and used the corresponding capillary tubes to get flash separation for a composition shift effect. Under the given operation conditions, the cycle performance improvement of the modified system in terms of COP, volumetric cooling capacity and exergy efficiency can reach up to 12.7%, 32.6% and 20%, respectively. Similar optimizations also concluded that the modified cycle can improve the cycle performance due to the composition shift effect of the zeotropic mixture during the flash separation process [18, 19]. The results show that the maximum COP of the modified system with R290/R600a and R134a/R236fa can be improved by 26.7% and 18.6%, respectively [19]. A modified ARC with a fractionation heat exchanger was experimentally studied by Zhang et al. [20]. It was found that the corresponding refrigeration capacity, power input and COP were reduced by 37.1–61.7%, 24.7–36.8% and 16.4–42.7%, respectively. Chen et al. [21] concluded that the addition of the subcooler in the ARC could improve both the energy and exergy performances, and the COP, volumetric cooling capacity and exergy efficiency of the modified cycle can be improved by up to an average of 37.5%, 42.3% and 34.3% compared to those of the basic cycle, respectively. Liu et al. [22] introduced an auxiliary separator into a conventional ARC, and found that the overall performance of the modified system was higher. Under a typical operating condition, the improvements of COP and exergy efficiency were increased by 16.1% and 10.23% respectively, and the overall cost rate was decreased by 2.51%. Research on the structural optimization and efficiency improvement of the energy systems was also carried out by Toghraie and co-workers [23–29]. Asgari et al. [30] used R600 as the refrigerant in an internal ARC, and all heat exchangers were modeled by taking pressure drops into consideration. The multi-objective optimization indicated that the improvements of total avoidable exergy destruction rate, total avoidable investment and total avoidable exergy destruction cost rates were 76.78%, 38.66% and 103.38%, respectively. Yan et al. [31] used R290/R600a as refrigerants in an internal ARC. The simulation results show that the internal ARC has 7.8–13.3% improvement in COP, 10.2–17.1% improvement in volumetric refrigeration capacity and 7.4–12.3% reduction in pressure ratio of compressor.
On the other hand, the environmentally benign refrigerants with low GWP values are used for the sustainability of ARC equipment [32]. Mota-Babiloni et al. [1] summarized the recent developments in ultra-low temperature refrigeration systems and working fluids, and concluded that the HC refrigerants of R170 and R1150 are the best solutions. Aprea and Maiorino [33] achieved − 150 °C in a space of 0.25 m3 for a medical application by using a mixture of R507, R245fa, R116, R23, R14, R740 and R290. Wang et al. [4] theoretically investigated the system performance of a two-stage ARC using six binary mixtures and concluded that the R170/R600 (0.55/0.45) was an ideal substitute at − 60 °C. Sivakumar and Somasundaram [34, 35] experimentally investigated a three-stage ARC using R290/R170/R14, R290/R23/R14 and R1270/R170/R14 and found that the system operating with R290/R23/R14 showed a better performance. Qin et al. [36] theoretically analyzed the thermodynamic characteristics of a three-stage ARC using four ternary mixtures composed of R1234yf, R1132a, R23, R41, R170 and R14. The results show that all the three medium-temperature alternatives of R1132a, R41 and R170 could be good drop-in replacements for R23. The COP and exergy efficiency of the ARC operating with R1234yf/R41/R14 with the mass fraction of 0.64/0.17/0.19 were 0.2713 and 13.91% at − 100 °C, respectively. Kilicarslan and Hosoz [37] studied the thermodynamic performance of a two-stage ARC using R404a/R23, R234a/R23, R152a/R23, R717/R23, R507/R23 and R290/R23. It was found that the R717/R23 system and R507/R23 system showed the highest and the lowest COP, respectively. Lizarte et al. [38] used R152a to replace R134a in the ARC system. The highest COP and exergy efficiency were 0.79 and 31.6% corresponding to organic Rankine cycle evaporation temperatures of 315 °C and 255 °C, respectively. Liu et al. [39] proposed a modified two-stage ARC with a self-recuperator. The energy and exergy analysis indicated that the COP of the modified ARC was increased by 6.24% and 24.17% when using R290/R170 and R600a/R1150, respectively. It was also found for the modified ARC that COP and refrigeration capacity were positively correlated with intermediate pressure. A zeotropic mixture of R600a/R744 was employed as a working fluid in an ARC system by Sobieraj [40]. It was found that the working mass concentration of R744 was higher, since it was closer to the nominal concentration and the discharge pressure was lower by 19% to even 39% when a recuperative heat exchanger was employed in the system. An increase of up to 20% in the COP was observed. Rui et al. [41] proposed a novel ternary mixture, R600a/R23/R14, for ARC systems for 190 K applications. The results demonstrated the feasibility of the proposed R600a/R23/R14 ternary mixture as an environmental benign alternative for ARC systems, and a mass ratio of 35/30/35 mixture was recommended. He et al. [42] studied the theoretical performance of a two-stage ARC system using R170/R600a, R170/R600, R1150/R600a, R1150/R600, and R23/R134a. The results showed that R170/R600 showed the best performance, and the exergy loss ratios of the heat exchanger in the R170/R600 and R23/R134a systems were the highest at 52.3% and 56.7%, respectively. A comparison study was conducted by Hamad et al. [43] to investigate the performance of an ARC using R290 and R600a. R290/R600a with four mass ratios (70/30, 60/40, 50/50 and 40/60) was used to investigate the performance of the system and compared with R134a. Results show that the mixed refrigerant with the mass fraction of 60/40 displayed a higher performance comparing with other mass fractions and R134a. Also, a 29% increase in COP and a 26% increase in refrigeration effect were achieved, respectively.
Generally, the low separation efficiency is an important reason for the poor performance of the ARC systems. It is seen from the literature review outlined above that the studies related to the energy and exergy analysis of the ARC have been based on the perspective of cycle structure modification to improve separation efficiency, in which the decrease of refrigerant flow to evaporator was not taken into account [18, 20]. On the other hand, some studies mentioned these effects without performing a detailed cycle analysis, especially for the three-stage ARC. To solve this problem, this paper proposed a modified three-stage ARC (MTARC) with an additional expansion valve installed between the condenser and the vapor–liquid separator for refrigeration applications at ultra-low temperatures around − 80 °C. The pressure regulator can effectively increase the refrigerant flow to the evaporator but has little effect on its composition (maintain a high separation efficiency), thereby the system performances can be further improved. Under consideration of the environmental issues and the process of sustainable development, the experimentally benign ternary mixture of R1234yf/R170/R14 with low GWP value was selected as the working fluid. This study is different from the ones in the literature because it presents a detailed first and second law analysis of the MTARC in comparison with the conventional three-stage ARC (CTARC) under various operating characteristics. The proposed MTARC offers new pathways for designing energy-efficient cryogenic refrigeration systems and applications that operate below − 80 °C for sustainable development.
Mathematical model of the modified three-stage ARC
Cycle description
Figure 1a and b are the schematic diagram and the lgp-h diagram for the MTARC operating with R1234yf/R170/R14, respectively. Compared with the MTARC, the structure of the CTARC doesn’t have the expansion valve between the condenser and the vapor–liquid separator, so the schematic diagram of the CTARC is not given again. For the MTARC, the zeotropic mixture from the compressor is partially condensed in the condenser. After that, the two-phase refrigerant is expanded in the first expansion valve EV1, and then enters the first vapor–liquid separator VLS1. The R1234yf-enriched liquid flows out from the bottom of VLS1, and the R170/R14-enriched vapor flows out from the top of VLS1. The saturated vapor at state point 7 is partially condensed in the first condensing evaporator CE1 and then enters the second vapor–liquid separator VLS2. At state point 5, the saturated liquid expands to vapor–liquid fluid by the second expansion valve EV2.Fig. 1 a The schematic diagram of the MTARC; b The schematic lgp-h diagram of the MTARC
The R14-enriched vapor coming out from the top of VLS2 is condensed efficiently in the second condensing evaporator CE2. After the pressure decreases in the fourth expansion valve EV4, the R14-enriched refrigerant becomes vapor–liquid state and then fully evaporates in the evaporator. The R170-enriched liquid out from the bottom of VLS2 is expanded to vapor–liquid fluid by the third expansion valve EV3. Afterwards, it mixes with the refrigerant exiting from the evaporator, and then the mixture cools the saturated vapor in CE2. After leaving CE2, the mixture at state point 16 mixes with the two-phase refrigerant out from EV2. The mixture at state point 17 cools the saturated vapor in CE1 and then is sucked into the compressor.
Thermodynamic model
To facilitate the calculations, some assumptions are adopted as follows [44]:The system operates in steady state;
The throttling processes are considered to be isenthalpic;
The compression process is isentropic and irreversible;
The heat losses in pipelines and equipment are neglected, and the pressure drop in the pipelines and heat exchangers is negligible.
Fluid exiting the phase separator is considered to be saturated. The mixture at state point 12 is saturated liquid.
The kinetic exergy and potential exergy of the refrigerant are ignored.
Energy and exergy balance
The governing equations of the system components satisfy the mass and energy conservation equations. The general expressions are as follows:
Mass conservation:1 ∑m˙in=∑m˙out
Energy conservation:2 ∑Q˙=∑m˙outhout-∑m˙inhin+∑W˙
The COP of the ARC can be determined by:3 COP=Q˙eva.W˙com.
Incorporating the second law of thermodynamics, the general expression of the exergy conservation equation of each system component can be expressed as:4 χ˙D=∑m˙inχ˙in-∑m˙outχ˙out±Q˙(1-T0/T)±W˙
The exergy carried by the stream can be expressed as:5 χ˙=m[˙h-h0-T0(s-s0)]
where h0 and s0 stand for the enthalpy and entropy at the reference temperature and pressure, respectively. Q˙ is the heat exchanged between the component and a heat source, T is the temperature of heat source (K), and the W˙ is the input power or output power of the system components.
The total exergy destruction can be obtained by:6 χ˙D,total=χ˙D,com.+χ˙D,con.+χ˙D, CE1+χ˙D, CE2+χ˙D, EV1+χ˙D, EV2+χ˙D, EV3+χ˙D, EV4+χ˙D,eva.
The percentage of contribution of the total exergy destruction in each component:7 βD,i=χ˙D,i/χ˙D,total
The exergy efficiency of the ARC is calculated as:8 ψ=1-χ˙D,total/W˙com.
The exergy and exergy conservation equations of the system components are shown as Table 1.Table 1 Equations for exergy and exergy analysis [45]
Component Energy balance Exergy balance
com. W˙com.=m˙1h2-h1
=m˙1h2,is-h1/ηcom.
χ˙D,com.=m˙1T0(s2-s1)
con. Q˙con.=m˙1(h2-h3) χ˙D,con.=m˙1T0s3-s2+Q˙con(1-T0/T3)
EV1 h3=h4 χ˙D,EV1=m˙5T0(s4-s3)
EV2 h5=h6 χ˙D,EV2=m˙5T0(s6-s5)
EV3 h9=h10 χ˙D,EV3=m˙9T0(s10-s9)
EV4 h12=h13 χ˙D,EV4=m˙12T0(s13-s12)
CE1 Q˙CE1=m˙7h7-h8
=m˙1h1-h17
χ˙D,CE1=m˙7h7-h8-T0s7-s8+m˙1[h17-h1-T0s17-s1]
CE2 Q˙CE2=m˙11h11-h12
=m˙16h16-h15
χ˙D,CE2=m˙11h11-h12-T0s11-s12+m˙15h15-h16-T0s15-s16
eva. Q˙eva.=m˙13h14-h13 χ˙D,eva.=T0[m˙s14-s13-Q˙eva.Tave+ΔT]
where Tave is the mathematic average temperature of the refrigerant at the inlet and outlet of the evaporator (K), and ΔT represents the temperature difference between the refrigerant and the cooled space, which is assumed to be 10 K
Basic conditions
Based on the above assumptions and models, the commercial software Aspen Plus 11.0 [46] is used to calculate the thermodynamic performance of the two cycles under the given operating conditions. The thermal properties of each state point in the system are calculated using the Redlich–Kwong–Aspen equation of state [47]. The environmentally benign ternary zeotropic mixture R1234yf/R170/R14 is used as the working fluid. The influence of the operating parameters on system performance will be evaluated. Table 2 lists the basic operating parameters for all the simulations below.Table 2 Input parameter values assumed in the simulation models
Parameter Value
Reference temperature/T0 (K) 298.15
Reference pressure/p0 (kPa) 101.325
Suction pressure/p1 (MPa) 0.2 [48]
Exhaust pressure/p2 (kPa) 2 [48]
Mass flow rate at compressor inlet/m˙1 (kg/s) 1 [10]
Vapor quality at state point 8/q8 0.5 [9]
Isentropic efficiency of compressor/ηcom. 0.8 [36, 37]
Simulation results and discussion
The initial composition
Usually, ternary mixtures are used in the three-stage ARC system to obtain refrigeration temperatures below − 80 °C. Calm [51] pointed out that refrigerants with low GWP value, such as R41, R170, R1132a and R1150, could be good replacements for R23 (GWP:12,000) with the standard boiling point around, ternary mixtures are used 80 °C. R1234yf is one of the most suitable replacements for R134a (GWP: 1430) [35, 36]. The standard boiling point of R14 is − 128.05 °C and can be used to obtain an evaporating temperature around − 100 °C. Thus, the ternary mixture of R1234yf/R170/R14 was chosen as the working fluid in the MTARC [50]. Table 3 lists the thermodynamic properties of the three pure refrigerants concerned [52].Table 3 Physical properties of the alternative refrigerants
Refrigerant Chemical name Molecular weight/kg mol−1 ODP GWP100-yr (CO2-eq) ASHRAE safety group NBP(°C)
R1234yf 2,3,3,3-tetrafluoropropene 114.04 0 < 1 A2L − 29.45
R170 Ethane 30.07 0 5.5 A3 − 88.58
R14 Tetrafluoromethane 88.01 0 6630 A1 − 128.05
In the operation process of the MTARC, the saturated liquid at state point 5 and state point 12 are R1234yf/R170-enriched mixture and R170/R14-enriched mixture, respectively. Thus, the initial composition of R1234yf/R170/R14 can be determined by combining the compositions of R1234yf/R170 and R170/R14. Figure 2a and b are the isobaric three-dimensional equilibrium diagram and isothermal-isobaric ternary equilibrium diagram of R1234yf/R170/R14, respectively. As shown in Fig. 2b, the bubble-surface and the dew-surface intersect with S1 at Line-1 and Line-2, respectively, since the condensation temperature is about 30 °C. Thus, the mass ratio of R1234yf/R170 can be obtained, which is about z1 = 0.815/0.185 [18]. Similarly, the mass ratio of z2 = 0.425/0.575 for R170/R14 can be obtained according to the intersection line between the S2 and the bubble-surface. Consequently, the initial composition of 0.65/0.15/0.20 for R1234yf/R170/R14 can be calculated.Fig. 2 a Isobaric three-dimensional phase equilibrium diagram at 2 MPa; b Isothermal-isobaric ternary phase equilibrium diagram of R1234yf/R170/R14
The performance comparison under a typical operating condition
Apart from the assumptions mentioned above and the input parameters listed in Table 1, the condenser outlet quality q3 and the intermediate pressure p4 are set as 0.65 and 1.5 MPa, respectively. In order to better compare the refrigeration performance, the mixture at the evaporator outlet is assumed to be saturated vapor (q14 = 1). Under this typical operating condition, thermodynamic characteristics of the MTARC and CTARC are calculated using the ternary mixture of R1234yf/R170/R14 (0.65/0.15/0.20) and are listed in Table 4.Table 4 The performance comparisons between two cycles under the typical operating condition
Properties CTARC MTARC Improvements
Input power (kW) 108.75 112.78 –
Cooling capacity (kW) 48.57 56.27 15.85%
COP 0.4467 0.4989 11.69%
Temperature (°C)
Evaporator inlet − 89.67 − 93.32 − 3.65
Evaporator outlet − 50.76 − 52.43 − 1.67
Compressor inlet − 11.47 − 2.71 8.76
Compressor outlet 92.27 101.29 9.02
Mass flow rate (kg/s)
m˙7 0.5953 0.6394 7.41%
m˙11 0.2682 0.2830 5.52%
Composition Z13 0.2577/0.2288/0.5135 0.2342/0.2387/0.5271 –
Total exergy destruction (kW) 67.12 66.31 1.21%
Exergy efficiency (%) 38.28 41.20 7.65%
From Table 4, we can see that the compressor input power of the MTARC is moderately greater than that of the CTARC, while the MTARC has a much larger cooling capacity. There are two factors that affect the input power, namely the refrigerant enthalpy at the compressor inlet and the compression ratio. As shown in Table 4, the quality in the separator will increase under the effect of intermediate pressure, and then the refrigerant enthalpy at the compressor inlet and the mass flow rate in the evaporator both increase, resulting in the increase of input power and cooling capacity of the MTARC. Consequently, the COP of MTARC reaches 0.4989, which is 11.69% higher than that of the CTARC. In addition, both the evaporator inlet and outlet temperatures of the MTARC are lower than those of the CTARC. This is because the mass fraction of the volatile component R14 is increased due to the increase of quality, thus the evaporating temperatures decrease when the evaporating pressure is fixed. However, the suction and exhaust temperatures of the MTARC are about 10 °C higher than that of the CTARC. It indicates that the MTARC can effectively prevent the compressor from liquid hammering under special circumstances. Compared with the CTARC, the MTARC has a smaller total exergy destruction and a greater input power. Consequently, the exergy efficiency of the MTARC is increased by 7.65%.
According to the operation process of the MTARC, it was found that the specific enthalpies of the refrigerant at the condenser outlet and VLS1 inlet are equal, but the temperature and pressure at the VLS1 inlet are greatly decreased. This is due to the effect of the isenthalpic throttling process of EV1. Therefore, when the suction and discharge pressures are fixed, the mass flow rate of the refrigerant in the low temperature circuit is increased due to the increase of quality at the VLS1 inlet. Besides, the mass fraction of the low boiling point component in the evaporator will not be decreased. That is, the cooling capacity and COP of the MTARC are increased without increasing the evaporating temperature. Thus, under the premise of ensuring no liquid in the compressor suction, the cycle performance can be improved when the suction and discharge pressures are fixed.
Effect of quality q3 on the system performance
In order to acquire an appropriate mass flow of the R170/R14-enriched refrigerant, the mixture should be partially condensed in the condenser. Thus, the refrigerant quality q3 at the condenser outlet is limited. By ensuring no liquid existence in the compressor suction and a proper exhaust temperature, the system performance was investigated under the q3 range of 0.58–0.75, and the refrigerant at the evaporator outlet is also assumed to be saturated vapor (q14 = 1). The results show that the evaporating temperatures of the MTARC are always lower than those of the CTARC within the entire q3 range. On the other hand, the compressor outlet temperature of the MTARC is higher than that of the CTARC. This means that the refrigerant temperature at the compressor inlet also increases, which can effectively prevent liquid hammer of the compressor.
Figure 3 shows the effect of quality q3 on the cooling capacity, COP, total exergy destruction and exergy efficiency. From Fig. 3a we can see that the cooling capacities of both the MTARC and CTARC increase with increasing q3. This is due to the increase of the mass flow of the refrigerant mixture in the evaporator. When q3 is 0.75, the cooling capacity and compressor input power of the MTARC are 65.51 kW and 126.87 kW, respectively, which are 31.04% and 24.67% greater than those of 49.99 kW and 101.76 kW when q3 is 0.58, respectively. That is, the growth rate of the cooling capacity is significantly higher than that of the input power. As a result, the COP gradually increases with increasing q3 as shown in Fig. 3a. On the other hand, the cooling capacity and COP of the MTARC are always greater than those of the CTARC within the entire q3 range as shown in Fig. 3b. Similar to the variation trend of the cooling capacity and COP, the total exergy destruction and exergy efficiency of the two cycles monotonically increase with increasing q3. Besides, the total exergy destruction of the MTARC is always slightly less than that of the CTARC, while the exergy efficiency of the MTARC is much higher than that of the CTARC under the same q3. This is because the input power of the MTARC is higher than that of the CTARC, resulting in the higher exergy efficiency according to Eq. (8). When q3 is 0.58 and 0.75, the exergy efficiency of the MTARC is 40.58% and 42.27% respectively, while those of the CTARC are 37.47% and 39.57%, respectively.Fig. 3 a Effect of quality q3 on the cooling capacity and COP; b Effect of quality q3 on the total exergy destruction and exergy efficiency
Effect of initial composition on the system performance
Since the strong zeotropic mixture has a large temperature glide when evaporating at a constant pressure, it is necessary to study the system performance of the two cycles with different initial compositions. In this section, the mixture at the evaporator outlet is assumed to be saturated vapor (q14 = 1). The calculated results show that the discharge temperatures of the two cycles monotonically increase with increasing initial mass fraction of R1234yf (ZR1234yf), but decrease with increasing initial mass fraction of R14 (ZR14). In addition, the compressor discharge temperature of the MTARC is higher than that of the CTARC at each initial composition. However, the evaporating temperatures of the two cycles decrease with increasing ZR1234yf and ZR14. The reason is that the increase of ZR1234yf will reduce the mass fraction of R170 (ZR170), which leads to the increase of the R14 mass fraction in the R170/R14-enriched mixture at state point 7. Then, the R14 mass fraction in the refrigerant mixture entering the evaporator is further increased when the quality at state point 8 (q8) is fixed as 0.5. On the other hand, the evaporator inlet temperatures of the MTARC is about 4 °C lower than that of the CTARC at each initial composition.
Figure 4 illustrates the variations of the cooling capacity and COP of the two cycles with different initial compositions. As shown in Fig. 4a, the cooling capacities of the two cycles decrease gradually with increasing ZR1234yf and ZR14. In addition, the cooling capacities of the MTARC are always greater than those of the CTARC within the entire composition range. When the initial composition of R1234yf/R170/R14 is 0.61/0.21/0.18, the MTARC has a cooling capacity of 60.01 kW, which is 16.41% greater than that of 51.55 kW for the CTARC. Contrary to the variation trend of the cooling capacity, the COP of the two cycles increase with increasing ZR1234yf and ZR14. According to Eq. (3), it indicates that the decrease rate of input power is higher than that of cooling capacity. When the initial composition of R1234yf/R170/R14 is 0.69/0.09/0.22, the MTARC has a COP of 0.5148, which is 11.62% higher than that of 0.4612 for the CTARC as shown Fig. 4b. When ZR14 is 0.20, the cooling capacity of the MTARC increases by 4.84% from 0.4893 to 0.5130 as ZR1234yf increases from 0.61 to 0.69.Fig. 4 a Effect of composition on cooling capacity; b Effect of composition on COP of the MTARC and CTARC
Figure 5 shows the effects of initial composition on the total destruction and exergy efficiency of the two cycles. We can see from Fig. 5a that the total exergy destruction of both the MTARC and CTARC decrease gradually with increasing ZR1234yf and ZR14. Although the input power also decreases with increasing ZR1234yf and ZR14, the growth rate is smaller than that of the total exergy destruction. As a result, the exergy efficiency increases with increasing ZR1234yf and ZR14 as shown in Fig. 5b. Within the entire composition range, the exergy efficiencies of the MTARC are always higher than those of the CTARC, which indicates that the additional pressure regulator can significantly reduce the exergy loss of the system. When the initial composition of R1234yf/R170/R14 is 0.69/0.09/0.22, the MTARC has an exergy efficiency of 44.35%, which is 7.33% higher than that of 41.32% for the CTARC.Fig. 5 a Effect of composition on total exergy destruction; b Effect of composition on exergy efficiency of the MTARC and CTARC
Effect of evaporating temperature on the system performance
The evaporating temperature is of great significance in influencing the performance of refrigeration systems. Figure 6a and b show the effects of evaporator outlet temperature T14 on the compressor temperature, cooling capacity, COP and exergy efficiency under the given operating conditions. As shown in Fig. 6a, all the temperatures increase gradually with increasing T14, and both the compressor inlet and outlet temperatures of the MTARC are higher than those of the CTARC. It should be noted that the liquid refrigerant exists at the compressor inlet of the MTARC when T14 is below − 75 °C, while the compressor of the CTARC will suck liquid when T14 is below − 70 °C. This demonstrates that the MTARC can acquire lower evaporating temperaure without liquid hammering of the compressor. In addition, the quality q14 at the evaporator outlet decreases with decreasing T14, which indicates that there is less liquid mixture evaporating in the evaporator. As a result, the cooling capacities of the two cycles decrease with decreasing T14 as shown in Fig. 6b. When T14 drops from − 55 to − 75 °C, the cooling capacity of the MTARC deceases by 42.66% from 52.74 kW to 30.24 kW. Meanwhile, the input power decreases by 11.20% from 110.95 to 98.52 kW. Consequently, the COP is decreased by 35.44% from 0.4754 to 0.3069. On the other hand, the performances of the MTARC are better than those of the CTARC in all given T14 ranges. When T14 is − 65 °C, the cooling capacity and COP of the MTARC are 41.41 kW and 0.3949 respectively, which show 28.20% and 17.98% improvements over the CTARC, respectively.Fig. 6 a Effect of evaporator outlet temperature on T1, T2, and q14; b Effect of evaporator outlet temperature on cooling capacity and COP; c Effect of evaporator outlet temperature on total exergy destruction and exergy efficiency
Figure 6c displays the variation trend of exergy performance with respect to T14. Both the total exergy destruction and exergy efficiency of the two cycles gradually increase with increasing T14. This indicates that the decrease rate of the total exergy destruction is greater than that of the total input power. Besides, the total exergy destructions of the MTARC are less, while the exergy efficiencies are higher than those of the CTARC within the entire T14 range. According to Eq. (8), the exergy efficiency is inversely proportional to the total exergy destruction, while is proportional to the input power. Therefore, it can be concluded that the MTARC can significantly reduce the input power of the compressor. This is because the pressure ratio is fixed as a constant, and the specific enthalpy difference of refrigerant at the compressor inlet and outlet of the MTARC is less than that of the CTARC. When T14 is − 65 °C, the exergy efficiency of the MTARC is improved by 9.89%, while that is improved by 9.03% when T14 is − 55 °C.
Effect of intermediate pressure on the MTARC performance
Under the action of the additional EV1, an intermediate pressure is obtained, and the relative independence between the refrigerant at VLS1 inlet and the refrigerant at condenser outlet is further realized. Therefore, it is possible for the MTARC to improve the system performance. Figure 7 shows the effect of intermediate pressure p4 on the thermodynamic performance of the MTARC under the premise of no liquid existence at the compressor inlet. In this section, the mixture at evaporator outlet is also assumed to be saturated vapor (q14 = 1). From Fig. 7a we can see that when p4 drops from 2 to 1 MPa, the refrigerant temperature T4 at VLS1 inlet decreases by 20.38 °C, while the quality q4 at the VLS1 inlet increases gradually. Thus, the mass flow of the refrigerant entering the low-temperature circuit (Streams 7 and 11) is further increased as shown in Fig. 7b. As a result, the cooling capacity of the MTARC increases with decreasing p4 as shown in Fig. 7c. As q4 increases, the increase of the specific enthalpy of the refrigerant at compressor inlet increases, accounting for the increase of input power. Finally, the MTARC shows an improvement of 35.43% in cooling capacity when p4 drops from 2 to 1 MPa. In addition, the evaporating temperatures also decrease with decreasing p4. When p4 drops from 2 to 1 MPa, the evaporator inlet temperature decreases by 7.23 °C from − 89.67 to − 96.90 °C, and the evaporator outlet temperature decreases by 3.43 °C from − 50.76 to − 54.19 °C.Fig. 7 a Effect of intermediate pressure on temperature (T4) and quality (q4) at VLS1 inlet; b Effect of intermediate pressure on mass flow rate; c Effect of intermediate pressure on evaporating temperature, input power and cooling capacity
Figure 8 illustrates the effect of intermediate pressure on the compressor outlet temperature, COP and exergy efficiency of the MTARC. Clearly, the decreasing p4 results in an increase of COP and exergy efficiency. This is because the growth rate of the cooling capacity is larger than that of the input power, which leads to an increase of COP. When the pressure is 1.2 MPa, the COP reaches 0.5340, and the compressor outlet temperature is 107.54 °C, which is an appropriate operating temperature. When p4 drops from 2 to 1 MPa, the COP and exergy efficiency are improved by 25.25% and 16.74%, respectively. However, the compressor outlet temperature increases by 19.93 °C from 92.27 to 112.20 °C. The reason is that the quality in the separator increases as p4 decreases, which leads to the increase of vapor refrigerant mass flowing to the low-temperature circuit (Steam 7 and 11) and the decrease of liquid refrigerant mass flow at state point 5. Because the quality at the evaporator outlet is fixed as 1, the mixed refrigerant at state points 17 and 15 cannot provide sufficient cooling capacity to condense the vapor refrigerant. As a result of the comprehensive effect, the temperature of the refrigerant at the compressor inlet increases, further increasing the discharge temperature. Therefore, the selection of the intermediate pressure should be comprehensively considered to ensure a desirable thermodynamic performance and a proper working temperature of the compressor in actual applications.Fig. 8 Effect of intermediate pressure on compressor outlet temperature, COP and exergy efficiency of the MTARC
In order to determine the main locations of irreversibility in the MTARC, the effect of p4 on the exergy destruction and exergy destruction percentage of each system component are depicted in Fig. 9. It can be seen from Fig. 9a that when p4 drops to 1 MPa, the compressor, condenser and EV1 contribute the most to the exergy destruction. With decreasing p4, the exergy destruction percentages of the condenser and EV1 increase gradually as show in Fig. 9b. This is attributed to the increase of heat transfer temperature difference in the condenser and the pressure drop in the EV1. On the contrary, the exergy destruction percentages of the CE1 and EV2 decrease with decreasing p4, while those of the compressor remain almost constant. This indicates that the exergy efficiency of the MTARC can be further improved mainly by enhancing the heat transfer performance of condenser and the structural optimization of EV1.Fig. 9 a Effect of intermediate pressure on exergy destruction; b Effect of intermediate pressure on exergy destruction percentage
Conclusions
At present, the studies related to the performance analysis of the ARC mainly focus on the improvement of separation efficiency, in which the decrease of the refrigerant flow to the evaporator was not considered. In order to solve this problem and propose an efficient refrigeration cycle to obtain the refrigeration temperatures around − 80 °C, this paper introduces a pressure regulator into a modified three-stage ARC, which can effectively decrease the refrigerant pressure and temperature in the separator to obtain a high separation efficiency, and can increase the vapor quality and the refrigerant flow to the evaporator. The environmentally benign ternary mixture of R1234yf/R170/R14 was used as the working fluid for sustainability concerns. Energy and exergy analyses of the CTARC and MTARC are conducted theoretically considering the key operating parameters of the composition, quality and intermediate pressure. The foregoing analysis results indicate that the MTARC is meaningful and manifest significant performance improvements. Major conclusions drawn from this research are summarized as follows:The MTARC can effectively increase the refrigerant flow rate to the evaporator, which rendering the MTARC always shows significantly better performance than the CTARC. Under a typical working condition, the cooling capacity, COP and exergy efficiency of the MTARC are improved by 15.85%, 11.69% and 7.65% comparing with those of the CTARC, respectively.
As the mass fraction of the less volatile component increases, the cooling capacity of two cycles are deteriorated, while the COP and exergy efficiency are increased due to the decline of the compressor input power. When the initial composition of R1234yf/R170/R14 is 0.69/0.09/0.22, the COP and exergy efficiency of the MTARC are 11.62% and 7.33% higher than those of the CTARC, respectively.
As the quality at condenser outlet increases, the COP, cooling capacity and exergy efficiency of the two cycles are improved gradually. When the quality is 0.75, the COP and exergy efficiency of MTARC are 10.25% and 6.82% higher than those of the CTARC.
The performance of the MTARC is improved with decreasing intermediate pressure. When the intermediate pressure drops from 2 to 1 MPa, the cooling capacity, COP and exergy efficiency of the MTARC are improved by 35.43%, 25.25% and 16.74%, respectively, while the compressor outlet temperature increases by 19.93 °C from 92.27 to 112.20 °C. Therefore, the selection of the intermediate pressure should be comprehensively considered to ensure a desirable thermodynamic performance and a proper working temperature for the compressor in actual applications.
In general, the MTARC can offer many advantages for its applications in low-temperature equipment down to − 80 °C, such as freezers, cryopreservation chamber, and the pre-cooling system for cryoablation devices. Because many assumptions were adopted in the modeling process, the analytical results still show some deviation from the actual operating conditions and the MTARC only verifies its improvements in theory. Thus, further experimental work will be necessary in the next step before practical application. Besides, the exergy analysis suggests that the heat transfer enhancement of the air-cooled condenser and the structure optimization of the throttle valves are the key improvements of the ARC systems.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (Grant No. 51906151), and the China Postdoctoral Science Foundation (Grant No. 2019M661572).
Author contributions
The specific contributions to this work of each author are listed as follows, which has been agreed by all authors. YQ contributed to software, investigation, writing—original draft, writing—review & editing, and funding acquisition. NL contributed to validation, investigation, and writing—review & editing. HZ contributed to methodology and supervision. BL contributed to conceptualization and resources.
Declarations
Conflict of interest
The authors declare that there is no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Energy and exergy evaluation of a modified three-stage auto-cascade refrigeration system using low-GWP refrigerants for sustainable development”.
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References
1. Mota-Babiloni A Mastani Joybari M Navarro-Esbrí J Mateu-Royo C Barragán-Cervera Á Amat-Albuixech M Ultralow-temperature refrigeration systems: configurations and refrigerants to reduce the environmental impact Int J Refrig 2020 111 147 158 10.1016/j.ijrefrig.2019.11.016
2. Rodríguez-Jara EÁ Sánchez-de-la-Flor FJ Expósito-Carrillo JA Salmerón-Lissén JM Thermodynamic analysis of auto-cascade refrigeration cycles, with and without ejector, for ultra low temperature freezing using a mixture of refrigerants R600a and R1150 Appl Therm Eng 2022 200 117598 10.1016/j.applthermaleng.2021.117598
3. Johnson N Baltrusaitis J Luyben WL Design and control of a cryogenic multi-stage compression refrigeration process Chem Eng Res Des 2017 121 360 367 10.1016/j.cherd.2017.03.018
4. Wang Q Li DH Wang JP Sun TF Han XH Chen GM Numerical investigations on the performance of a single-stage auto-cascade refrigerator operating with two vapor–liquid separators and environmentally benign binary refrigerants Appl Energy 2013 112 949 955 10.1016/j.apenergy.2013.01.081
5. Harby K Hydrocarbons and their mixtures as alternatives to environmental unfriendly halogenated refrigerants: an updated overview Renew Sustain Energy Rev 2017 73 1247 1264 10.1016/j.rser.2017.02.039
6. Qin Y Li N Zhang H Liu B Thermodynamic performance of a modified −150 °C refrigeration system coupled with Linde-Hampson and three-stage auto-cascade using low-GWP refrigerants Energy Convers Manag 2021 236 114093 10.1016/j.enconman.2021.114093
7. Sarkar J Ejector enhanced vapor compression refrigeration and heat pump systems—a review Renew Sustain Energy Rev 2012 16 6647 6659 10.1016/j.rser.2012.08.007
8. Lawrence N Elbel S Theoretical and practical comparison of two-phase ejector refrigeration cycles including First and Second Law analysis Int J Refrig 2013 36 1220 1232 10.1016/j.ijrefrig.2013.03.007
9. Yan G Chen J Yu J Energy and exergy analysis of a new ejector enhanced auto-cascade refrigeration cycle Energy Convers Manag 2015 105 509 517 10.1016/j.enconman.2015.07.087
10. Tan Y Wang L Liang K Thermodynamic performance of an auto-cascade ejector refrigeration cycle with mixed refrigerant R32 + R236fa Appl Therm Eng 2015 84 268 275 10.1016/j.applthermaleng.2015.03.047
11. Boyaghchi FA Asgari S A comparative study on exergetic, exergoeconomic and exergoenvironmental assessments of two internal auto-cascade refrigeration cycles Appl Therm Eng 2017 122 723 737 10.1016/j.applthermaleng.2017.05.065
12. Hao X Wang L Wang Z Tan Y Yan X Hybrid auto-cascade refrigeration system coupled with a heat-driven ejector cooling cycle Energy 2018 161 988 998 10.1016/j.energy.2018.07.201
13. Yu J Zhao H Li Y Application of an ejector in autocascade refrigeration cycle for the performance improvement Int J Refrig 2008 31 279 286 10.1016/j.ijrefrig.2007.05.008
14. Bai T Yan G Yu J Experimental investigation of an ejector-enhanced auto-cascade refrigeration system Appl Therm Eng 2018 129 792 801 10.1016/j.applthermaleng.2017.10.053
15. Bai T Yan G Yu J Experimental investigation on the dynamic malfunction behavior of the two-phase ejector in a modified auto-cascade freezer refrigeration system Energy Convers Manag 2019 183 382 390 10.1016/j.enconman.2018.12.099
16. Cheng Z Wang B Shi W Li X Performance evaluation of novel double internal auto-cascade two-stage compression system using refrigerant mixtures Appl Therm Eng 2020 168 114898 10.1016/j.applthermaleng.2020.114898
17. Chen Q Zhou L Yan G Yu J Theoretical investigation on the performance of a modified refrigeration cycle with R170/R290 for freezers application Int J Refrig 2019 104 282 290 10.1016/j.ijrefrig.2019.05.037
18. Sobieraj M Rosiński M High phase-separation efficiency auto-cascade system working with a blend of carbon dioxide for low-temperature isothermal refrigeration Appl Therm Eng 2019 161 114149 10.1016/j.applthermaleng.2019.114149
19. Yu M Yu J Thermodynamic analyses of a flash separation ejector refrigeration cycle with zeotropic mixture for cooling applications Energy Convers Manag 2021 229 113755 10.1016/j.enconman.2020.113755
20. Zhang L Xu S Du P Liu H Experimental and theoretical investigation on the performance of CO2/propane auto-cascade refrigerator with a fractionation heat exchanger Appl Therm Eng 2015 87 669 677 10.1016/j.applthermaleng.2015.05.016
21. Chen J Yu J Yan G Performance analysis of a modified autocascade refrigeration cycle with an additional evaporating subcooler Appl Therm Eng 2016 103 1205 1212 10.1016/j.applthermaleng.2016.05.029
22. Liu J Liu Y Yan G Yu J Theoretical study on a modified single-stage autocascade refrigeration cycle with auxiliary phase separator Int J Refrig 2021 122 181 191 10.1016/j.ijrefrig.2020.11.009
23. Mei B Barnoon P Toghraie D Su C-H Nguyen HC Khan A Energy, exergy, environmental and economic analyzes (4E) and multi-objective optimization of a PEM fuel cell equipped with coolant channels Renew Sustain Energy Rev 2022 157 112021 10.1016/j.rser.2021.112021
24. Ahmadi G Toghraie D Akbari OA Efficiency improvement of a steam power plant through solar repowering Int J Exergy 2017 22 1 10.1504/IJEX.2017.083015
25. Ahmadi GR Toghraie D Energy and exergy analysis of Montazeri steam power plant in Iran Renew Sustain Energy Rev 2016 56 454 463 10.1016/j.rser.2015.11.074
26. Ma Y Fazilati MA Sedaghat A Toghraie D Talebizadehsardari P Natural convection energy recovery loop analysis, part I: energy and exergy studies by varying inlet air flow rate Heat Mass Transf 2020 56 1685 1695 10.1007/s00231-019-02766-z
27. Heydari O Miansari M Arasteh H Toghraie D Optimizing the hydrothermal performance of helically corrugated coiled tube heat exchangers using Taguchi’s empirical method: energy and exergy analysis J Therm Anal Calorim 2021 145 2741 2752 10.1007/s10973-020-09808-3
28. Adeli J Niknejadi M Toghraie D Full repowering of an existing fossil fuel steam power plant in terms of energy, exergy, and environment for efficiency improvement and sustainable development Environ Dev Sustain 2020 22 5965 5999 10.1007/s10668-019-00461-x
29. Miansari M Valipour MA Arasteh H Toghraie D Energy and exergy analysis and optimization of helically grooved shell and tube heat exchangers by using Taguchi experimental design J Therm Anal Calorim 2020 139 3151 3164 10.1007/s10973-019-08653-3
30. Asgari S Noorpoor AR Boyaghchi FA Parametric assessment and multi-objective optimization of an internal auto-cascade refrigeration cycle based on advanced exergy and exergoeconomic concepts Energy 2017 125 576 590 10.1016/j.energy.2017.02.158
31. Yan G Hu H Yu J Performance evaluation on an internal auto-cascade refrigeration cycle with mixture refrigerant R290/R600a Appl Therm Eng 2015 75 994 1000 10.1016/j.applthermaleng.2014.10.063
32. Rezayan O Behbahaninia A Thermoeconomic optimization and exergy analysis of CO2/NH3 cascade refrigeration systems Energy 2011 36 888 895 10.1016/j.energy.2010.12.022
33. Aprea C Maiorino A Autocascade refrigeration system: experimental results in achieving ultra low temperature Int J Energy Res 2009 33 565 575 10.1002/er.1492
34. Sivakumar M Somasundaram P Exergy and energy analysis of three stage auto refrigerating cascade system using Zeotropic mixture for sustainable development Energy Convers Manag 2014 84 589 596 10.1016/j.enconman.2014.04.076
35. Sivakumar M Somasudaram P Thermodynamic investigations of Zeotropic mixture of R290, R23 and R14 on three-stage auto refrigerating cascade system Therm Sci 2016 20 2073 2086 10.2298/TSCI140103091S
36. Qin Y Li N Zhang H Liu B Energy and exergy performance evaluation of a three-stage auto-cascade refrigeration system using low-GWP alternative refrigerants Int J Refrig 2021 126 66 75 10.1016/j.ijrefrig.2021.01.028
37. Kilicarslan A Hosoz M Energy and irreversibility analysis of a cascade refrigeration system for various refrigerant couples Energy Convers Manag 2010 51 2947 2954 10.1016/j.enconman.2010.06.037
38. Lizarte R Palacios-Lorenzo ME Marcos JD Parametric study of a novel organic Rankine cycle combined with a cascade refrigeration cycle (ORC-CRS) using natural refrigerants Appl Therm Eng 2017 127 378 389 10.1016/j.applthermaleng.2017.08.063
39. Liu J Liu Y Yan G Yu J Thermodynamic analysis on a modified auto-cascade refrigeration cycle with a self-recuperator Int J Refrig 2022 137 117 128 10.1016/j.ijrefrig.2022.02.012
40. Sobieraj M Experimental investigation of the effect of a recuperative Heat exchanger and throttles opening on a CO2/isobutane autocascade refrigeration system Energies 2020 13 5285 10.3390/en13205285
41. Rui S Zhang H Zhang B Wen D Experimental investigation of the performance of a single-stage auto-cascade refrigerator Heat Mass Transf 2016 52 11 20 10.1007/s00231-015-1577-4
42. He Y Wu H Liu Y Wang T Wu X Cheng C Theoretical performance comparison for two-stage auto-cascade refrigeration system using hydrocarbon refrigerants Int J Refrig 2022 142 27 36 10.1016/j.ijrefrig.2022.06.008
43. Hamad AJ Hussien FM Yousif SS Comparative study of auto cascade refrigeration system performance using alternative mixed refrigerants Int J Eng Res Ind Appl 2015 8 111 126
44. Chen J Zhu K Huang Y Chen Y Luo X Evaluation of the ejector refrigeration system with environmentally friendly working fluids from energy, conventional exergy and advanced exergy perspectives Energy Convers Manag 2017 148 1208 1224 10.1016/j.enconman.2017.06.051
45. Mousavi SA Mehrpooya M A comprehensive exergy-based evaluation on cascade absorption-compression refrigeration system for low temperature applications-exergy, exergoeconomic, and exergoenvironmental assessments J Clean Prod 2020 246 119005 10.1016/j.jclepro.2019.119005
46. ASPEN Plus. Aspen Technology Inc., 200 Wheeler Road Burlington, MA, USA 2020.
47. Mathias P A versatile phase equilibrium equation of state Ind Eng Chem Process Des Dev 1983 22 3 385 391 10.1021/i200022a008
48. Navarro-Esbrí J Mendoza-Miranda JM Mota-Babiloni A Barragán-Cervera A Belman-Flores JM Experimental analysis of R1234yf as a drop-in replacement for R134a in a vapor compression system Int J Refrig 2013 36 870 880 10.1016/j.ijrefrig.2012.12.014
49. Mendoza-Miranda JM Mota-Babiloni A Ramírez-Minguela JJ Muñoz-Carpio VD Carrera-Rodríguez M Navarro-Esbrí J Comparative evaluation of R1234yf, R1234ze(E) and R450A as alternatives to R134a in a variable speed reciprocating compressor Energy 2016 114 753 766 10.1016/j.energy.2016.08.050
50. Sun Z Wang Q Xie Z Liu S Su D Cui Q Energy and exergy analysis of low GWP refrigerants in cascade refrigeration system Energy 2019 170 1170 1180 10.1016/j.energy.2018.12.055
51. Calm JM The next generation of refrigerants—historical review, considerations, and outlook Int J Refrig 2008 31 1123 1133 10.1016/j.ijrefrig.2008.01.013
52. Lemmon EW, Huber ML, Mclinden MO. NIST Standard Reference Database 23: reference fluid thermodynamic and transport properties—REFPROP, version 9.1, Standard Reference Data Program, National Institute of Standards and Technology 2010.
| 0 | PMC9734607 | NO-CC CODE | 2022-12-14 23:28:29 | no | J Therm Anal Calorim. 2022 Dec 7;:1-14 | utf-8 | J Therm Anal Calorim | 2,022 | 10.1007/s10973-022-11721-w | oa_other |
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J Prev Alzheimers Dis
J Prev Alzheimers Dis
The Journal of Prevention of Alzheimer's Disease
2274-5807
2426-0266
Springer International Publishing Cham
36471008
97
10.14283/jpad.2022.97
Article
15th Conference Clinical Trials Alzheimer’s Disease, November 29–December 2, 2022, San Francisco, CA, USA: Posters (Clinical Trial Alzheimer’s Disease)
3 12 2022
2022
9 Suppl 1 51248
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Clinical Trial Alzheimer’s Disease
CLINICAL TRIALS: METHODOLOGY
P1- FEASIBILITY OF VIRTUAL AMYLOID PET DISCLOSURE WITH COGNITIVELY UNIMPAIRED RESEARCH PARTICIPANTS. C. Erickson1, N. Chin1, H. Rosario1, A. Peterson1, S. Johnson1, L. Clark1(1. University Of Wisconsin-Madison — Madison (United States))
Background: Sharing AD biomarker results with older adult cognitively unimpaired research participants is safe and has been effective at educating individuals about the meaning of their results. As biomarkers become more widely available, more cognitively unimpaired older adults may learn their results through clinical trial enrollment and participation in observational cohort studies. Many prior studies, however, have been conducted in-person. Pushes towards telemedicine accelerated during the COVID-19 pandemic and presented opportunities to research virtual return of results. Objectives: We virtually returned beta-amyloid PET results to cognitively unimpaired older adults enrolled in a longitudinal observational cohort study (Wisconsin Registry for Alzheimer’s Prevention; WRAP). One of the primary goals of the WRAP Amyloid Disclosure Study was to assess protocol feasibility for virtual beta-amyloid PET results disclosure. Methods: The study consists of three virtual visits conducted via televideo (education, disclosure, and brain health counseling) and three telephone follow-ups over a 9-month period. Participants are given the option to complete visits at home or onsite over televideo in a separate room from study staff. Feasibility was assessed by measures of participation, retention, adherence to meeting brain health goals, clinician competence in including intervention elements, and safety. Additionally, we assessed participant satisfaction and preparedness for the study visits. Safety was measured through assessment of mood, anxiety, and suicidality using Patient Health Questionnaire (PHQ-9), Geriatric Anxiety Scale 10-item form (GAS-10), and Columbia Suicide Severity Rating Scale (C-SRRS), respectively. Severe depression was indicated by PHQ-9 scores ≥20. Severe anxiety was indicated by GAS-10 scores ≥18. Participant Preparedness and Satisfaction was measured through separate questionnaires assessing usefulness of study materials, utility of visit, and qualitative feedback for study improvement for both the disclosure and brain health counseling visits. We assessed distributions of study materials usefulness and visit utility. We compiled themes of participant feedback for study improvement. Results: Data collection is ongoing and will include approximately 100 participants upon study completion in December 2022. The measures reported are current as of March 3rd, 2022. 72.6% of participants contacted chose to enroll. Three enrolled participants withdrew themselves prior to disclosure based on clinician interviewing of participant and reported hesitance to learn results (96.9% retention). 32 participants completed all study procedures. The sample was predominantly female (69.1%), college-educated (72.7%), White (96.4%), has a family history of dementia (69%), and the average age was 71.2+/-4.6. Approximately 30% of participants had elevated amyloid PET results. 83.3% of follow-up scores indicated participants made progress on their brain health SMART goals. Study clinicians leading disclosure on average hit 23.4 of 24 essential visit components (>97%) and reported that the visit went “very well” (average quality rating: 4.1). Participants reported an average satisfaction rating of 3.9 for the disclosure visit (median: 4, “very much satisfied”). Clinicians leading the brain health counseling on average hit 23.1 of 24 essential visit components (>96%) and reported that the visit went “very well” (average quality rating: 4.2). Participants reported an average satisfaction rating of 3.3 for counseling visit (median: 4, “very much satisfied”). Only 2 participants expressed suicidality and they were withdrawn before disclosure. No participants endorsed severe depression or anxiety, or suicidality after disclosure. To date, all participants have denied regretting learning their beta-amyloid result. Overall, participants endorsed that the disclosure visit was useful (96% reported the visit was “very” or “somewhat” useful) and they were satisfied with the visit (98% were “very” or “somewhat” satisfied). All participants recommended we continue with the disclosure visits. 86.4% of participants reported that the brain health counseling visit was “very” or “somewhat” useful, with 81.8% reporting they were “very” or “somewhat” satisfied. 81.8% of participants also recommended that we continue with the brain health counseling visit. Upon asking participants to share any feedback on the study, the most common responses included requesting a more detailed result (as opposed to a binary elevated/non-elevated result), showing a visual image of the PET result, and more check-ins about their brain health goal progress. Many participants reported enjoying the virtual visits, though 24.5% reported a preference for in-person disclosure. To date, 37.6% of participants came onsite for televideo visits due to technological inaccessibility. Conclusion: Eligible participants were interested, enrolled, and remained in the study. Virtual data collection has been successful and streamlined the data entry process. Both study clinicians/staff and participants report that the disclosure and brain health counseling visits have gone well. Participants shared that being in their homes provided them comfort and a sense of safety when learning amyloid PET results; however about one-third of participants needed to complete the visit onsite due to technological inaccessibility for an at-home televideo visit. Most importantly, virtual disclosure has been safe and not resulted in increased depression, anxiety, or suicidality. Overall, the Amyloid Disclosure Study has demonstrated that virtual return of beta-amyloid PET results to cognitively unimpaired research participants is feasible.
P02- USING COMMON-CLOSE TRIAL DESIGNS FOR EFFICIENTLY DETECTING SLOWING OF PROGRESSION IN ALZHEIMER’S DISEASE. L.L. Raket1, J. Cummings2(1. Novo Nordisk — Søborg (Denmark), 2. Chambers-Grundy Center For Transformative Neuroscience, Pam Quirk Brain Health And Biomarker Laboratory, Department Of Brain Health, School Of Integrated Health Sciences, University Of Nevada Las Vegas (unlv) — Las Vegas (United States))
Background: The combination of slow clinical progression and great heterogeneity of early Alzheimer’s disease (AD) makes it very difficult to detect disease-modifying treatment effects that manifest as slowing of disease progression. While longer trial duration can address this problem, the variability in measurement endpoints increases with time since baseline as greater divergence of patient trajectories occurs. Furthermore, longer follow-up leads to greater trial drop-out and increases development timelines and associated time for new drugs becoming available to patients. Objectives: To explore if a common-close trial design where patients have variable degree of follow-up combined with disease progression modeling improves detection of disease-modifying treatment effects. Methods: We modeled a common-close design where all patients stayed on randomized treatment until the last randomized patient had the opportunity to complete 24 months of treatment. The follow-up time of individual patients depended on when they were recruited and how long trial recruitment took. We assumed that clinical endpoints were assessed every 6 months until the 24-month visit (0, 6, 12, 18, and 24 months since baseline) and yearly after that (36 and 48 months since baseline) for the subjects having the opportunity to do so before the common close. We evaluated several methods for estimating the treatment effects and how including data collected beyond the 24-month visit affected the power to detect a slowing of disease progression. We simulated trials in subjects with mild cognitive impairment due to Alzheimer’s disease (clinical diagnosis of MCI; amyloid positivity [CSF/PET]; MMSE ≤28) with the 13-item ADAS-cog as the outcome measure. Subject-level trajectories were simulated based on modeling of 356 subjects in the Alzheimer’s Disease Neuroimaging Initiative meeting our inclusion criteria: A baseline-constrained mixed model for repeated measures (MMRM) of the ADAS-cog scores was used to estimate the mean trajectory and covariance matrix using data collected at the baseline visit and visits 6, 12, 18, 24, 36 and 48 months after baseline. Placebo group subject-level trajectories were simulated from the estimated model and active treatment group trajectories were simulated the same way except the mean parameters were modified to reflect an average 20% slowing of disease progression. A 5% cumulative drop-out rate for every additional post-baseline visit was implemented and recruitment time (first to last patient randomized) was assumed to be 30 months with recruitment rate assumed to follow a quadratic pattern (4%, 16%, 36%, 64%, 100% recruited after 6, 12, 18, 24, and 30 months respectively). On average, this meant that at study completion, 81% of patients had data at 24 months, 28% had data at 36 months and 3% had data at 48 months. Trials with 300 to 1000 subjects per arm were simulated. The trial data both with and without post-24-month data were analyzed using a conventional MMRM and two different Progression Model for Repeated Measures (PMRMs) with assumptions of proportional reduction in decline and proportional slowing of disease progression. Using the MMRM, the treatment effects were quantified in two ways: treatment difference at 24 months and difference in area under the curve (AUC) between active therapy and placebo across the entire study duration. For each method and scenario, significance cut offs were re-calibrated based on simulations under the null hypothesis of no effect to ensure a comparable 2.5% one-sided significance level across methods. Results: Without post-24-month data, trials would require approximately 920 patients per arm to achieve 80% power to detect a 20% slowing of progression using a conventional MMRM analysis with the treatment effect quantified as the treatment difference at 24 months. For the difference in AUC more than 1000 patients per arm were needed. For the proportional decline PMRM, 650 patients per arm were needed, while the slowing PMRM needed 440. Including post-24-month data that would be collected as part of the common-close design did not change the 920 patients needed to achieve 80% power with the 24-month MMRM treatment difference. The patients needed with AUC difference was reduced to 680 per arm. The proportional decline PMRM needed 460 patients per arm to achieve 80% power and the slowing PMRM needed 400 patients per arm. Conclusion: Compared to conventional clinical trial designs and statistical methods such as the MMRM, a common-close design where double-blind longer-term follow up data is available for a subset of patients can greatly increase power to detect slowing of AD progression when paired with statistical models that quantify treatment effects across multiple visits.
P03- EVALUATING KARXT (XANOMELINE—TROSPIUM) AS A TREATMENT FOR PSYCHOSIS ASSOCIATED WITH ALZHEIMER’S DISEASE DEMENTIA: DESIGN OF THE PHASE 3, ADEPT-1, RELAPSE PREVENTION STUDY. C. Watson1, J. Cummings2, G. Grossberg3, M. Kang1, R. Marcus1(1. Karuna Therapeutics — Boston (United States), 2. University Of Nevada Las Vegas School Of Integrated Health Sciences — Las Vegas (United States), 3. Saint Louis University School Of Medicine — Saint Louis (United States))
Background: Psychosis is a common, serious unmet medical need in patients with Alzheimer’s disease (AD) dementia. There are presently no approved pharmacologic treatments for psychosis in AD dementia. Current treatment includes off-label use of antipsychotics with modest efficacy and significant safety concerns. Xanomeline, a brain-penetrant M1/M4 preferring muscarinic receptor agonist, previously showed antipsychotic efficacy in placebo-controlled trials in subjects with AD in a completers analysis [Bodick NC et al. 1997; DOI: 10.1001/archneur.1997.00550160091022]. Despite promising efficacy, further clinical development of xanomeline was limited by cholinergic adverse events. The investigational antipsychotic KarXT combines xanomeline with trospium, an FDA-approved nonspecific muscarinic receptor antagonist that does not measurably cross the blood-brain barrier. Trospium acts to mitigate the peripheral procholinergic side effects of xanomeline, providing a strategy for using xanomeline to stimulate brain muscarinic receptors with a decreased side effect burden. The decrease in adverse events was observed in KarXT pharmacokinetic studies in normal healthy volunteers as well as a phase 2 inpatient efficacy trial (EMERGENT-1) for the treatment of schizophrenia in which KarXT met the primary endpoint of reduction in Positive and Negative Syndrome Scale total score as well as other secondary efficacy endpoints. Unlike currently available antipsychotics, KarXT has no direct dopamine D2-blocking activity, and as such, its safety and tolerability profile differs from conventional and atypical antipsychotics. In the phase 2 trial there were no differences in weight gain, metabolic parameters, or changes on extrapyramidal symptom scales between active treatment and placebo. Objectives: To evaluate relapse prevention in subjects with psychosis associated with AD dementia treated with KarXT compared with placebo. A key secondary objective is to evaluate the time from randomization to discontinuation for any reason. Additional secondary objectives are to evaluate the safety and tolerability of KarXT in this patient population. Methods: The phase 3 ADEPT-1 trial is a double-blind, flexible-dose, placebo-controlled randomized withdrawal study to evaluate the safety and efficacy of KarXT in decreasing the risk of relapse in subjects with psychosis (with or without symptoms of agitation or aggression) associated with AD dementia. Subjects aged 55–90 years with moderate to severe psychosis associated with mild to severe AD dementia (Mini-Mental State Exam score range 8–22) will be enrolled into the study. Subjects will receive single-blind KarXT for 12 weeks during the single-blind treatment period. Each subject will be flexibly titrated to the maximum dose of KarXT 200 mg xanomeline/20 mg trospium/day. At the end of the single-blind treatment period, eligible responders will be randomized to either continue KarXT or be switched to matched placebo for a 26-week double-blind treatment period. The total study treatment duration is 38 weeks. A responder is defined as a subject with a ≥40% decrease (improvement) on the Neuropsychiatric Inventory-Clinician: Hallucinations + Delusions (NPI-C: H+D) score compared with baseline (day 1) and a Clinician Global Impression—Change (CGI-C) score of 1 or 2 (very much improved or improved). The primary endpoint of the study, time from randomization to relapse during the double-blind, randomized withdrawal treatment period, will be evaluated by survival analysis using Kaplan-Meier methodology. A key secondary endpoint is the time to discontinuation for any reason. Additional secondary endpoints are the safety and tolerability of KarXT compared with placebo. The study is planned to start mid-2022 and will enroll approximately 400 subjects to randomize approximately 200 subjects with psychosis associated with AD dementia into the double-blind randomized discontinuation period of the trial. Subjects completing the study will be offered the opportunity to receive KarXT in a 1-year, open-label safety extension study. Conclusion: The trial design of the ADEPT-1 study is an efficient way to assess the potential for KarXT to provide clinically meaningful benefit in preventing the return of psychosis associated with AD dementia in patients who have responded and have been stabilized on KarXT. If ADEPT-1 is successful, KarXT has the potential to be the first in a new class of treatments based on muscarinic receptor agonism for psychosis in patients with AD dementia.
P04- NUMBER OF DAYS BETWEEN INITIAL CONTACT AND IN-PERSON VISIT PREDICT ATTENDANCE RATES FOR POTENTIAL ALZHEIMER’S DISEASE TRIAL PARTICIPANTS. S. Starling1, G. Munoz1, M. Evans1, J. Engler1, S. Rutrick1(1. Adams Clinical — Watertown (United States))
Background: Alzheimer Disease (AD) clinical trials can be challenging in regard to recruitment and retention of participants, including high no-show or cancellation rates for screening visits. Identifying strategies to increase attendance rates will speed up enrollment in AD trials1. The lag time between the site’s first contact with a potential participant and their scheduled in-person prescreening visit date is one factor that impacts attendance rates in psychiatry clinical trials2, yet it has not been explored in AD trials. We examined if shorter scheduling lag time was associated with higher attendance rates for AD trial prescreening visits. Methods: Our sample includes prospective AD trial participants recruited from April 2021 through April 2022 by advertising with Facebook and Google. After potential subjects submitted contact information online, a recruiter called them to conduct a remote interview. The recruiter then scheduled potentially eligible subjects for an in-person prescreening visit with a clinician, with scheduling lag ranging from the same day as the phone screen to up to 6 weeks later. This analysis examined the impact of scheduling lag (number of days between phone screen and date of scheduled prescreening visit) on prescreening visit attendance. Results: From April 2021 to April 2022, 5,816 individuals applied to participate in AD trials at our site through online advertisements. Of those, 16% (956) completed a phone screen interview and of those interviewed, 46% (436) were scheduled for an in-person prescreening visit. Scheduling lag ranged from 0 days to 42 days (M=7.6, SD=6.6). The overall attendance rate was 55%. Scheduling lag was found to be a significant predictor of prescreening visit attendance, with subjects who were scheduled sooner (i.e., fewer days between their phone screen and scheduled prescreening visit) being more likely to attend their visit (β=-.052, p=.001). Age was also correlated with attendance, with older participants being more likely to show (β=1.03, p=.015); however, scheduling lag remained a significant predictor of prescreening visit attendance, even when controlling for subjects’ age. Conclusions: In line with findings from psychiatry trial recruitment data, our results suggest that scheduling prescreening visits sooner could result in improved attendance rates in AD trials as well. Encouraging potential participants to come in sooner for their prescreening visits could be an effective way to speed up enrollment. Anecdotally, although AD trial-seekers often prefer to schedule prescreening appointments weeks out, our results suggest encouraging subjects to come in sooner may be more effective for recruitment. References: 1. Puffer, S., & Torgerson, D. (2003). Recruitment difficulties in randomized controlled trials. Controlled Clinical Trials, 24, 214–215; 2. Evans, M., Sauder, C., Thorpe, D., Engler, J., & Domilici, D. (May 2020). Increasing show rates for major depressive disorder clinical trial screening visits: The impact of scheduling speed on screening visit attendance. [Poster presentation]. American Society of Clinical Psychopharmacology Conference, Virtual. The authors have no conflicts of interest to report.
P05- POWER ANALYSIS OF A PROGNOSTIC ENRICHMENT PROCEDURE BASED ON AD COURSE MAP, A SIMULATION STUDY. E. Maheux1, I. Koval1, J. Ortholand1, C. Birkenbihl2, V. Bouteloup3, S. Durrleman1(1. Sorbonne Université, Institut du Cerveau — Paris Brain Institute — ICM, CNRS, Inria, Inserm, AP-HP, Hôpital de la Pitié Salpêtrière, F-75013 — Paris (France), 2. Fraunhofer Institute for Algorithms and Scientific Computing SCAI — Sankt Augustin (Germany), 3. Université de Bordeaux, Inserm 1219, CIC1401-EC — Bordeaux (France))
Background: Many longitudinal studies have demonstrated the large heterogeneity of progression encountered by patients suffering from Alzheimer’s disease (AD). While knowledge improved a lot and trials shifted to enrolling biomarker-confirmed patients at earlier stage of their disease, the heterogeneity remains. This heterogeneity is dramatically hardening the drug development for AD and it calls for precision drug development, as advocated by Cummings and colleagues. Today, the emergence of trial-ready cohorts together with the broad availability of retrospective AD data and the development of disease progression models, is providing the means to effectively implement the triptych of selecting the right patient, at the right time, in a right trial. Objective: To evaluate a new enrichment technique, based on a prognostic biomarker automatically computed from multimodal screening data. Methods: We trained a disease progression model called AD Course Map using all available visits of amyloid positive subjects from ADNI. We used the open-source software Leaspy (https://gitlab.com/icm-institute/aramislab/leaspy). The model summarizes the distribution of trajectories of the following endpoints from asymptomatic to symptomatic stages of AD: cognitive and functional assessments (MMSE, ADAS-Cog13, CDR-SB), CSF biomarkers, whole-brain amyloid PET SUVR, normalized volumes of the hippocampus and the lateral ventricles. From three external cohorts (AIBL, J-ADNI, MEMENTO) and held-out ADNI subjects, we selected the 828 subjects with 1) an early AD, 2) high levels of brain amyloid according to PET or CSF, 3) 50 to 85 years old at baseline, 4) a follow-up visit 18 months after their baseline visit. We disclosed the multimodal data of those selected individuals at their baseline visit only. We personalized our AD Course Map to those data, that is to say we estimate the random effects of our model per individual. We were then able to forecast all endpoints, per individual, at any timepoint. We defined our prognostic biomarker as the predicted primary outcome of our simulated trial, chosen to be the change from baseline of CDR-SB after 18 months. Finally, we constructed an enriched population of our trial by considering subjects above a clinically meaningful cutoff for this prognostic biomarker. We then split the enrolled individuals into two arms: a placebo and a treated arm. The placebo arm is supposed to follow the natural disease history (e.g. no placebo effect); the treated arm is simulated by applying a given treatment effect on the observed progression. We computed the sample size required to adequately power the trial for a hypothetical 25% treatment effect (two-sided t-test with 5% significance, 80% power, no drop-out included). We bootstrapped the procedure to get empirical confidence intervals. We also compared our data-driven enrichment strategy with a genetic enrichment consisting in restricting to APOE-e4 carriers. Results: When using our enrichment technique, the sample size is reduced by 41.5% (95% confidence interval: [39.0%, 44.3%]), while targeting 52.6% of initial subjects as compared to no enrichment. In comparison, the sample size reduction when selecting only APOE-e4 carriers is only of 12.2% ([8.2%, 16.3%]), while targeting 62.9% of initial subjects. Conclusion: From a pool of trial candidates, AD Course Map is able to identify the ones at risk of experiencing a significant progression of the outcome. The selected progressors show a greater and more homogenous progression, thus resulting in a more powered trial. Our enrichment procedure leads to more than 40% sample size reduction, outperforming enrichment based on the APOE genotype. These findings demonstrate the benefits of such a companion software tool for patient recruitment in trials and, in the future, for supporting clinicians in prescribing the right treatment to the right patient at the right time. References: 1. Cummings, J., Feldman, H. H. & Scheltens, P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimers Res. Ther. 11, 76 (2019); 2. Jutten, R. J. et al. Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity. Neurology 96, e2673–e2684 (2021); 3. Schiratti, J.-B., Allassonnière, S., Colliot, O. & Durrleman, S. A Bayesian Mixed-Effects Model to Learn Trajectories of Changes from Repeated Manifold-Valued Observations. J. Mach. Learn. Res. 18, 1–33 (2017); 4. Koval, I. et al. AD Course Map charts Alzheimer’s disease progression. Sci. Rep. 11, 8020 (2021).
P06- IMPLEMENTING NOVEL CLINICAL TRIAL DESIGNS IN DEMENTIA WITH LEWY BODIES: A ROADMAP TO PERSONALIZED MEDICINE. C. Abdelnour1, J.B. Toledo2, D. Ferreira3, F. Rodríguez-Porcel4, P. Choudhury5, M. Okafor6, S. Scholz7, B. Boeve5, I. Litvan8, J. Leverenz9, L. Bonanni10, J.P. Taylor11, S.J.G. Lewis12, D. Aarsland13, K. Poston1(1. Neurology And Neurological Sciences Department, Stanford University — Palo Alto (United States), 2. Department Of Neurology University Of Florida College Of Medicine — Gainesville (United States), 3. Division Of Clinical Geriatrics, Department Of Neurobiology, Care Sciences And Society, Karolinska Institutet—Stockholm (Sweden), 4. Department Of Neurology, Medical University Of South Carolina — Charleston (United States), 5. Department Of Neurology, Mayo Clinic — Rochester (United States), 6. Department Of Neurology, Emory University School Of Medicine — Atlanta (United States), 7. Neurodegenerative Diseases Research Unit, National Institute Of Neurological Disorders And Stroke. Laboratory Of Neurogenetics, National Institute On Aging — Bethesda (United States), 8. Parkinson and Other Movement Disorders Center, Department of Neurosciences, University of California San Diego — La Jolla (United States), 9. Lou Ruvo Center for Brain Health, Neurological Institute, and Department of Neurology. Cleveland Clinic — Cleveland (United States), 10. Department of Neuroscience Imaging and Clinical Sciences and CESI, University G d’Annunzio of Chieti-Pescara — Chieti (Italy), 11. Translational and Clinical Research Institute, Newcastle University — Newcastle (United Kingdom), 12. Forefront Parkinson’s Disease Research Clinic, Brain And Mind Centre, University Of Sydney — Camperdown Nsw 2050 (Australia), 13. Institute of Psychiatry, Psychology, & Neuroscience, King’s College London — London (United Kingdom))
Background: Dementia with Lewy Bodies (DLB) is a heterogeneous disorder. Clinically, patients can present with a wide variety of cognitive, neuropsychiatric, motor, sleep, and autonomic symptoms that may be differentially expressed throughout the course of the disease. From the neuropathological standpoint, the typical α-synucleinopathy is commonly found in combination with features of Alzheimer’s disease (AD) neuropathologic change, cerebrovascular disease, and TDP-43 proteinopathy. These co-pathologies are likely to influence the clinical presentation and disease progression. Several prodromal presentations have been proposed in DLB including: isolated REM-sleep behavior disorder (iRBD), mild cognitive impairment, delirium-onset, and a psychiatric-onset. The prodromal stage is a potential target window for disease-modifying treatments, but little is known about predicting the disease course of these prodromal entities. For example, iRBD patients can phenoconvert to Parkinson’s disease (PD), multiple system atrophy, or DLB with differing lag times from symptom onset. Thus, the natural history of DLB poses challenges for the design of clinical trials. Adaptive methodologies and master protocols provide opportunities to address these challenges and may be a roadmap to personalized medicine. Objectives: To analyze the potential benefit of adaptive methodologies and master protocols in DLB. Methods: In this review, we discuss the specific characteristics of DLB that justify the potential benefit of new clinical trial designs. Also, we discuss the concepts of adaptive methodologies and master protocols, and their potential advantages and pitfalls in DLB trials. Finally, we present illustrative examples where platform trials have been utilized in AD, PD, and ALS. Results: Adaptive methodologies in clinical trials are innovative designs that allow pre-specified modifications to a clinical trial protocol during the period of data collection. These modifications may include: sample size re-estimation, changes to eligibility criteria, endpoints, dosage or patient allocation; as well as the addition or termination of treatment arms. Alternatively, master protocols are a type of clinical trial design that use a single protocol to test multiple therapies (separately or in combination), and/or multiple diseases in parallell. They are classified as basket, umbrella, and platform trials. It is envisaged that adaptive methodologies and master protocols could be implemented in DLB to improve cost-efficacy and enable the detection of clinical benefit. Specific benefits of new designs for DLB trials include improving operational efficiency, the inclusion of diverse patient populations, sharing a single common control group for multiple therapies (thus requiring fewer participants), facilitating comparison across sub-studies, cycling between therapies, and increasing the number of treatments tested. Nevertheless, clinical trial design in DLB poses some challenges. Firstly, there are no specific validated outcome measures for monitoring DLB accurately, and the current evaluation of potential therapeutic benefit relies on tools developed for AD and PD. Secondly, there is lack of disease-specific diagnostic and prognostic biomarkers. Finally, patients are often under-and/or misdiagnosed leading to very slow recruitment rates in clinical trials. Adaptive methodologies and master protocols have been implemented in several neurodegenerative diseases, including AD, PD, and amyotrophic lateral sclerosis (ALS). Some examples are the DIAN-TU platform, a secondary prevention trial in participants with dominantly inherited AD mutations; the Australian Parkinson’s Mission clinical platform (APM001), a phase II clinical trial of three repurposed drugs in patients with moderate PD; and the HEALEY ALS Platform Trial, a multicenter adaptive platform trial investigating multiple treatments in parallel for ALS patients. It is hoped that lessons learned from these clinical trials could be adapted to enhance clinical trial design in DLB. Conclusion: New clinical trial designs are needed in DLB due to its heterogeneous clinical presentation, presence of co-pathologies, and variable clinical trajectory. Platform trials in AD, ALS an PD fields have shown promise. Although the implementation these type of trials in DLB will face some challenges, innovative clinical trial designs are required to address the specific characteristics of DLB and improve the efficacy and efficiency of drug development. Conflicts of interest: none.
P07- ADULT-ONSET LEUKOENCEPHALOPATHY WITH AXONAL SPHEROIDS AND PIGMENTED GLIA (ALSP) IS COMMONLY MISDIAGNOSED AS ALZHEIMER’S DISEASE (AD) AND FRONTOTEMPORAL DEMENTIA (FTD). S. Papapetropoulos1, A. Pontius2, S. Zappia1, M. Brennan2, L. Leahy2(1. Vigil Neuroscience — Cambridge (United States), 2. Consultant To Vigil Neuroscience — Cambridge (United States))
Background: ALSP is a progressive, fatal autosomal dominant neurodegenerative disease caused by CSF1R gene mutations that result in microglial dysfunction and lead to profound white matter changes primarily affecting the corpus callosum and periventricular regions of the frontal and parietal lobes. The prevalence of ALSP is estimated to be 10,000 in the US alone. The predominant phenotype associated with ALSP is cognitive impairment and is believed to be frequently misdiagnosed as AD or FTD. Diagnostic accuracy of ALSP has modestly improved due to publication of diagnostic criteria but the rate of initial misdiagnosis remains high. Disease awareness and correct diagnosis of ALSP are critical to avoid inclusion of such patients in dementia clinical trials and for initiation of early therapy of this debilitating and lethal disorder. Methods: A systematic literature review of clinical and genetic features of ALSP was conducted with published case studies (January 1,1980 through March 22, 2022) from a MEDLINE search using prespecified selection criteria. The search identified 87 published case reports with data extracted from 292 ALSP patients and is currently the largest case series of ALSP. Data were extracted, entered electronically into a Master Excel table under specific demographic and clinical characteristic headings, independently reviewed and examined for accuracy. Categorical variables were stratified by initial diagnosis, dichotomized by ALSP versus dementia and presented as frequency distribution. P-values for differences in frequency distribution between stratification factors were generated by the Chi-square test. Results: Demographic data revealed the mean (SD) age (years) of patients was 43.2 (11.6) with a median (minimum, maximum) of 42.0 (18.0, 86.0). Family history of ALSP was identified in 58.9% of patients with a greater frequency of females (48.3%) compared to males (42. 5%). A slightly greater percentage of patients with ALSP was found in Asia (34.2%) compared to Europe (32.2%) and North America (28.1%). Misdiagnosis of ALSP involved a broad spectrum of neurodegenerative, neuroimmune and vascular disorders. Due to phenotypic heterogeneity at disease onset, accurate initial diagnosis was detected in only 31.5% of ALSP patients. Frontotemporal dementia (11.6%), and Alzheimer’s disease (4.5%) were common misdiagnoses. Cognitive impairment (45.9%) and behavioral and psychiatric dysfunction (26.4%) were the most common initial symptoms. Comparison of patients with a correct diagnosis of ALSP to a diagnosis of patients with dementia (FTD, AD, other) revealed interesting observations. Dementia-diagnosed patients were significantly older with mean (SD) years 50.7 (9.05) vs 43.5 (12.2) (p<0.001) and reported family history more frequently (73.9% vs 53.8%), p=0.0048) compared to patients with ALSP. Conclusions: This systematic review confirms that ALSP is commonly misdiagnosed as a cognitive disorder, AD or FTD. To avoid misdiagnosis and inclusion of patients with ALSP in dementia clinical trials, screening patients for family history, white matter MRI lesions and early-onset cognitive impairment with behavioral and/or motor dysfunction should be considered. This combination of symptoms should trigger suspicion for ALSP and initiate early genetic testing. Larger prospective studies are warranted to further investigate presenting symptoms of ALSP. Increased disease awareness and genetic testing should improve diagnostic accuracy. Disclosures: This systematic review was financially supported by Vigil Neuroscience, Inc. S. Papapetropoulos and S. Zappia are fulltime employees of Vigil Neuroscience, Inc and hold stock or stock options in Vigil Neuroscience. A. Pontius and M. Brennan are consultants for Vigil Neurosciences and hold stock or stock options in Vigil Neuroscience. L. Leahy is consultant for Vigil Neuroscience.
P08- UPDATE ON THE TOGETHER STUDY: A PATIENT-AND INVESTIGATOR-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY EVALUATING THE EFFICACY, SAFETY AND TOLERABILITY OF BEPRANEMAB, UCB0107, IN PRODROMAL-TO-MILD ALZHEIMER’S DISEASE. M.E. Barton1, B. Van Den Steen2, H.L.G. Van Tricht2, W. Byrnes1, F.E. Purcell3, S.A. Southcott1, D. Raby3, Y.I. Starshinov3, C. Ewen2(1. UCB Pharma — Raleigh, North Carolina (United States), 2. UCB Pharma — Brussels (Belgium), 3. ICON plc — Dublin (Ireland))
Background: Bepranemab (formerly known as UCB0107) is a recombinant, humanized, full-length IgG4 monoclonal antibody that binds to a central tau epitope (amino acids 235–250). Here, we provide an update on the progress of the TOGETHER study (AH0003; NCT04867616) with bepranemab in people living with early Alzheimer’s disease (AD). Objective: The objective of the TOGETHER study is to evaluate the efficacy, safety and tolerability of bepranemab in patients living with prodromal-to-mild AD. Methods: TOGETHER is a global, multicenter, patient- and investigator-blind, placebo controlled, parallel-group study investigating the efficacy, safety and tolerability of bepranemab versus placebo. Patients with prodromal (National Institute on Aging-Alzheimer’s Association [NIA-AA] Stage 3) or mild (NIA-AA Stage 4) AD (target N=450) will be randomized (1:1:1) to receive one of two doses of bepranemab or placebo (intravenous, every 4 weeks), over an 80-week treatment period, followed by an optional 48-week open-label-extension period. Participants will have a global Clinical Dementia Rating (CDR) score of 0.5 (prodromal AD) or 0.5–1.0 (mild AD) and a CDR-Memory Box score ≥0.5 at screening and baseline, a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), mini-mental state examination (MMSE) ≥20 at screening and must meet the NIA-AA 2018 definition of cerebral beta-amyloid (Aβ) accumulation, by either a positive centrally read positron emission tomography (PET) scan or a positive cerebrospinal fluid (CSF) pTau181/Aβ1–42 ratio. The primary endpoint is change from baseline to Week 80 in CDR scale Sum of Boxes total score. Secondary endpoints include: pharmacokinetics; safety and tolerability; tau PET imaging and change from baseline in AD Assessment Scale-Cognitive Subscale 14, Amsterdam Instrumental Activities of Daily Living questionnaire and MMSE at Weeks 56 and 80. Results: As of June 1, 2022, 101 planned centers have enrolled participants across 10 countries: Belgium, Canada, France, Netherlands, Poland, Spain, Italy, Germany, UK and USA. Of the 1,079 participants who entered screening, 173 have been randomized so far and 693 failed screening. Predominant reasons for screen failure include not meeting RBANS, MMSE or Aβ positivity (measured by CSF or PET) criteria. Conclusion: This proof-of-concept study employs clinical outcome measures, imaging, pharmacokinetics, and biomarkers to assess the ability of bepranemab to slow progression of AD when administered in the early stages of disease. Enrollment and randomization of participants are well on the way, with over half of the study centers active. Conflicts of interest: Matthew Barton, Bart Van Den Steen, Hans L.G Van Tricht, William Byrnes and Colin Ewen are employees of UCB Pharma and may hold/have access to stock options. The full disclosure of conflicts of interest will be detailed in our presentation. Funding: This study is funded by UCB Pharma.
P09- THE IMPACT OF ERRATIC CHANGES ON 1 YEAR CHANGE IN CDR-SB. AN EXPLORATORY ANALYSIS. A. Kott1, X. Wang2, D. Miller2(1. Signant Health — Prague (Czech Republic), 2. Signant Health — Blue Bell (United States))
Background: Erratic changes represent large opposite changes in scale scores at a minimum of 3 consecutive visits. We have previously demonstrated the detrimental impact of erratic changes on placebo response and drug placebo separation in schizophrenia clinical trials. Objectives: In this analysis, we assessed the impact of erratic changes in the CDR-SB over 1-year post-baseline in a pooled dataset of early Alzheimer’s Disease (AD) clinical trial data. The goal was to see whether the pattern found in schizophrenia also existed in AD. Methods: Blinded data were pooled from 6 clinical trials in early AD. We defined as erratic those CDR-SB changes where the visit-to-visit change exceeded 1 point and these changes were in opposite direction at consecutive visits. A generalized linear model estimating the 1-year CDR-SB change from baseline was fitted with the presence of erratic ratings, baseline CDR-SB score and protocol as predictors. Results: Our dataset consisted of a total of 4,023 subjects, where the presence or absence of erratic changes could be established and 1-year change values were available. Compared to baseline, the CDR-SB in the whole sample worsened at 1-year on average by 1.25 points (SD=1.97). Erratic changes were identified in a total of 210 subjects (5.2%). The presence of erratic ratings significantly decreased the CDR-SB change by 0.55 points (CI = 0.28 – 0.82; p < 0.001). Subjects not affected by erratic changes worsened by 1.35 points (CI = 1.27 – 1.43), while subjects affected by erratic changes worsened by 0.80 points (CI = 0.53 – 1.07). Conclusions: Our results indicate that when present, erratic changes on the CDR-SB over 1-year had a substantial impact on the data. Specifically, the presence of erratic changes reduced the 1-year worsening by over 40%. Based on our prior analyses in schizophrenia, subjects affected by erratic changes failed to separate drug from placebo. It is thus important to replicate this analysis in unblinded datasets in AD trials as well. While it is possible that some erratic changes are driven by an unusual group of subjects, in the vast majority erratic changes likely represent a number of measurement errors that result into the zig-zag pattern of disease severity fluctuation over time. Identifying the raters at increased risk of having erratic changes and remediating these raters may positively translate into an increased signal. Conflict of interest: All authors are full-time employees of Signant Health.
P10- EARLY ENGAGEMENT WITH THE ALZHEIMER’S DISEASE COMMUNITY TO GAIN INSIGHTS INTO DESIGNING THE SKYLINE TRIAL FOR PRE-SYMPTOMATIC ALZHEIMER’S DISEASE. F. Rose1, N. Lynn2, J.B. Langbaum3, C. Langlois3, E.L. Dodd1, J. Roeser4, G. Respondek4, S. Ostrowitzki4(1. Roche Products Ltd — Welwyn Garden City (United Kingdom), 2. BrightFocus Foundation — Clarksburg (United States), 3. Banner Alzheimer’s Institute — Phoenix (United States), 4. F. Hoffmann-La Roche Ltd — Basel (Switzerland))
Background: Recruiting cognitively healthy older adults at risk for developing Alzheimer’s disease (AD) is challenging. Preemptively seeking to understand the needs and concerns of these individuals, as well as their motivations for participation in clinical trials, could help inform how best to identify and engage them and determine what will improve their experience and retention within a clinical trial setting. Collecting and incorporating feedback from the targeted participant population during the protocol development stage is critical to improving participants’ experiences during the trial, thereby aiding in retention. In addition, it is anticipated that such a protocol would be more accessible and sensitive to a broad variety of prospective volunteers, thus making recruitment easier. Objectives: To gather insights from global representatives within the AD community to help customize the design of clinical trials to improve participants’ trial experience. Methods: Advisory boards were held with two groups made up of individuals with diverse backgrounds from multiple countries. These groups included CareRing, comprising five Roche employees who all care for people living with AD, and a group of representatives from twelve global AD advocacy organizations. Feedback was gathered on participant and study partner perceptions of the draft protocol design for SKYLINE: a global Phase III, multicenter study to evaluate the efficacy and safety of gantenerumab in participants at risk for or in the earliest stages of AD (NCT05256134). Groups were asked to share recommendations for the holistic and individualized support required to enable a positive trial experience. Feedback was then assessed and implemented into the SKYLINE protocol design and supporting materials. Results: Feedback highlighted the importance of tailoring study materials and design to specifically engage with a cognitively healthy, at-risk, or asymptomatic AD population and their study partners. Feedback also identified that flexibility of dosing options was seen as an essential part of the SKYLINE trial design in order to maintain personal lifestyle choices. Varied and tailored supporting materials were highlighted as a requirement to ensure successful trial participation, such as those to explain the trial expectations and what would be required for home administration. Furthermore, having a sensitive and supportive disclosure process managed by professionals for both brain amyloid status and APOE genotype was seen as crucial. This highlights the importance of tailoring materials specific to unique participant population needs, and providing guidance and training for trial site staff, to ensure suitable support measures are available for participants and their families. Conclusion: This collaboration with the wider AD patient advocacy community demonstrates the importance of early dialogue with participant and study partner representatives to build a patient-centric study design to ensure holistic supporting materials and processes are implemented for this unique study population. Conflict of interest: Fiona Rose is an employee and shareholder of F. Hoffmann-La Roche Ltd.
P11- CONTRASTING THE NIH TOOLBOX EMOTIONAL BATTERY OUTCOMES BETWEEN CAUCASIANS AND AFRICAN AMERICAN OLDER ADULT PARTICIPANTS IN A RANDOMIZED CLINICAL TRIAL: I-CONECT STUDY. K. Yu1, L. Silbert1,2, L. Struble3, H.H. Dodge1(1. NIA-Layton Aging and Alzheimer’s Disease Center, Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA — Portland (United States), 2. Portland Veterans Affairs Health Care System, Portland, OR, USA — Portland (United States), 3. Department of Health Behavior and Biological Sciences, School of Nursing, University of Michigan Ann Arbor, Michigan, USA — Ann Arbor (United States))
Background: Challenges in recruiting minority older adults for clinical trials have been widely documented. However, the sample selection bias within minority groups has not been sufficiently addressed. The more difficult it is to recruit participants, the less likely they are to be representative of the group. Objectives: This study compared the emotional wellbeing of Caucasian and African American (AA) participants recruited for a year-long behavioral intervention study which aimed to enhance cognitive functions by increasing social interactions among socially isolated participants with normal cognition or mild cognitive impairment (MCI). Methods: We used data from the baseline of the Internet-Based Conversational Engagement Clinical Trial (I-CONECT, ClinicalTrial.gov: NCT02871921). Individuals were eligible to participate if they aged 75 and older and met the operational definition of social isolation (Yu et al., 2022). Emotional characteristics of participants were assessed with the NIH toolbox emotion battery (NIHTB-EB) collected at baseline before the intervention started. NIHTB-EB includes three domains that consist of 17 subscales. The three domains are negative affect, psychological wellbeing, and social satisfaction. We ran linear regression models comparing the NIHTB-EB outcomes between Caucasian and AA participants, controlling for age, sex, years of education, marital status, depressive symptoms, and cognitive status (MCI vs. normal). MCI status were diagnosed with National Alzheimer’s Coordinating Center Uniform Data Set Version 3 (UDS V3). Results: Out of 1139 individuals screened over phone calls,186 participants were randomized (9% of the screened AA, 20% of the screened Caucasian). The 163 participants who completed the NIHTB-EB at baseline were included in this study. The mean age of the sample is 81.22 (SD=4.65), 70.99% were female, 53.09% with MCI diagnosis, and 20.73% (n=34) self-identified as AA. The AA participants scored higher in psychological wellbeing (B=5.67, SE=1.59, p<.001) and social satisfaction (B=7.92, SE=1.80, p<.001) than Caucasians. In terms of subscales, AA participants had lower sadness (B=-5.39, SE=1.97, p<.01), higher positive affect (B=4.74, SE=1.58, p<.01), and higher meaning and purpose (B=7.70, SE=1.55, p<.001) scores than their Caucasians counterparts. Conclusion: Individuals who live in isolation are a “hidden” population and are rarely included in clinical trials. The findings comparing NIBTB-EB outcomes show that AA participants were better off than their Caucasian counterparts in psychological wellbeing and social satisfaction. This finding might suggest possible selection biases: individuals enrolled in trials could be different from those who declined the opportunity, especially when the recruitment was challenging. Merely increasing the proportion of minority participants might introduce some unexpected bias in trial results.
P12- DEVELOPMENT AND FEASIBILITY OF A DATA-DRIVEN APPROACH TO PRECLINICAL ALZHEIMER’S DISEASE CLINICAL TRIAL RECRUITMENT THROUGH CENTRALIZED PRE-SCREENING DATA COLLECTION. D. Kirn1, J. Grill2, P. Aisen3, K. Ernstrom3, S. Gale4, J. Heidebrink5, G. Jicha6, G. Jimenez-Maggiora3, L. Johnson7, E. Peskind8, R.S. Turner9, D. Sultzer2, S. Wang3, R. Sperling4, R. Raman3(1. Department of Neurology, Massachusetts General Hospital — Boston (United States), 2. Institute for Memory Impairments and Neurological Disorders, Department of Psychiatry and Human Behavior, University of California Irvine — Irvine (United States), 3. Alzheimer’s Therapeutic Research Institute, University of Southern California — San Diego (United States), 4. Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School — Boston (United States), 5. Department of Neurology, University of Michigan — Ann Arbor (United States), 6. Sanders-Brown Center on Aging, University of Kentucky — Lexington (United States), 7. Institute for Translational Research, University of North Texas Health Science Center — Fort Worth (United States), 8. VA Northwest Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System — Seattle (United States), 9. Department of Neurology, Georgetown University Medical Center — Washington D.c. (United States))
Background: Recruiting to multi-site preclinical Alzheimer’s Disease (AD) trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger population at risk. Though Black or African American and Hispanic or Latino individuals are at increased risk for AD, they are underrepresented in trials. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they do not investigate whether disparities exist in the recruitment process prior to consent. Sites may include a participant prescreening process (pre-consent) for trials to conserve resources by limiting in-person consent and screening to participants most likely to be eligible. Capturing these prescreening data centrally has been rare in multi-site clinical trials, as data collected prior to formal consent is typically not included in trial databases. Better understanding of the pipeline of participants who do and do not continue past the prescreening phase of trials could aid efforts to improve recruitment of groups traditionally underrepresented in clinical trials research. Objective: The Alzheimer’s Clinical Trials Consortium (ACTC) Recruitment Unit developed infrastructure to centrally collect a subset of prescreening variables for the AHEAD 3–45 study (NCT NCT04468659). By collecting these data, we aim to evaluate potential selection bias and improve our understanding of recruitment initiative effectiveness, particularly related to participants from historically underrepresented groups. Methods: A vanguard phase captured participant-level prescreening data from seven sites actively recruiting for the AHEAD 3–45 study. The AHEAD 3–45 study is examining the safety and efficacy of Lecanemab (BAN2401, Eisai Inc.) in a cohort of cognitively unimpaired participants aged 55–80, at increased biological risk of developing AD dementia. The following variables, a subset of the variables used for the study, were collected in this phase for each participant prescreened at the site: age, biological sex, race, ethnicity, education, occupation, zip code, recruitment source, prescreening eligibility, reason for pre-screen ineligibility, and study ID for those who continued to an in-person screening visit. Sites had the option of providing the data by direct entry or through bi-weekly batched upload. This study received a Waiver of HIPAA and Waiver of Consent from the central IRB (Advarra, Columbia, MD). Results: All seven vanguard sites provided prescreening data on 1029 participants. The total number of prescreened participants varied widely by site (range 3–611), with the differences in numbers driven mainly by the time to receive site approval for the main study. The study website consistently produced meaningful proportions (range: 36–75%) of prescreen activity across sites. Hispanic participants more often were identified from recruitment registries (14%) and local recruitment efforts (37%), compared to non-Hispanic participants (6% and 30%, respectively). At these sites, a higher proportion of American Indian and Alaska Natives (56%) and lower proportion of Blacks (9.1%) were eligible for an in-person screening compared to non-Hispanic Whites (22%), though many participants remained in the prescreening process. Conclusion: We demonstrated that it is feasible for multi-center trials to successfully collect prescreening data across vanguard sites for an ongoing multi-site preclinical AD trial. Measuring the impact of recruitment interventions, even before participants sign consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, accelerate evaluation timelines, and inform the science of recruitment. This initiative has now been expanded to include all interested U.S. based study sites in the study.
P13- DESIGN OF PRAGMATIC TRIALS FOR INTERVENTIONS TARGETING COGNITIVE DECLINE: BENCHMARKS FROM THE COCOA SUPPLEMENT AND MULTIVITAMIN OUTCOMES STUDY OF THE MIND (COSMOS-MIND). M. Espeland1, J. Manson2, S. Rapp1, H. Sesso2, S. Gaussoin1, S. Shumaker1, L. Baker1(1. Wake Forest School of Medicine — Winston-Salem (United States), 2. Brigham and Women’s Hospital — Boston (United States))
Background: COSMOS-Mind (NCT03035201) was a large, pragmatic clinical trial that examined whether daily treatment with 500 mg/day cocoa extract (CE) versus placebo (primary) or standard multivitamin-mineral (MVM; Centrum Silver) versus placebo (secondary) for 3 years in 2262 older adults (>65 years) protected cognitive function and attenuated the cognitive decline associated with normal and pathological aging, including Alzheimer’s disease (AD). CE was not found to affect cognitive function. MVM produced a mean [95% confidence interval] relative benefit in a global cognitive composite score of 0.07 [0.02, 0.12] SDs, p=0.007, which corresponded to a 60% slowing of expected cognitive decline in the cohort over 3 years. Objectives: We present findings from COSMOS-Mind that provide support for the conduct of future pragmatic trials with cognitive outcomes. We use benchmark data from the trial to inform 1) choices and parametric models for outcomes, 2) trial duration, 3) sampling targets for special populations, and 4) targeted effect sizes. Methods: We used COSMOS-Mind data — cognitive outcomes (composite scores of global cognition, executive function, memory), retention, subgroup analyses — to guide simulation-based comparisons of differing design options for future pragmatic trials. Results: The COSMOS-Mind cognitive test battery of telephone-based assessments provided a high degree of statistical efficiency based on their repeatability over time and, in general, higher efficiency (and statistical power) projected for a global composite than for subdomains (e.g., executive function) or single tests (e.g., Digit Symbol). The primary outcome chosen for COSMOS-Mind, the average difference from baseline in test scores over 3 annual assessments, provided better overall statistical power than alternative choices for outcomes based on slopes or scores at close-out. To achieve comparable statistical power for the COSMOS-Mind primary outcome, a 2-year trial would have required 32%–72% more enrollees than our 3-year trial. Enrolling participants with more diversity in baseline cognitive function, education, and ethnicity may yield greater statistical power than cohorts with less diversity: participants with lower baseline cognitive test scores, less formal education, and from minoritized communities had qualitatively (although not significantly) greater benefits from MVM in COSMOS-Mind. To achieve sufficient power to replicate COSMOS-Mind findings, it is important to target clinically significant effect sizes smaller than what were observed to allow for imprecision in estimated benefits: a future sufficiently targeted trial of MVM will require a larger sample size. Conclusions: COSMOS-Mind demonstrates that pragmatic randomized clinical trials can be designed and implemented to identify approaches to slow cognitive decline and potentially reduce risk for Alzheimer’s disease and other dementias. Funding: COSMOS-Mind: NIH/NIA 5R01AG050657-02; NIH/NIA P30AG049638-01A1; COSMOS: Investigator-initiated grant and donation of study pills by Mars Edge; partial provision of study pills and packaging by Pfizer Consumer Healthcare (now GSK Consumer Healthcare); WHI: NIH/NHLBI HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Conflict of Interest: Dr. Espeland receives research funding from the Alzheimer’s Association and the NIH and is a paid member of a Steering Committee for a trial sponsored by Nestle.
P14- USE OF THE DIGIT SYMBOL SUBSTITUTION TEST (DSST) AS AN ENTRY CRITERION FOR A COGNITIVE STUDY OF A B2-AR AGONIST. G. Vargas1, R. Martin1, P. Butera1, J. Reynolds1, T. Anderson2, A. Asher3, E. Buntinx4, A. Ford1, J. Harrison5(1. CuraSen — San Carlos (United States), 2. New Zealand Brain Research Institute — Christchurch (New Zealand), 3. MAC Clinical Research — Manchester (United Kingdom), 4. Anima Research Center — Alken (Belgium), 5. Metis Cognition — Kilmington Common (United Kingdom))
Background: The locus coeruleus (LC) is a small nucleus located in the pons and is the primary source of noradrenaline in the forebrain. LC axons project to multiple cortical and subcortical regions that underlie memory including the hippocampus, frontoparietal cortex, and amygdala. Through its binding to both α and β adrenoceptors, noradrenaline plays a key role in a variety of essential central nervous system (CNS) functions such as learning and memory, arousal, attention, emotional processing and cognition. CuraSen is developing CNS-penetrant β2-AR agonists for the treatment of neurodegenerative disorders including Alzheimer’s disease (AD). CuraSen’s ongoing and completed early phase studies demonstrate that the β2-AR agonist CST-103 increases cerebral perfusion in healthy individuals and those living with Parkinson’s disease (PD) and mild cognitive impairment (MCI). Data using a well-established cognitive assessment system suggests improved cognitive performance in healthy volunteers. The CLIN-011 study seeks to evaluate the safety and efficacy of CST-103 when dosed with nadolol in individuals with MCI, PD and Lewy body dementia. The key efficacy measures will evaluate the effects of treatment on cognition and mood. Early-stage disease can vary with respect to the presenting cognitive deficits. Individuals presenting with dementia commonly exhibit memory deficits. However, a significant proportion express deficits in other cognitive domains, such as attention, executive function and working memory. Selecting individuals with evidence of impairment based on Mini-Mental State Exam (MMSE) performance has been a common method of ensuring that study candidates show a rescuable memory deficit. However, the MMSE is deficient with respect to the assessment of other key cognitive domains. Thus, when enrollment of subjects with attention and/or executive function is required, the MMSE is an inadequate means of enriching the study population. We have therefore employed a different enrichment strategy. Study participation is contingent upon candidates exhibiting cognitive deficits on the Digit Symbol Substitution Test (DSST), a brief, reliable and well-validated cognitive test which is recognized by regulators as a measure of timed executive function. It is also an index of attention, working memory and other key cognitive domains known to be compromised early in AD. Objectives: The CLIN-011 study is a signal-seeking clinical trial to identify responsive patient populations as well as efficacy measures that are relevant for treatment with a β2-AR agonist. In order to maximize the prospects of detecting treatment effects we are enriching the MCI study population for the presence of objective measured cognitive deficits using the DSST. Methods: The study is a randomized, placebo-controlled, double-blind, crossover, study of the pharmacodynamic effects of CST-103 co-administered with nadolol on the CNS in subjects with neurodegenerative disorders. At enrollment, the eligibility of subjects with MCI are evaluated using the following inclusion criteria: Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26. A score of greater than or equal to one standard deviation below age and educational norms in the DSST during screening. Results: In this abstract we report the baseline cognitive characteristics of the MCI population recruited into this study. In total 41 patients were recruited: 25 with PD, 13 with MCI and 3 with Lewy body dementia. In addition to the MoCA and DSST, all patients had cognitive testing using the Cambridge Neuropsychological Test Automated Battery at multiple scheduled time points throughout the study. The range of MoCA scores for enrolled subjects was between 18–27 with a mean of 22.7. The range of DSST scores was between 22–51 with a mean of 39.4. The ages of the subjects ranged between 52–69 and the average age was 61.2. The range of DSST scores for subjects who screen failed due to this criterion was between 42–80 with a mean of 58.4. As acknowledged above, attention and working memory deficits are unlikely to be observed in all subjects with early-stage disease and implicit in the use of this enrichment strategy is the possibility of significant rates of screen failure. Of the 44 individuals screened for inclusion in the MCI cohort there were 31 (70.5%) screen failures, 11 (35%) solely due to DSST performance exceeding the cut-off for inclusion. Conclusion: Selecting a patient population which has objectively identified cognitive deficits is essential in order to demonstrate positive drug effects on cognition. In the present study we have utilized an enrichment strategy based on use of the DSST, a well validated cognitive test which measures multiple cognitive domains. Use of the DSST as an entry requirement led to a number of screen failures but at a rate that is an acceptable trade-off to ensure that the population recruited into the study has cognitive deficits which can be remediated by treatment.
P16- ENHANCING RECRUITMENT OF UNDERREPRESENTED COMMUNITIES WITH THE DEPLOYMENT OF A MOBILE RESEARCH UNIT. J. Smith1, J. Dwyer1, D. Batchuluun1, T. Magee Rodgers1, L. Zisko1(1. Global Alzheimer’s Platform Foundation — Washington Dc (United States))
Background: The prevalence of Alzheimer’s disease is twice as high in the African American/Black population and 1.5 times higher in the Hispanic/Latino population when compared to the white/Caucasian counterparts. (2019 Alzheimer’s disease facts and figures. Alzheimers Dement. 15, 321–387. doi: 10.1016/j.jalz.2019.01.010). In addition to increased rates, health care disparities continue to impact their access to health care and lack of awareness of clinical trial opportunities. Increasing awareness, education, and access to available clinical trial opportunities are essential to include a diverse candidate pool in Alzheimer’s disease and Alzheimer’s disease prevention studies, to ensure future treatments benefit patients of all races and ethnicities and growing expectations of regulators and payors are met. To do this, community-based engagement efforts embedded in local neighborhoods may be more successful than traditional recruitment methods, asking these same individuals to go to established clinical research sites. Additional efforts to bring clinical trial procedures directly to them in a community-setting may help engender trust and decrease reluctance to participate in research. Objectives: GAP’s [STUDY] Mobile Unit will support prescreening efforts for an Alzheimer’s prevention study. Additionally, to build trust and relationships within neighborhoods, it will provide education about Alzheimer’s disease, Alzheimer’s disease prevention, and memory loss in traditionally underrepresented communities, as well as access to free memory screenings. These efforts will occur at local settings such as libraries, senior centers, churches, and other neighborhood centers. The [STUDY] Mobile Unit will broaden the reach and capacity of 10–12 southern Florida Alzheimer’s research sites, beyond their general reach as established brick and mortar clinical research sites. Conducting low risk, low-cost genetic prescreening assessments within predominantly minority communities will also provide well characterized and a potentially more qualified diverse cohort of participants for screening, resulting in accelerated enrollment in the [STUDY] clinical trial. Methods: A customized 29’ mobile research unit was designed with a reception area, a consultation/testing room, and phlebotomy suite. Some clinical research staff teams lack diversity, making it difficult to connect with local minority populations. Two permanently assigned staff members, who are Hispanic and Haitian Creole, will travel on the mobile research unit throughout Florida to partner with local research center staff at community outreach and engagement events. They will connect with local seniors to offer prescreening and educational activities in English and Spanish, further increasing local access to these resources. Along with site staff representatives from local research centers, staff on the mobile unit will: 1. Provide education, awareness and access to an Alzheimer’s prevention study in communities in 7 distinct Florida regions where traditionally underrepresented senior populations reside. 2. Genetically prescreen people aged 60–80 for Alzheimer’s disease at community outreach events, including health fairs, storefronts, churches, libraries, neighborhood senior centers and other local gathering locations. 3. Disseminate information about brain health, memory loss, and local resources via GAP’s Acti-v8 Your Brain program and NIH materials. Results: The [STUDY] Mobile Unit will be deployed on July 1, 2022. Within a 60–90-day period of operations, GAP will be prepared to report on the number of: 1. Locations visited; 2. Events planned; 3. People reached with racial/ethnic breakdowns; 4. Prescreens conducted and referrals made. Additional comparisons may be made for these same metrics from within the sites’ traditional efforts, not utilizing a mobile unit, further showing the effectiveness to consent with seniors in more local settings vs clinical settings. Conclusions: GAP’s mobile unit is an innovative resource providing minority communities with increased education and access to an Alzheimer’s prevention research study, resulting in materially significant numbers of referrals and enrollment of diverse populations. Successful strategies and tactics will inform best practices to be executed across other indications of AD trials. This significant investment will result in expedited enrollment overall and statistically significant increases in enrollment of traditionally underrepresented populations. * Note: [STUDY] name will be provided on study poster upon review of the final data by the partnering sponsor.
P17- GENOTYPIC EFFECTS OF THE TOMM40’523 VARIANT AND APOE ON LONGITUDINAL COGNITIVE CHANGE OVER 4 YEARS: THE TOMMORROW STUDY. H. Zou1, S. Luo2, M.W. Lutz2, D.A. Bennett3, B.L. Plassman2, K.A. Welsh-Bohmer2(1. University of North Carolina- Chapel Hill — Chapel Hill (United States), 2. Duke University — Durham (United States), 3. Rush University — Chicago (United States))
Background: Carriage of the APOE ε4 allele is a major risk factor for Alzheimer’s disease (AD) symptom onset and accelerates the clinical progression of disease in the mild to moderate stages of AD dementia (Qian et al., 2021). Variations in a poly-T variant (rs10524523, ‘523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, have also been shown to influence AD expression within APOE ε3/3 carriers, who are typically considered as a group at a lower risk of AD relative to APOE ε4 carriers (data from the ROS-MAP cohorts: Yu et al., 2017). It is unclear whether variations in APOE and TOMM40 haplotypes contribute to the heterogeneity in disease expression occurring during the preclinical stages of AD. Objectives: To determine the impact of these genes in early preclinical expression, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance, repeated every 6 months for up to four years, in clinically normal, older individuals enrolled in the trial. Methods: Participants from the TOMMORROW trial were stratified according to APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified based on TOMM40’523 genotype (i.e., we included individuals with “S/S”, “S/VL”, and “VL/VL” genotypes). The test battery of cognitive assessments contained a total of 12 tests, assessing 5 cognitive domains: episodic memory (short & long delay recall from California Verbal Learning Test-II [CVLT-II]; Brief Visuospatial Memory Test -Revised [BVMT-R] delayed recall), executive function (Trail Making Test Part B, WAIS-R Digit Span backwards span), expressive language (Multilingual Naming Test [MiNT], lexical fluency & “animal” verbal fluency test), attentional processing (Trail Making Test- Part A, WAIS-R Digit Span forward span), and visuospatial function (Clock drawing & figure copy BVMT-R). The final analysis dataset consisted of 1,330 patients and 7,001 visits, with a mean follow-up period of 2.21 (SD = 1.14) years. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40’523 genotypes. Results: All genetic subgroups showed improving cognitive performance across all measures over the first two years of observation, regardless of APOE and TOMM40 genotypes. This finding is not unexpected given that individuals across all genotypic groups were cognitively healthy at enrollment into the study. In cognitively normal adults, test-retest improvement is anticipated with repeated cognitive measurement. However, there were performance differences across the different genotypes both in terms of initial level of performance and rates of cognitive decline. Within the APOE groups, APOE ε3/4 and APOE ε4/4 genotypes were associated with worse baseline performance on measures of global cognition, episodic memory, and expressive language, compared to those with the APOE ε3/3 genotype. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40’523-S/S genotype showed better baseline global cognition and accelerated rates of cognitive decline on tests of global cognition, working memory, and attentional processing compared to APOE ε3/3 carriers with TOMM40’523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers. These genotypic findings are broadly consistent with prior reports in APOE ε3/3 carriers who are cognitively healthy and showed that the TOMM40’523-S/S genotype in APOE ε3/3 carriers was associated with accelerated rates of cognitive decline when compared to APOE ε3/3 carriers with TOMM40’523-S/VL and VL/VL genotypes (Yu et al., 2017), although the domains most impacted were episodic memory and expressive language/semantic memory in that report. Methodological differences across the studies in terms of the length of overall observation in the cohorts (4 years in TOMMORROW vs 20+ years in ROS-MAP dataset) and the frequency of measurement (every 6 months in TOMMORROW trial vs annual observations in ROS-MAP) as well as other sample differences (clinical trial cohort vs community cohorts) may explain the differences in the cognitive domains most affected across the genotypic groups. Conclusions: Variations in the TOMM40 poly-T have an influence on cognitive function over time and can be observed in APOE ε3/3 carriers where a confounding influence of an APOE ε4 allele are not an issue. We suggest that both APOE and TOMM40 genotypes may contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD. References: Qian, J., Betensky, R.A., Hyman, B.T., & Serrano-Pozo, A. (2021). Association of APOE Genotype with heterogeneity of cognitive decline rate in Alzheimer disease. Neurology, 96 (19) e2414–e2428. Yu, L., Lutz, M. W., Wilson, R. S., Burns, D. K., Roses, A. D., Saunders, A. M., Gaiteri, C., De Jager, P. L., Barnes, L. L., & Bennett, D. A. (2017). TOMM40’523 variant and cognitive decline in older persons with APOE ε3/3 genotype. Neurology, 88(7), 661–668.
P18- RACIAL/ETHNIC GROUP DIFFERENCES IN RESPONSE RATE TO A MAIL INVITATION TO PARTICIPATE IN A LIFESTYLE INTERVENTION TRIAL TO PREVENT COGNITIVE DECLINE (U.S. POINTER TRIAL). V. Pavlik1, M. Yu1, A. Alexander2, J. Valenta2, R. Elbein3, A. Mcdonald3(1. Baylor College Of Medicine — Houston (United States), 2. Kelsey Research Foundation — Houston (United States), 3. Alzheimer’s Association — Houston (United States))
Background: There is an urgent need to identify efficient and effective methods to increase the diversity of participants in Alzheimer’s disease treatment and prevention trials. Objective: To determine whether there are racial/ethnic group differences in response rate to a mailed recruitment letter inviting participation in a multi-modal lifestyle intervention trial to prevent cognitive impairment in older individuals with a high cardiovascular risk factor burden. Methods: Two clinic systems at one of five sites implementing the U.S. POINTER trial identified potential age and medical history eligible trial participants through an electronic medical record (EMR) query. Participants received a recruitment letter describing the trial and directing them to a web site to begin the eligibility screening process. A major goal of recruitment was to achieve a demographically diverse patient population. To assess the success of a mailed letter campaign as a recruitment tool, we analyzed the response rates to the letter in different race/ethnicity groups, adjusting for age, sex, and neighborhood. Five neighborhoods were defined based on broad geographic regions containing distinct urban and suburban communities within a large metropolitan area. Results: Of 81,302 patients who were sent recruitment letters, 76,163 (93.9%) had complete EMR data for analysis. The most common missing variable was race/ethnicity. The racial/ethnic distribution of letter recipients was 45.3% non-Hispanic white (NHW), 25.2% Black/African American (AA), 16.6% Hispanic, and 12.9% other. Overall, 1.6% of letter recipients responded by providing screening information on the study website. The highest response rate was in NHW recipients (2.3%) and the lowest in Hispanic recipients (0.9%). Within ethnic group, the response rate varied by neighborhood. For example, in NHW recipients the response rate ranged from 1.5%–3.1% and in Hispanic recipients it ranged from 0.6%–1.3%. Except for one neighborhood with a lower response rate, the response rate in AA recipients was 1.4% regardless of neighborhood. In logistic regression modeling, age, sex, race/ethnicity, neighborhood, and clinic system were independent predictors of response rate. Of the 1246 responders, 44.5% represented racial/ethnic groups other than NHW. Conclusions: Although response rates may vary by ethnic group, mailed invitations to participate in a dementia prevention trial can yield a diverse study population. Oversampling of some groups to achieve desired recruitment targets can compensate for response rate variability among specific racial/ethnic group. Special methods, such as community engagement or bilingual recruitment materials, which have not yet been deployed at our clinical site for the U.S. POINTER study, may be needed to increase recruitment yields in certain groups. All demographic variables included in this analysis were associated with differential response rates, indicating that complex factors in addition to race/ethnicity drive recruitment yields in a particular clinical trial context. Some potentially relevant variables, such as education and household income, were not available in the EMR for inclusion in the analysis. Covid-19 surges throughout the recruitment period may have contributed to the observed variability in response.
P19- DEVELOPMENT OF AN ABBREVIATED PRE-SCREENING COGNITIVE BATTERY TO ENHANCE REFERRAL TO CLINICAL TRIALS. A. O Connell1, E. Fischer1, L. Latham1, L. Baker1, S. Craft1(1. Wake Forest Alzheimer’s Disease Research Center — Winston-Salem (United States))
Background: Timely enrollment of an eligible cohort into Alzheimer’s disease (AD) clinical trials is critical in accelerating AD research, but as these trials increasingly target prodromal and preclinical AD, clinical trial sites face difficulty in determining whether prospective participants will meet cognitive eligibility criteria. This is especially problematic in prodromal trials, as these individuals often report subjective memory complaints but have not received any clinical evaluation of cognitive status and therefore lack any previous diagnosis or available neuropsychological testing to aid in evaluating study eligibility prior to conducting the clinical trial screening visit. As a result, screen fail rates based on screening cognitive assessments for these studies is high, study sponsors and clinical trial sites invest considerable time and resources in conducting screening visits, and the duration required to complete study enrollment is prolonged. Objectives: To develop and pilot a brief cognitive battery for use as a pre-screening tool in the evaluation of volunteers to the Wake Forest Alzheimer’s Disease Research Center (ADRC) who lack prior cognitive testing. The aims of this pilot were: 1) to determine preliminary cognitive status of these participants and provide them feedback on this information, 2) screen out cognitively normal individuals with subjective complaints prior to referral to prodromal clinical trials, and 3) enhance referral to the Center’s enrolling studies by using the results obtained to assess eligibility based on study-specific inclusion criteria. Methods: A working group comprised of the Wake Forest ADRC Directors, neuropsychologists, clinical study management team members, and Outreach Director collaborated to devise a cognitive battery that could be administered in under one hour, provide a preliminary assessment of a broad cross-section of cognitive domains, and obtain enough information to enable evaluation of cognitive eligibility for referral to Center-conducted studies enrolling cognitively normal, mild cognitive impairment (MCI), or mild AD participants. The resulting protocol included the administration of Montreal Cognitive Assessment (MoCA), WMS-III Logical Memory, Number Span Test Forward and Backward, Trail Making Tests A and B, Rey Auditory Verbal Learning Testing (RAVLT), and Benson Complex Figure Copy and Recall, and was implemented as a one-hour visit titled the Memory Screening Clinic (MSC). At the point of initial intake to the ADRC, all potential participants completed a preliminary telephone screen that included the telephone interview for cognitive status (TICS), self-report of cognitive complaints, and collection of basic demographic and medical history information. Participants with TICS scores ≥ 34 who did not self-report as cognitively normal, or those with any TICS score who did not have a known diagnosis of MCI or AD with supporting neuropsychological testing, were then offered the one-hour MSC visit for preliminary cognitive screening and feedback. The visit included the informed consent presentation, completion of a brief medical history form, and the neuropsychological battery. A Center neuropsychologist then reviewed the cognitive assessments and medical history information to determine a preliminary cognitive impression, and these results were then reviewed by a referral coordinator to evaluate eligibility for currently enrolling studies. The preliminary cognitive impression and potential study options were then discussed with each participant, and a referral made to the appropriate study team as applicable. All individuals who completed the MSC received feedback that included whether they were eligible for further testing via a study-specific screening visit, materials with information about potential study opportunities, and their MoCA score. Results: Between October 2019 and June 2022, 459 individuals completed a phone screen intake with the Wake Forest ADRC and met eligibility for referral to the MSC. Of those participants, 268 (58%) completed a MSC visit (mean age= 68.1 (50–88), 181 Female/87 Male; 134 Normal Controls/134 Probable Impairment) while 191 (42%) did not continue following the phone screen (lost to follow-up, not interested in study participation, or ineligible based on global exclusion criteria). Of those who completed the MSC visit, 162 (60%) were not referred to a clinical trial (did not meet eligibility criteria, were not interested in available study options, or were interested in cognitive screening and feedback only) and 106 (40%) participants were interested in and eligible for referral to a clinical trial. Participants who completed the MSC visit and feedback only and were not referred to subsequent studies were generally cognitively normal and had self-referred to the ADRC with interest in cognitive screening and evaluation for MCI studies. Of the MSC participants referred to a clinical trial, 62 (58%) were eligible at screening and enrolled in a clinical trial, 37 screen-failed (35%), and 7 did not complete a screening visit (7%). Conclusion: The implementation of the MSC visit and abbreviated cognitive battery created a cost-effective, low-burden method of connecting with prospective research participants, providing preliminary cognitive feedback, and enhancing successful referral to and enrollment in Center clinical trials. Disclosures: The authors have no disclosures to share.
P20- LONG-TERM NICOTINE TREATMENT OF MILD COGNITIVE IMPAIRMENT (THE MIND STUDY): BASELINE CHARACTERISTICS AND STUDY PROGRESS. P. Newhouse1, R. Raman2, A. Saykin3, J. Dumas4, E. Levin5, K. Kellar6, P. Aisen2(1. Vanderbilt University — Nashville (United States), 2. USC/ATRI — San Diego (United States), 3. Indiana University — Indianapolis (United States), 4. University of Vermont — Burlington (United States), 5. Duke University — Durham (United States), 6. Georgetown University — Washington, Dc (United States))
Background: Cognitive decline in AD/MCI is related to loss of cholinergic neurons. However, inhibition of acetylcholine degradation has not sustained improvement nor slowed progression in patients with mild cognitive impairment (MCI). Treatment directly targeting nicotinic cholinergic receptors may be more helpful. We have shown proof of concept in a 6-month multicenter trial (Newhouse et al, Neurology, 2012; 78: 91–100) that transdermal nicotine provides significant improvement in attention, episodic memory, and global ratings of functioning with minimal side effects in MCI. The MIND trial (Memory Improvement with Nicotine Dosing) is a larger and longer (2-year) trial to determine whether long-term transdermal nicotine treatment results in persistence of cognitive improvement and attenuation of cognitive decline in patients with MCI. Methods: At 42 sites, MCI participants were randomized 1:1 to either transdermal nicotine, beginning at 3.5 mg/day, increasing to 21 mg/day or matching placebo by 5 weeks. Sample size was planned to be 300. Participants were assessed at 0, 3, 6, 12, 18, and 24 months, with a subset undergoing MRI scans at 0, 12, and 24 months, and CSF collection at 0 and 24 months. Primary cognitive outcomes included reaction time standard error change-from-baseline (Connors CPT) for attention and delayed word recall (Cogstate) for memory. Primary clinical outcome is the CGIC. Secondary clinical measures include behavioral/functional scales and the CDR-SOB. An MRI substudy is examining possible neural mechanisms. Results: To date, 684 participants were screened and 322 were randomized including 138 females (43%) and 184 males (57%). Mean age was 73.7±7.1, education 16±2.9 years. Mean MMSE was 27.4±1.8 and CDR Global was 0.5. Randomization of ethnoracial underrepresented populations (URPs) was 9.1% (Black/African-American 4%, Asian 2%, Hispanic/Latinx 3%). Treatment/Study discontinuations were higher than expected at 32% due in part to pandemic-related disruptions. The sample size has been increased to 380 to maintain statistical power. There are 115 completers thus far. Baseline MRI scans are 60 and LPs are 37. Safety results show that treatment has been generally well tolerated with no SAEs definitively or probably tied to study participation or investigational product thus far. Conclusions: If the hypotheses are validated, this will support a novel, broadly available, and inexpensive repurposed intervention for MCI and would encourage early treatment to improve symptoms, attenuate progression of cognitive impairment, and lead to combined trials with agents that interact with Aβ, tau or other mechanisms. Low URP recruitment and higher dropout rate remain challenging and are being specifically addressed in recruitment/enrollment/retention efforts moving forward to complete the trial. Disclosures: None relevant to this presentation.
P21- USING AN END-TO-END DEEP LEARNING MODEL IN OLDER ADULTS WITH MCI TO IDENTIFY AD RISK FACTORS ON CHROMOSOME 19 THAT EXACERBATE COGNITIVE DECLINE. J. Bae1, L. Apostolova1, V. Pentchev1, D. Hammers1, A. Polsinelli1, K. Nudelman1, A. Saykin1, K. Nho1(1. IUPUI — Indianapolis (United States))
Background: Research into genetic mapping possesses strong potential to inform precision medicine and drug discovery in Alzheimer’s disease (AD). The development of CRISPR — a technology, that allows the replacement of a given single nucleotide polymorphism (SNP) with another, opens the possibility for genome-level therapy. Due to the enormous size of the human genome and the countless genetic interactions, identifying the most relevant AD-risk SNPs remains challenging. Previous research has relied on feature selection methods to eliminate portions of the data based on presumed irrelevance to the model. However, this approach limits discovery opportunity. Here we implemented a novel feature selection-free end-to-end deep learning model developed to reduce the dimensionality of omics data without losing key genetic information. We chose to focus on chromosome 19. First, our hypothesis-free model was trained on correctly predicting AD dementia vs cognitively unimpaired (CU) subjects. Next, the model was extended to further characterize all AD-relevant SNPs based on their interactive effects. Individual SNP impact was quantified by calculating a risk impact score (RIS). The identified SNPs were then tested for their ability to characterize participants with mild cognitive impairment (MCI) who were likely to convert to AD dementia (MCI-C) vs not (MCI-NC) over 3 years. Objectives: We hypothesized that AD-risk SNPs would have a higher RIS in MCI-C and would predict the rate of cognitive decline. Our second objective was to perform computational CRISPR-like experiment to determine the nucleotides with the greatest influence on the probability of progression from MCI to dementia. Method: A novel deep learning model utilizing Capsule Network was developed to analyze 266,161 SNPs from chromosome 19, from 313 AD and 457 CU participants enrolled in the Alzheimer’s Disease Neuroimaging Initiative. The dataset was divided into train, validation, and test sets with a ratio of 60:20:20 (N=462, 154, and 154). The model examined the genetic interactions between all GWASed chromosome 19 SNPs and produced probability scores for AD and CU. Each SNP was sequentially deleted and the corresponding change in the prediction scores was measured. The SNP’s RIS, corresponding to the averaged prediction decrease across participants when deleted, was computed. All 266,161 SNPs were rank-ordered based on their RIS. The highest RIS-ranked 35 SNPs were utilized to differentiate MCI-C (n=203) and MCI-NC (n=213) participants. Next, we predicted the rate of cognitive decline in MCI using multiple regression with 5 SNPs’ RIS as predictors. All possible 5-SNP-combinations among the top 35 SNPs were tested for association with 4 cognitive composites (memory, language, executive, and visuospatial function) in participants with MCI. Lastly, we performed computational CRISPR to demonstrate the impact of SNP rs56131196 (APOC1), which represented the SNP with the greatest RIS value. Results: The model achieved 68.18% accuracy in classifying AD vs. CU. The SNPs with the highest 35 RIS included 11 SNPs from APOC1 gene, 10 SNPs from TOMM40, 5 SNPs from APOC2, and 1 SNP each from ERCC1, ZNF473, VRK3, and NECTIN2. The APOE haplotype SNPs, i.e., rs429358 and rs7412, which are well-known AD-risk SNPs, were not included in the highest RIS-ranked 35 SNPs. The same model was applied to predict MCI-C vs. MCI-NC, and RIS for the highest 35 SNPs were calculated. SNPs in APOC1, TOMM40, and NECTIN2 showed significantly stronger RIS for MCI-C than MCI-NC participants, p < 0.001. All regression models were significant using RIS for the 5 SNPs with the highest correlation coefficient as predictors of performance in each cognitive domain while controlling for age, sex, education, and APOE E4 genotype, p < 0.001. The r2-adjusted values were 0.279, 0.163, 0.098, and 0.178, for the memory, language, executive, and visuospatial models, respectively. The 5 top performing SNPs once again mapped to APOC1, TOMM40, ERCC1, and NECTIN2. The presence of adenine(A) at rs56131196 (APOC1) increases the risk of AD. Approximately 68.47% of MCI-C participants (N = 139) in our sample had either the AA or AG genotype at rs56131196 in APOC1. Using CRISPR simulations, we substituted the risk genotypes with GG in MCI-C participants. MCI-C participants with this substitution were predicted to have significantly lower likelihood of AD occurrence than those without substitution, p < .001. Conclusions: Our hypothesis-free deep learning model trained on AD and CU participants successfully determined SNPs that predict conversion from MCI to AD dementia. 5 SNPs accounted for a significant amount of the variance in cognitive decline across multiple cognitive domains. Genetic screening based on this information could be useful for patient selection in clinical trials with disease-modifying therapies. Furthermore, our computational CRISPR simulations in MCI-C confirm the significant promise of CRISPR for precision medicine. In vitro and in vivo animal and human studies exploring nucleotide-level substitutions are warranted to fully appreciate their role in translational neuroscience.
P22- PANDEMIC EFFECTS ON DUPLICATE SUBJECTS IN CLINICAL TRIALS OF ALZHEIMER’S DISEASE. T. Shiovitz1, C. Steinmetz2, B. Steinmiller2(1. California Neuroscience Research, CTSdatabase LLC — Sherman Oaks, Ca (United States minor outlying islands), 2. CTSdatabase LLC — Sherman Oaks, Ca (United States minor outlying islands))
Background: Duplicate and professional subjects are a significant issue in clinical trials, particularly those in CNS and pain, where subjective endpoints allow potential subjects to magnify there symptoms in order to meet inclusion criteria. Even in Alzheimer’s Disease trials, subjects may participate in concurrent trials to take advantage of different MOAs or to increase the chances of getting an effective treatment. Alternatively, they may be professional subjects, who, for instance, may participate in a Cognition in Schizophrenia study at one site and an Early AD study at another. The failure to address the problem of duplicate and professional subjects can lead to problems with both subject safety and data integrity. Objectives: To determine if there were pandemic-associated effects on the percentage of duplicate subjects found in clinical trials of Alzheimer’s Disease by comparing those added to the CTSdatabase subject registry in the 2 years before the onset of the pandemic compared to the two years during the pandemic. Methods: We looked at pooled study data for all subjects that screened for an Alzheimer’s Disease study in protocols that used CTSdatabase between February 2018 and March 2022. Actionable matches are defined as those that violated protocol I/E (including concurrent enrollment, participation in another study less than the number of days required or previously enrolled in a study for a prohibited indication). The number of actionable matches was divided by the number of subjects screened to determine the percentage of inappropriate subjects (duplicates or otherwise) for that study. The number of screened subjects was also divided into two equal parts for each study based on enrollment date, with March, 2020, as the dividing point for when the pandemic began in earnest. Actionable matches were tallied for each half of enrollment. Results: Of 1279 subjects entered into Phase 3 Alzheimer’s Disease studies using CTSdatabase over the last 4 years, 4.7% (60) were excluded due to participating in another study concurrently, within an exclusionary timeframe or for an exclusionary diagnosis. While there was a trend toward more subjects being excluded during the pandemic, there was no significant difference in the percentage of those excluded before the onset of the pandemic and after the pandemic (3.9 vs 5.5%, p= 0.18). Conclusion: While there was a trend toward a higher percentage of potential Alzheimer’s Disease subjects excluded during the pandemic, this was not significant. The percentage excluded (4.7%) overall was striking, given the indication. We hypothesize that while some of these subjects (and their cagregivers were professional subjects, many may have been seeking an effective treatment, i.e they were duplicate, but not professional, subjects. A subject registry such as CTSdatabase is an important tool in identifying these subjects and either eliminating them or understanding how they may affect study results.
P23- THE TIME COMPONENT TEST IS INHERENTLY MEANINGFUL BECAUSE IT COMBINES EVIDENCE ACROSS OUTCOMES TO MEASURE THE IMPACT OF TREATMENT ON PROGRESSION RATE IN DEGENERATIVE DISEASES. S. Dickson1, S. Hendrix1(1. Pentara Corporation — Salt Lake City (United States))
Background: Degenerative diseases like Alzheimer’s Disease and other progressive diseases present unique measurement challenges. Multiple components of disease occur over time like cognitive, functional, and global aspects which change at varying rates during different stages of disease partially due to ceiling and floor effects in the assessment tools. Additionally, the results of treatments that are intended to modify disease progression will be best measured when they account for all aspects of the disease, whereas symptomatic treatments may focus on only a single dimension of disease. These challenges make it difficult to create a single outcome to measure disease-modifying effects for all stages of disease. But requiring significance on multiple primary outcomes imposes an unusually high standard for approval of treatments for under-treated diseases that often have relatively small populations. We propose the Time Component Test (TCT), a global statistical test that combines outcomes to obtain an estimate of the impact of treatment on progression rate of the disease. Objectives: The objective of this presentation is to demonstrate that the TCT is inherently clinically meaningful because it is more effective method at marking disease progression than individual outcomes alone. Methods: Using historic data from ADCS, we demonstrate how the ADAS-cog, CDR-SB, and ADCS-ADL align with disease progression using principal component analysis individually and when combined into a TCT. We also use simulation to demonstrate how the TCT behaves asymptotically and in the presence of outcomes of varying discreteness. We simulate a treatment effect on top of historic data to compare power across outcomes. Results: The TCT more closely aligns with disease progression than any individual outcome. It achieves greater power without inflating type I error. Requiring co-primary outcomes can inflate sample size by as much as tenfold compared to the TCT. A TCT can be performed based on summary data and achieve similar performance as on the individual-level. Interpretation can be provided in terms of specific time savings of disease progression. Conclusion: The TCT can estimate time saved from disease progression, which is inherently meaningful to patients. Failure to appropriately account for disease progression by using all aspects of disease in a single outcome unnecessarily increases the sample size of clinical trials, creating a greater burden on those suffering from the disease, while also making it harder for effective treatment to make it to a broader market.
LP1- EFFECT OF TREATMENT WITH THE CHOLINERGIC PRECURSOR CHOLINE ALPHOSCERATE IN MILD COGNITIVE DYSFUNCTION (CARL): RESEARCH PROTOCOL E. Traini1, A. Carotenuto1, V. Andreone2, F. Amenta1(1. University of Camerino — Camerino (Italy), 2. Neurology Complex Unit, Cardarelli Hospital — Naples (Italy))
Background: Cognitive dysfunctions are characterized by a decrease in the weight and volume of the brain, due to cortical atrophy, with widening of the grooves and flattening of the convolutions. Brain atrophy involves mainly the hippocampus. It is related to the progression of cognitive impairment and the conversion from mild cognitive impairment (MCI) to over dementia. Objectives: A previous trial on Alzheimer’s disease (AD) has shown that a marked cholinergic challenge obtained by associating the cholinergic precursor choline alphoscerate with the cholinesterase inhibitor donepezil counters the progression of brain atrophy in AD patients with vascular damage. Currently there is no treatment approved for MCI. We have decided to investigate if choline alphoscerate may have a therapeutic role on MCI. Methods: The study CARL (Choline Alphoscerate in mild cognitive dysfunction) is an explorative, no-profit, monocentric, randomized, double-blind and controlled vs placebo clinical trial, with a study duration of 12 (24) months. A total of 120 patients will be enrolled and randomized to choline alphoscerate arm or placebo arm, at a fixed dose of 1200 mg/day for 12 (24) months or until treatment is stopped prematurely. The trial: The CARL study intends to evaluate the efficacy of choline alphoscerate in patients with MCI and associated vascular damage, as the ability to induce: stability and / or slowing of hippocampal, entorhinal, cortical atrophy and ventricular dilation; Improvement of cognitive symptoms and / or slowing of their progression and Improvement of behavioral symptoms (mood and motivation disorders). The study will be carried out at the AORN Cardarelli of Naples, while for the organization and statistical analysis, will be under the responsibility of the Clinical Research Center of the University of Camerino. The data, collected at the site, will be entered in a dedicated Database. An electronic system, created and validated by the university Information Technology Group, will include the data entry pages prepared on the basis of the study flow-chart. Conclusion: The study will be conducted in compliance with either the Declaration of Helsinki or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study will be conducted according to the ICH Guideline for Good Clinical Practice. The protocol was reviewed and approved by the competent Independent Ethics Committee (IEC) and by the competent Italian Regulatory Authority (AIFA). Key words: Mild cognitive impairment, hippocampus, choline alphoscerate, neuroimaging.
LP2- A TRICHOTOMY METHOD FOR DEFINING HOMOGENEOUS SUBGROUPS IN A DEMENTIA POPULATION. G. Rosenberg1(1. University of New Mexico — Albuquerque (United States))
Background: Multiple pathological changes in the aging brain, including cerebrovascular disease, have confounded treatment trials with monotherapies. Use of multimodal biomarkers to create homogeneous patient groups could improve the success of clinical trials. In addition, biomarkers can aid in diagnosis of mixed dementia (MX), which is the most common type of dementia, and is difficult to diagnose during life. Earlier we showed that a 2-way clustering method with Alzheimer’s disease (AD) and vascular disease (VD) improved diagnostic accuracy. Here we show that adding cognition further improves classification. Objectives: Smaller sample sizes with more homogeneous subgroups of participants improves efficiency of clinical trials. We hypothesized that a 3-way clustering method employing biological biomarkers for AD, VD, and cognition (COG) could be used to improve patient classification and to identify MX patients. Methods: Classification was based on three diagnostic axes: 1) AD proteins in CSF (amyloidb1–42 and phosphoTau181), 2) vascular disease as shown by diffusion tensor imaging of mean free water and peak width of skeletonized mean diffusivity (PSMD) in white matter, and 3) executive and memory function as indicators of cognition. Previously, the double dichotomy concept was validated in the UNM cohort (N=80). The trichotomy method is applied to a larger group of Alzheimer’s disease neuroimaging initiative (ADNI) (N=538) subjects. We defined continuous normalized composite scores for Alzheimer’s disease (ADS), vascular disease (VDS), and cognition (CGS) with values from 0 to 1 and cut-offs of 0.5. Results: The trichotomy 3-way classification based on cut-off values divided the population into eight biologically defined subgroups. Cognition divided the cohorts into those with normal and poor cognition. These two groups were further divided into four groups each, based on the presence or the absence of AD and VD factors. The biological MX group had poor cognition with AD and VD factors. Four groups will need more study with long term follow-up: 1) leukoaraiosis (LA) group that had normal cognition with absence of AD factors and presence of VD factors; 2) poor cognition without AD or VD factors; 3) normal cognition with AD factors, and 4) normal cognition with both AD and VD factors. We found that using cognition, in addition to AD and VD factors to define subgroups, leads to homogenous clusters with well-defined characteristics. The classification results in the ADNI cohort were compared to those at UNM. In the UNM cohort there were 25% MX patients, but only 9.3% in the ADNI cohort, reflecting that the UNM group was enriched in vascular patients while AD was the focus of the ADNI study. In ADNI about 20% of the subjects had normal cognition with either AD or VD factors. VDS correlated with executive function and ADS with memory function. Finally, pTau181 contained information that was different from that of white matter damage, while Ab1–42 was correlated with white matter damage. Executive function was lowest in MX. Conclusions: We propose that expanding the ATN formula by adding vascular (V) and cognitive (C) factors to form ATNVC creates homogeneous patient groups and identifies MX patients during life. In addition, it justifies exclusion from clinical trials of asymptomatic leukoaraiosis subjects with white matter hyperintensities. Further studies will be needed to determine if a 3-way clustering method with multimodal biological biomarkers improves success of clinical trials. None of the authors have any conflicts of interest.
LP3- COMPLIANCE AND SATISFACTION IN THE ALZHEIMER’S PREVENTION INITIATIVE AUTOSOMAL-DOMINANT ALZHEIMER’S DISEASE COLOMBIA TRIAL. N. Acosta-Baena1, C. Muñoz1, P. Ospina1, S. Del Rio1, L. Lopez1, M. Giraldo1, S. Duque1, A. Navarro1, E.M. Reiman2, N. Hu3, K. Asik3, P.N. Tariot2, J.B. Langbaum2, F. Lopera1, S. Rios-Romenets1(1. Grupo de Neurociencias de Antioquia (GNA), Universidad de Antioquia, Medellín, Colombia. — Medellín (Colombia), 2. Banner Alzheimer’s Institute — Phoenix (United States), 3.Genentech Inc. — San Francisco (United States)
Background: This double-blind, randomized, placebo-controlled Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease (API ADAD) Colombia Trial (NCT01998841) evaluated crenezumab in cognitively unimpaired adults (age 30–60). Study period A evaluated the efficacy and safety of crenezumab versus placebo in participants who carry the PSEN1 E280A autosomal-dominant mutation. A cohort of non-mutation carriers was enrolled in the placebo arm to maintain genetic status blinding. Crenezumab was administered for at least 5 years, given subcutaneously (SC) every 2 weeks or intravenously (IV) every 4 weeks. In study period B, mutation carriers had the opportunity to receive only crenezumab until post-trial access becomes available or development is discontinued. The retention strategies approved by the local research ethics committee included: monetary compensation for the inconvenience and time spent and travel assistance for trial visits and procedures; annual surveys of participants to assess satisfaction; strong and trusted relationships with participant and their families; comfortable environment; 24/7 availability of staff by phone; efforts to reduce visit duration; annual meetings for participants and study partners; a social plan developed with input from the trial’s social and ethics advisory committee, with educational programs and other aid for family members; and a health plan where participants received earlier attention than would have been possible via their normal insurance, including access to contraception, care by specialists, including psychiatrist and psychologist (for early diagnosis, treatment and follow up of depressive symptoms) AD-related behavioral alteration, and adverse events. Objectives: To describe participant satisfaction and the retention rate of randomized participants who completed study period A. Methods: Annual “Adherence and Satisfaction surveys” were conducted by site staff by phone or in person during the corresponding visit to evaluate the participant’s perception of protocol procedures and of quality of care provided by each staff member; to identify personal, family and job difficulties of each participant; and to detect those at risk of withdrawal. Here, we provide a descriptive summary of trial activities for participants who withdrew consent and of survey results. Results: Study period A ran from December 20, 2013 to April 01, 2022. 252 participants were included. At the main site in Medellin: 182 (72%). Participants in satellites sites: Yarumal 48 (19%), Armenia 15 (6%) and Bogotá 7 (3%). In June, 2019 the drug administration route was switched optionally from SC to IV. With the change to IV administration, the Yarumal satellite was closed and the participants had to attend Medellín every month. Participants from Bogota and Armenia were attended Medellin every 6 months. Approximately 84 participants (33%) attended the main site but lived in distant location, which required travel by bus more than four hours. At the end of period A, 228 active participants still received study medication [SC: 31(13.6%), IV:197 (86.4%)]. Neuropsychologists performed 3775 cognitive assessments, with an average of 15 visits per participant (3–19 evaluations). Four participants missed a cognitive assessment during the pandemic, and one was missed due to work-related reasons. The overall retention rate was 94% (237 subjects completed study period A). 90.5% completed treatment (228 participants). 24 discontinued investigational product and 9 were followed per protocol, without receiving study drug. Among the 24 who discontinued treatment, 5 (2.0%) participants discontinued due to an adverse event, 4 (1.6%) due to pregnancy, 2 (0.8%) due to non-compliance, 1 (0.4%) participant due to physician decision and 12 (4.8%) withdrew consent. The main reasons for withdrawal were change of residency to another country and work-related problems. Based on surveys conducted until 2021, 29 (12.7%) active participants had at some point considered withdrawing from the trial, due to depressive symptoms, health problems, or difficulties at work; 6% had jobs problems due to the trial visits; 4.2% lost employment due to participating in this trial. 86 % reported moderate or great satisfaction with the trial. 86% active participants rated their health as equal to or better than before they started the trial. Conclusions: Clinical trials in healthy adults, many of whom work, are challenging; here we had a high retention rate. The study population has been followed up for 30 years by the Neurosciences Group of Antioquia (GNA). Participants are familiar with and trust GNA. The API ADAD Colombia trial is an example of a collaborative effort among the PSEN1 E280A kindred members, researchers, and sponsors in the search for an effective preventive treatment for AD. Preserving or improving quality of life of trial participants is the responsibility of sponsors and investigators. The social and health plans and the other adherence/retention strategies implemented strengthened this trial and may help with future ones, and demonstrates how ethical research is possible, contributing to the well-being of these people and their families.
LP4- THE GLOBAL ALZHEIMER’S PLATFORM FOUNDATION’S® (GAP’S) INCLUSIVE RESEARCH INITIATIVE: ENHANCING RECRUITMENT OF UNDERREPRESENTED COMMUNITIES THROUGH COMMUNITY CONNECTORS. D. Batchuluun1, T. Rodgers1, L. Zisko1, M. Key1, L. Thurman1, J. Dwyer1(1. Global Alzheimer’s Platform Foundation — Washington (United States))
Background: It is estimated that Alzheimer’s disease (AD) clinical trials recruit between 1–5% of individuals from underrepresented populations. However, Blacks/African Americans are 2–3 times more likely and Hispanic/Latinos are 1.5 times more likely to develop Alzheimer’s disease when compared to non-Hispanic whites (Alzheimer’s Association, 2019). Diverse representation in AD clinical trials is not only critical in assessing safety and efficacy of treatment but helps to ensure equity and inclusion in the clinical research process. The benefits and risks of treatment cannot be fully investigated and understood without adequate representation of the entire population. The Global Alzheimer’s Platform Foundation® (GAP) has created the Inclusive Research Initiative (IRI) for sites participating in its network (GAP-Net). GAP-IRI includes four Community Connectors who provide concierge level services throughout the East, West, Midwest and Southeast regions of the US to GAP-Net sites. Community Connectors plan customized community events, network within diverse communities, and conduct targeted outreach and recruitment strategies aimed at increasing diverse representation in AD clinical trials. Objectives: GAP’s Community Connectors aim to improve recruitment of underrepresented and underserved communities into AD clinical trials through a) community mapping efforts, b) relationship building with community partners and c) Primary Care Provider (PCP)/Healthcare Provider (HCP) engagement. Methods: GAP-IRI was launched February 2022 as a direct response to positive outcomes from GAP’s inclusive research support on GAP’s investigator-initiated trial, Bio-Hermes. As of September 2022, the Bio-Hermes study has enrolled 22% from underrepresented communities. Six diverse Community Connectors were hired between February 2022 and September 2022 because of their experience in community outreach, advocacy, and engagement with underrepresented populations. Key responsibilities of Community Connectors include: a) Community mapping of each site/community to identify community partners, key influencers and leaders; b) Building relationships and creating partnerships with identified, trusted organizations that serve Black/AA, Hispanic/Latino and other underrepresented communities. — Leveraging those relationships to coordinate and speak at community health fairs, community senior centers, education / awareness events, memory screening events, etc. c) Engaging community healthcare providers (HCP) that serve in underrepresented communities to identify patients at heightened risk of Alzheimer’s with potential to serve as referral pathways for clinical trials, memory care support, etc. d) Supporting sites with other recruitment and outreach strategies deemed appropriate and beneficial to recruit diverse participants in AD trials. Results: GAP’s Inclusive Research Initiative (IRI) was launched February 2022 and Community Connector support with GAP-Net sites initiated in April 2022. The following outcomes will be measured: -The total number of GAP-Net sites that receive GAP-IRI/Community Connector support. -The total number of Community Connector visits to GAP-Net sites. -The total number of community partners identified in each region. -The total number of community outreach events held in each region. -The total number/ percentage of underrepresented participants screened. -The total number/percentage of underrepresented participants randomized. Interim results and progress will be shared during CTAD’s 2022 Annual Conference. Conclusions: Achieving representation in AD clinical trials involves grassroots initiatives and intentional efforts in relationship building and community engagement. GAP’s Community Connectors aim to increase recruitment of underrepresented communities in AD clinical trials through these efforts to help ensure both equity and inclusivity. Key learnings and metrics from GAP’s Inclusive Research Initiative and Community Connector role will help to inform the creation of future initiatives and roles in other therapeutic areas in addition to AD. Acknowledgements: We thank Joshua Travis, Mia Chester, Paula Atkinson, Philip Macias, Roldyne Dolce, and Janay Austin Todd for their contributions to the Inclusive Research Initiative. References: Alzheimer’s Association (2019). 2019 Alzheimer’s disease facts and figures. Alzheimers Dement. 15, 321–387. doi: 10.1016/j.jalz.2019.01.010
LP5- MITIGATING LOSS OF STATISTICAL POWER DUE TO OUTCOME IMBALANCE IN CLINICAL TRIALS. A. Tam1, C. Laurent1, C. Dansereau1(1. Perceiv AI — Montreal (Canada))
Background: Although cognitive changes are typical primary outcomes in Alzheimer’s disease clinical trials, a significant proportion of participants will remain stable throughout a trial. Furthermore, randomization does not guarantee equal rates of decline between placebo and treatment arms. This outcome imbalance between the arms can reduce a trial’s power and/or lead to erroneous conclusions on treatment efficacy. Objectives: We used machine learning models to identify individuals as likely decliners or likely non-decliners. We aimed to demonstrate that these prognostic labels can be used to increase a trial’s power and mitigate the impact of outcome imbalance in two ways: post-randomization subgroup analysis of likely decliners and pre-randomization enrichment of likely decliners. Methods: We trained a machine learning model to classify decliners and non-decliners on 1329 individuals with mild cognitive impairment or Alzheimer’s dementia from the ADNI (adni.loni.usc.edu) and NACC (naccdata.org) datasets. Decliners were defined as individuals who had increased CDR-SB scores at 24 months of follow-up compared to baseline, and the prevalence of decliners in this sample was 65%. Age, sex, APOE4 status, and gray matter volumes of brain regions extracted from MRI at baseline were used as input features. The model was trained and tested with nested 5-fold cross-validation. To assess the probability of outcome imbalance across placebo and treatment arms, we simulated 100,000 trials by randomly assigning individuals to placebo and treatment groups (n=250 per arm, based on a Phase 2 trial by Swanson et al, 2021, Alzheimers Res Ther), while also stratifying for APOE4 and diagnosis, and we measured the differences in prevalence of decliners and non-decliners across the arms. We then assessed the impact of such imbalance on power to detect a 25% treatment effect across 1000 simulated trials at various levels of imbalance (ranging from 1% to 5% more decliners in the treatment arm). Furthermore, we studied whether covariate adjustment and enrichment with likely decliners predicted by the machine learning model can mitigate the loss in power associated with that imbalance. Results: The probability of observing at least a 5% outcome imbalance across arms (i.e. 5% more or fewer decliners in the treatment compared to placebo) was 22.4%. A perfectly balanced trial obtained a mean (± std) power of 89.2 ± 17.9% to detect a 25% treatment effect, while a trial that contained 5% more decliners in the treatment arm obtained only 73.8 ± 28.3% power, resulting in a drastic loss of 15% power. Covariate adjustment on common prognostic factors (e.g. APOE4 status, baseline diagnosis, baseline outcome score) increased power across levels of imbalance (97.2 ± 9.4% and 87.8 ± 21.5% in a perfectly balanced trial and a trial with 5% imbalance, respectively), but a 10% reduction in power still occurred at 5% imbalance. A subgroup analysis of the likely decliners (excluding the likely non-decliners) identified by the machine learning model increased power regardless of imbalance (balanced: 92.6 ± 14.1%; 5% imbalance: 85.2 ± 21.2%), despite the reduction in sample size (63% of the original size of 250 per arm), compared to using data from the full sample. A subgroup analysis of likely decliners with covariate adjustment achieved even greater power (balanced: 97.4 ± 8.2%; 5% imbalance: 92.2 ± 16.0%). Enriching a trial at the original sample size with 250 likely decliners per arm increased the power (balanced: 97.0 ± 9.4%; 5% imbalance: 92.1 ± 16.9%). We observed that the 5% imbalance resulted in only a 5% power reduction when using the enriched population, compared to the 15% reduction on the unenriched population. Finally, covariate adjustment on an enriched sample with 250 likely decliners per arm obtained the greatest statistical power (balanced: 99.1 ± 4.7%; 5% imbalance: 96.2 ± 11.8%). Compared to using the unenriched population where a 5% imbalance resulted in a 10% power reduction, using the enriched population led to a 3% power reduction, rendering the statistical analysis robust to imbalance. Conclusion: An outcome imbalance across trial arms as little as 5% significantly reduces a trial’s power to detect a treatment effect. The likelihood of enrolling imbalanced samples is approximately 1 in 5 (for a 5% discrepancy between the placebo and treatment arms) for a typical Phase 2 trial with 250 individuals per arm, despite randomization and balancing for common prognostic factors. Therefore, trials need additional strategies to enroll balanced arms. Our prognostic model can prevent imbalance by identifying individuals as likely decliners and likely non-decliners prior to randomization. Enriching with likely decliners can mitigate the loss in power due to imbalance and boost power when there is perfect balance. Combining our enrichment strategy of selectively enrolling likely decliners with covariate adjustment enables even greater statistical power.
LP7- A SEAMLESS PHASE 2A-PHASE 2B MULTI-CENTER TRIAL TO TEST THE BENEFITS OF BENFOTIAMINE ON THE PROGRESSION OF ALZHEIMER’S DISEASE (BENFO-TEAM). H. Feldman1,2, J. Luchsinger3, K. Messer2,4, D. Jacobs1,2, D. Salmon1, C. Revta1,2, J.L. Lupo1,2, G. Gibson5,6(1. Department of Neurosciences, University of California San Diego — La Jolla (United States), 2. Alzhimer’s Disease Cooperative Study, University of California San Diego — La Jolla (United States), 3. Departments of Medicine and Epidemiology, Columbia University Irving Medical Center — New York (United States), 4. Division of Biostatistics, University of California San Diego — La Jolla (United States), 5. Brain and Mind Research Institute, Weil Cornell Medicine — New York (United States), 6. Burke Neurological Institute — White Plains (United States))
Introduction: There is an urgent need to accelerate and diversify therapeutic possibilities for patients with Alzheimer’s disease (AD). Achieving clinical Proof of Concept (POC) represents a critical milestone for such candidate treatments. Benfotiamine provides an important novel therapeutic direction in AD with potential to achieve POC and with possible additive or synergistic effects to other current mainstream approaches. It has a unique mechanism of action, raising blood thiamine 50–100 times to pharmacological levels. In doing so, it addresses and treats a well-characterized tissue thiamine deficiency and related changes in glucose metabolism in AD, as well as post-translational modifications that are linked to thiamine-dependent processes including neuroinflammation, abnormalities of advanced glycation end products (AGEs), plaques and tangles, and downstream neurodegeneration. Results from a single-site pilot 12 month placebo controlled randomized clinical trial (RCT) of benfotiamine in persons with early AD demonstrated that this medication was safe and well tolerated, with encouraging pharmacokinetic (PK) and pharmacodynamic (PD) responses (Gibson et al., 2020). It also provided preliminary evidence of efficacy of benfotiamine on cognitive and functional outcomes. Taken together these results provide the Proof of Principle to justify benfotiamine advancing to a larger phase 2 RCT to further establish POC in early AD. Objectives: To conduct a seamless phase 2A–2B trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule treatment for early AD. The primary objective of phase 2A is to initially determine the highest safe and well-tolerated dose of benfotiamine (600 mg or 1200 mg) to advance to long-term clinical endpoints. Phase 2B will assess the efficacy of benfotiamine on global function and cognition over 72 weeks. Secondary objectives include evaluating the effects of benfotiamine on other measures of cognitive function as well as its PK relationships with primary clinical outcome measures, imaging measures and PD biomarkers. Methods: This is a double-blind, placebo-controlled RCT of 18-months of benfotiamine in early AD with a randomized total sample of 406 participants. Participants will be amyloid positive (C2N Precivity AD plasma test) with MCI or mild AD dementia (NIA-AA Diagnostic Criteria) ages 50–89. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The primary safety outcome in phase 2A is the rate of tolerability events (TE’s) defined as any of the following: participant dropout; a post-randomization moderate or severe adverse event; failure to take at least 80% of prescribed doses of study medication. The phase 2A primary analysis will test whether the rate of TE’s is unacceptably high in this high-dose arm compared to placebo. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Following the identification of the optimal dose in phase 2A, all of its participants will switch to this optimal dose or remain on placebo while 256 new participants will be randomized 1:1 to this optimal dose or placebo. Phase 2B will allow the assessment of efficacy and longer-term safety of benfotiamine of all participants through 72 weeks of treatment. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog-13. Secondary endpoints include safety and tolerability measures; PK measures of thiamine and its esters as PD blood markers of efficacy of drug delivery; FAQ and MoCA as additional measures of efficacy. Exploratory outcomes include the NPI, Neuropsychological Test Battery and cognitive composites (CFC2, ADAS-Cog Exec); neuroimaging (volumetric measures and regional cortical thickness); AGE levels in plasma and disease relevant plasma biomarkers (Ab42/ Ab40 ratio, total tau, p-tau 231, NfL and GFAP). Results: Results from the BENFO-TEAM trial are expected to identify the highest well-tolerated dose that has an acceptable safety profile. With the availability of measurable PK and PD biomarkers and a constellation of downstream plasma AD and neurodegenerative biomarkers, the trial will be able to test the sufficiency of target engagement and dose while evaluating longer term efficacy and safety of benfotiamine. The sample size is powered to determine if benfotiamine will benefit cognition and everyday function in individuals with early AD. Conclusion: The BENFO-TEAM trial is deploying an innovative seamless phase 2A–2B design to achieve POC. It includes an adaptive dose decision rule, thus optimizing the exposure to the highest and best-tolerated dose. Through its use of a plasma based amyloid biomarker test for inclusion, we add to the trial’s important contributions by shifting away from invasive testing using lumbar puncture or expensive PET scanning with its significant radiation exposure. A positive phase 2 clinical POC trial of benfotiamine that is powered to provide evidence of clinically important benefit will further validate our approach of deploying seamless designs with adaptive dose finding and provide measures and effect sizes that can become new benchmarks. The BENFO-TEAM trial is funded by the National Institute on Aging (R01 AG076634).
LP8- SIMULATION-BASED POWER ANALYSIS COULD IMPROVE THE DESIGN OF CLINICAL TRIALS IN ALZHEIMER’S DISEASE. D. Andrews1,2,3, D.L. Arnold3,4,5, D. Bzdok1,3,6, S. Ducharme7,8,3, H. Chertkow9,10,11,12, D.L. Collins1,3,4(1. Department of Biomedical Engineering, McGill University — Montreal (Canada), 2. Department of Bioengineering, McGill University — Montreal (Canada), 3. McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University — Montreal (Canada), 4. Department of Neurology and Neurosurgery, McGill University — Montreal (Canada), 5. NeuroRx Research — Montreal (Canada), 6. Mila — Quebec Artificial Intelligence Institute — Montreal (Canada), 7. Department of Psychiatry, McGill University—Montreal (Canada), 8. Douglas Mental Health University Institute, McGill University — Montreal (Canada), 9. Baycrest Centre for Geriatric Care — Toronto (Canada), 10. Kimel Centre for Brain Health and Wellness and Anne & Allan Bank Centre for Clinical Research Trials, Baycrest — Toronto (Canada), 11. Canadian Consortium on Neurodegeneration in Aging (Canada), 12. Division of Neurology, Department of Medicine, University of Toronto — Toronto (Canada))
Background: A two-sample t-test is often used in power analysis to determine the sample size needed to obtain a statistically significant estimate for an anticipated treatment effect size. This approach was used in the Phase 3 trials of aducanumab, the first FDA-approved drug to potentially slow cognitive decline by attacking brain amyloid plaques in early-stage Alzheimer’s disease (AD) patients. In AD, however, the t-test power analysis approach does not factor the uncertainty related to inter-individual variations in cognitive decline. In statistical terms, power analysis helps to avoid Type 1 (false positive) and Type 2 (false negative) errors by ensuring enough samples, given certain assumptions about the trial’s future results. Two core assumptions of t-test power analysis are that the outcome metric will be normally distributed, and that the measured effect size will be greater than or equal to that anticipated. If these assumptions do not hold, the recommended sample size could be too small. An insufficient sample increases Type 2 error risk, potentially blinding the trial to an effect that is truly present. We propose a simulation-based power analysis approach that accounts for effect size uncertainty and does not require normally distributed outcome metrics. Objectives: 1) Use our method to analyse power in trials similar to the Phase 3 aducanumab trials EMERGE (NCT02484547) and ENGAGE (NCT02477800). 2) Compare our power results with those reported in the published EMERGE and ENGAGE Statistical Analysis Plans (SAPs). Methods: All our simulations use the observation sampling scheme specified in the above SAPs: 4 observations per subject spaced approximately 26 weeks apart, and 30% dropout by the Week 78 final observation [1]. We also use the same outcome metric: change from baseline in Clinical Dementia Rating Sum of Boxes (CDRSBΔbl). Instead of using categorical time in a mixed model with repeated measures to estimate the end point difference, we use a continuous time linear mixed effects model on the actual simulated visit dates to estimate group differences in slope for treated subjects vs. placebo. Simulated subjects fit the aducanumab trials’ key inclusion criteria at baseline: subjects have mild AD or mild cognitive impairment due to AD, are between 50 and 85 years old, have a CDR score of 0.5 and an MMSE score between 24 and 30, are APOE genotyped, and are positive for abnormal amyloid levels [1]. We simulate many trials, each containing a different set of cognitive decline trajectories but the same overall treatment effect and sampling characteristics. “Power” is the proportion of simulations where a statistically significant treatment effect is detectable using the linear mixed effects model. We use this approach to analyze power with 10,000 simulated trials. Results: In Experiment 1 we asked: How many subjects per group are required to have 90% power at α = 0.05 to detect a 25% reduction in the rate of CDRSBΔbl increase? Here our 10,000 simulations show that 750 subjects per group are required. This is 215 subjects more than the 535 subjects per group recommended by the two-sided t-test power analysis at this power and α level in the EMERGE and ENGAGE SAPs [1]. In Experiment 2 we asked: What is the power at α = 0.05 to detect the 25% treatment effect described above if the trial has 535 subjects per group, as recommended by the SAPs? We obtained a statistically significant estimate for this treatment effect in 7,977 out of 10,000 simulations, signifying 79.77% power. This power is 10.23% lower than the 90% power at α = 0.05 implied in the SAPs. In Experiment 3 we asked: How many subjects per group are required to have 90% power at α = 0.05 to detect a 22% reduction in the rate of CDRSBΔbl increase, the amount measured as the statistically significant treatment effect in the EMERGE high dose group (2)? Our 10,000 simulations show that 950 subjects per group are required. This is 415 more subjects than were recommended by the SAPs’ two-sided t-test power analysis. Also, our simulation-recommended number of subjects per group here is at least 402 more than were included in the real-world EMERGE high dose and placebo groups (547 and 548 subjects, respectively) (2). Conclusion: Our approach accounts for the cognitive decline variability that implicitly affects treatment effect size and trial power. Our simulations show that the number of subjects in the Phase 3 aducanumab trials’ SAPs and the number included in the real trials may have been insufficient to give a high power to detect both the anticipated and measured treatment effect sizes. The SAPs may have overestimated the effect size without adequately considering uncertainty, potentially leading to underestimated sample size requirements. This could partly explain the detection of a statistically significant treatment effect in only one of the two Phase 3 aducanumab trials. 1) Biogen (2018). clinicaltrials.gov/ct2/show/NCT02484547; 2) Dhillon, S. (2021). Drugs, 10.1007/s40265-021-01569-z.
LP9- THE ALZMATCH STUDY: REMOTE PLASMA ACQUISITION TO PRE-SCREEN FOR PRECLINICAL ALZHEIMER’S DISEASE TRIALS. S. Walter1, R. Raman1, G. Jimenez-Maggiora1, R. Rissman1, J. Grill2, J. Karlawish2, O. Langford1, S. Bruschi1, M. Donohue1, K. Yarasheski3, M. Racke4, R. Sperling5, J. Cummings6, P. Aisen1(1. Alzheimer’s Therapeutic Research Institute, USC — San Diego (United States), 2. University of California, Irvine — Irvine (United States), 3. C2N Diagnostics — St. Louis (United States), 4. Quest Diagnostics — Secaucus (United States), 5. Brigham And Women’s Hospital, Massachusetts General Hospital, Harvard Medical — Boston (United States), 6. Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada — Las Vegas (United States))
Background: Despite the tremendous public health need, enrollment in Alzheimer’s disease (AD) clinical trials has encountered challenges that include lengthy enrollment periods, great expense, and failure to recruit cohorts that represent the diversity of the population at risk. These challenges have been notably acute in trials testing potential disease-modifying drugs in the pre-symptomatic or “preclinical” stage of disease. Enrollment was also thwarted during the COVID-19 pandemic. Advances in the ability to accurately assess AD pathology using plasma biomarkers have provided powerful new tools to address many of these challenges. These biomarkers reduce reliance on in-person, on-site assessments. Tools and mechanisms that reduce the need for in-person assessment are urgently needed to access broader socioeconomic groups and minimize future pandemic-related disruptions. This project leverages two recent advances in the field of AD research. (1) The establishment of online registries to develop “trial ready cohorts”, like the Alzheimer’s Prevention Trials (APT) Webstudy, where participants are recruited and followed through remote assessments, allow for efficient identification of large numbers of individuals and the ability to collect risk information. (2) The ability to quantify plasma biomarkers, specifically concentration ratios of Aβ42/40 and phosphorylated tau species, as early screeners for eligibility in preclinical AD trials, allows researchers to rule out individuals who have low probability of brain amyloid pathology, thereby reducing burden to participants and reducing the number and cost of amyloid PET scans, which are typically required to determine trial eligibility. Objectives: The AlzMatch study examines the feasibility of blood testing at community-based laboratories that provide suitable plasma to qualified diagnostic laboratories. Validated biomarkers for AD pathology are quantified and used to assess eligibility for preclinical AD trial screening. Methods: The project will utilize the APT Webstudy, that has consented over 50,000 participants as of September 27, 2022. Participants enrolled in the registry must be over 50 years of age, with no diagnosis of dementia. After consent, the primary measures are engagement of eligible participants and collection of blood samples. Secondary measures include invitation responses, biomarker values obtained, completion of telephone communication of eligibility to screen for a study, and referral to either remote or in person research. Participants will be recruited in two stages; the first stage enrolls 500 participants, and the second stage will enroll up to 5,000. Participants are invited either from an online registry or from a community setting, sign electronic consent, and are given information to schedule their appointment a local Quest Diagnostics’ phlebotomy lab. Plasma is aliquoted, frozen according to standardized procedures, and shared with multiple biofluid assay labs. AlzMatch eligibility status will be evaluated using a predictive algorithm that includes C2N Diagnostics’ biomarker assay. All participants, irrespective of eligibility status, will be contacted by telephone and informed of their eligibility to be screened for a clinical study. Participants are told whether they are eligible or not eligible to be screened for a research study at a clinical trial site near where they live. Eligible participants that agree to referral will be connected to a local research site for in-person evaluation. Results: Initial findings from the first stage of the AlzMatch study will be presented. Conclusion: The AlzMatch study will improve our understanding of the feasibility of community-based plasma collection for in-person research. Referral of these pre-screened participants to clinical trial sites may offer a more efficient and decentralized screening approach that reaches a more representative group of participants for currently enrolling preclinical trials like AHEAD 3–45. Samples collected for this project may help refine the optimal cutpoints to identify participants with early AD pathology. The results of this study will also inform design of large-scale prevention trials.
LP10- DISEASE PROGRESSION MODELLING IDENTIFIED MRI-BASED SUBTYPES WITH COGNITIVE HETEROGENEITY IN A4 STUDY PRECLINICAL TRIAL COHORT. C. Shand1, N.P. Oxtoby1, M.C. Donohue2, D.A. Alexander1, F. Barkhof1,3(1. University College London (United Kingdom), 2. Alzheimer’s Therapeutic Research Institute, University Of Southern California (United States), 3. Amsterdam UMC (Netherlands))
Background: Biological and clinical heterogeneity can confound clinical trials, where differences in subsequent disease progression independent of treatment effect are not detected/screened via typical inclusion criteria. This is particularly challenging in preclinical trials, where neuropsychological screening is augmented by biomarker measurements, usually with predefined cut-points for inclusion. Machine learning methods such as data-driven disease progression modelling can characterize subtle differences in high-dimensional data that traditional screening methods cannot. Objectives: First, to detect and characterize MRI-based heterogeneity (subtypes) in a large preclinical cohort from the A4 Study (1). Second, to look for subtype-cognition associations at baseline. Third, to generate hypothetical forecasts for A4 by analyzing cognitive decline in a matched ADNI subset. Methods: In brief, we fed MRI data into the Subtype and Stage Inference (SuStaIn) algorithm (2) to estimate neurodegeneration subtypes in the A4 Study pre-randomization data. We then compared demographic variables and cognitive scores across subtypes. Finally, we selected a subset of ADNI that matched the A4 Study inclusion criteria, and investigated longitudinal cognitive decline across the assigned subtypes. In detail, we used 3-Tesla T1-weighted MRI scans from the A4 Study, and processed them using FreeSurfer 7.1.1 to obtain cortical and subcortical volumes in bilateral averages of 13 regions of interest. 1240 Aβ+ individuals from the A4 Study were used as input into SuStaIn, following covariate adjustment and z-scoring relative to a control group of 407 Aβ— individuals. Cross-validation was performed to find the model that best fit the data, and to identify the most likely number of subtypes. This model was then used to assign a maximum-likelihood subtype and (disease) stage to the A4 cohort. The subtype groups were compared pairwise for differences (at baseline) in the trial’s primary outcome (PACC — Preclinical Alzheimer Cognitive Composite) and a secondary outcome (CFI — Cognitive Function Index) using a two-tailed Mann-Whitney U-test, corrected for multiple comparisons. To understand the potential impact this could have on the trial, a simulation of the placebo arm was performed by selecting a subset of ADNI individuals that matched the A4 Study inclusion criteria (and had a 3T scan available, processed using the same FreeSurfer 7.1.1 pipeline). This subset was assigned a subtype and disease stage by the A4-trained SuStaIn model. A linear mixed effects model was used to assess cognitive decline, using the modified PACC (mPACC) and Clinical Dementia Rating Sum of Boxes (CDR-SB) as outcomes. The model included age at baseline, time since baseline (continuous), and subtype-by-time interactions as fixed effects, as well as allowing for participant-specific random intercepts. This analysis was restricted to data obtained over a length similar to the A4 trial (4 years from baseline). Results: Following cross-validation, SuStaIn identified three distinct subtypes: Typical, Cortical, and Subcortical. The Typical subtype showed early atrophy (z-score > 2 relative to Aβ— controls) in the hippocampus, amygdala, and temporal lobe, the Cortical subtype showed early atrophy in the cortical regions (including the cingulate gyrus), and the Subcortical subtype showed early atrophy in the putamen and thalamus. 523 (42.2%) of individuals belonged to these subtypes, with the remaining 717 (57.8%) assigned to Subtype Zero, having no abnormality (z-score < 1). There were no significant differences in demographic variables across the subtypes. There were statistically significant cognitive differences across subtypes in both the PACC and CFI. In particular, the Cortical subtype had the worst median cognitive scores, and worse PACC scores compared to Subtype Zero (P < 0.0001) and the Subcortical subtype (P = 0.0006), as well as worse CFI scores compared to Subtype Zero (P = 0.0003). In ADNI, the Cortical subtype displayed greater cognitive decline in the mPACC (-0.28/yr; 95% CI, -0.61 to 0.04; P = 0.09). Both the Cortical (+0.14/yr; 95% CI, 0.07 to 0.20; P < 0.0001) and Subcortical (+0.14/yr; 95% CI, 0.09 to 0.19; P < 0.0001) subtypes displayed greater cognitive decline on CDR-SB. Conclusion: We used an MRI-based data-driven disease progression model to identify clinically relevant baseline heterogeneity in the A4 Study cohort. The different neurodegeneration patterns, or subtypes, were associated with different cognitive profiles at baseline (in A4) and longitudinally (in ADNI). These findings have important ramifications for the design of secondary prevention trials in Alzheimer’s disease, which could leverage disease progression modelling for screening, stratification, or covariate adjustment short of stratification. References: 1. Sperling RA, Rentz DM, Johnson KA, et al. The A4 Study: Stopping AD Before Symptoms Begin? Sci Transl Med. 2014;6(228). doi:10.1126/SCITRANSLMED.3007941; 2. Young AL, Marinescu R v., Oxtoby NP, et al. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference. Nature Communications 2018 9:1. 2018;9(1):1–16. doi:10.1038/s41467-018-05892-0.
LP11- LATAM-FINGERS STUDY DESIGN: A MULTICULTURAL HARMONIZATION WORK ACROSS LATIN AMERICA. L. Crivelli1, C. Suemoto2, I. Calandri1, P. Caramelli3, F. Lopera4, R. Nitrini5, A.L. Sosa6, R.M. Salinas6, L.M. Velilla4, M. Yassuda5, R.F. Allegri1, H. Snyder7, M. Kivipelto8, M. Carrillo7(1. Fleni — Buenos Aires (Argentina), 2. Division of Geriatrics, University of Sao Paulo Medical School — Sao Paulo (Brazil), 3. Behavioral and Cognitive Neurology Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais — Belo Horizonte (Brazil), 4. Neuroscience Group of Antioquia Medical School, Antioquia University — Antioquia (Colombia), 5. Department of Neurology, University of São Paulo School of Medicine — Sao Paulo (Brazil), 6. Laboratorio de demencias del Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez — Mexico City (Mexico), 7. Alzheimer’s Association — Chicago (United States), 8. Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet — Stockholm (Sweden))
Background: At least 40% of dementia cases worldwide might be attributable to potentially modifiable risk factors. In Latin America (LA), 56% of dementia cases are attributable to these risk factors. Thus, interventions on these risk factors can significantly benefit dementia prevention in LA. LatAm-FINGERS is the first non-pharmacological multicenter randomized clinical trial (RCT) to prevent cognitive impairment in LA. It gathers 12 countries, including the Spanish- and Portuguese-speaking populations. The project is harmonized with both the original Finnish trial for the prevention of cognitive decline (FINGER) (Kivipelto et al., 2020) and the study to Protect Brain Health through a Lifestyle Intervention to Reduce Risk (U.S. POINTER). However, LA is a heterogeneous region with ethnic, linguistic, and cultural diversity. Thus, a harmonization process within LA, considering the cross-cultural variability of neuropsychological tests, was necessary to adapt eligibility criteria, outcomes, and interventions. Objectives: To investigate the feasibility of a multi-domain lifestyle intervention in LA and the efficacy of the intervention in improving cognitive function in 1200 participants (100 per country) within two years. We aim to present the study design and discuss strategies used for multicultural harmonization. Methods: The study design included an external harmonization process carried out to follow the original FINGER model and an internal harmonization to make this study feasible and comparable across the 12 countries. A workgroup of experts representing all the consortium countries was assembled. The aim of the inclusion criteria harmonization was to achieve a homogenous selection of participants in all countries. For that purpose, we compared normative values in neuropsychological tests across LA, considering different levels of education and age. Regarding outcomes, harmonization included using shared cognitive protocols for each variable. This task required comparing versions and arriving at a harmonized version in Spanish and Portuguese for each test and measure. Finally, regarding interventions, working groups (WG) of experts with at least one expert from each country were convened. WG included nutrition, physical activity, cognitive intervention, health monitoring, biobank, and neuroimaging subgroups. Results: Inclusion criteria harmonization was achieved using each country’s normative z-scores. Educational level and age from each region were included to make the assessment fit regional standards. Barriers to these processes included the absence of normative data for many countries regarding commonly used cognitive tests, such as the MMSE and CERAD. Outcome harmonization resulted in a Latin American Neuropsychological Test Battery (LatAm NTB). Finally, the intervention harmonization included local perspectives from participating countries, looking for feasibility and adherence. Interventions were adapted to have a common core but flexibility to allow local idiosyncrasies. LatAm-FINGERS recruitment started on December 2021, and up to date, 986 participants were screened, and 731 were randomized to the interventions. Regarding the sample’s demographic characteristics, we must highlight the overrepresentation of women (from 60% in Peru to 89% in Colombia). The mean age is 67.8 (±4.8) years, the level of education is 12.4 years (±4.8), and the MMSE scores 27.3 (±1.7). The diversity of the population is reflected in self-reported ethnicity: 56% of the participants self-reported being Mestizo, and 35% as Caucasian. Other reported ethnicities included Mulatto (2.1%), African-American (1.9%), and Asian (0.7%). The preliminary recruitment results show a significant opportunity for improvement in cardiovascular and metabolic risk factors: 10% are current smokers, 42% have high systolic blood pressure (>130mmHg), 20% have blood diastolic pressure over (>85mmHg), 81% of participants were overweight (BMI ≥25 kg/m2), 42% had low HDL (<40 mg/dL in men or 50 mg/dL in women), 37% had hypertriglyceridemia(fasting triglyceride >150mg/dL), and 63% of had central obesity (waist circumference over 88 cm for women or 102 cm for men), 32% have abnormal fasting glucose (>100mg/dL), which indicate a metabolic syndrome prevalence of 38% in our sample. Conclusion: This is the first non-pharmacological lifestyle intervention trial to prevent cognitive decline, including participants from 12 LA countries. LatAm-FINGERS faces a significant challenge in combining the region’s diversity into a single healthy lifestyle intervention feasible across LA. This report presents the results of the effort achieved by effective multicultural teamwork. Furthermore, LatAm-FINGERS is building the largest data set on people at risk of dementia in LA. With longitudinal follow-up, it has already grown to be the region’s largest cognitive, imaging, biomarker, and genetic database of individuals at risk for dementia. LatAm-FINGERS aspires to be the foundation stone of dementia teamwork in LA, confirming the potential value of collaboration in the region.
LP12- RECRUITMENT ACCELERATOR FOR DIVERSITY. M. Sano1, J. Vasconcellos2, M. Sewell3, J. Neugroschl3, M. Umpierre3, S. Chin3, S. Brangman4, S. Mcnamara4, N. Smith4, K. Royal4, M. Splaine2(1. Icahn School of Medicine at Mount Sinai—New York City (United States), 2. Recruitment Partners LLC — Columbia (United States), 3. Icahn School of Medicine at Mount Sinai—New York (United States), 4. Upstate)
Background: The RADAR-CLD R-24 grant leverages an Accelerator model to assist in improving recruitment of diverse participants in aging research on cognition at two study sites. The Accelerator model brings together a trans-disciplinary team of patients, advocates, clinicians, researchers, public health and industry leaders, to catalyze study operations by insuring communication between scientific and non-scientific stakeholders, improving the efficiency and effectiveness of research conduct. Over time, these collaborative teams become highly knowledgeable and effective in addressing needs of the community in cognition studies and understanding the unique skills and resources available in their communities to facilitate recruitment education and outreach. This report describes one of the Accelerator meetings at the Mount Sinai site. Objectives: The Sinai Accelerator group convened to engage in discussion regarding the role of registries in recruiting diverse older adults into research. The objectives of the meeting were to explore strategies to increase recruitment into research registries, identify the pros and cons of participating in a registry, and understand how to manage a research registry to maximize efficiency and recruitment success. Methods: Accelerator members of diverse backgrounds included (7) researchers, research staff and clinicians, (2) dementia caregivers, (2) community-based organization representatives, and (1) senior from the local community. The meeting was held over Zoom with a short question guide, designed to inspire open conversation. Meeting facilitators introduced a research registry as a database of research projects and personal information of potential research participants. The registry can be used by researchers to identify individuals that fit their eligibility criteria and can be used by potential participants to find study opportunities of interest for themselves and those they care for. Results: Major themes included building trust through relationship building and transparency. These themes are echoed in subsequent meetings that focus on actively enrolling studies at both sites. Additionally, stakeholders provided insight into the maintenance of registry data.Relationship building. Accelerator members suggested researchers provide community presentations and attend informal community gatherings. An example included a weekly coffee group at the local senior center. Accelerator members also stressed that outreach would ideally be in-person and would be enhanced by inclusion of community partners. A community partner could be someone well-known and trusted within the community, or someone who is generally familiar with the community and culture. Finally, dissemination of study findings back to community helps solidify the relationship and allows community members to see firsthand the impact of their contribution. The theme of relationship building has been echoed in subsequent Accelerator meetings at both Sinai and Upstate. Cultural Competency. Participants also noted that prior to soliciting research help, researchers need to have a level of ‘cultural competency’, a basic understanding of the community culture, and have had experiences and personal interactions with community members. At Upstate this concept is being successfully tested through community engagement by their Community Research Liaison and a team of Resident Health Advisors who are themselves residents of the target community. Transparency of Information Security. The group stressed the importance of researchers explaining their plan to keep personal information safe. As one caregiver expressed, a drawback to participating in research is forfeiture of some privacy. Greater data security transparency could quell some fears, and potentially make them more comfortable participating. Transparency of Registry Goals. Participants want to know why the research is important and how their participation will be beneficial. Additionally, researchers should convey to potential participants how entering a research registry will aid in efforts to increase diverse participation and why that is important. Information Collection. Maximizing the information provided upfront when joining a research registry is mutually beneficial for both researchers and participants. Participants would be contacted directly for studies that they are eligible for. This is in contrast to the traditional recruitment process, whereby the individual carries the burden of finding the studies they could be eligible for and then reaching out to the study themselves. Frequency of Registry Updates. Suggestions for how often to update registry data varied considerably. Those that suggested more frequent updates explained that for older adults with ADRD, their health status and care situation is often rapidly evolving. Method of Registry Updates. Some suggested that there should be multiple methods of communication (phone, email and mail) available for participants due to varied technological abilities. Each individual’s communication preference should be listed in the registry, so that the research team knows how to best contact them. Similarly, if the participant wants to offer updated information, they should be able use whichever communication method they so choose. Conclusion: The nature of the researcher-participant relationship can sometimes feel like a one-way transaction, in which the researcher’s sole purpose is to collect information. By engaging in sustained community engagement efforts, trust can be built between researchers and the community, leading to successful and diverse registry recruitment and research recruitment.
LP13- PHYSICIAN-DRIVEN PATIENT RECRUITMENT ADDRESSES BARRIERS IN AD CLINICAL TRIAL ENROLLMENT. E. Beck1, M. Eimerbrink1, K. Tyler1, D. Gautieri1(1. SiteRx — New York (United States))
Background: In April 2022, the Food and Drug Administration (FDA) released draft guidance for industry to develop, submit, and implement a plan to enroll participants representative of racial/ethnic diversity in the US. This is especially important in Alzheimer’s disease (AD) clinical trials where enrollment of minority racial groups falls far behind US Census Bureau data. For example, 8.9% and 8.5% of US individuals 65 and older are Black/African American and Hispanic, respectively. However, a 2022 systematic review found only 1.2% of AD clinical trial participants were Black/African American and 5.6% were Hispanic. Establishing and acting on plans to achieve representative samples requires thought partnership and collaboration across sponsors, clinical trial sites, community-based treating physicians and patients. SiteRx, a physician-driven recruitment platform, uniquely bridges these stakeholders, democratizing access to clinical research for diverse communities and enabling patients to learn about relevant study opportunities from their trusted, treating physician. Objectives: This study seeks to investigate how the U.S. clinical research infrastructure is prepared to meet the current, growing and changing needs for diverse enrollment into AD clinical trials. We aim to evaluate the overlap between regional density of underrepresented minority persons with dementia (PWD), SiteRx Provider Network of community-based physicians and trial sites, with attention to how alignment impacts the ability to enroll study participants representative of the national population diagnosed with AD. Methods: Prevalence of AD by county and race was collected via the 2019 US Census Bureau. Trial site data was gathered using clinicaltrials.gov and a third-party service. Trial sites were mapped by ZIP code and limited to sites that were US-based and had open Phase 1–3 AD clinical trials as of June 2022. The SiteRx Provider Network and trial sites were mapped using ZIP codes from a proprietary database. Distance between SiteRx Provider Network and trial sites were analyzed using ZIP code, with attention to density of racially/ethnically diverse AD patients by county. Additionally, Orlando, FL, New York, NY and Los Angeles, CA, were used as case studies for evaluating referral and randomization of underrepresented minority participants through SiteRx community-based physicians. Results: The analysis revealed 78% of patients with AD live within 50 miles of a trial site and 92% live within 100 miles. Among underrepresented minority patients with AD, 84% live within 50 miles of a trial site and 92% live within 100 miles. This analysis suggests that density of non-white AD patients and clinical trial sites is reasonably aligned, buffering the travel barrier for many potential participants. SiteRx’s physician-driven platform generated the following referral activity by race/ethnicity in the key geographies assessed: Orlando 26% Hispanic, 14% Black/African American, 3% Other, 2% Asian/Pacific Islander; NYC 27% Hispanic, 2% Other, 4% Asian/Pacific Islander; LA 60% White/Caucasian, 23% Hispanic, 13% Black/African American, 4% Asian/Pacific Islander. Importantly, the largest dropoff from referral to randomization is observed among the non-white participants indicating eligibility criteria and site dynamics may contribute to disparities in enrollment. Conclusion: As diversity goals become standard in AD clinical trials, new methods are needed to establish pathways for diverse communities to participate in research. The analysis demonstrated that sites are relatively well co-located with diverse AD patients across the U.S. and SiteRx HCP Network provides a unique bridge to community providers in these areas. SiteRx referral activity highlights the importance of leveraging longitudinal relationships with community providers for increasing diverse participation in research. However, exclusionary protocols and site limitations to support patients from diverse backgrounds results in disproportionately high screen fail rates among non-white participants. As key areas of trial design and planning continue to evolve, SiteRx offers a sustainable vehicle for industry sponsors and trial sites to increase diverse participation in AD research and further develop the science of recruitment.
LP14- A PHASE 3 CLINICAL TRIAL PROTOCOL TO EVALUATE THE EFFICACY AND SAFETY OF NA-831 IN SUBJECTS WITH EARLY ONSET OF ALZHEIMER’S DISEASE. L. Tran1, M. Kurkinen1, F. Vu1(1. Biomed Industries, Inc. — San Jose (United States))
Background: This phase 3 study consists of a Core and Open Label Extension (OLE) Phase in 465 participants with Early Alzheimer’s Disease (EAD), and is being conducted to evaluate the efficacy and safety of NA- 831. The Core is a 52-week treatment, multicenter, double blind, placebo controlled parallel group study. Methods: Core Study: Participants will receive one capsule of 30 milligram (mg) NA-831 orally once a day in the morning. The core study will be double blinded. Placebo Comparator: The core study will be double blinded. Experimental: Open Label Extension Phase: Participants completing the core study will receive one 30 milligram (mg) NA-31 capsule orally once a day in the morning. Key Outcome Measures: 1. Core Study: Change from Baseline in the Clinical Dementia Rating; — Sum of Boxes (CDR-SB) Score at 48 Weeks [Time Frame: Baseline, Week 52]. 2. Open-Label Extension Phase: Number of Participants With Treatment-Emergent Adverse Events (AEs) [Time Frame: Up to Week 52 of Extension Phase] Secondary Outcome Measures: Cognition-13 (ADAS-Cog-13) at Weeks 24, 52 [Time Frame: Baseline, Week 24, Week 52 of Extension Phase] CORE STUDY: Mild cognitive impairment due to AD or mild AD dementia including 1. MMSE score equal to or greater than 24; 3. CDR global score of 0.5 3. CDR Memory Box score of 0.5 or greater. The Phase 3 clinical trial of NA-831 is being conducted in multicenters in the US and several countries. The details of the Phase 3 methodology and protocol will be presented and discussed.
LP14A- DEVELOPMENT OF AN ABBREVIATED PRE-SCREENING COGNITIVE BATTERY TO ENHANCE REFERRAL TO CLINICAL TRIALS. A. O’connell1, E. Fischer1, L. Latham1, L. Baker1, S. Craft1(1. Wake Forest Alzheimer’s Disease Research Center — Winston-Salem (United States))
Background: Timely enrollment of an eligible cohort into Alzheimer’s disease (AD) clinical trials is critical in accelerating AD research, but as these trials increasingly target prodromal and preclinical AD, clinical trial sites face difficulty in determining whether prospective participants will meet cognitive eligibility criteria. This is especially problematic in prodromal trials, as these individuals often report subjective memory complaints but have not received any clinical evaluation of cognitive status and therefore lack any previous diagnosis or available neuropsychological testing to aid in evaluating study eligibility prior to conducting the clinical trial screening visit. As a result, screen fail rates based on screening cognitive assessments for these studies is high, study sponsors and clinical trial sites invest considerable time and resources in conducting screening visits, and the duration required to complete study enrollment is prolonged. Objectives: To develop and pilot a brief cognitive battery for use as a pre-screening tool in the evaluation of volunteers to the Wake Forest Alzheimer’s Disease Research Center (ADRC) who lack prior cognitive testing. The aims of this pilot were: 1) to determine preliminary cognitive status of these participants and provide them feedback on this information, 2) screen out cognitively normal individuals with subjective complaints prior to referral to prodromal clinical trials, and 3) enhance referral to the Center’s enrolling studies by using the results obtained to assess eligibility based on study-specific inclusion criteria. Methods: A working group comprised of the Wake Forest ADRC Directors, neuropsychologists, clinical study management team members, and Outreach Director collaborated to devise a cognitive battery that could be administered in under one hour, provide a preliminary assessment of a broad cross-section of cognitive domains, and obtain enough information to enable evaluation of cognitive eligibility for referral to Center-conducted studies enrolling cognitively normal, mild cognitive impairment (MCI), or mild AD participants. The resulting protocol included the administration of Montreal Cognitive Assessment (MoCA), WMS-III Logical Memory, Number Span Test Forward and Backward, Trail Making Tests A and B, Rey Auditory Verbal Learning Testing (RAVLT), and Benson Complex Figure Copy and Recall, and was implemented as a one-hour visit titled the Memory Screening Clinic (MSC). At the point of initial intake to the ADRC, all potential participants completed a preliminary telephone screen that included the telephone interview for cognitive status (TICS), self-report of cognitive complaints, and collection of basic demographic and medical history information. Participants with TICS scores ≥ 34 who did not self-report as cognitively normal, or those with any TICS score who did not have a known diagnosis of MCI or AD with supporting neuropsychological testing, were then offered the one-hour MSC visit for preliminary cognitive screening and feedback. The visit included the informed consent presentation, completion of a brief medical history form, and the neuropsychological battery. A Center neuropsychologist then reviewed the cognitive assessments and medical history information to determine a preliminary cognitive impression, and these results were then reviewed by a referral coordinator to evaluate eligibility for currently enrolling studies. The preliminary cognitive impression and potential study options were then discussed with each participant, and a referral made to the appropriate study team as applicable. All individuals who completed the MSC received feedback that included whether they were eligible for further testing via a study-specific screening visit, materials with information about potential study opportunities, and their MoCA score. Results: Between October 2019 and June 2022, 459 individuals completed a phone screen intake with the Wake Forest ADRC and met eligibility for referral to the MSC. Of those participants, 268 (58%) completed a MSC visit (mean age= 68.1 (50–88), 181 Female/87 Male; 134 Normal Controls/134 Probable Impairment) while 191 (42%) did not continue following the phone screen (lost to follow-up, not interested in study participation, or ineligible based on global exclusion criteria). Of those who completed the MSC visit, 162 (60%) were not referred to a clinical trial (did not meet eligibility criteria, were not interested in available study options, or were interested in cognitive screening and feedback only) and 106 (40%) participants were interested in and eligible for referral to a clinical trial. Participants who completed the MSC visit and feedback only and were not referred to subsequent studies were generally cognitively normal and had self-referred to the ADRC with interest in cognitive screening and evaluation for MCI studies. Of the MSC participants referred to a clinical trial, 62 (58%) were eligible at screening and enrolled in a clinical trial, 37 screen-failed (35%), and 7 did not complete a screening visit (7%). Conclusion: The implementation of the MSC visit and abbreviated cognitive battery created a cost-effective, low-burden method of connecting with prospective research participants, providing preliminary cognitive feedback, and enhancing successful referral to and enrollment in Center clinical trials. Disclosures: The authors have no disclosures to share.
NEW THERAPIES AND CLINICAL TRIALS
P24- POTENTIAL REVERSAL OF ALZHEIMER’S DISEASE. S. Rasool1, J. Johansson1, L. Voloboueva1, S. Lee1, N. Lan1, T. Ahmed1, D. Sun1 (1. Truebinding Inc. — Foster City (United States))
Background: Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder caused by multiple pathogenic factors including Amyloid-β (Aβ), phospho-Tau (pTau), a-synuclein, and ApoE4, etc. It is widely accepted that intermediate oligomeric forms, rather than monomers or mature fibrils, are more neurotoxic. Galectin-3 (Gal-3) was reported to be involved in Aβ oligomerization. Here, we show that Gal-3 promotes oligomerization of Aβ and other pathogenic factors, and TB006, a monoclonal antibody targeting Gal-3, acts as a possible treatment for AD by degrading neurotoxic oligomers and reducing inflammation. Pre-clinical studies show that TB006 is an efficacious therapeutic entity through preventing formation of toxic oligomers and blocking or even reversing AD progression. Objectives: Gal-3 expression is increased in brains from AD patients, particularly in microglia associated with amyloid plaques. Our objectives were to examine the role of Gal-3 in Aβ aggregation (conformational oligomer formation) and to investigate the therapeutic efficacy of our novel Gal-3 antibody for treatment of AD. Methods: We used two anti-Gal-3 antibodies, our clinical lead TB006 and a mouse cross-reactive surrogate, mTB001, to establish the benefits of Gal-3 neutralization in AD in vitro and in vivo. The effects of mTB001 were tested in three AD mouse models (two transgenic mouse models (APPSwe, 5xFAD) and an Aβ42-injected mouse model). After a two-week treatment, a spatial memory function test was conducted, followed by biochemical and immunohistochemical characterizations. Results: Amyloid aggregation is a hallmark of several neurodegenerative diseases (including AD, Parkinson’s disease and amyotrophic lateral sclerosis) affecting the brain or peripheral tissues, whose intermediates (oligomers, protofibrils) and final mature fibrils display different toxicity. In vitro, Gal-3 intrinsically and selectively promoted, while mTB001 and TB006 degraded, oligomerization of only pathogenic protein forms like Ab42/40, a-synuclein, pTau and ApoE4, but not of non-pathogenic normal Tau and ApoE2/3. Gal-3 enhanced, while mTB001 blocked, Ab42-induced lysosomal dysfunction and pro-inflammatory activation in BV2 microglial cells. Additionally, Ab42 and Gal-3 synergistically induced, while mTB001 reversed, neuronal death. In vivo, in three mouse models of AD, cognitive deficits were strongly attenuated after just two weeks of mTB001 treatment. Mechanistically, Gal-3 antibody blocked the initiating events in AD (Aβ aggregates), reduced inflammation and rescued neuronal damage. Furthermore, microhemorrhages, a potential safety liability seen in clinical stage drugs, were reduced. Conclusion: Pre-clinical studies show that TB006 is an efficacious therapeutic entity through preventing formation of toxic oligomers and blocking or even reversing AD progression. Clinically, TB006 has shown a superior safety profile without any drug-related adverse events in a nearly finished healthy volunteer trial. Promising efficacy data are expected in Q2/2022 from the ongoing phase I/II AD trial.
P25- WHOLE-BRAIN LOW-INTENSITY PULSED ULTRASOUND THERAPY FOR EARLY STAGE OF ALZHEIMER’S DISEASE (LIPUS-AD): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL. H. Shimokawa1,2, T. Shindo1, A. Ishiki3, N. Tomita3, K. Eguchi1, T. Shiroto1, J. Takahashi1, K. Shiratsuchi4, S. Yasuda1, H. Arai3(1. Tohoku University Graduate School Of Medicine — Sendai (Japan), 2.International University of Health and Welfare — Narita (Japan), 3.Institute Of Development, Aging And Cancer, Tohoku University — Sendai (Japan), 4. Sound Wave Innovation, Co. — Tokyo (Japan))
Background: Along with society aging, the prevalence of Alzheimer’s disease (AD) has been rapidly increasing worldwide. However, effective and safe treatment of AD remains to be developed. For the last decades, amyloid β (Aβ) cascade hypothesis has been in the center of the pathogenesis of the disorder. Based on the hypothesis, a number of pharmacological agents that inhibit Aβ synthesis or promote its degradation have been developed without convincing success. It is widely known that AD and vascular dementia (VaD) share common risk factors, such as hypertension, hypercholesterolemia, and diabetes mellitus. Long-term exposure to these risk factors result in common outcome, i.e. impairment of vascular endothelial functions. Indeed, endothelial dysfunction with reduced nitric oxide (NO) availability has been suggested to play an important role in the pathogenesis of AD. Furthermore, the combination of amyloid pathology (e.g. Aβ deposition and neurofibrillary change) and cerebral ischemic pathology has been found as major triggering mechanisms of dementia. Thus, vascular dysfunction, especially cerebral microcirculatory dysfunction, should also be regarded as an important pathology of AD. We have developed a low-intensity pulsed ultrasound (LIPUS) therapy that upregulates endothelial NO synthase (eNOS) with resultant therapeutic angiogenesis and suppression of chronic inflammation. We demonstrated that the LIPUS therapy is effective and safe in animal models of chronic myocardial ischemia, myocardial infarction, and left ventricular diastolic dysfunction. We also demonstrated that the LIPUS therapy ameliorates cognitive dysfunctions in mouse models of AD, VaD and cerebral infarction. The effects of the LIPUS therapy is mainly mediated by upregulation of eNOS as its beneficial effects are absent in eNOS-deficient mice. Objectives: We thus performed a pilot study to address the efficacy and safety of our LIPUS therapy in patients with AD. Methods: We performed two trials of the LIPUS therapy for AD (mild cognitive impairment due to AD and mild AD); a roll-in open trial for safety and a randomized, double-blind, placebo-controlled (RCT) trial in a 1:1 fashion for efficacy and safety. The LIPUS therapy was performed for whole brain through the bilateral temporal bones alternatively for one hour 3 times per week as one session under the special conditions (1.3MPa, 32 cycles, 5% duty cycle) that we identified. The LIPUS therapy was performed for one session in the roll-in trial (N=5), and 6 sessions with a 3-month interval in the RCT trial (N=22). The primary efficacy endpoint was the changes in ADAS-J cog scores from baseline at 72 weeks. Results: Roll-in Trial. The 5 patients (M/F 4/1) were 70.8±9.5 year-old with MCI due to AD in 4 and mild AD in one and had MMSE-J score 24.8±3.4. Twelve weeks after the therapy, no adverse effects or abnormal MRI findings were noted. RCT Trial. In this trial, although the planned number of patients was 40, due to the COVID-19 pandemic in Japan, the trial was terminated prematurely, upon approval by the Pharmaceuticals and Medical Device Agency of Japan (PMDA) with a final number of 22 patients. Among them, 4 did not complete the planned protocol (withdrawal of consent in 1, operation for cholelithiasis in 1, worsening of cognitive functions in 2). Another patient was found to receive prohibited concomitant medications and was excluded from the analysis. Another 2 patients completed 4 sessions due to the early termination of the trial. Thus, a total of 19 patients were analyzed for efficacy and 18 for safety. Among them, 9 had MCI due to AD and 10 had AD. There were no significant differences in baseline clinical characteristics or cognitive functions between the 2 groups. For the safety issue, there was no adverse effects of the LIPUS therapy including brain MRI findings. For the efficacy issue, the changes in ADAS-J cog scores from baseline progressively worsened at 24, 48, and 72 weeks in the placebo group, whereas they remained unchanged in the LIPUS group. The difference in ADAS-J cog scores at 72 weeks between the 2 groups, which is the primary efficacy endpoint, did not reach a statistically significant level (P=0.257) due to a small number of patients. A number of 40∼50 patients in each group would reach a statistically significant level. Importantly, the prevalence of responders with improvement or no worsening from baseline to 72 weeks was 50% (5/10) in the LIPUS group but 0% (0/5) in the placebo group. The prevalence of responders progressively increased only in the LIPUS group. There were no significant differences in other parameters between the 2 groups. Conclusion: These results suggest that the LIPUS therapy could suppress the progression of cognitive impairment in patients with AD. The present findings need to be confirmed in a next pivotal trial with a large number of patients. (Ref.) Eguchi K, et al. Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia -Crucial roles of endothelial nitric oxide synthase- Brain Stim 2018;11:959–973.
P26- CYP46A1 ACTIVATION BY LOW-DOSE EFAVIRENZ ENHANCES BRAIN CHOLESTEROL METABOLISM IN SUBJECTS WITH MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE. A. Lerner1,2, S. Arnold3, E. Maxfield4, A. Koenig3, M. Toth1, B. Fortin3, B. Trombetta3, A. Pieper5,6,7,8, C. Tatsuoka9, I. Pikuleva4(1. Brain Health And Memory Center, Neurological Institute, University Hospitals Cleveland Medical Center — Cleveland (United States), 2. Department of Neurology, Case Western Reserve University — Cleveland (United States), 3. Alzheimer’s Clinical And Translational Research Unit, Massachusetts General Hospital — Boston (United States), 4. Department Of Ophthalmology And Visual Sciences, Case Western Reserve University — Cleveland (United States), 5. Harrington Discovery Institute, University Hospitals Cleveland Medical Center — Cleveland (United States), 6. Department Of Psychiatry, Case Western Reserve University — Cleveland (United States), 7. Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center — Cleveland (United States), 8. Institute For Transformative Molecular Medicine, Case Western Reserve University — Cleveland (United States), 9. Department Of Population And Quantitative Health Sciences, Case Western Reserve University — Cleveland (United States))
Background: Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Objectives: We sought to determine whether CYP46A1 could be activated by a low-dose efavirenz in human subjects. Methods: This pilot study (Clinical Trials. gov NCT03706885) enrolled 5 subjects with mild cognitive impairment due to AD. Participants were randomized to placebo (n=1) or two daily efavirenz doses (50 mg and 200 mg, n=2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain statistical significance of CYP46A1 engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results: In all subjects receiving efavirenz, there was a statistically significant increase (P < 0.001) in the levels of plasma 24HC. The levels of 24HC in the CSF of subjects on the 200 mg-dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions: Our findings provide evidence of efavirenz target (CYP46A1) engagement in human subjects with AD. This supports pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug effects on AD biomarkers and clinical symptomatology.
P27- A PHASE 2 STUDY OF THE SIGMA-2 LIGAND CT1812 IN PARTICIPANTS WITH DEMENTIA WITH LEWY BODIES. J. Galvin1, M. Tolea1, M. Grundman2, M. Hamby3, A. Caggiano4(1. Comprehensive Center for Brain Health, Department of Neurology, University of Miami Miller School of Medicine — Boca Raton, Fl (United States), 2. Grnd Partners — San Diego, Ca (United States), 3. Cognition Therapeutics — Pittsburgh, Pa (United States), 4Cognition Therapeutics — Purchase, Ny (United States))
Background: CT1812 is an experimental orally delivered, brain penetrant, small molecule therapeutic in clinical development by Cognition Therapeutics for treatment of dementias related to both alpha-synuclein and beta-amyloid oligomers. CT1812 selectively binds the sigma-2 receptor, displaces toxic oligomers, and has been shown in non-clinical studies to normalize disrupted cellular processes, protect neurons, and restore cognitive function in transgenic animals. CT1812 is currently in clinical trials for Alzheimer’s dementia (AD). In addition to the trial described here, the pharmacokinetics, safety and tolerability of CT1812 have been explored in multiple studies in healthy volunteers and individuals with AD. CT1812 has been generally well tolerated with headache and nausea as the most frequent adverse events (AEs). No serious AEs have been related to CT1812 use. CT1812 has been associated with transient and mild elevations in liver enzymes without concurrent changes in bilirubin or other signs of liver injury. Objectives: This will be the first study of CT1812 in patients with dementia with Lewy bodies (DLB) and is designed to explore safety and tolerability, cognitive function, and exploratory biomarkers of target engagement and disease modification. Methods: This is a parallel group, randomized, double-blind, placebo-controlled study (COG1201; NCT05225415) of up to 120 subjects with mild-to-moderate DLB as defined by the 4th report of the DLB Consortium. After consenting and meeting study criteria, subjects are randomized 1:1:1 to receive once-daily oral doses of 300 mg CT1812, 100 mg CT1812, or placebo for six months. Patients will be followed during the trial using the Montreal Cognitive Assessment, Cognitive Drug Research Battery, Alzheimer’s Disease Cooperative Study — Activities of Daily Living scale, Neuropsychiatric Inventory, Alzheimer’s Disease Cooperative Study — Clinical Global Impression of Change, Unified Parkinson’s Disease Rating Scale Part III, Clinician Assessment of Fluctuation, Epworth Sleepiness Scale and other standard measures. Cerebrospinal fluid and plasma will be acquired before and after the six-month treatment regimen to assess biomarkers via unbiased proteomics and standard ELISA. Results: This study is being conducted at academic and clinical research centers throughout the United States including many of the Lewy Body Dementia Association Research Centers of Excellence. This study recently opened for enrollment, remains blinded and top-line results are anticipated in 2024. Conclusion: CT1812 may provide a novel approach to the treatment of DLB. This phase 2 proof-of-concept study is being conducted by collaborating academic and industry organizations and is supported by the National Institute of Aging (R01AG071643). When completed, this study will provide key data on whether CT1812’s blockade of alpha-synuclein and beta-amyloid oligomer toxicities via sigma-2 receptor modulation impacts clinical endpoints in people who have DLB. This study will also provide data on DLB-related proteins and disease pathways that may be affected by CT1812. CT1812 is an experimental therapeutic that is currently not approved for any indication. Author conflicts of interest: Anthony Caggiano and Mary Hamby are employees and shareholders of Cognition Therapeutics which is the sole owner of CT1812. Michael Grundman is a consultant to Cognition Therapeutics. James Galvin is supported by grants from NIH: R01AG071514, R01AG071514S1, R01AG069765, R01NS101483, R01NS101483S1, R01AG057681, R01AG071643, P30AG059295, P01AG066584, and serves on Advisory Board for Alpha-Cognition, Biogen, Cognivue and Eisai. Magdalena Tolea has no conflicts to report.
P28- ALZLIGHT PILOT: PRELIMINARY REPORT ON SAFETY AND FEASIBILITY FROM A RANDOMIZED CONTROLLED TRIAL OF LIGHT-BASED BRAIN STIMULATION WITH 40 HZ INVISIBLE SPECTRAL FLICKERING LIGHT IN PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE. M. Agger1,2, M. Carstensen3, M. Horning1,2, E. Danielsen4, A. Baandrup4, M. Nguyen5, M. Henney5, C.R.B. Jensen5, K. Madsen6,7, T.W. Kjær1,2, K. Miskowiak8,9, P.M. Petersen3, P. Høgh1,2(1. Department of Neurology, Zealand University Hospital — Roskilde (Denmark), 2. Department of Clinical Medicine, University of Copenhagen — Copenhagen (Denmark), 3. Dept. of Electrical and Photonics Engineering, Technical University of Denmark — Kgs. Lyngby (Denmark), 4. Department of Radiology, Zealand University Hospital — Roskilde (Denmark), 5. OptoCeutics ApS — Copenhagen (Denmark), 6. Dept. of Applied Mathematics and Computer Science, Technical University of Denmark — Copenhagen (Denmark), 7. Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital — Amager and Hvidovre — Copenhagen (Denmark), 8. Neurocognition and Emotion in Affective Disorders (NEAD) Group, Copenhagen Affective Disorder research Centre (CADIC), Psychiatric Centre Copenhagen — Copenhagen (Denmark), 9. Department of Psychology, University of Copenhagen — Copenhagen (Denmark))
Background: There is no available disease modifying treatment for Alzheimer’s disease (AD), except for limited US approval of Aducanumab which targets amyloid-β (1). The European Medical Agency (EMA) did not grant similar approval citing safety concerns and lack of evidence (2). Thus, novel treatment options are still needed. This study does this by a novel approach based on targeting neural networks through non-invasive light temporally modulated at 40 Hz using Invisible Spectral Flicker (ISF)(3,4). Induction of 40 Hz neural activity is shown to reduce the load of amyloid-β and tau as well as increase the visuo-spatial memory in transgenic mice (5). Although Human trials studying induction of 40 Hz neural activity are still limited and in a small scale, early indications points towards potential benefit (6). Both the studies in mice and humans have been conducted with the use of stroboscopic light, which may be associated with some amount of discomfort and therefore, may result in decreased adherence and compliance during clinical trials and real-world applications. As it has been suggested that the treatment should consist of 1-hour daily exposure there is a need for an easy-to-use and comfortable solution which may lead to increased adherence. Objectives: To investigate the feasibility and safety of a Light Therapy System (LTS) (EVY LIGHT, Optoceutics ApS, Copenhagen, Denmark) for induction of 40 Hz neural activity in future Phase 2/3 randomized controlled trials. The LTS used in this study is an easy-to-use device designed for use in the home of persons with AD. Methods: The ALZLIGHT S1 and S2 clinical trials are randomized, double-blinded, placebo-controlled, parallel-group, single-centre, pilot trials. They have been approved by the local scientific ethics committee of region Zealand (SJ-806) and the Danish Medicines Agency (CIV-19-12-031124). The trial was monitored by an external monitoring committee (The Good Clinical Practice Unit at Frederiksberg Hospitals). ClinicalTrials.gov Identifier: NCT04574921. ALZLIGHT S1 aimed for 4 healthy participants, age matched to patients with AD for 7 days of intervention. ALZLIGHT S2 aimed for recruitment of 10 patients with mild to moderate AD for 6 weeks of intervention followed by 6 weeks of no intervention. Both ALZLIGHT S1 and S2 used 1:1 allocation to active treatment of placebo. Both active treatment and placebo treatment was delivered by an identical LTS device set to either active setting or placebo setting. The active treatment consisted of 40 Hz ISF and the placebo setting consisted of color and intensity matched non-flickering white light, thus rendering the placebo mostly indistinguishable from the active providing good blinding of both subjects, caregivers, and study personnel. Results: ALZLIGHT S1 screened 10 potential participants before inclusion of 5 participants with 1 drop-out, due to events in their personal life. ALZLIGHT S2 screened 35 patients with mild to moderate AD of which 11 were included. No serious adverse events were observed, and all events were categorized as mild. Three events were evaluated to have a possible or probable relation to the intervention. The probable related event were troubles falling asleep related to improper use of device late in the evening. The two events with possible relation to the intervention were eyestrain and tiredness. Adherence to the intervention were measured by percentages of days with device turned on of the total number of days (i.e., 42 days ± 7 days depending on exact delivery of device and day of follow-up). In the healthy participants in ALZLIGHT S1 the adherence was 89.8 % (active treatment: 86.1 %, placebo treatment: 95.4 %). In the patients with mild to moderate AD the adherence was 94 % (Active treatment: 97.9 % placebo treatment: 90.1 %). Conclusion: These preliminary findings demonstrated that 40 Hz stimulation with ISF seems to be safe to use with a considerably high feasibility in terms of user adherence. Thus, the findings motivate the transition to comprehensive Phase 2/3 randomized controlled trials for evaluation of efficacy in mild-to-moderate Alzheimer’s disease. References: 1) Dunn B et al 2021. 10.1001/jamainternmed.2021.4607 2) Mahase E et al 2021. 10.1136/bmj.n3127 3)Carstensen MS et al 2020. 10.1117/12.2544338 4) Agger MP et al 2022, 10.3233/JAD-220081 5) Adaikkan C et al 2020. 10.3233/JAD-220081 6) Chan D et al 2021 10.1101/2021.03.01.21252717. Conflict of Interest: MPA and MH have received direct, or indirect funding from Optoceutics ApS through management of collaborative grants. MSC, MN, MAH, and CRBJ are employees at Optoceutics ApS. MSC, MN, ERD, and PMP has partial ownership of Optoceutics ApS. AO, KHM, TWK, KM and PH have no conflicts of interest.
P29- CHARACTERIZATION OF AMYLOID-BETA PROTOFIBRILS IN ALZHEIMER’S DISEASE BRAIN AND THE UNIQUE BINDING PROPERTIES OF LECANEMAB. L. Lannfelt1, L. Söderberg1, M. Johannesson1, N. Fritz1, E. Gkanatsiou1, A. Rachalski1, H. Kylefjord1, G. Osswald1, C. Möller1(1. BioArctic AB — Stockholm (Sweden))
Background: Immunotherapy against amyloid-beta (Aβ) has emerged as a promising treatment option for Alzheimer’s disease (AD). Although many challenges remain, Aβ immunotherapy from late-phase clinical trials have shown promising results. Soluble Aβ aggregates, oligomers and protofibrils, are believed to be the most toxic species of Aβ. Lecanemab is a humanized IgG1 monoclonal antibody, selectively targeting Aβ protofibrils. In a Phase 2b clinical trial in early AD subjects, lecanemab demonstrated potential disease-modifying effects on both clinical endpoints and clearance of Aβ plaques in the brain, with an incidence of the side-effect ARIA-E (amyloid related imaging abnormalities-edema) of approximately 10% at the highest dose. Objectives: We have characterized the main target for lecanemab, i.e. Aβ protofibrils, in AD brain, describing the content of Aβ, as well as levels and size of Aβ protofibrils, in relation to the APOE genotype. The binding of lecanemab to Aβ protofibrils and the mechanism of action in clearance of Aβ was studied. Methods: Soluble species of Aβ were extracted from post-mortem human AD brain tissue (n=24) and non-demented controls (NDE, n=12), and characterized regarding AD pathologies and APOE status using tissue from the Netherlands brain bank. Aβ protofibril levels were measured by immunoprecipitation (IP) using the protofibril selective antibody mAb158, the murine precursor to lecanemab. Size exclusion chromatography (SEC) and density gradient ultra-centrifugation were used to characterize protofibrils and to evaluate lecanemab’s binding profile. The specificity of lecanemab in binding to synthetic Aβ protofibrils was evaluated by IP in the presence of a 1000-fold excess of Aβ monomers. The lecanemab-mediated uptake of synthetic Aβ protofibrils was also studied in a human monocytic THP-1 cell model. The clearance of Aβ plaques in human AD brain section, mediated by lecanemab, was investigated. Results: Aβ protofibril levels in AD brain (mean 168 ng/g tissue) were shown to be statistically significantly elevated compared to levels in non-demented control brain (mean 1.5 ng/g tissue). AD subjects, especially APOE E4 carriers, had the highest protofibril levels. Protofibrils were shown to be predominantly composed of Aβ42, with approximately 40 times higher levels of Aβ42 compared to Aβ40. SEC and density gradient ultracentrifugation showed that protofibrils extracted from AD brain were heterogenous in size, between 80 to >500 kDa, and lecanemab was shown to bind similarly to protofibrils of all sizes. Dose-dependent lecanemab-mediated phagocytosis of protofibrils in THP-1 cells (EC50 3 nM) was demonstrated as well as dose-dependent clearance of Aβ plaques in human brain sections. Lecanemab’s binding to protofibrils remained strong and was not affected by a 1000-fold excess of Aβ monomers, further supporting the unique selectivity of the antibody. Conclusion: Soluble aggregated Aβ species, i.e. toxic protofibrils, are significantly elevated in AD brains, especially in ApoE4 carriers when compared to non-demented controls. Lecanemab has a unique binding profile with a high selectivity for protofibrils and has been shown to effectively clear Aβ protofibrils and amyloid plaqu
P30- AD101 — THE CLINICAL PROFILE OF A NEW, FIRST-IN-CLASS TREATMENT FOR ALZHEIMER’S DISEASE. J. Burmeister1, S. Gauthier2, S. Rogers1(1. AmyriAD Pharma, Inc. — Los Angeles (United States), 2. McGill University — Montréal (Canada))
Background: AD101 is a new small molecule agent ready for Phase 3 clinical trials as a treatment to improve the core symptoms of Alzheimer’s Disease (AD). AD101 is a modulator of low-voltage-gated T-type calcium channels. In animal studies it produced improvement in a variety of learning and memory models, including models both dependent and independent of beta amyloid and tau for the creation of learning and memory deficits. These effects were concurrent with increases in basal release of acetylcholine. The data suggested AD101 would be a promising agent for improving the core symptoms of AD, particularly in those already receiving stable cholinesterase inhibitor therapy where basal ACh is protected from degradation. Objectives: To characterize the pharmacokinetics, tolerability, and potential for efficacy of AD101. Methods: AD101 was investigated in a series of randomized, double-blind and placebo-controlled Phase 1 clinical pharmacology and Phase 2 preliminary efficacy studies, along with one open-label extended safety study. Primary outcomes across all studies were safety and tolerability. Pharmacokinetics and QTc interval duration were characterized in Phase 1 and effects of AD101 on global function and cognition were examined in Phase 2, using the ADCS-CGIC and the ADAS-cog 11 as efficacy variables. Results: A total of 446 subjects have received AD101 in clinical studies. Of them, 365 subjects with AD have been exposed to AD101 at doses up to 180 mg once daily (QD) for a total duration of up to 6 months. AD101 generally has been well tolerated without identification of clinical risks or safety signals of potential clinical concern that were considered related to its administration to healthy adult volunteers and to patients with AD. In single- and multiple- dose Phase 1 studies of 10 through 180 mg, pharmacokinetic parameters were proportional across the dose range. Time to tmax averaged 1 hour and mean half-life was 13 hours. At all dose levels, AD101 exhibited linearity in its PK over time and steady-state conditions were obtained by Study Day 5. There were no dose-limiting adverse events and detailed QTc analysis demonstrated no impact of AD101 on QT, QTcF, or QTcB intervals across treatment groups, plasma drug concentrations or in association with the duration of exposure to AD101. The primary Phase 2 study examined safety and the potential for efficacy of 10, 60 or 120 mg of AD101 vs. placebo as an add-on therapy for AD patients who were on a stable 10 mg dose of donepezil for at least 90 days prior to screening (n=∼50/group, 210 total). In this 12-week proof-of-concept study, pooled analysis of scores 1–3 on the ADCS-CGIC demonstrated twice as many patients were considered to be clinically improved 12 weeks after the addition of AD101 to their treatment regimen (p = 0.0294 Per Protocol population). This occurred in conjunction with improvement on ADAS-cog that was statistically significant at 12 weeks after treatment initiation (p = 0.0434, Per Protocol analysis). Across both Phase 2 studies and the open-label extended safety study, the most commonly reported adverse events were urinary tract infections (8.4% AD101 vs 6.5% placebo), falls (6.2% AD101 vs 4.3% placebo) and dizziness (5.9% AD101 vs 8.6% placebo) There were no abnormalities in clinical laboratory values or shifts in values related to any dose of AD101. There were no clinically significant treatment-emergent arrhythmias and interval duration analyses demonstrated no changes in QTcB or QTcF related to any study treatment. The double-blind Phase 2 studies reported a total of 26 serious adverse events (SAEs) within the approximately 378 patients (n=284 AD101 and n= 94 placebo) enrolled. The number of subjects with SAEs per treatment group were: 6 — Placebo, 4 – 10 mg, 1 – 30 mg, 7 – 60 mg, 3 – 90 mg, 1 – 120 mg and 3 – 180 mg. Only 1 of the events was assessed as possibly related to study drug. This was a woman with aphasia/seizure in the 90 mg dose group. Conclusion: AD101 represents a new first-in-class treatment for improvement of global function and cognition when added on to donepezil, the current standard of care for AD. Deficiencies in function drive the cost of care in AD and these data from controlled clinical trials suggest AD101 could be an important addition to patient management. The overall safety profile is favorable for dosages up to 180 mg daily.
P31- IMPACT OF PIMAVANSERIN ON COGNITIVE MEASURES IN PATIENTS WITH NEUROPSYCHIATRIC MANIFESTATIONS OF ALZHEIMER’S DISEASE: RESULTS FROM 3 PLACEBO-CONTROLLED CLINICAL STUDIES. C. Ballard1, V. Abler2, S. Pathak1, P. Tariot1, B. Coate2, A. Berrio2, J.M. Youakim2, S. Stankovic2(1. Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania — Philadelphia (United States), 2. ACADIA Pharmaceuticals Inc. — Princeton (United States))
Background: Neuropsychiatric symptoms associated with Alzheimer’s disease (AD), including psychosis, are common among patients with dementia and are associated with poorer clinical outcomes. There are no therapies approved by the Food and Drug Administration to treat dementia-related psychosis. Off-label use of atypical antipsychotics is common but is associated with significant adverse outcomes, including acceleration of cognitive decline. Pimavanserin is a selective 5-HT2A receptor inverse agonist/antagonist approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis and is being studied in AD psychosis. In earlier studies, unlike atypical antipsychotics, pimavanserin did not have a negative impact on cognitive function and the incidence and types of adverse events were comparable with pimavanserin versus placebo. Objectives: Evaluate the impact of pimavanserin treatment on cognitive measures in patients with neuropsychiatric manifestations of Alzheimer’s disease pooled from 3 clinical studies. Methods: Cognitive function (as measured by Mini-Mental State Examination [MMSE]) was a pre-specified safety outcome evaluated in 3 double-blind (DB), placebo-controlled, parallel design studies with pimavanserin (34 mg) treatment to assess the effects on cognition in a pool of elderly subjects with Alzheimer’s disease. A meta-analysis of the treatment difference comparing pimavanserin to placebo in the change from Baseline in MMSE from mixed-effect model repeated measures (MMRM) analysis for Studies 019, 032, and 046 were performed using the DerSimonian and Laird random effects model. Treatment-emergent adverse events (TEAEs) associated with cognition were examined across studies using a Standardized Medical Dictionary for Regulatory Activities Query based on the High-Level Group Term “Cognitive and attention disorders and disturbances,” plus one other relevant Preferred Term (“confusional state”), for a total of 14 terms. Whole-population mean changes in MMSE observed cases over time and outlier analyses of individual patient-level data were also evaluated. Study 019 (NCT02035553) was a phase 2 study in patients with Alzheimer’s disease (AD) psychosis living in care homes randomized to receive pimavanserin 34 mg or placebo for 12 weeks. Patients with MMSE scores ≥1 and ≤22 were eligible. Results on Day 85 from a MMRM (observed cases) fit to the Safety Analysis Set were used for meta-analysis. Study 032 (NCT02992132) was a DB, placebo-controlled phase 2 study evaluating the safety and efficacy of pimavanserin (20 mg and 34 mg) for the treatment of agitation and aggression in AD. Patients with MMSE scores ≥5 and ≤26 were eligible. Results at Week 12 from a MMRM (observed cases) fit to the Full Analysis Set (MMSE was an exploratory efficacy endpoint in Study 032) were used for meta-analysis. Study 046 (NCT03575052) is an ongoing DB phase 3b study of the safety of pimavanserin (34 mg) for up to 8 weeks in patients with NPS related to neurodegenerative disease. Patients with MMSE scores ≥6 were eligible. Results at Week 8 from an MMRM (observed cases) fit to the Safety Analysis Set were used for meta-analysis. Results: Data from an integrated analysis of these studies showed no decline in cognitive function, as measured by MMSE score with pimavanserin treatment compared with placebo. Mean baseline (standard error [SE]) MMSE scores were similar for pimavanserin (14.7 [0.35]; n=292 and placebo (14.8 [0.37]; n=276). The pooled difference in MMRM least-squares (LS) mean (SE) was not significantly different for pimavanserin versus placebo (difference in LS means [SE]: 0.29 [0.325]; 95% CI of Difference [-0.34, 0.93]). Of the terms queried, only confusional state (reported in 6 [2.1%] pimavanserin and 2 [0.7%] placebo patients) was reported as a TEAE. Conclusions: Evidence from 3 randomized, placebo-controlled clinical studies of patients with Alzheimer’s disease treated with pimavanserin show that mean changes in MMSE scores were small and similar to placebo. Cognition-related TEAEs were reported infrequently. These results demonstrate that treatment with pimavanserin did not have a negative impact on cognitive function with up to 12 weeks of treatment. Disclosures: CB: received grants and personal fees from ACADIA and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline, and Pfizer. VA, SP, PT, BC, AB, JY, SS: employees of ACADIA Pharmaceuticals Inc (San Diego, CA, USA).
P32- IMPACT OF PIMAVANSERIN TREATMENT ON MOTOR FUNCTION IN PATIENTS WITH NEUROPSYCHIATRIC MANIFESTATIONS OF ALZHEIMER’S DISEASE: RESULTS FROM 3 CLINICAL STUDIES. D. Weintraub1, V. Abler2, C. Ballard1, B. Coate2, A. Berrio2, S. Pathak2, J.M. Youakim2, S. Stankovic2(1. Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania — Philadelphia (United States), 2. ACADIA Pharmaceuticals Inc. — Princeton (United States))
Background: Patients with dementia, including Alzheimer’s disease (AD), commonly experience hallucinations and delusions, called dementia-related psychosis (DRP). There are no therapies approved by the Food and Drug Administration to treat DRP. Commonly used off-label antipsychotics have substantial safety concerns, including worsening motor function, and extrapyramidal symptoms (EPS) specifically, perhaps primarily due to brain dopamine receptor antagonism. Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist without appreciable affinity for dopamine receptors in vitro and is currently approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). In clinical studies of patients with PDP, pimavanserin did not show an impact on motor function, suggesting it might be well-tolerated and is being studied in AD psychosis. Objectives: Evaluate changes in motor function during pimavanserin treatment in patients with neuropsychiatric manifestations of AD pooled from 3 double-blind, placebo-controlled, randomized controlled trials (RCT). Methods: Motor function was evaluated in a subset of patients with neuropsychiatric manifestations of Alzheimer’s disease (AD) from 3 independent studies. Logistic regression analysis was performed to obtain the odds ratios comparing pimavanserin to placebo in the incidence of extrapyramidal symptoms (EPS) performed on the 3 pooled studies. The logistic regression model included the binary outcome of EPS event (Yes, No) with treatment group as a factor. Treatment-emergent adverse events (TEAEs) related to motor function were examined across studies using a Standardized Medical Dictionary for Regulatory Activities Query for Extrapyramidal syndrome. Motor function was directly measured using validated scales. Study 019 (NCT02035553) was a phase 2 RCT study in patients with AD psychosis living in care homes randomized to receive pimavanserin 34 mg or placebo for 12 weeks. Study 032 (NCT02992132) was a phase 2 RCT study evaluating the safety and efficacy of pimavanserin (20 mg and 34 mg) for the treatment of agitation and aggression in AD. Study 046 (NCT03575052) is a phase 3b study of the safety of pimavanserin (34 mg) for up to 8 weeks in a subgroup of AD patients with neuropsychiatric symptoms related to neurodegenerative disease. Results: Data from the integrated clinical development program in a subset of subjects with AD showed no evidence of a worsening of motor function, as measured by EPS events with 34 mg pimavanserin treatment compared with placebo in these 3 short-term studies. Incidence rates of EPS were similar for pimavanserin (3.4%; 10/292) and placebo (4.3%; 12/282). Moreover, the odds of an EPS event demonstrated no difference in the pimavanserin arm when compared to placebo with an odds ratio (OR, 95% Confidence Interval [CI]) of 0.80 (0.34, 1.88). TEAEs related to motor function included tremor (PBO=3 [1.1%], PIM=3 [1.0%]), mobility decreased (PBO=3 [1.1%], PIM=2 [0.7%]), restlessness (PBO=3 [1.1%], PIM=1 [0.3%]), dyskinesia (PBO=1 [0.4%], PIM=1 [0.3%]), gait disturbance (PBO=0, PIM=2 [0.7%]), muscle rigidity (PBO=0, PIM=2 [0.7%]), parkinsonism (PBO=1 [0.4%], PIM=1 [0.3%]), akathisia (PBO=0, PIM=1 [0.3%]) and musculoskeletal stiffness (PBO=1 [0.4%], PIM=0), none of which were different between pimavanserin and placebo. Conclusions: Decrease in motor function was minimal in pimavanserin-treated patients and similar to placebo across 3 randomized placebo-controlled studies in patients with Alzheimer’s disease. In pimavanserin-treated patients, TEAEs related to motor dysfunction were reported infrequently and at similar rates to placebo. Pimavanserin did not have a negative impact on motor function in this aggregated subset of data in patients with Alzheimer’s disease. Disclosures: DW: received research funding or support from the Michael J. Fox Foundation for Parkinson’s Research, Alzheimer’s Therapeutic Research Initiative (ATRI), Alzheimer’s Disease Cooperative Study (ADCS), the International Parkinson and Movement Disorder Society (IPMDS), and National Institute on Aging (NIA); honoraria for consultancy from ACADIA, CHDI Foundation, Clintrex LLC (Aptinyx, Avanir, Otsuka), Eisai, Janssen, Sage, Signant Health, and Sunovion; and license fee payments from the University of Pennsylvania for the QUIP and QUIP-RS. VA, BC, AB, SP, JMY, and SS: employees of ACADIA Pharmaceuticals Inc. (San Diego, CA, USA). CB: received grants and personal fees from ACADIA and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline, and Pfizer.
P33- INTRAVENOUS TREATMENT WITH BRICHOS MOLECULAR CHAPERONE DESIGNED AGAINST AMYLOID-B TOXICITY IMPROVES FEATURES OF ALZHEIMER DISEASE PATHOLOGY IN MICE. J. Johansson1(1. Karolinska Institutet — Huddinge (Sweden))
Background: Attempts to treat Alzheimer’s disease with immunotherapy against the amyloid-β peptide (Aβ) or with enzyme inhibitors to reduce Aβ production have not yet resulted in an effective treatment, suggesting that alternative strategies may be useful. Recombinant human (rh) BRICHOS can inhibit Aβ42 fibril formation, and it also prevents neurotoxicity of Aβ42, both in hippocampal slice preparations and in a Drosophila melanogaster fly model. The neurotoxicity of Aβ42 is prevented by a unique mechanism: rh BRICHOS efficiently blocks the kinetic step that generates a major part of neurotoxic Aβ42 oligomers and BRICHOS can also rescue already established Aβ42 induced deterioration of hippocampal neural network activity in vitro. Objectives: We aimed to explore the possibility to target the toxicity associated with Aβ aggregation by using a blood brain barrier permeable rh Bri2 BRICHOS chaperone domain, mutated to act selectively against Aβ42 oligomer generation and neurotoxicity in vitro. Methods: We treated Aβ precursor protein (App) knock-in mice with repeated intravenous injections of rh Bri2 BRICHOS R221E, from an age close to the start of development of Alzheimer-like pathology or about four months after Alzheimer-like pathology was already established. Results: Rh Bri2 BRICHOS R221E treatment improved recognition and working memory assessed during novel object recognition and Y-maze tests, and reduced Aβ plaque deposition and activation of astrocytes and microglia. When treatment was started after pathology was established Aβ plaque deposition and gliosis were reduced, and substantially reduced astrocyte accumulation in the vicinity of Aβ plaques was observed. The degrees of treatment effects observed in the App knock-in mouse models correlate with the amounts of Bri2 BRICHOS detected in brain sections after the end of the treatment period. Conclusions: This is the first study showing the effects of intravenous treatment with rh Bri2 BRICHOS R221E in Alzheimer mouse models and the results motivate further work to enable evaluation of BRICHOS treatment in clinical trials of Alzheimer disease.
LP15- COMPUTERIZED COGNITIVE TRAINING RESTORES NEURAL ACTIVITY WITHIN THE COGNITION AND APATHY-RELATED NETWORK IN MILD COGNITIVE IMPAIRMENT. J.M. Kang1, N. Kim2, S.K. Yun3, H.E. Seo4, S. Kim5, S.J. Cho6(1. Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine — Incheon (Korea, Republic of) — Incheon (Korea, Republic of), 2. Department of Biomedical Engineering Research Center, Gachon University, Incheon, Republic of Korea. — Incheon (Korea, Republic of), 3. Department of Nursing, Saekyung University College of Nursing, Yeongwol, Republic of Korea — Yeongwol (Korea, Republic of), 4. Neuroscience Research Institute, Gachon University — Incheon (Korea, Republic of), 5. Department of Psychiatry, Gachon University Gil Medical Center — Incheon (Korea, Republic of), 6. Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine — Incheon (Korea, Republic of))
Background: Computerized cognitive training (CCT) is accepted as a potential therapy for cognitive decline. However, the neural basis of multidomain CCT is unclear. Objective: The aim of this study is to find neural basis of CCT in patients with mild cognitive impairment (MCI) in a randomized controlled trial. Methods: Twenty-seven patients with MCI were recruited and randomized into either CCT group (n=14) or control group (n=13). CCT group were trained by five-domain CCT and control group conducted an educational book reading twice a week for two months. All participants underwent comprehensive neuropsychological function and psychiatric symptom tests and resting-state functional MRI (rsfMRI) at baseline and after training. Group comparisons, pre-post time comparisons, and generalized linear model were used in descriptive data and seed-to-voxel analyses in relative networks were used in MRI data. In all analyses, confounders such as age, sex, years of education, vision state, family history of dementia, alcohol consumption, and mild behavioral impairment scores were adjusted. Results: CCT group showed improvements in memory (p = 0.020), executive function (p = 0.024), positive affect (p = 0.037), and apathy (p = 0.047) after CCT compared to control group. In rsfMRI, functional connectivity was increased in memory-related hippocampal network, executive function-related frontal pole network, and apathy-related insula network. Conclusion: Two months of CCT improved the typical two domains of cognition, memory and executive function, and apathy in MCI patients. CCT also restored the functional connectivity in memory, executive function, and apathy-related networks. These results can add an evidence in neural basis for CCT compared to classical training as well as general cognitive interventions in the prodromal stage of dementia. Future trials with larger sample size, various intervention method, and sophisticated design would find the effect of the CCT. The authors have no conflicts of interest to declare.
LP16- ALZHEIMER’S COGNITIVE DECLINE STOPPED FOR AT LEAST 2% YEARS BY IN-HOME TRANSCRANIAL ELECTROMAGNETIC TREATMENT. G. Arendash1, H. Abulaban2,3, S. Steen2, R. Andel4, Y. Wang5,6, Y. Bai5, R. Baranowski7, X. Lin5,8, N. Shen9, A. Aljassabi5,6, Y. Li5, C. Cao5,6(1. NeuroEM Therapeutics, Inc. — Phoenix (United States), 2. Axiom Clinical Research of Florida — Tampa (United States), 3. University of South Florida/Byrd Alzheimer’s Institute — Tampa (United States), 4. Edson College of Nursing and Health Innovation, Arizona State University — Phoenix (United States), 5. MegaNano Biotech — Tampa (United States), 6. Taneja College of Pharmacy, University of South Florida — Tampa (United States), 7. Left Coast Engineering — Escondido (United States), 8. Taneja College of Pharmacy, University of South Florida — Tampa (United States), 9. School of Arts and Sciences, University of South Florida — Tampa (United States))
Background: Up until recently, there were no published papers showing that any therapeutic intervention can stop/stabilize or reverse the progressive cognitive decline of Alzheimer’s Disease (AD) — especially over an extended period of time. However, publication of our 2019 (1) and 2022 (2) clinical papers involving a new bioengineering-based technology against AD called Transcranial Electromagnetic Treatment (TEMT) may be changing that. Our pre-clinical studies consistently showed that TEMT protects against or reverses cognitive impairment in AD transgenic mice and affect AD markers. To translate these AD mouse findings to human AD subjects, NeuroEM developed a self-contained device called the “MemorEM”, which allows near-complete mobility while providing in-home 1-hour sessions once or twice daily, as administered by their caregivers. Through eight highly-specialized emitters embedded between an inner and outer head cap connected to a small EMF generator and battery worn on the arm, the MemorEM device provides TEMT that easily penetrates the human bony cranium to provide electromagnetic waves in the RF range to all neurons in the entire human forebrain. Our initial clinical study (1) showed that 2 months of daily TEMT to eight mild/moderate AD subjects reversed their cognitive impairment in several tasks, including ADAS-cog13 and Rey AVLT. Moreover, fMRI after these 2 months of daily treatment revealed enhanced functional connectivity in the cingulate cortex of all subjects, FDG-PET scans showed enhanced energy utilization in some subjects, and CSF/blood AD markers in all subjects collectively were affected. OBJECTIVES: The present study extends this initial study by providing TEMT through 31 months from the initial study’s baseline in five of the original mild/moderate AD subjects. Results from our just-published paper (2) and new up-dated analyses from that study will be presented. METHODS: Mild/moderate AD subjects were all given daily TEMT over a total of 31 months, with breaks between 2–10 months and between 14–19 months during this period (18 months of daily TEMT total). At multiple time points during the 2%-year treatment period, cognitive/functional assessments were performed, blood/CSF collected, and MRI scans performed. Safety was continually monitored. RESULTS: TEMT administration was completely safe over the 2½-year period, with no deleterious side effects. Six cognitive/functional tasks (including ADAS-cog13, Rey AVLT, MMSE, and ADL) were analyzed separately or collectively using a multivariate mixed-effects model. For all tasks, separately or collectively, no significant decline in any cognitive measure occurred over the 2½-year treatment period. As well, caregiver assessment of the GDS stage of cognitive decline indicated no decline of treated AD subjects to a worse stage of cognitive functioning throughout the entire 2½ years of TEMT. Qualitative assessment of anatomic MRI imaging at 19 and/or 31 months from baseline commonly indicated no progression of cerebral atrophy, particularly in the hippocampus/temporal lobe. Long-term TEMT induced substantial reductions in both CSF and plasma levels of C-reactive protein, which is consistent with the “rebalancing” of both brain and peripheral (blood) cytokines by TEMT that we have recently reported in AD subjects (3). Long-term reductions in CSF levels of p-tau217, Aβ1–40, and Aβ1–42 were also observed, while a modulation of CSF oligomeric Aβ levels was present. In plasma, long-term TEMT modulated/rebalanced levels of both p-tau217 and total tau. CONCLUSION: Although only a limited number of AD patients were involved in this long-term study and no placebo group was included, the results suggest that TEMT can stop the cognitive decline of AD over a period of at least 2½ years, and do so with no safety issues. This stoppage of AD cognitive decline appears to be due to the multi-mechanistic actions of TEMT that include: 1) disaggregation of both Aβ and p-tau oligomers, 2) enhancement of intraneuronal mitochondrial function, and 3) a “rebalancing” of the immune system in both brain and peripherally. A placebo-controlled, double-blinded Phase IIb/III clinical trial is currently being initiated. References: 1. Arendash G, Cao C, Abulaban H, Baranowski R, Wisniewski G, Becerra L, Andel R, Lin X, Zhang X, Wittwer D, Moulton J, Arrington J, Smith A. A Clinical Trial of Transcranial Electromagnetic Treatment in Alzheimer’s Disease: Cognitive Enhancement and Associated Changes in Cerebrospinal Fluid, Blood, and Brain Imaging. J Alzheimers Dis. 2019;71(1):57–82. doi: 10.3233/JAD-190367.2. Arendash G, Abulaban H, Steen S, Andel R, Wang Y, Bai Y, Baranowski R, McGarity J, Scritsmier L, Lin X, Shen N, Aljassabi A, Li Y, Cao C. Transcranial Electromagnetic Treatment Stops Alzheimer’s Disease Cognitive Decline over a 2½-Year Period: A Pilot Study. Medicines (Basel). 2022 Aug 3;9(8):42. doi: 10.3390/medicines9080042.PMID: 36005647. 3. Cao C, Abulaban H, Baranowski R, Wang Y, Bai Y, Lin X, Shen N, Zhang X, Arendash GW. Transcranial Electromagnetic Treatment «Rebalances» Blood and Brain Cytokine Levels in Alzheimer’s Patients: A New Mechanism for Reversal of Their Cognitive Impairment. Front Aging Neurosci. 2022 May 2;14:829049. doi: 10.3389/fnagi.2022.829049. eCollection 2022.PMID: 35585867.
LP17- FIRST-IN-HUMAN CLINICAL TRIAL OF IBC-AB002, A PROPRIETARY HUMAN ANTI-PD-L1 ANTIBODY, IN PERSONS WITH EARLY ALZHEIMER’S DISEASE: TRIAL DESIGN AND OBJECTIVES. J. Cedarbaum1, P. Scheltens2, C. Mummery3, C. David4, D. Bracha4, E. Yoles4, K. Baruch4, M. Schwartz5(1. Immunobrain Checkpoint — Woodbridge, Ct (United States), 2. Amsterdam UMC, Alzheimer Center — Amsterdam (Netherlands), 3. Dementia Research Centre, Institute of Neurology, University College London — London (United Kingdom), 4. Immunobrain Checkpoint — Nes Ziona (Israel), 5. Weizmann Institute — Rehovot (Israel))
Background: The difficulty in finding an effective disease-modifying therapy for Alzheimer’s disease (AD) highlights the need for a renewed look at the mechanisms that drive pathophysiology. Aging is the greatest risk factor for AD, and it is associated with senescence/exhaustion of the adaptive immune system as well as chronic brain inflammation. The roles of the immune system in brain maintenance and repair have been increasingly recognized over the last two decades. Activity of the peripheral immune system outside the brain can impact progression of these processes and mitigate brain pathology. Inhibitory immune checkpoints maintain the immune system under tight control, preventing overreaction that may lead to autoimmune diseases. Immune checkpoint activity also contributes to immune exhaustion, which may restrict ability to cope with disease pathology. Well-controlled, intermittent blockade of the PD-1/PD-L1 immune checkpoint pathway is a potential means of releasing “brakes” from the peripheral immune system, thereby augmenting the body’s natural defenses against neurodegeneration. Anti-PD-L1 antibody treatment reduced brain levels of aggregated proteins, modulated neuroinflammation and improved cognitive performance in five transgenic Ab and tau models. IBC-Ab002 is a proprietary anti-PD-L1 antibody engineered to treat AD, with a reduced potential to generate autoimmune adverse effects (Baruch et al., 2020). Objectives: Here we describe the design of the First-in-Human (FIH) clinical trial of IBC-Ab002 in persons with Early AD (EAD) and the rationale and preclinical data underlying this novel therapeutic approach. Methods: This combined Single and Multiple-Ascending Dose study will enroll approximately 40 participants with AD-like CSF profiles in Clinical Stages 3 and 4, at 12 sites in Israel, Netherlands and the UK. The primary objective will be to assess safety and tolerability of IBC-Ab002 in this population. Secondary objectives include description of pharmacokinetics and detection of anti-drug antibodies. Exploratory Objectives are demonstration of target engagement and pharmacodynamics in blood assessed by measuring Receptor Occupancy on peripheral T cells, levels of soluble PD-L1 and changes in immune cell populations. Effects on disease biology will be assessed using plasma and CSF fluid biomarkers and resting-state EEG. Clinical outcomes include the Amsterdam Cognitive-Functional Composite (CFC), CDR-SB, and NPI. Results: The study is planned to start in Q4 of 2022. Conclusion: Immune checkpoint blockade via inhibition of the PD-1/PD-L1 pathway is a novel and promising potential approach for modulating the adaptive immune system to treat AD, and perhaps other neurodegenerative conditions as well.
LP19- PEPINEMAB, A SEMA4D BLOCKING ANTIBODY, IS A NOVEL POTENTIAL TREATMENT FOR NEURODEGENERATIVE DISEASE: CLINICAL PROOF OF CONCEPT IN PHASE 2 HD STUDY SUPPORTS CLINICAL DEVELOPMENT IN AN ONGOING PHASE 1/2 AD STUDY. T. Fisher1, E. Evans1, M. Boise1, V. Mishra1, C. Mallow1, E. Smith1, J. Leonard1, A. Feigin2, E. Siemers3, E. Sheldon4, R. Turner5, M. Farlow6, A. Porteinsson7, W. Bond8, M. Zauderer1(1. Vaccinex, Inc. — Rochester (United States), 2. NY Langone Health, and for HSG and SIGNAL-HD PIs and coordinators — New York (United States), 3. Siemers Integration LLC — Zionsville (United States), 4. JEM Research Institute — Atlantis (United States), 5. Re-cognition Health — Fairfax (United States), 6. Indiana University — Indianapolis (United States), 7. University of Rochester — Rochester (United States), 8. Neuropsychiatric Research Center of Southwest Florida — Fort Myers (United States))
Background: Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons during Huntington’s Disease (HD) and Alzheimer’s Disease (AD) progression and triggers astrocytes that express plexin-B1/B2 receptor to undergo reactive gliosis with concomitant loss of normal astrocyte functions1. Drivers of glial cell activation represent novel targets to modify progression of neurodegenerative pathology. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in the SIGNAL-HD (NCT02481674) Phase 2 trial2 as well as in preclinical models of HD and AD. These studies provided clinical rationale for the ongoing Phase 1/2 SIGNAL-AD study (NCT04381468). Objectives: Present the updated safety, efficacy, and biomarker data from the completed SIGNAL-HD trial2. In addition, describe how neuroimaging and subgroup analysis of the clinical HD results provide further rationale for investigation in AD, and present the trial design, enrollment status, and updated blinded safety data for the Phase 1b/2a double-blind, randomized, placebo-controlled SIGNAL-AD trial. Methods: The SIGNAL-HD phase 2 study included 301 subjects with late prodromal (LP) and early manifest (EM) HD. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD-CAB). Imaging endpoints included structural MRI to assess brain atrophy and FDG-PET to assess brain metabolism. The SIGNAL-AD study is in progress and is planned to enroll up to 40 subjects with early AD treated for approximately 1 year. Objectives include safety, change in brain metabolism via FDG-PET, and clinical endpoints including the Alzheimer’s Disease Assessment Scale — cognition (ADAS-cog) and Clinical Dementia Rating Scale — sum of boxes (CDR-SB). Results: In SIGNAL-HD, pepinemab was well-tolerated and was shown to cross the BBB at a concentration sufficient to engage its target. While co-primary efficacy outcome measures did not achieve statistical significance in this study, multiple exploratory and post-hoc measures indicated significant cognitive benefit and were supported by pre-specified FDG-PET imaging that indicated significant reversal of decline in metabolic activity (p≤0.05) in 15/26 brain regions of interest. Treatment effects were observed in EM but not LP subjects. In 179 EM subjects, a treatment benefit was observed in 6/6 components of the HD-CAB cognitive assessment battery, with a significant treatment effect on the HD-CAB composite index (p=0.007). Post-hoc analysis of the HD-CAB results showed pepinemab treatment preserved the ability of EM subjects to learn from experience during sequential administration of HD-CAB and that the cognitive treatment benefit was greater in subjects that were more cognitively impaired at baseline, as judged by Montreal Cognitive Assessment (MoCA) score <26 vs. ≥26. The largest metabolic decline in HD is observed in caudate and putamen. It is, therefore, striking that a treatment effect on FDG-PET SUVR was not observed in caudate and putamen of either EM or LP subjects. Since degeneration of medium spiny neurons in striatum is an early event in prodromal HD that continues following motor diagnosis, this could account for reduced glucose utilization that is not SEMA4D-dependent and, therefore, not affected by pepinemab treatment. Our data support an important glial contribution to glucose utilization in other brain regions that is reduced by reactive gliosis and restored by pepinemab treatment. This suggests distinct early and late stages of pathology during disease progression. The ongoing blinded SIGNAL-AD trial has enrolled approximately half of the 40 planned subjects, and top line data for a full year of randomized, double-blind treatment is anticipated in Q1 2024. It will be of particular interest to determine whether metabolic changes in the entorhinal cortex, a region of early degeneration in AD, are less SEMA4D-dependent than for other cortical regions that degenerate somewhat later in disease progression. Conclusions: SIGNAL-HD showed a favorable safety profile and positive trends in cognition and imaging endpoints that encourage continued development in both HD and AD. The Phase 1b/2a study in AD (SIGNAL-AD), is currently enrolling and initial blinded safety review has suggested pepinemab is well tolerated in AD as well. References: 1. Evans et al, Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity. J Neuroinflammation, 2022. 10.1186/s12974-022-02509-8; 2. Feigin et al, Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial. Nature Medicine, 2022. 10.1038/s41591-022-01919-8.
LP20- DOES BRAIN-GUT PHOTOBIOMODULATION HAVE THERAPEUTIC POTENTIAL IN ALZHEIMER’S DISEASE? DESIGN OF A PIVOTAL SHAM-CONTROLLED, RANDOMIZED, DOUBLE-BLIND, MULTICENTRIC CLINICAL INVESTIGATION. J. Delrieu1, A. Relano-Gines2, P. Cristofini2, J. Bisiaux3, S. Guillemin3, G. Blivet2, J. Touchon4(1. Toulouse University Hospital Gerontopole — Toulouse (France), 2. REGEnLIFE — Paris (France), 3. RCTs — Lyon (France), 4. University of Montpellier — Montpellier (France)
Background: Alzheimer’s disease (AD) represents a serious public health problem, for which no clearly efficient treatment is currently available. REGEnLIFE RGn600 is a brain-gut photobiomodulation (PBM) medical device. Results from a first pilot clinical trial demonstrated safety, patient compliance and revealed efficacy trends in 53 mild-to-moderate AD patients treated with PBM therapy (Blivet et al., A randomized, double-blind, and sham-controlled trial of an innovative brain-gut photobiomodulation therapy: safety and patient compliance. J Alzheimer’s Dis. 2022, 90: 2, in press). This study provides valuable insights for the design of the next phase, a pivotal investigation, which will evaluate the cognitive benefits of PBM therapy, in a larger sample of AD patients. Objectives: The primary endpoint of this pivotal clinical trial is the evolution of patient’s cognition after 26 weeks of PBM therapy as measured with the ADAS-cog score. Neuropsychological functions, autonomy, overall clinical response, quality of life, blood and fecal markers as well as medico-economic interest will be investigated as secondary endpoints. The safety of RGn600 treatment will also be evaluated. Methods: The RGn600 is a non-invasive medical device, manufactured by REGEnLIFE, which takes the form of a helmet and an abdominal belt combining PBM technology from red to near-infrared wavelengths and static magnetic stimulation. A multicentric, double-blind, randomized, sham-controlled, pivotal clinical trial will be initiated at S1 2023 at the Toulouse University Hospital Gerontopole. In total, 96 patients with NIA-AA diagnosis criteria of AD will be included and randomized into a treated group (n=48) and sham group (n=48). They will receive 84 PBM therapy sessions of 20 min over 26 weeks. Results: The First Patient First Visit is expected for February 2023. The analysis will be performed in the Full Analysis Set, Per Protocol populations and Treated Set. Conclusion: REGEnLIFE RGn600 brain-gut PBM therapy, as a disease-modifying treatment, could potentially offer a safe, well-tolerated method, with medical and economic benefits, to treat mild-to-moderate AD patients. The design of this study, named LIGHT4LIFE, evaluating such an innovative medical device for the treatment of AD will be detailed. The advantages and limitations of such a clinical trial will be discussed. Conflict of Interest/Disclosure Statement: Guillaume Blivet: employee, stock ownership, REGEnLIFE. Aroa Relano-Gines: employee, REGEnLIFE. Patrice Cristofini: CEO, stock ownership, REGEnLIFE. Julie Bisiaux, employee, RCTs. Sara Guillemin, employee, RCTs.
LP21- AC-0027875, A NOVEL GAMMA-SECRETASE MODULATOR FOR THE TREATMENT OF ALZHEIMER’S DISEASE. J. Sandin1, M. Dahlström1, V. Lidell1, A. Rasti1, P. Forsell1, S. Juric1, M. Halldin1, M. Backlund1, G. Nordvall1(1. AlzeCure Pharma AB — Huddinge (Sweden))
Background: The process of amyloid beta (Aβ) amyloidosis plays a pivotal role in the onset of Alzheimer’s Disease (AD) and starts decades prior to symptoms onset. It is conceivable that an Aβ-targeting drug would be most beneficial as a chronic therapy initiated during the pre-symptomatic or preclinical phase, i.e. at the earlier stages of Aβ amyloidosis. As such, the therapy needs to be safe and well tolerated while still effective. Aβ is a family of postproteolytical peptides (Aβ31 to 43) and is generated as the result of gamma-secretase mediated processing of the amyloid precursor protein (APP). Aβ42 is particularly prone to aggregate and is also the primary Aβ component of amyloid plaques, whereas shorter Aβ peptides appear less amyloidogenic. Recent studies in humans have also shown that the shorter Aβ38 peptide may have some protective properties. Gamma-secretase modulators (GSMs) are a class of anti-amyloidogenic agents that exhibit several key features that make them suitable for the treatment of preclinical AD: 1) they target and reduce amyloidogenic Aβ42 production, while stimulating the formation of the shorter peptides Aβ37 and 38, 2) they modulate but do not affect all gamma-secretase activity, i.e. for other substrates such as Notch, a property that is of central importance from a safety perspective, and 3) they do not affect the total amount of Aβ, so if Aβ does have a physiological function it only alters the ratio between longer vs. shorter fragments. A GSM is suitable as a stand-alone preventive therapy but may also be an attractive option as a conjunctive treatment together with Aβ-antibody therapies. Objectives: The promising profile of a new class GSMs led us to develop a novel GSM for the treatment of early Alzheimer’s disease. Herein we present preclinical data of AC-0027875. Methods: The effect of AC-0027875 on Aβ42 production was explored both in HEK/APPswe cells and mouse primary cortical neurons (mPCN) and analyzed with an Aβ42 specific ELISA. After oral administration of AC-0027875 to C57BL/6J mice as well as Wistar rats, plasma and brain were collected and compound exposure in plasma and brain tissue was determined by LC-MS/MS. The reduction of soluble Aβ42 in the brain was determined by ELISA. The pharmacokinetic profile of AC-0027875 was determined in both rat and mouse. Results: The GSM AC-0027875 displays high potency in HEK/APPswe cells as well as in primary cortical neurons with an IC50 of 10 nM. In vivo studies shows that it is highly efficacious in lowering Aβ42 levels in both mice and rats. Dose-response studies as well as time-response studies in mice indicate a potent reduction of Aβ42 over time. The PK properties indicate a rapid uptake of the drug and good exposure as well as an excellent brain-to-plasma ratio indicating a suitable profile for further progression. Conclusion: The newly developed GSM AC-0027875 is a promising candidate for further development for the treatment of Alzheimer’s disease.
LP22- IMPACT OF ICOSAPENT ETHYL ON ALZHEIMERS DISEASE BIOMARKERS IN PRECLINICAL ADULTS: BRAIN AMYLOID AND VASCULAR EFFECTS OF EIOSCAPENTAEOIC ACID (BRAVE-EPA) STUDY DESIGN AND BASELINE CHARACTERISTICS. C. Van Hulle1,2, H. Zylstra3, C. Aleshia4, E. Allison5, E. Beckman6, K. Lazar7, B. Madeleine8, C. Kate1, C. Gleason2, S. Johnson1,2,9, S. Asthana1,2,10, C. Cynthia1,2,10,11(1. Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison — Madison (United States), 2. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison — Madison (United States), 3. School of Medicine and Public Health, University of Wisconsin-Madison — Madison (United States), 4. Wisconsin Alzheimer’s Institute Center, University of Wisconsin-Madison — Madison (United States), 5. Medical College of Wisconsin-Green Bay—Madison (United States), 6. Bold Insight — Downer’s Grove (United States), 7. Exact Sciences — Madison (United States), 8. Cleveland Clinic Lerner College of Medicine — Cleveland (United States), 9. Wisconsin Alzeimer’s Institute, University of Wisconsin-Madison—Madison (United States), 10. Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital—Madison (United States), 11. Wisconsin Alzheimer’s Institute, University of Wisconsin-Madisonn (United States))
Background: Veterans are at higher risk for dementia due to Alzheimer’s disease (AD) than the general population, possibly due to increased exposure to factors that accelerate AD pathology, including vascular risk factors, traumatic brain injury (TBI), and post-traumatic stress disorder (PTSD). AD pathology occurs decades before cognitive symptoms occur and is characterized by amyloid plaques, neurofibrillary tangles, and reduced regional cerebral blood flow (rCBF) in areas of the brain related to memory and learning. Objectives: Here we describe baseline characteristics for a proof-of-concept randomized, placebo-controlled, double-blind, parallel-group clinical trial assessing the efficacy of icosapent ethyl (IPE) (Vascepa, Amarin Corp.), a purified prescription form of the omega-3 fatty acid eicosapentaenoic acid (EPA). Outcomes include the effect of IPE on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and cognitive biomarkers for AD in cognitively-unimpaired Veterans ages 50–75 years. The primary aim of the trial is to assess whether IPE increases 18-month rCBF in a statistically-defined region of interest compared to placebo. Secondary aims assess whether IPE modifies CSF β-amyloid (Aβ) and improves cognitive performance on the ADCS-PACC battery compared to placebo. Methods: VA-eligible Veterans living in WI and parts of IL, IA, and MN were invited to enroll; 788 interested Veterans were prescreened, 179 consented and 131 randomly assigned in a 1:1 ratio to either placebo or 4g/day IPE. Prior to enrollment, participants were screened for suspected memory impairment. Other exclusion criteria included inability to safely take study medication or participate in study procedures. The Montreal Cognitive Assessment (MoCA), body mass index (BMI), waist-hip ratio (WHR), blood pressure, and cholesterol levels were obtained prior to randomization. After randomization, MRI, lumbar puncture, and cognitive testing occurs at baseline, 9 months, and 18 months. Participants’ self-reported medication use, health conditions, physical and mental activities are also recorded at baseline, 9-month and 18-month visits. At baseline, participants reported on their military experience, TBI exposure, and PTSD symptoms. CSF samples are collected in the morning after a 12-hour fast with a Sprotte 25- or 24-gauge needle using gentle extraction into polypropylene collection syringes. Twenty mL of CSF are collected into sterile polypropylene syringes, then combined, gently mixed, and centrifuged prior to freezing in 0.5 mL aliquots. rCBF is measured using arterial spin labeling (ASL). Additional scans include pcVIPR to measure cerebral velocity and pulsatility, T1*weighted MRI to provide anatomic information, T2 fluid-sensitive inversion recovery (FLAIR) to quantify white matter hyperintensities, and diffusion tensor imaging to measure white matter structural integrity. Results: Participants were primarily non-Hispanic white (125/131; 95%) and male (112/131; 85%) and had a parental history of dementia (69/131; 57%). Mean age at baseline was 65.8 (7.0) years. Most participants served in the Army (40%) followed by the Navy (24%), Air Force (15%) and Marines (11%); 80/131 (61%) went on one or more deployments. The proportion of participants with a four-year degree, 48/131 (36%), was higher than the state average of 30%. Although 51% of participants reported witnessing a traumatic event, none reported having PTSD symptoms. One in five participants reporting losing consciousness for more than 1 minute after a blast or crash and 37/131 (28%) reported having a concussion or head injury. The average total cholesterol was 175.4 mg/dL (43.2 mg/dL) which is lower than the state average for ages 40–65 (200.2 mg/dL) and ages >65 (187.1 mg/dL). Self-reported chronic conditions included high cholesterol (48.5%), high blood pressure (48.5%), and diabetes (18.9%). The sample was mildly obese, with a mean BMI and WHR of 30.1 (4.82) and 0.978 (0.07) respectively. Likewise average blood pressure was slightly elevated (mean systolic = 136 [16.5], mean diastolic = 82.5 [7.8]). The frequency of chronic conditions, BMI and blood pressure are broadly in line with the WI state population. The average MOCA score at baseline was 25.6 (2.6); 46/131 (35%) of participants fell below the suggested cut-off of 25 for cognitively unimpaired participants. Participants with a college degree scored slightly higher on ADCS-PACC constituent measures: Logical Memory delayed recall (p=.08), Logical memory immediate recall (p=.02), digit symbol substitution (p=.02), and Mini Mental State Exam (p=.02). However, baseline cognitive scores were unrelated to age, having one or more chronic conditions, number of deployments, or possible TBI. 116/131 (89%) participants had a successful LP and 115/131 (89%) participants had useable MRI scans. Mean total hippocampal volume was 7,941.9 mm3 (844.14). After adjusting for white and gray matter volume, total hippocampal volume at baseline was unrelated to age, education level, number of deployments, having one or more chronic conditions, or possible TBI. Conclusions: US military Veterans are an important cohort to study in identifying mechanisms to reduce AD risk. These data support the feasibility of recruiting cognitively unimpaired Veterans into a randomized, placebo-controlled clinical trial assessing the impact of IPE on MRI, CSF, and cognitive AD biomarkers. Trial data collection is ongoing and will be completed in September 2023.
LP23- A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED ASCENDING DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS (PK) AND PHARMACODYNAMIC (PD) EFFECTS OF POSIPHEN® IN SUBJECTS WITH MILD ALZHEIMER’S DISEASE/ MCI. D. Galasko1, M. Farlow2, B. Lucey3, L. Honig4, A. Moghekar5, D. Elbert6, R. Bateman3, J. Momper1, R. Thomas1, R. Rissman1, A. Balasubramaniam1, M. Maccecchini7, H. Feldman1(1. UC San Diego — San Diego (United States), 2. Indiana University — Indianapolis (United States), 3. Washington University — St. Louis (United States), 4. Columbia Unversity — New York (United States), 5. Johns Hopkins University — Baltimore (United States), 6. University of Washington — Seattle (United States), 7. Annovis Pharmaceuticals — Berwyn (United States))
Background: Preclinical studies show that posiphen acts as a post-transcriptional repressor at iron-responsive elements and can decrease the production of APP and Aβ. Prior clinical studies have explored different dose regimens, but data on pharmacokinetics and pharmacodynamics are still limited to inform dosing for phase 2 or 3 clinical trials. Objectives: To conduct a Phase 1b multicenter, double-blind, placebo-controlled RCT evaluating safety, tolerability, PK and PD of Posiphen, with sequential ascending dose cohorts (NCT02925650). To determine PK and PD at a steady state of drug dosing, serial CSF sampling with an indwelling lumbar CSF catheter to allow analysis of Stable Isotope Labeling and Kinetics (SILK™). To study feasibility of SILK at multiple centers and acceptability by patients. Methods: Subjects with MCI or mild AD dementia (age 55–89, MMSE 17–30, CDR = 0.5–1.0), in good general health, with CSF Aβ42/40 < 0.131, measured by mass spectrometry, were enrolled at 5 centers. Subjects were randomized to posiphen or placebo (5:3) in 3 sequential dose cohorts: 60 mg once/day, 60 mg twice/day and 60 mg 3 times/day for 21 days. On day 22, participants were admitted for confinement, placement of a CSF catheter and venous lines and intravenous loading with 14C-leucine. They received dosing with Posiphen/placebo and had serial plasma and CSF collection over 36 hours to allow SILK analysis. As outcome measures, safety and tolerability were assessed with clinical and laboratory tests. PK of Posiphen, N1 and N8 metabolites in plasma and CSF were measured during confinement. For PD, the fractional synthesis rate (FSR) of Aβ40 in CSF was calculated. Feasibility was assessed by accuracy of collection of CSF catheter and blood samples and acceptability by patient satisfaction surveys. Secondary analyses included changes in CSF Aβ38, Aβ40, Aβ42, sAPPα, sAPPβ and t-Tau from screening to confinement, FSR of Aβ38 and Aβ 42 and changes in cognitive tests and behavioral assessments including ADAS cog 12, MMSE and NPI. Results: Dose cohorts 1 (n=9) and 2 (n=8) were completed from 2018 – 2021. Cohort 3 (n=2) closed in December 2021, when the study was closed due to end of funding. There were substantial delays and challenges due to Covid-19 related restrictions and the 14C-leucine supply chain. Among the 19 subjects who were randomized, one did not have any post-randomization visits, therefore the mITT population included 7 placebo and 11 posiphen subjects. They were well-matched for demographic and clinical measures. 3 subjects had early termination: 1 had unsuccessful CSF catheter placement; for 2 others, catheterization was not done because 14C-leucine had expired. Posiphen was safe and well-tolerated, with no significant differences in vital signs, laboratory tests, AEs or SAEs between active drug and placebo subjects. 8/19 participants reported headache either during CSF sampling (4), after the procedure (3), or both (1). 5 had blood patches with rapid resolution of headache. 15/16 CSF catheterizations were successfully completed. We obtained > 89% of all scheduled plasma and CSF samples from these 15 subjects and could model SILK data adequately. Measures of research satisfaction of participants using the modified Research Satisfaction Questionnaire were favorable. PK parameters for posiphen and its N1 and N8 metabolites were correlated with one another in plasma and CSF. The mean posiphen elimination half-life in plasma was 3.8 hours. Posiphen Cmax was 56.4 ng/mL in plasma and 2.9 ng/mL in CSF following 60 mg once daily dosing. Exposures of posiphen and metabolites in CSF and plasma increased less than proportionally when dosed two and three times per day, raising the possibility of a potential food effect on bioavailability. SILK data were modeled using two approaches. A model using nonlinear fitting yielded the most accurate slopes. Mean FSRs (SD) for Aβ40 did not differ in the placebo, 60 mg once/day or 60 mg BID groups. Concentrations of Aβ38, 40, 42, sAPPα, sAPPβ and total tau in CSF were not significantly changed from baseline to confinement in treatment vs placebo groups, regardless of dose. There were no differences in changes from screening to 21 days for cognitive tests or for NPI scores. Conclusions: A multi-Center CSF catheter and SILK study was feasible, with high success of obtaining the necessary CSF and plasma samples. Patients were generally positive about participation. The study was impacted by COVID 19 and did not achieve full recruitment. Data on 60 mg three times daily are limited. Posiphen was safe and well-tolerated at 60 mg once or twice per day. PK data showed a short T ½ in plasma. The longer T ½ in CSF, minimal differences in PK and lack of differences in FSR and other SILK data for the 60 mg once/day and BID groups suggest that once per day dosing may be adequate. Posiphen treatment did not show an effect on FSR for Aβ40. Further analyses of slopes and other parameters derived from the SILK data are in progress.
LP24- PRECLINICAL CHARACTERIZATION OF ACD856, A COGNITIVE ENHANCER IN CLINICAL DEVELOPMENT FOR THE TREATMENT OF COGNITIVE DYSFUNCTION IN ALZHEIMER’S DISEASE, DEMONSTRATES INCREASED PLASTICITY, NEUROPROTECTION AND A POSSIBLE DISEASE MODIFYING EFFECT. C. Parrado-Fernández1, G. Nordvall1, S. Juric1, N. Madjid1, M. Backlund1, M. Dahlström1, J. Sandin1, P. Forsell1(1. Alzecure Pharma AB — Huddinge (Sweden))
Background: Neurotrophins are a class of growth factors that regulate neuronal function, survival, differentiation and plasticity. The neurotrophins, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin (NT) 3 and NT-4/5, bind and mediate their effects through the tropomyosin-receptor kinase (Trk) family of receptors (TrkA, TrkB and TrkC). A large body of pathological and mechanistic evidence suggests that loss of NGF contributes significantly to the dysfunction of basal forebrain cholinergic neurons observed in Alzheimer’s disease (AD). Indeed, the characteristic impairments in formation and retrieval of episodic memory observed in the disease have been reported to be partly due to this cholinergic dysfunction. Another area that is affected early in AD is the hippocampus, which plays a critical role in learning and memory processes. Interestingly, neurotrophic signalling, and in particular BDNF signalling, plays a pivotal role in hippocampal neurogenesis, synaptogenesis and synaptic plasticity. Several studies have also shown a decrease in BDNF levels in the hippocampus and in CSF in disorders with cognitive decline, including AD. Interestingly, the BDNF-Val66Met polymorphism has been demonstrated to affect the anatomy of hippocampus and prefrontal cortex in normal individuals and to moderate effects on episodic memory, hippocampal function and hippocampal volume in patients with either sporadic or familial AD. Thus, existing data strongly support and validate the development of enhancers of neurotrophin signaling as novel and promising therapeutic strategies for AD. AlzeCure Pharma has developed novel positive modulators of Trk-receptors and has with ACD856 demonstrated clear effects in various in vitro and in vivo models. Considering the neuroprotective and neuro-regenerative effects of neurotrophins, there is also a potential for ACD856 to demonstrate disease-modifying effects in neurodegenerative disorders like AD. Objective: Based on the extensive amount of supporting data for the role of neurotrophins in neuronal support and protection, the objective of these studies was to assess whether ACD856 exert any effect on neuronal plasticity and possible disease-modification effects in vitro and in vivo. Methods: Positive allosteric modulators of BDNF and NGF were identified and characterized using the TrkA- or TrkB cell-based assays in U2OS cells overexpressing human TrkA or TrkB receptors, respectively. In vitro functional modulation of the TrkB receptor was evaluated in SHSY5Y-TrkB cells treated with BDNF and increasing concentrations of ACD856. A phospho-TrkB ELISA was used to determine the levels of phosphorylated TrkB. Regulation of endogenous BDNF release was quantified in mouse embryonal primary cortical neurons (PCN). Effects of ACD856 were evaluated in NGF-induced neurite outgrowth in PC12 cells by immunostaining for SNAP-25 and tubulin III. Furthermore, effects on ATP levels and cellular permeability were investigated in mice PCN using energy-deprivation neurotoxicity assay, being glutamine the main source of energy. In vivo effects were studied in models assessing cognitive function using scopolamine-induced memory impairment using the passive avoidance model and antidepressant-like effects using the forced swim-test in mice. Results: We identified ACD856 as a potent positive modulator of human TrkA and TrkB receptors with EC50 of 314 nM and 226 nM, respectively. In the in vitro functional studies, ACD856 enhances the phosphorylation of TrkB in SHSY5Y-TrkB cells and upregulate the release of endogenous BDNF in mouse PCN. Studies in NGF-differentiated PC12 cells demonstrate that ACD856 increases both NGF-induced neurite outgrowth and SNAP-25 levels in neurites, suggesting neurorestorative effects. Furthermore, mouse PCN treated with ACD856 in media deprived of glucose and pyruvate, exhibits neuroprotective effects that correlate with an improved mitochondrial function in terms of increased ATP levels. In the in vivo behavioral studies, ACD856 demonstrated sustained antidepressant-like effects in FST, even up to three days after the last administration. This long-term effect was comparable to the long-term effects of ketamine in the same model. ACD856 could also reverse scopolamine-induced memory impairment, an effect that was significantly more pronounced after repeated dosing using 0.1 mg/kg as compared to a single administration using 0.1 mg/kg, which was ineffective. Minimal effective dose for a single administration was determined to 0.3 mg/kg. Furthermore, repeated administration was without any effects on motor function or anxiety. Conclusion: We identified ACD856 as a positive allosteric modulator of Trk-receptors acting as a cognitive enhancer in vivo and demonstrate herein promising results supporting increased plasticity, neurorestorative and neuroprotective properties. The results of repeated administration of ACD856 indicate that the compound improves neuronal plasticity or in other ways increase network connectivity in regions of importance for depression and cognition. In summary, repeated administration induces long-term effects, thus supporting a role of ACD856 in long-term modification and increased plasticity. This notion is in line with the positive findings of ACD856 on neurite outgrowth, SNAP25 expression and increased BDNF levels in cortical neurons. The fact that ACD856 shows potential disease-modifying effects is of high importance for the future treatment of cognitive dysfunction in Alzheimer’s disease.
LP25- OVERVIEW OF THE PRECLINICAL PROGRAM FOR OLX-07010 — A NOVEL INHIBITOR OF TAU SELF-ASSOCIATION. J. Moe1, B. Levine2, E. Cheesman1, P. Lopez1, W. Erhardt1, E. Davidowitz1(1. Oligomerix, Inc. — White Plains (United States), 2. Levine Tox Consulting, LLC — Chicago (United States))
Background: Tau has been implicated in the pathogenesis of multiple neurodegenerative diseases associated with the accumulation of abnormal species of tau, collectively called tauopathies. Mutations in MAPT can cause a range of rare inherited tauopathies to develop due to overproduction of specific tau isoforms or changes in the structure of tau, both of which can cause tau to aggregate. In AD, tau pathology is driven by numerous posttranslational modifications that lead to loss of normal function and/or gain of toxic function. Neurofibrillary tangles, composed primarily of tau, accumulate in a highly reproducible spatiotemporal order starting in the transentorhinal/entorhinal regions and spreading through the hippocampal structure to the neocortex demonstrating a close association between tau aggregation and AD progression. Tau prion-like propagation through neuronal communication pathways uses a seeding mechanism of templated misfolding and is accelerated by the presence of brain Aβ. Multiple studies have shown that tau oligomers, not fibrils or tangles, are closely correlated with neuronal loss and memory impairment. We have shown that tau oligomers cause disruption of neuronal signaling and inhibit the formation of memory in mice (Fá M et al., 2016). Memory formation was impaired following administration of oligomeric tau to hippocampi, areas of the brain involved in short-term memory formation. But similar treatment with tau monomer (tau that did not self-associate) did not have an effect. This impairment of memory was also found using oligomers formed from hyperphosphorylated tau purified from human AD brain specimens. Memory-specific mechanisms involved in gene regulation were shown to be disrupted by these extracellular tau oligomers. We have found that certain forms of tau oligomers are toxic when applied to cultured neurons, whereas tau monomer was not toxic at the same concentrations (Tian H et al., 2013). Our in vivo efficacy studies were carried out in two different transgenic mouse models, the htau model that expresses all 6 human isoforms with no mutations, and the JNPL3 model that has 4R0N tau with a P301L mutation. Treatment with the lead caused significant reduction in tau aggregates in blinded preventive studies (Davidowitz EJ et. al., 2020) in the htau model and also showed efficacy in both preventive and therapeutic studies in JNPL3 mice modeling 4R tau aggregation in tauopathies. Taken together these studies support the development of OLX-07010. Objectives: The overall goal of this program is to develop a small molecule therapeutic targeting tau self-association for Alzheimer’s disease and related tauopathies. The aim of this preclinical development program was to perform the studies needed for an IND application for a first-in-human clinical study for the safety and pharmacokinetics of OLX-07010. To achieve this aim, studies were required to evaluate the pharmacodynamics, pharmacokinetics, metabolism and toxicity of the candidate. Process development and manufacture of the drug substance (DS) for the non-clinical studies (non-GMP) and for the GMP manufacture of drug product (DP) were needed to perform the safety studies and to evaluate the stability of the DS and DP. Methods: All toxicology, metabolism, and transporter studies, as well as DS and DP manufacture and testing were performed at CROs. The 14-day toxicity studies (non-GLP) had once daily oral gavage to rats at dose levels of 100, 300, and 1,000 mg/kg/day, and once daily oral gavage to Beagle dogs at dose levels of 50 and 150 mg/kg/day. The dose levels in the 28-day toxicity studies (GLP) were 30, 100 and 300 mg/kg/day in rats and 15, 50 and 150 mg/kg/day in dogs. The Functional Observational Battery was performed as part of the 28-day rat study to evaluate CNS effects. Results: OLX-07010 demonstrated: pharmacologic activity in two mouse models of tauopathy; reasonable pharmacokinetic characteristics; minimal DDI potential; lack of genotoxicity; minimal off-target activity in safety pharmacology profiling with tier 1 and 3 safety panels; lack of/minimal effects on cardiovascular, pulmonary and CNS systems; relatively modest findings which were not considered adverse were observed in 28-day rat and dog GLP toxicity studies; the drug substance showed high purity and stability, and the drug product showed good stability. Conclusion: The preclinical development program demonstrated that OLX-07010 is an excellent candidate for clinical development. Long-term treatment for chronic diseases such as AD requires safe, effective, and economically feasible approaches. This small molecule, CNS drug-like lead substantially fulfills these requirements based on our preliminary results and the fact that it would not need cold-storage nor expensive infusion centers for administration for ease of treatment to address the unmet global health crisis. References: Fá M et al., Sci Rep. 2016 Jan 20;6:19393. PMC4726138; Tian H, et. al., Int J Cell Biol. 2013, 260787. PMC3789488; Davidowitz EJ et al., J Alzheimers Dis. 2020; 73(1):147–161. PMC6957711.
CLINICAL TRIALS: RESULTS
P34- CLINICAL OUTCOMES FROM A PHASE 2, OPEN-LABEL STUDY OF NE3107 IN PATIENTS WITH COGNITIVE DECLINE DUE TO DEGENERATIVE DEMENTIAS. E. Rindner1, K. Mahdavi1,2, J. Haroon1, K. Jordan1, M. Zielinski1, V. Venkatraman1,3, D. Goodenowe4, C. Ahlem5, C. Reading5, J. Palumbo5, B. Pourat6, S. Jordan1,3(1. The Regenesis Project — Santa Monica (United States), 2. Synaptec Network, — Santa Monica (United States), 3. Synaptec Network—Santa Monica (United States), 4. Prodrome Sciences USA LLC—Temecula (United States), 5. Biovie Inc. — Carson City (United States), 6. Pourat MD — Beverly Hills (United States))
Background: Therapies targeting amyloid beta (Aβ) and phosphorylated tau (P-tau), two of the most well-characterized biomarkers of Alzheimer’s disease (AD), have been associated with unclear clinical benefit. During the past decade, brain glucose hypometabolism, insulin resistance (IR), and neuroinflammation have emerged as important contributors to the pathophysiology of AD. Chronic inflammation is thought to induce IR and promote Aβ and P-tau accumulation, oxidative stress, and apoptosis, eventually leading to neuronal death and reduced cognitive performance. Studies suggest that increasing insulin sensitivity might reduce AD incidence and improve cognitive performance and brain glucose metabolism in AD patients. NE3107 is an oral, small, blood-brain—permeable molecule that binds and selectively inhibits inflammatory mediators and, as a consequence, improves insulin signaling. Across several clinical studies, NE3107 increased insulin sensitivity and restored metabolic homeostasis in patients with type 2 diabetes and inflammation, altered inflammatory biomarkers that have been associated with cognitive decline, and was well tolerated. Objectives: The present Phase 2, open-label study was designed to evaluate the potential efficacy of NE3107 in patients with mild cognitive impairment (MCI) or mild dementia through neuroimaging, cognitive performance testing, assessments of glucose and insulin homeostasis, and changes in AD and inflammatory biomarkers. Clinical outcomes of this study included changes in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 12) evaluations in addition to a battery of neuropsychological testing. Methods: Twenty-three participants were enrolled and received 20-mg oral NE3107 twice daily for 3 months. Participants were between 50–89 years old with MCI or mild dementia (Quick Dementia Rating Scale [QDRS] cutoff range: 1.5–12.5; Clinical Dementia Rating [CDR] score range: 0.5–1). AD markers (Aβ and P-tau) were evaluated at baseline and treatment termination. Primary endpoints evaluated neurophysiological health using multi-modal brain MRIs at baseline and treatment termination, including changes in glutathione levels, arterial perfusion, and functional connectivity of the nucleus basalis of Meynert (NBM) with both hippocampi. Secondary endpoints evaluated changes in serological inflammatory markers, glucose and insulin homeostasis, and cognitive functioning (clinical outcomes) using the QDRS, CDR score (estimated by the QDRS), ADAS-Cog 12 (scored from 0–70), the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). Upon completion of the protocol, participants and their families were asked to report a Global Rating of Change (GRC) and complete a Patient Health Questionnaire-9 (PHQ-9). Results: Participants had a mean age of 71.6 (SD = 9.63) years and 15 (65%) were females. At baseline, the mean QDRS score was 5.07, 18 (78%) participants had a CDR score of 0.5, and 5 (22%) participants had a CDR score of 1. Results from clinical outcomes will be presented at the conference. Conclusion: Using an array of well-established neuropsychological assessments to ascertain participants’ cognitive abilities before and after treatment with NE3107, this study aimed to demonstrate the potential therapeutic efficacy and cognitive improvements associated with NE3107 treatment in patients with MCI. Funded by: BioVie Inc. Disclosures: ER, KM, KJ, JH, MZ, VV, and SJ have received grant support from BioVie Inc. DG has nothing to disclose. BP has nothing to disclose. CA, CR, and JP are employees of BioVie Inc.
P35- META-ANALYSIS OF HIGH-CLEARANCE ANTI-AMYLOID IMMUNOTHERAPIES TRIALS IN EARLY ALZHEIMER’S DISEASE: A SIGNIFICANT CLINICAL EFFECT BUT A LOW BENEFIT/RISK RATIO. N. Villain1, V. Planche2(1. Ap-Hp Sorbonne Université, Hôpital Pitié-Salpêtrière, Department Of Neurology, Institute Of Memory And Alzheimer’s Disease — Paris (France), 2. Univ. Bordeaux, Cnrs, Imn, Umr 5293 — Bordeaux (France))
Background: In the last three years, three over four phase II or III clinical trials using high-dose anti-amyloid immunotherapies in early Alzheimer’s disease (AD) have turned out to be positive on clinical outcomes: aducanumab (one of two), donanemab, and lecanemab. These results contrast with the previous failures of anti-amyloid immunotherapies. Despite different pharmacodynamic properties, these drugs share a new characteristic: the high clearance of amyloid load as measured with amyloid positron emission tomography. In the meantime, the Food and Drug Administration’s conditional approval of aducanumab has led to unprecedented scientific controversies. Method: We used the data from the highest dose group (i.e., the groups used for approval application or ongoing phase III trials) versus placebo after 18 months of the lecanemab and donanemab phase II trials and of the two aducanumab phase III trials to perform a meta-analysis. Regarding clinical efficacy, we analyzed the CDR-SB, ADASCog, and MMSE data. Regarding safety, we analyzed the occurrence of any Amyloid-Related Imaging Abnormalities (ARIA), of ARIA-edema (ARIA-E), of ARIA-hemorrhage (ARIA-H), and of symptomatic and serious ARIA. The analyses were performed using RevMan 5.4.1 and a random effect model. Results: High-clearance anti-amyloid immunotherapies were shown to significantly slow down cognitive decline after 18 months as measured with CDR-SB (weighted mean=-0.24 points; p=0.04), and ADAS-Cog (weighted mean=-1.25 points; p=0.0003), but not with MMSE (weighted mean=+0.31 points; p=0.23) when compared to placebo. In parallel, the drugs significantly increased the occurrence of any ARIA (risk ratio=3.68; p<0.0001), of ARIA-E (risk ratio=13.39; p<0.0001), of ARIA-H (risk ratio=2.78; p=0.0002), and of symptomatic and serious ARIA (7/1321=0.53% in the high dose groups versus 0/1446 in the placebo groups; risk ratio=6.44; p=0.04). Conclusion: When pooled together, the data from high-clearance anti-amyloid immunotherapies trials confirm a significant clinical effect after 18 months. However, this effect remains below the established minimal clinically relevant values. Safety remains an issue with 0.5% of symptomatic and serious ARIA, significantly beyond chance, despite thorough in-trial monitoring and management. The benefit/risk ratio of this class of drugs in early AD is thus questionable after 18-months. Identifying subgroups of better responders and the perspective of combination therapies may help improve their clinical relevance.
P36- LILYPADD TRIAL: TARGETING HIPPOCAMPAL HYPERCONNECTIVITY IN COGNITIVELY NORMAL OLDER ADULTS AT RISK FOR ALZHEIMER’S DISEASE WITH AGB101. S.J. Li1, A. Bakker2, B.D. Ward3, Y. Wang4, S. Schold5, P. Antuono5, E.D. Granadillo5, M. Franczak5, J. Goveas6(1. Department of Biophysics, Department of Radiology, Department of Psychiatry and Behavioral Medecine, Medical College of Wisconsin — Milwaukee (United States), 2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University — Baltimore (United States), 3. Department of Biophysics, Medical College of Wisconsin — Milwaukee (United States), 4. Department of Biophysics, Department of Radiology, Department of Psychiatry and Behavioral Medecine, Department of Neurology, Medical College of Wisconsin — Milwaukee (United States), 5. Department of Neurology, Medical College of Wisconsin — Milwaukee (United States), 6. Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin — Milwaukee (United States))
Background: The burden of Alzheimer’s disease (AD), with a predicted prevalence rising to over 100 million patients worldwide by 2050, could be dramatically reduced by effective interventions. Aging represents the greatest risk for AD although the boundary between healthy aging and the earliest emergence of AD remains poorly understood. Amnestic mild cognitive impairment (aMCI) due to AD is recognized as a prodromal phase between normal aging and a clinical diagnosis of AD dementia. aMCI is characterized by greater memory impairment than expected for a person’s age and by augmented hippocampal hyperactivity. Strong evidence from both studies of animal models and humans have observed that hyperactivity in neuronal circuits contributes to the accumulation and spread of AD pathology and forecasts subsequent cognitive decline. Evidence also shows that hippocampal hyperactivity as well as altered functional connectivity between neuronal networks occurs in cognitively normal (CN) older adults. In elderly CN individuals elevated hippocampal connectivity at rest is associated with lower age-related episodic memory performance and greater subsequent decline in memory function (Salami et al., 2014), conferring increased risk for progression to dementia. In patients with aMCI low dose levetiracetam was previously demonstrated to normalize hippocampal hyperactivity and improved memory function on an episodic memory task designed to tax hippocampal functioning (Bakker et al., 2012). The current study was aimed to examine whether low dose levetiracetam can be used to reduce functional connectivity of the hippocampus in cognitively normal older adults as a primary endpoint, with secondary endpoints examined by neuropsychological assessments. Objectives: To assess the efficacy of AGB101, a once daily extended-release formulation containing 220 mg of levetiracetam, on bilateral hippocampus functional connectivity measured by resting-state functional MRI when compared to placebo. Secondary outcomes determined the efficacy of AGB101 versus placebo on performance on neuropsychological assessment of episodic memory using the Rey Auditory Verbal Learning Test. Methods: Participants were cognitively normal older adults between the ages of 55–75 who were free of major neurological, psychiatric conditions or medically unstable conditions. Participants completed a randomized, double-blind, placebo-controlled crossover trial conducted at the Medical College of Wisconsin in Milwaukee, Wisconsin, between May 2018 and March 2021. Group A subjects received an oral placebo tablet daily for two weeks followed by a four-week wash-out period. Those participants subsequently received an oral AGB101 tablet daily for two weeks (two weeks placebo treatment — four weeks washout — two weeks AGB101 treatment). Group B participants received the treatment protocol using the reverse sequence (two weeks AGB101 treatment — four weeks washout — two weeks placebo treatment). At each study visit, participants completed a neurological exam, neuropsychological assessment, MRI session and a blood draw. Results: Thirty-five cognitively normal older adults were evaluated for eligibility and enrollment. Nine participants did not meet criteria and were not enrolled. One subject did not have detectable levetiracetam in their blood sample after treatment and was excluded from analysis. A total of 25 participants, including 15 women (mean [SD] age of 65.9 [3.8]) and 10 men (mean [SD] age of 66.7 [5.5]) were randomized (12 participants to group A and 13 participants to group B) were included in the analysis. Blood plasma values (mean [SD] of 4.34 [1.32] mg/ml) were consistent with previous reports (Bakker et al., 2012). No effect of treatment order was observed in the study. Treatment with AGB101 significantly decreased bilateral functional connectivity of the bilateral hippocampus network (p < 0.0098). No effect of treatment was observed on episodic memory performance on the Rey Auditory Verbal Learning Test. Conclusions: In this clinical study two weeks of daily treatment with AGB101 was well tolerated and although no treatment effect on episodic memory performance was observed, treatment with AGB101 significantly decreased functional connectivity of the hippocampus network when compared to placebo. These proof-of-concept results warrant further assessment of AGB101 in cognitively normal older adults in the earliest phases of the AD continuum before symptomatic cognitive impairment and a diagnosis of aMCI. A more extended treatment protocol could be used to determine whether progression of impairment can be attenuated by such intervention. ClinicalTrials.gov Identifier: NCT03461861. Supported by National Institute on Aging: R21MH126479. References: A. Salami, S. Pudas, L. Nyberg. (2014). Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging. Proceedings of the National Academy of Sciences, 111, 49: 17654–17659. A. Bakker, G. Krauss, M.S. Albert, C.L. Speck, L.R. Jones, C.E. Stark, M.A. Yassa, S.S. Bassett, A.L. Shelton, M. Gallagher. (2012). Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron, 74: 467–474.
P37- PLANNING THE NEXT GENERATION OF ALZHEIMER’S DISEASE CLINICAL TRIALS USING DIVERSE PATIENT-LEVEL DATABASE FROM THE CRITICAL PATH FOR ALZHEIMER’S DISEASE (CPAD) CONSORTIUM. S. Sivakumaran1, N. Cullen1, Z. Cui1, E. Priest1, C. Lau1, H. White1, M. Irizarry2, K. Romero1, Y. Karten1(1. Critical Path Institute — Tucson (United States), 2. Eisai Inc. — Nutley (United States))
Background: Critical Path Institute (C-Path) coordinates the Critical Path for Alzheimer’s Disease (CPAD) Consortium. To accelerate drug development for Alzheimer’s Disease (AD), CPAD has previously developed two regulatory-endorsed clinical trial simulators (CTS) that sponsors can use to help optimize clinical trial design in 1) the pre-dementia stages of AD, using CDR-SB as the primary endpoint, and 2) mild-to-moderate AD, using ADAS-cog as the primary cognitive endpoint. These models incorporate demographic covariates, like sex and age, as well as baseline severity (MMSE), and APOE4 genotype. The pre-dementia model incorporates baseline hippocampal volume, as an enrichment biomarker. The natural next step in the evolution of these quantitative tools requires the consideration of additional baseline and longitudinal biomarkers. Recently, CPAD members have begun to share data from several contemporary Phase III clinical trials, offering an opportunity to enrich and expand these model-based tools with additional fluid and imaging biomarker information, data from predementia subjects and treatment arms. Method: By integrating patient-level data from high quality Alzheimer’s disease (AD) clinical trials, models will be developed to model natural AD progression for multiple cognitive and functional endpoints, as well as biomarkers, adjusted for demographics, baseline severity, time from and to diagnosis, and genetic status (APOE4). Such progression models will be fit using non-linear mixed effects methods and Monte Carlo simulations will be performed to evaluate model fit across a variety of covariates. Moreover, the rich collection of biomarker data will be leveraged to build statistical models which will address unmet needs at multiple points in the clinical trial design process: reducing unnecessary PET scans by screening with accessible blood-based biomarkers, optimized patient selection by contributing to PET analysis pipelines, and reduced trial size (and/or increased statistical power) with the help of enrichment models that predict cognitive decline using combinations of AD biomarkers. Finally, longitudinal biomarker data will be modelled against longitudinal cognitive trajectories to better understand the selection of biomarker-based endpoints to measure reduction in AD pathology in response to treatment. Results: As of January 2022, CPAD’s clinical trial repository contains 61 studies with 40,122 individual anonymized patient records. Analysis subsets generated from 6 key datasets, rich in fluid and imaging biomarkers, were used to develop of a preliminary set of disease progression models that characterize the time course of clinically relevant measures (ADAS-Cog, CDR-SB, other clinical assessment scales and biomarkers). A two-level regression model was applied to predict baseline CDR-SB using baseline covariates (demography, ApoE4 status, fluid and imaging biomarkers) and identify significant variables. Base models using parametric mixed-effects approaches were developed with selection based on goodness-of-fit plots. In terms of addressing clinical trial design needs, a screening model has been developed to predict amyloid PET status from a combination of demographics, cognition, and blood-based biomarkers, an enrichment model has been developed to predict longitudinal cognitive decline from a combination of screening biomarkers plus amyloid PET, and the association between longitudinal CSF and plasma biomarkers versus longitudinal cognitive has been evaluated. Conclusion: The disease progression models will serve as the basis for clinical trial simulation tools to facilitate informed decision making in the drug development process and optimize patient and endpoint selection, as well as design of efficacy studies. The trial design models will serve to influence core clinical trial design decisions and thereby usher in the next generation of biomarker-driven clinical trials characterized by greatly improved efficiency and reduced costs. CPAD will advance the tools through the formal FDA Fit for Purpose pathway, to achieve regulatory endorsement and provide confidence to sponsors for the adoption of the tools.
P38- CRITICAL PATH FOR ALZHEIMER’S DISEASE (CPAD) CONSORTIUM: ACCELERATING AND DE-RISKING THERAPEUTIC DEVELOPMENT IN AD BY BUILDING REGULATORY DECISION-MAKING TOOLS. S. Sivakumaran1, N. Cullen1, C. Lau1, E. Priest1, H. White1, M. Irizarry2, K. Romero1, Y. Karten1(1. Critical Path Institute — Tucson (United States), 2. Eisai — Nutley (United States))
Background: The Critical Path Institute (C-Path) coordinates the Critical Path for Alzheimer’s Disease (CPAD) Consortium, a global, neutral convener, bringing together diverse stakeholders across industry, regulatory agencies, patient advocacy organizations and academia within a pre-competitive forum under a data-driven, regulatory framework to accelerate therapeutic innovation in Alzheimer’s disease (AD). In partnership with C-Path’s Quantitative Medicine Program, CPAD members, and regulatory agencies (FDA, EMA), CPAD’s Quantitative Modeling Working (QMWG) and Focus Groups identify key questions and unmet needs in AD drug development. To address the unmet needs, we use our core competencies in data management and standards, advanced quantitative analytics, biomarkers, clinical outcome assessment tools and regulatory science to develop actionable solutions that help de-risk decision making in the AD drug development process. Method: Patient-level data and neuroimages from contemporary Phase II and Phase III AD clinical trials and observational studies re acquired through formal data contribution agreements with CPAD. Clinical data is curated in collaboration with data contributors, standardized to common structure and terminology, and assembled into analysis subsets. From the integrated data, analysis ready subsets are created for development of a comprehensive set of disease progression models across the continuum of the disease. Models characterize the time course of clinically relevant measures (ADAS-Cog, CDR-SB, other clinical assessment scales and biomarkers). The models will serve as the basis for clinical trial simulation tools to facilitate informed decision making in the drug development process and optimize patient and endpoint selection and design of efficacy studies. To incorporate imaging biomarkers as key covariates in the disease progression modeling, there is a need for post-acquisition data ‘harmonization’ tools and analysis methods that reduce variance across studies, sites, and scanners, while retaining the power to study complex disease related effects. To that end, we will develop a harmonized image analysis methodology for the purpose of deriving imaging biomarkers. Results: As of May 2022, CPAD’s clinical trial repository contains 61 studies with 40,122 individual anonymized patient records. Analysis subsets generated from 6 key datasets, rich in fluid and imaging biomarkers, were used to develop a preliminary set of disease progression models that characterize the time course of clinically relevant measures (ADAS-Cog, CDR-SB, other clinical assessment scales and biomarkers). In addition, we initiated a collaboration with the USC Laboratory of Neuro Imaging (LONI) and Global Alzheimer’s Association Interactive Network (GAAIN) on an image analysis pipeline developed by LONI, to develop a multimodal harmonized neuroimage analysis tool, based on the LONI Pipeline and GAAIN research interface. The tool will be leveraged for automated quantification of image-derived biomarkers, which will be used in disease progression modeling. Examples of such neuroimaging biomarkers include amyloid (amyloid PET), tau (tau PET), and neurodegeneration (hippocampal volume). CPAD will also leverage this pipeline to advance our understanding of ARIA, in partnership with members and collaborators. Finally, we will integrate various modeling and analytical approaches being pursued by all stakeholders within CPAD into a comprehensive disease progression model as the basis to develop a clinical trial simulation tool. Conclusion: C-Path provides the legal, scientific, and regulatory infrastructure to generate a unique neutral environment for relevant stakeholders in the AD drug development field to collaborate. The precompetitive space is imperative to stakeholders sharing information and data and transforming those into actionable tools and solutions that address specific unmet needs in the drug development process. Through formal submissions for regulatory review and potential endorsement of solutions, CPAD can build consensus among experts and stakeholders and provide confidence to sponsors for the adoption of the tools.
P39- EFFECTIVENESS OF A DIGITALLY SUPPORTED CARE MANAGEMENT PROGRAM FOR FAMILY AND OTHER INFORMAL DEMENTIA CAREGIVERS: BASELINE DATA AND FIRST RESULTS FROM THE GAIN RANDOMIZED CONTROLLED TRIAL. I. Kilimann1, O. Klein2, J.R. Thyrian3, M. Boekholt3, S. Teipel1, W. Hoffmann4(1. Deutsches Zentrum Für Neurodegenerative Erkrankungen Dzne Rostock/greifswald And University Medical Center Rostock, Department Psychosomatics And Psychotherapy — Rostock (Germany), 2. Deutsches Zentrum Für Neurodegenerative Erkrankungen Dzne Rostock/greifswald — Rostock (Germany), 3. Deutsches Zentrum Für Neurodegenerative Erkrankungen Dzne Rostock/greifswald — Greifswald (Germany), 4. Deutsches Zentrum Für Neurodegenerative Erkrankungen Dzne Rostock/greifswald And University Hospital Greifswald, Institute For Community Medicine — Greifswald (Germany))
Background: Almost two-thirds of people with dementia (PwD) living at home receive care from a family or other informal caregiver. For the caregiver this can result in a work load comparable or above a full-time employment position. Evidence shows that family caregivers have a higher risk for psychiatric and non-psychiatric diseases like depression, anxiety, and arterial hypertension compared to non-caregivers. A dyadic approach on disease management and the assessment of unmet needs can help to reduce the burden of care and increase the quality of life of caregivers and PwD. The cluster randomized trial “Gesund Angehörige Pflegen” (GAIN) conducted in general practitioner (GP) practices and memory clinics in Northern Germany aimed to evaluate the effectiveness of a 6-months digitally supported care management program to reduce unmet needs of informal caregivers of PwD. Methods: Primary outcomes are the number of identified and addressed caregivers’ self-reported unmet needs (related to the caregiver and related to the PwD, Camberwell Assessment of Need for the Elderly, CANE) and the health-related quality of life (EQ-5D-5L). The recruitment for the GAIN trial began in October 2020 and ended in January 2022 with a total number of n=192 participants (mean age: 65 years, women 75%). The intervention and all follow-up visits will be completed by August 2022. In addition to the primary outcomes, caregivers’ burden (Zarit Burden Interview, ZBI), social support (Lubben Social Network Scale, LSNS), use of medical and non-medical services (FIMA), and resource utilization (RUD) were assessed. Results: Results from the effectiveness analysis will be available and presented at the conference. Baseline data showed that the GAIN questionnaire has a high potential to identify unmet needs. On average 8.66 unmet needs were identified in a dyad: 3.99 unmet needs related to the caregiver and 4.67 unmet needs were in relation to the PwD. The number of identified unmet needs was higher compared to previous studies e.g. from the European Actifcare Study. The intervention targeting caregiver burden was triggered the most (n=141), followed by interventions addressing a missing disability certificate) (n=116) and reduced physical activity (n=90). Conclusion: The use of a tablet-based expert assessment system GP practices and in memory clinics to identify unmet needs is well feasible and identifies a higher number of unmet needs compared to previous studies. The high average number of unmet needs among family caregivers indicates the importance of a structured and in-depth assessment to allow a personalized and dyadic treatment of family caregivers and the PwD. Further results from the primary outcome analysis will be presented at the conference.
P40- REPEAT IV AND SC DOSING OF THE ANTI-SORTILIN ANTIBODY AL101. M. Ward1, F. Yeh1, L. Park1, D. Maslyar1, Y. Liao1, H. Long1, H. Picard1, M. Kurnellas1, M. Vadhavkar1, A. Silva1(1. Alector, Inc. — South San Francisco (United States))
Background: Variants in GRN, the coding gene for progranulin (PGRN), have been implicated in a number of neurodegenerative disorders, including Frontotemporal dementia (FTD), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Sortilin, expressed on neurons and microglia, is a key regulator of PGRN levels through sortilin-mediated degradation. Increasing PGRN levels, may be an effective therapeutic approach, potentially reducing the rate of neuronal loss and clinical decline in individuals with neurodegenerative diseases. AL101 is a human IgG1 monoclonal antibody that downregulates sortilin and increases PGRN levels in preclinical models. AL101 is being developed by Alector for the treatment of neurodegenerative disorders, including AD and PD. Objectives: The extension of this first-in-human Phase 1 study is designed to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following repeated administration of AL101, administered intravenously (IV) and subcutaneously (SC). Methods: Healthy volunteers received repeat doses of AL101 in two cohorts: 300 mg SC q2w for a total of 7 doses and 30 mg/kg IV q4w for a total of 4 doses. Assessments included standard clinical safety measures, pharmacokinetic (PK) and pharmacodynamic (PD) markers in plasma and CSF. Plasma profiles of AL101 and PGRN were measured up through day 113 for the SC cohort and day 141 for the IV cohort. CSF was sampled at baseline and at timepoints after the last administered dose. Safety follow-up was conducted for up to 20 weeks in the IV cohort and up to 16 weeks in the SC cohort. Results: Reported AEs were generally mild to moderate in severity and self-limiting, in line with preliminary AL101, single dose safety data. There were no severe or serious adverse events related to repeat dose administration. Subjects in the SC repeat-dose cohort reported a higher number of overall injection site reactions although these were all mild in severity. Repeat-dose AL101 increased the levels of PGRN in the CSF of healthy volunteers up to approximately 80% above baseline levels. PK/PD modeling, based on PK and PD data from these repeat-dose cohorts, supports dosing intervals of q8w. Conclusion: Multiple IV or SC administration of AL101 is generally safe and well tolerated in healthy volunteers. AL101 is a potent modulator of PGRN levels in the CSF, with a PK/PD profile that supports its further development in chronic neurological conditions such as Alzheimer’s and Parkinson’s disease.
P41- SAL-AD: A PHASE 1B, 12-MONTH, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND PRELIMINARY EFFICACY OF SALSALATE IN PATIENTS WITH MILD TO MODERATE ALZHEIMER’S DISEASE. P. Ljubenkov1, L. Vandevrede1, J. Rojas1, M. Honey2, A. Lario Lago1, R. Tsai3, M. Koestler1, R. La Joie1, K.A. Johnson4, L. Gan5, S. Lessig6, J. Brewer6, H. Feldman6, C. Teunissen7, A. Boxer1(1. UCSF Memory and Aging Center — San Francisco (United States), 2. Amsterdam UMC — Amsterdam (Netherlands), 3. Denali Therapeutics — San Francisco (United States), 4. Harvard Medical School — Boston (United States), 5. Weill Cornell Medical College — New York (United States), 6. UC San Diego — San Diego (United States), 7. Amsterdam UMC — Amsterdam (United States))
Background: Tau acetylation at Lys174 may impair tau clearance and is an early pathological change present in patients with Alzheimer’s disease (AD) and murine models of tauopathy. Salsalate is a nonsteroidal anti-inflammatory (NSAID) which inhibits p300 acetyltransferase and thereby reduces tau acetylation. In a PS19 transgenic mouse model of tauopathy, salsalate treatment lowered p300 activity, decreased acetylation at Lys174, decreased total tau levels, increase tau turnover, reduced memory deficits, and prevented hippocampal atrophy. Given salsalate’s potential utility in a preclinical model, we sought to conduct a phase 1b randomized, double-blind, placebo-controlled of salsalate in patients with mild to moderate Alzheimer’s disease. Objectives: The primary objective was to assess the safety and tolerability of salsalate in patients with mild to moderate AD. Secondary objectives were to assess blood and CSF pharmacokinetic (PK) measures of salsalate. Exploratory objectives included assessment of salsalate’s pharmacodynamic (PD) impact on cerebrospinal fluid (CSF) biomarkers of AD severity (total tau [t-tau], phosphorylated tau [p-tau181], and amyloid beta [Aβ1–42] measured on the Elecsys platform), CSF neurofilament light chain [NfL], CSF acetylated tau, CSF acetylated histones, measures of AD clinical severity, volumetric brain MRI measures, and brain uptake of 18F-MK6240 positron emission tomography (PET) tracer. Methods: N=40 patients with biomarker confirmed (via amyloid PET or CSF amyloid and tau) AD and mild to moderate dementia (Mini Mental Status Exam [MMSE] Scores≥14) were enrolled from August 2017 to February 2020 at University of California, San Francisco, and University of California, San Diego. Patients were randomized 1:1 to one year of blinded treatment with either placebo or salsalate 3000 mg daily. CSF, plasma, volumetric imaging, and exploratory clinical measures were collected at baseline, 6 months, and 12 months. The final 21 participants were enrolled in a secondary cohort that included assessment with brain 18F-MK6240 PET imaging at baselined and at 12 months of treatment. Linear mixed effect models determined interactions between treatment assignment (salsalate vs placebo) and time in determining change in exploratory measures. Results: Patients randomized to salsalate and placebo were comparable in terms of baseline mean age (66.7 [SD 8.5] years vs 65.8years [10.5] respectively), gender distribution (12 women/8 men, 13 women/7 men), Clinical Dementia Rating Scale (CDR) global score (0.9 [0.4]) vs 0.8 [0.4]), MMSE score (20.8 [5] vs 21.1 [4.5]), CSF total tau (353.9pg/ml [154.6] vs 349.4pg/ml [225.3]), CSF p-tau181 (34.7pg/ml [15.7] vs 34.2pg/ml [24.3]), and CSF NfL (1571.2pg/ml [746.7] vs 1362.5pg/ml [504.8]). However, patients randomized to salsalate tended to have a greater baseline cognitive impairment on the eleven item Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS Cog 11) (45.4 [16.1] vs 38.4 [12.3], p=0.016), and lower baseline CSF Aβ1–42 values (447.7pg/ml [142.0] vs 536.4pg/ml [151.4], p=0.01). The trial experienced a high rate of early discontinuations (45%) in the context of the COVID-19 pandemic; the number of early terminations was higher in patients randomized to salsalate (n=11) compared to the placebo group (n=7; Fisher’s exact test p=0.043). The number of patients who experienced adverse events was otherwise similar between cohorts (salsalate n=16, placebo n=15). In intention-to-treat and on treatment analyses, no beneficial effects of salsalate treatment were observed on 52-week changes in CSF biomarkers of AD biology (t-tau, p-tau181, Aβ1–42), NfL, or acetylated tau; or on clinical endpoints. Further analyses of primary, secondary, and exploratory endpoints including tau PET are ongoing and will be presented. Conclusion: Salsalate was safe and well tolerated, without evidence of beneficial treatment effects on CSF biomarkers or clinical measures. Further analysis of PK and PD results (including tau PET to evaluate target engagement) are pending. The trial’s high dropout rate and baseline differences in cohorts may have impacted the interpretability of the results.
P42- EARLY EXPERIENCE WITH HOME ADMINISTRATION OF SUBCUTANEOUS GANTENERUMAB BY STUDY PARTNER (NON-PROFESSIONAL CARE PARTNER) IN THE GRADUATION STUDY. R. Perry1, F. Boess2, M. Scelsi3, T. Grimmer4, R. Arroyo5, C. Lane3, C.J. Lansdall2, J. Smith3(1. Imperial College London — London (United Kingdom), 2. F. Hoffmann-La Roche Ltd — Basel (Switzerland), 3. Roche Products Ltd — Welwyn Garden City (United Kingdom), 4. Klinikum rechts der Isar, Technical University of Munich — Munich (Germany), 5. Quirónsalud Madrid University Hospital — Madrid (Spain))
Background: Gantenerumab is an investigational, fully human anti-amyloid-beta (Aβ) immunoglobulin G1 monoclonal antibody in development as a subcutaneous (SC) treatment for early (prodromal-to-mild) and preclinical Alzheimer’s disease (AD). Gantenerumab has high affinity for aggregated Aβ and promotes its removal via Fcγ receptor-mediated microglial phagocytosis.1,2 Open-label extensions of the Phase III SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) trials showed robust Aβ removal after treatment with SC gantenerumab.3 Two multicenter, randomized, double-blind, placebo-controlled, Phase III studies, GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) are ongoing to assess the efficacy and safety of SC gantenerumab in early AD, using a titration over 9 months and a target dose of 510 mg every 2 weeks (Q2W) with change from baseline to Week 116 in Clinical Dementia Rating scale — Sum of Boxes as the primary endpoint. The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once-weekly (Q1W) SC administration of gantenerumab (255 mg) in participants with early AD. AD has a substantial, all-encompassing impact on the daily life of both patients and their care partners.4 SC Q1W administration of gantenerumab in the home setting by a care partner may allow for additional flexibility and convenience and reduce the burden of frequent clinic visits. The GRADUATION trial allows for home dosing by a willing study partner (non-professional care partner), deemed able to administer SC gantenerumab by the treating physician after a standardized training. SC administration has potential benefits over intravenous administration, as it enhances access to diverse populations, reduces costs for payers, and allows flexibility for people living with Alzheimer’s and care partners. Care partners will respond to a questionnaire to assess their confidence, ease of use, convenience, and overall satisfaction of SC gantenerumab administration in the home setting. Objectives: The primary objective of the GRADUATION study is to evaluate the PD effect of a Q1W dosing regimen of gantenerumab on brain amyloid load, measured by positron emission tomography (PET). Secondary objectives include the assessment of gantenerumab administration by the care partner in the home setting, safety, and PK/PD relationships. Exploratory objectives include additional imaging and plasma biomarkers, and cognitive and functional assessments. The focus of this interim analysis is to evaluate care partner confidence and overall satisfaction with home administration. The corresponding endpoint consists of the responses to the care partner questions of the home administration questionnaire. Methods: In this open-label, single-arm, Phase II study, participants will receive gantenerumab by SC injection over a 2-year period, starting with 120 mg every 4 weeks (Q4W), followed by 255 mg Q4W and Q2W for 12 weeks each, and a target dose of 255 mg Q1W. This target dose is hypothesized to be equivalent to the 510 mg Q2W studied in the GRADUATE trials. Eligibility criteria include: age 50–90 years at screening; clinical diagnosis of early AD, operationalized as prodromal AD (mild cognitive impairment due to AD) or probable AD dementia according to the National Institute on Aging — Alzheimer’s Association diagnostic criteria; and evidence of AD pathology confirmed by amyloid PET scan. The home administration questionnaire will be completed at site visits, and includes items addressing the confidence with administration, convenience, ease of use, and overall satisfaction. Each item is rated on a 4-point verbal Likert scale and respondents will be asked to consider their most recent at home administration. Week 52 analyses of the subset of participants with care partners willing and capable to administer SC injections in the home setting will be analyzed and presented using descriptive statistics. Results: Recruitment for GRADUATION is complete. One hundred and ninety-two participants were enrolled from 8 countries (Belgium, France, Germany, Italy, Poland, Spain, United Kingdom, and United States). Baseline characteristics for home administration participants and their care partners and results from a pre-specified Week 52 interim analysis of home administration questionnaire responses with database lock in Q3/2022 will be presented. Conclusions: The GRADUATION study will determine the effect of Q1W administration of SC gantenerumab on pharmacodynamics (including brain amyloid load), pharmacokinetics and safety in participants with early AD, and assess the feasibility of administration by care partners at home. The option of home administration with gantenerumab may provide additional convenience and reduced burden for people living with Alzheimer’s and their care partners. References: 1. Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69:198–207; 2. Bohrmann B, Baumann K, Benz J, et al. Gantenerumab: A novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis. 2012;28:49–69; 3. Klein G, Delmar P, Kerchner G, et al. Thirty-six-month amyloid positron emission tomography results show continued reduction in amyloid burden with subcutaneous gantenerumab. J Prev Alzheimers Dis. 2021;8:3–6; 4. WHO. Dementia. www.who.int/news-room/fact-sheets/detail/dementia Accessed 1 June 2022. Conflict of interest: Frank Boess is a full-time employee and shareholder of F. Hoffmann-La Roche Ltd.
P43- A PHASE 1B STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND PHARMACODYNAMICS OF PRI-002 IN MCI AND MILD AD. O. Peters1, N.C. Cosma1, J. Kutzsche1, D. Willbold1(1. Charité hospital — Berlin (Germany))
Background: PRI-002 is an orally available anti-amyloid beta (Aβ) prionic compound developed to disassemble toxic Aβ oligomers. PRI-002 has shown to improve cognition in animal models and has demonstrated its safety profile in healthy volunteers (Kutzsche et al. 2020). Objectives: To evaluate the safety, tolerability and pharmacodynamics of PRI-002 in early stages of AD. Methods: 20 patients in early AD disease stages were recruited to participate in a single center, randomized, placebo —controlled, double-blind study. All participants had to fulfill the ATN-criteria for AD. Patients received once daily oral doses of 300 mg PRI-002 or placebo for 28 days. Safety and efficacy assessments were executed at baseline, day 14, day 28 and day 56 (follow up). Blood sampling was carried out at each time point, EEG and CSF measurements before and at the end of treatment. Imaging (MRI) and functional tests (CERAD, CDR) were performed in parallel to EEG/CSF and additionally at follow up. Results: 10 patients (age 76.9±3.4, MMSE 28±1.6) received placebo and 9 patients PRI-002 (72.4±6.9, 27.2±2.9). One patient withdraw informed consent before treatment was initiated. 13 patients reported in total 27 adverse events while no serious adverse event was noted. There was no statistical difference regarding adverse events between treatment and placebo. EEG and MRI revealed no changes after treatment. Especially no ARIA-E or ARIA-H were noted. No significant changes were detected in p-TAU, Abeta1-42 and Aβ oligomers in CSF before and after treatment. Patients that had received PRI-002 for four weeks significantly performed better than those receiving placebo in the CERAD word list 28 days after treatment had ended (p≤0.05). Conclusions: PRI-002 showed an excellent safety profile in AD patients. No biomarker changes were detected after short treatment period of 4 weeks, while a slight improvement of memory function was noted at follow up. A multicenter phase 2 study will be initiated in the near future. Kutzsche J, Jürgens D, Willuweit A, Adermann K, Fuchs C, Simons S, Windisch M, Hümpel M, Rossberg W, Wolzt M, Willbold D. Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020 Mar 20;6(1):e12001. doi: 10.1002/trc2.12001.
P44- ENABLING SUBCUTANEOUS DOSING OF GANTENERUMAB IN ALZHEIMER’S DISEASE. B. Bittner1, D. Schwab1, A. Portron1, D. Lott1, F. Boess1, R. Kohler1, J. Wojtowicz1, C. Hofmann1(1. F. Hoffmann-La Roche Ltd — Basel (Switzerland))
Background: Subcutaneous (SC) dosing of biotherapeutics such as monoclonal antibodies (mAb) represents a convenient and resource-efficient dosing alternative to more invasive intravenous (IV) infusions across different therapeutic areas. In light of increasingly cost-constrained global healthcare markets and the coronavirus pandemic, SC administration of mAbs is a key enabler for a flexible care setting in which people living with Alzheimer’s disease (pwAD) and care partners can choose the place of drug administration according to their preferences and capabilities. Today, technical challenges associated with high-dose SC mAb administration are increasingly overcome with the development of high-concentration dosing solutions, co-administration of the dispersion enhancer hyaluronidase, as well as ready-to-use and automated injection devices. Objectives: Gantenerumab is a fully human anti-amyloid-beta (Aβ) immunoglobulin G1 mAb with highest affinity for aggregated Aβ that removes Aβ via microglia-mediated phagocytosis. It is in development for the treatment of AD with a SC administration regimen. The development of SC dosing has to consider factors of local tolerability and associated pain at the injection site. Respecting the needs of individual patients, the feasibility of care partner-assisted at-home dosing is currently being assessed (NCT04592341). Methods: To generate initial safety and efficacy data, early clinical trials with gantenerumab were conducted with the IV formulation, such that SC formulation development and SC tolerability assessments could be conducted in parallel. Assessment of local tolerability following SC administration is part of the standard safety assessments in clinical trials. A dedicated randomized placebo-controlled crossover study was conducted in healthy participants investigating injection pain following SC administration of gantenerumab versus placebo. Plasma concentrations of gantenerumab were collected throughout the clinical studies and the pharmacokinetic characteristics of gantenerumab with SC dosing were characterized by integrating the data from different clinical trials in a population pharmacokinetic model analysis. Possible home-administration is supported with human factors (HF) studies and a care partner questionnaire. Results: Gantenerumab entered the clinic with an IV formulation, but solely utilized SC administration in Phase II and III trials after bridging to SC dosing in a healthy volunteer study. Thus, a large clinical database is available for gantenerumab following SC administration. Gantenerumab was locally well tolerated with predominantly mild, reversible, and self-limited injection- site reactions observed as main adverse effects associated with the SC route of administration (Ostrowitzki 2017). The evolving development program included a dedicated randomized, placebo-controlled, crossover study in healthy participants investigating injection pain following SC administration by means of a disposable handheld syringe equipped with a flange to assist with injection force and a spacer to help setting the needle depth and angle. This study demonstrated minimal to slight pain after needle insertion with minor differences in pain recorded for gantenerumab or placebo administered. Visual analogue scales (VAS scale from 0 (no pain) to 100 (worst pain possible)) least square means were at 15.006 vs. 9.526, respectively (mean difference 5.48; 95% CI (-1.971 to 12.931)). Pain was reported only directly after injection and did subside within 5 minutes (VAS < 5 mm); this data was complemented by a verbal rating scale resulting in minimal to slight pain reporting after needle insertion and immediately after injection only. The pharmacokinetics of gantenerumab administered SC provided comparable results across studies and were well characterized by population pharmacokinetic analysis (Retout 2022). To guide adequate dosing in a decentralized setting, the overall clinical data package is complemented with HF data collected in usability studies with pwAD, lay care partners, and healthcare professionals (HCPs). Additionally, a home-administration questionnaire is included in an ongoing Phase II study in participants with early AD (NCT04592341) to assess confidence of non-professional care partners as drug administrators, ease of use, and convenience of SC gantenerumab administration in the home setting. Conclusion: Gantenerumab SC administration is locally well tolerated and provides reliable drug exposure with minimal pain experience in the range of what was observed previously for other SC administered mAbs. The SC dosing regimen is expected to support convenient and cost-efficient dosing in a flexible care setting. To further support compliance with the drug administration procedure in a non-HCP supervised setting, the value of connected devices and corresponding health apps will be assessed for their potential to complement conventional patient support programs. 1. Ostrowitzki S, et al. SCarlet RoAD Investigators. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017 Dec 8;9(1):95. DOI: 10.1186/s13195-017-0318-y. Erratum in: Alzheimers Res Ther. 2018 Sep 27;10(1):99. 2. Retout S, et al. Disease modeling and model-based meta-analyses to define a new direction for a phase III program of gantenerumab in Alzheimer’s disease. Clin Pharmacol Ther. 2022 Apr;111(4):857–866. DOI: 10.1002/cpt.2535. Epub 2022 Feb 28. Lead author disclosure: Beate Bittner is a full-time employee and shareholder of F. Hoffmann-La Roche Ltd.
P45- THE INTERNET-BASED CONVERSATIONAL ENGAGEMENT CLINICAL TRIAL (I-CONECT) IN SOCIALLY ISOLATED ADULTS 75+ YEARS OLD: PRIMARY ANALYSES RESULTS. H. Dodge1, P. Pruitt1, K. Yu1, C.Y. Wu1, J. Kaye1, L. Silbert1, I. Conect-Team1(1. Oregon Health & Science University — Portland (United States))
Background: Social isolation is a risk factor for dementia. Increasing social interactions using webcam/internet could offer a cost-effective prevention approach that provides cognitive stimulation and slows cognitive decline. This paper describes the results of the primary and secondary outcomes and an exploratory outcome of the recently completed project named “Internet-Based Conversational Engagement Clinical Trial (I-CONECT)” (ClinicalTrial.gov: NCT02871921) where socially isolated subjects with normal cognition (NOC) or mild cognitive impairment (MCI) aged 75 and older were recruited through mass-mailing and community outreach. Methods: I-CONECT is a multi-site, assessor-blind, randomized controlled behavioral intervention trial (RCT) aimed to enhance cognitive reserve by providing frequent video chats to socially isolated older old subjects. The detailed protocol was published previously (Yu, et al., 2021). The intervention group had video chats with trained study staff for 30 minutes per day, 4 times per week for 6 months (high dose), and then twice per week for additional 6 months (maintenance dose). Both video chat intervention and control groups had a brief (10 minute) telephone check-in with study staff once per week. We used linear regression and repeated measure mixed-effects models (MMRM) to assess the efficacy of global and domain-specific cognitive test scores at month 6 and month 12. As a part of exploratory analyses, among a subgroup of participants with MCI or NOC who completed both baseline and month 6 MRI assessments, we examined the difference between the two arms in resting-state functional MRI-derived (rsfMRI) connectivity for the following 4 large networks at month 6, controlling for potential confounders: Default Mode Network (DMN), Salience Network (SN), Front-Parietal Network (FPN) and Dorsal Attention Network (DAN). Results: We aimed to randomize 160 subjects each of non-white and white socially isolated subjects aged 75 and older. Despite the COVID-19 pandemic and resultant research hiatus, we achieved 96% of the targeted sample size for white participants. However, we achieved only 23% of non-white participants. Overall, we randomized 186 non-demented socially isolated adults 75+ years old either with MCI or NOC (mean age: 81.1 (sd = 4.6), women: 69.9 %, MCI: 53.8%, African Americans: 19.9%) into either the video chat intervention Group (N=94) or the control group (N=92). Compared with the control group, the experimental group had 1.75 (p=0.03) higher Montreal Cognitive Assessment (MoCA) scores (primary outcome, tapping global cognition) at month 6 with cohen’s d=0.73, and 2.19 higher Craft Story Immediate Recall scores at month 12 (p=0.03) (secondary outcome, immediate memory/encoding ability) with cohen’s d of 0.66 among the participants with MCI. Aa for rsfMRI results, the experimental group was associated with higher connectivity within the DAN at month 6, compared with the control group (p=0.03), based on linear regression models controlling for age, sex, scanner motion, site, and connectivity at baseline. Conclusions: Despite the challenges induced by the COVID-19 pandemic and the resultant reduced sample size and other protocol modifications, we found significant efficacy in the primary and secondary outcomes along with potential biological modification in specific brain connectivity. The intervention that provides social interactions through user-friendly subject-centered video chats has the potential to impact the overall dementia prevalence by delaying the cognitive decline associated with MCI. Phase III study will confirm the efficacy in delaying the onset of dementia. Conflict of Interest: No author has a conflict of interest in presenting this work. Funding sources: National Institute on Aging (NIA) Grant Nos. R01AG051628, R01AG056102. References: Yu K, Wild K, Potempa K, Hampstead BM, Lichtenberg PA, Struble LM, Pruitt P, Alfaro EL, Lindsley J, MacDonald M, Kaye JA, Silbert LC and Dodge HH (2021) The Internet-Based Conversational Engagement Clinical Trial (I-CONECT) in Socially Isolated Adults 75+ Years Old: Randomized Controlled Trial Protocol and COVID-19 Related Study Modifications. Front. Digit. Health 3:714813. doi: 10.3389/fdgth.2021.714813. (PMC8521795) Key words: ADRD; Behavioral intervention; RCT; Trial protocol; Cognitive health; Cognitive reserve, Social interaction; Technology-ICT; Social isolation and loneliness.
P46- COMPUTERIZED GAMES VERSUS CROSSWORDS TRAINING IN MILD COGNITIVE IMPAIRMENT. D. Devanand1, T. Goldberg1, M. Qian1, M. Doraiswamy2(1. Columbia University Medical Center — New York (United States), 2. Duke University — Durham (United States))
Background: Mild cognitive impairment (MCI) increases the risk of progression to dementia. The efficacy of cognitive training in MCI is unclear. Methods: In a two-site, blinded, 78-week trial, patients with MCI, stratified by age, severity (early/late MCI) and site, were randomized to 12 weeks of intensive, home-based, computerized training with web-based cognitive games or crossword puzzles, followed by 6 booster sessions. In mixed model analyses, the primary outcome was change in Alzheimer’s Disease Assessment Scale (ADAS-Cog). Secondary outcomes were neuropsychological composite, UCSD Performance-Based Skills Assessment (UPSA, functional outcome) and the Functional Activities Questionnaire (FAQ, functional outcome). Changes in MRI hippocampal volume and cortical thickness were assessed. Results: In 107 patients (51 games, 56 crosswords), mean (+/-SD) age was 71.2 years (8.8) and 42% were male. ADAS-Cog showed a small decline for games compared to improvement for crosswords at week 12 (LS means difference -1.35, 95% CI -2.71, 0.00) and week 78 (LS means difference -1.44, 95% CI -2.83, -0.06; p=0.04). From baseline to week 78, mean ADAS-Cog worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). Late MCI, but not early MCI, showed this difference. Change in UPSA and neuropsychological composite showed no group differences. FAQ showed greater worsening with games than crosswords at week 78. Adjusted for stratification variables, decreases in hippocampal volume and cortical thickness were smaller for crosswords than games. Conclusions: Home-based computerized training with crosswords demonstrated superior efficacy to games on cognitive and functional measures with reduced brain atrophy over 78 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03205709.
P47- PIMAVANSERIN AND CARDIOVASCULAR/ELECTROCARDIOGRAM SAFETY IN PATIENTS WITH ALZHEIMER’S DISEASE. P. Tariot1, V. Abler2, S. Pathak2, B. Coate2, M.E. Turner2(1. Banner Alzheimer’s Institute and University of Arizona College of Medicine — Phoenix, AZ (United States), 2. Acadia Pharmaceuticals Inc. — San Diego, CA (United States))
Background: Cardiovascular adverse events (AEs) contribute to increased mortality associated with antipsychotic use in elderly patients with dementia-related psychosis and prolonged QT intervals in such patients increase risk of serious/fatal arrhythmias. Thus, cardiovascular safety is an important consideration when treating patients with neurodegenerative disorders, including Alzheimer’s disease (AD). This is particularly relevant when considering that patients with AD are often older adults with multiple comorbid conditions. Pimavanserin is a selective 5-HT2A receptor inverse agonist/antagonist approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis and is being studied for AD psychosis. Objectives: To evaluate the cardiovascular safety of pimavanserin in a large population of patients with AD. Methods: Safety data were pooled from three studies (NCT02035553, NCT02992132, and NCT03575052) of patients with AD treated with ≥1 dose of pimavanserin (34 mg) or placebo once daily. Electrocardiograms were reviewed centrally, and electrocardiogram parameters from this evaluation were summarized with descriptive statistics as changes from baseline to last-postbaseline assessment and proportion of patients with potentially clinically important electrocardiogram changes. The QT interval was corrected using the Fridericia’s formula (QTcF). Results: Among the 292 and 282 patients treated with pimavanserin and placebo, respectively, median ages were 76.0 and 78.0 years, 91.8% and 93.5% were white. The majority of the patients in both groups had vascular disorders (61.3% of pimavanserin and 63.1% of placebo) and 45.5% and 48.2%, had hypertension, respectively. Mean (SE) change in QTcF from baseline to last-postbaseline assessment was 6.2 ms (1.03) in the pimavanserin group and −1.1 ms (1.01) in the placebo group. Change from baseline to last post-baseline assessment in QTcF >500 ms and QTcF >60 ms was reported in 0.4% of the pimavanserin group and none of the patients in the placebo group. Overall, the number of patients with cardiovascular AEs were numerically higher for pimavanserin (6.2%) than placebo (4.3%). Electrocardiogram-associated treatment-emergent AEs reported in ≥1% were prolonged QT (1.4% pimavanserin, 1.4% placebo). Other cardiovascular AEs reported in ≥1% were peripheral edema (3.1% pimavanserin, 1.1% placebo). There were no reports of torsade de pointes or ventricular tachycardia. There was one fatal case of cardiopulmonary failure reported in the placebo group. Conclusions: Baseline characteristics demonstrated that many of these patients with AD were older and comorbidities were common, including vascular disorders and hypertension. These higher-risk characteristics underscore the importance of a thorough understanding of the safety of medications used in these patients. Data from this large group of patients with AD shows that pimavanserin prolonged the QTcF interval by an average of 6.2 ms and resulted in a change from baseline in elevated QTcF intervals (ie, >60 or >500 ms) in less than 0.5% of patients, each. Results were consistent with previous findings in AD and prescribing information for pimavanserin. Disclosures: This study was sponsored by Acadia Pharmaceuticals Inc. PT: received research support from and Novartis. Dr. Tariot has received consulting fees from Acadia Pharmaceuticals, AC Immune, Axsome, Bioexcel, Otsuka, Syneos Health, and T3D. Dr. Tariot has received consulting fees and research support from Abbvie, Biogen, Cortexyme, Eisai, Lilly, Lundbeck, Merck & Co., and Roche. Dr. Tariot also owns stock in Adamas Pharmaceuticals and is supported by the National Institute on Aging (RF1 AG041705, 1UF1AG046150, R01 AG031581, R01 AG055444, P30 AG19610), the Arizona Department of Health Services, Alzheimer’s Association, Banner Alzheimer’s Foundation, FBRI, GHR, Nomis Foundation, Flinn Foundation, and the Geoffrey Beene Foundation. VA, SP, BC, MET are employees of Acadia Pharmaceuticals Inc.
P48- THE EFFECTS OF THE NOVEL PHOSPHODIESTERASE 9 (PDE9) INHIBITOR E2027 (IRSENONTRINE) ON CSF CGMP, ADDITIONAL CSF AND PLASMA BIOMARKERS, AND CLINICAL OUTCOMES IN AMYLOID POSITIVE AND AMYLOID NEGATIVE PATIENTS WITH DEMENTIA WITH LEWY BODIES (DLB) AND PARKINSON’S DISEASE DEMENTIA (PDD). P. Sachdev1, K. Pinner2, T. Devins1, L. Reyderman1, D. Li1, S. Dhadda1, L. Kramer1, A. Koyama1, M. Irizarry1, S. Hersch1(1. Eisai Inc. — Nutley (United States), 2. Eisai Ltd. — Hattfield (United Kingdom))
Background: Irsenontrine is a potent and selective PDE9 inhibitor that increases cellular cGMP and enhances glutamatergic synaptic function currently under investigation to improve cognition in Lewy Body Dementia (LBD; DLB and PDD). Data from Eisai’s recent phase II study in DLB patients suggested that irsenontrine could be more effective for cognition in DLB patients without amyloid copathology. The suggestion of efficacy in the “pure” DLB subgroup, lacking AD co-pathology, led to the hypothesis that irsenontrine preferentially increases CSF cGMP in pure DLB relative to mixed AD/DLB due to relative preservation of synapses (the site of action of PDE9 inhibition) in patients lacking amyloid co-pathology. Objectives: The primary objective of the current study was to assess whether the presence or absence of amyloid co-pathology could differentially affect pharmacodynamic response based on CSF levels of cGMP in patients with either DLB or PDD treated with irsenontrine. Exploratory outcomes included other biomarkers and clinical scales. Methods: 83 subjects were screened to enroll 34 subjects meeting diagnostic and eligibility requirements for DLB or PDD who were assigned to four different subgroups — DLB amyloid positive (n=11), DLB amyloid negative (n=10), PDD amyloid positive (n=3), and PDD amyloid negative (n=10) using the plasma PrecivityAD™ Aβ42/40 ratio (cut-point of 0.092). All subjects were treated with 50 mg irsenontrine daily (QD) for 12 weeks. Lumbar puncture was performed at baseline and 9 weeks with change from baseline of CSF cGMP being the primary outcome. Clinical assessments included the electronic Montreal Cognitive Assessment (eMOCA), Wechsler Adult Intelligence Scale IV — Digit Symbol Coding subtest (WAIS-IV DSC), Clinicians Interview Based Impression of Change (CIBIC-Plus), Mini-mental State Examination (MMSE), Cognitive Function Inventory (CFI), Scale for the Assessment of Positive Symptoms (SAPS-PD), Functional Activities Questionnaire (FAQ), and Clinicians Global Impression of Change (CGI-C). Biomarkers included ApoE4; plasma Aβ42/40, p-tau181, NfL, GFAP, and CSF Aβ42/40, p-tau181, total tau, neurogranin, and NfL at baseline and nine weeks. Exploratory analyses were also performed using CSF Aβ42/40 ratio (cut-point of 0.0571) to assign subgroups. The study was designed to identify a >50% increase in CSF cGMP in amyloid negative subjects compared to amyloid positive subjects, considered to be pharmacologically relevant. Analyses were not controlled for multiplicity or powered for the detection of statistically significant differences; the small number of PDD amyloid negative subjects limits interpretation of comparisons between the PDD groups. Results: Amyloid positive and negative DLB patients and amyloid negative PDD patients were readily enrolled, however amyloid positive PDD patients were uncommon and enrollment was closed before reaching the targeted numbers. The treatment was well tolerated with the majority of treatment-emergent adverse events being mild/moderate. There was a robust increase in CSF levels of cGMP for all groups averaging 239% of baseline, which was consistent across each diagnostic cohort. For amyloid status defined by plasma Aβ42/40, the comparison of percent change from baseline of the cGMP in the DLB amyloid negative (n=7) vs positive (n=10) groups showed Least Square Mean (LSM)s at Week 9 of 230% vs 250%, respectively (LSM diff. (95% CI) -20% (-78%, 38%)), for PDD amyloid negative (n=8) vs positive (n=3) 187% vs 363%, respectively (LSM diff. (95% CI) –176% (-287%, -64%)). The effects of treatment on the MoCA at Week 12, using plasma amyloid definitions, were inconsistent (change from baseline mean, SD) DLB- (-0.4, 2.7), DLB+ (–1.9, 4.0), PDD- (1.8, 3.3) and PDD+ (-4.7, 3.5). When amyloid status was defined by CSF Aβ42/40, subgroup assignment and CSF cGMP results were still consistent across diagnostic cohorts:, DLB amyloid negative (n=6) vs positive (n=11) groups showed LSMs at Week 9 of 274% vs 225%, respectively (LSM diff. (95% CI) 50% (-6%, 105%)), for PDD amyloid negative (n=10) vs positive (n=1) 212% vs 466%, respectively (LSM diff. (95% CI) -254% (—429%, -79%)). CNS biomarkers were unchanged over 9 weeks of treatment. Conclusion: Irsenontrine was safe and well-tolerated in LBD and achieved robust pharmacodynamic responses in all subgroups regardless of amyloid status. The results did not support a differential pharmacodynamic effect of irsenontrine with regards to presence or absence of amyloid copathology within DLB or PDD patients. Acknowledgements: We thank Robert Lai and June Kaplow for contributing to protocol and translational medicine strategy development and Takuya Yagi for serving as medical monitor.
P49- CLINICAL ACTIVITY OF THE P38A KINASE INHIBITOR NEFLAMAPIMOD ON VERBAL LIST LEARNING MAY BE TAU PATHOLOGY DEPENDENT IN DEMENTIA WITH LEWY BODIES (DLB). J. Alam1, J. Conway1, H.M. Chu2, K. Blackburn1(1. EIP Pharma, Inc — Boston (United States), 2. Anoixis Corporation — Natick (United States))
Background: Neflamapimod (NFMD) targets pathogenic mechanisms that underlie basal forebrain cholinergic (BFC) neurodegeneration (Pensalfini et al, 2020; Alam & Nixon, 2021), considered to be a major driver of dementia in DLB; and in preclinical studies neflamapimod rescues neurodegeneration in the basal forebrain (Jiang, 2019). The final results from an exploratory 91-patient, 16-week placebo-controlled phase 2a study (“AscenD-LB Study”) in mild-to-moderate DLB were reported at last year’s CTAD meeting. In that study, NFMD demonstrated clinically meaningful, statistically significant improvement, relative to placebo, on cognition (evaluated by Neuropsychological Test Battery designed to assess attention and executive function), motor function (evaluated by Timed Up and Go (TUG) Test, and on the Clinical Dementia Rating Scale Sum-of-Boxes (CDR-SB). The results were dose-dependent, with the most prominent effects being seen at 40mg TID (for the cognitive effect the results were only significant for NFMD 40mg TID vs placebo; while for TUG and CDR-SB both all NFMD, which included both 40mg BID and 40mg TID recipients, vs. placebo and the comparison of NFMD 40mg TID vs placebo were significant). Also presented at last year’s meeting, were the results of AscenD-LB stratified by baseline plasma p-tau181 levels, a biomarker for the absence or presence of AD co-pathology (most specifically absence or presence of medial temporal lobe tau pathology by PET scan; van der Lee et al, 2021). Compared to the results in the overall population, the magnitude of the neflamapimod treatment effect relative to placebo for the individual clinical endpoints was 1.5 to 2.0fold greater in the population without elevated plasma ptau181 (i.e., less than the prospectively defined cut-off of 2.2 pg/mL at baseline), with effect sizes ranging from 0.56 (NTB) to 0.74 (TUG, CDR-SB) for the comparison of 40mg TID vs. placebo. As the endpoints that were positively impacted may be connected in DLB to cholinergic function, the reported clinical results from the AscenD-LB study are consistent with the preclinical results, i.e., neflamapimod positively impacts the function of the basal forebrain cholinergic system. Herein we report on the effects of neflamapimod, stratified by baseline plasma ptau181 on the International Shopping List Test (ISLT), a verbal list learning test that is considered to be primarily a measure of hippocampal function (though modulated by cholinergic input). Objectives: To evaluate the effects of neflamapimod on the International Shopping List Test (ISLT), stratified by baseline plasma ptau181. Methods & Patients: Mild-to-moderate (MMSE 15–28) probable DLB by consensus criteria (McKeith et al, Neurology, 2017; 89:88–100), including a positive DaTscan™, and currently receiving cholinesterase inhibitor therapy. Treatment: 40 mg NFMD capsules or matching placebo capsules administered with food for 16 weeks; dosing regimen was based on weight: subjects weighing <80 kg received capsules twice-daily (BID) and those weighing ≥80 kg received capsules TID. Plasma ptau181 levels were determined by Simoa® pTau181 Assay (Quanterix) at the VU Medical Center, where the in-house defined cut-off for AD pathology was set at 2.2 pg/mL. To evaluate treatment effects, linear mixed effects model for repeated measures with baseline as a covariate was utilized. Results: At baseline, 22 of 41 (53%) of placebo and 22 of 42 (54%) of neflamapimod participants in the efficacy analysis population (baseline and on-treatment data on at least one efficacy endpoint) had ptau181 below the cut-off (2.2 pg/mL). Baseline CDR-SB at 5.6 (SD=2.8) in subjects with ptau181≥2.2 pg/mL was higher than in subjects below the cut-off [4.5(2.3), p=0.053 for the difference). Similarly, baseline ISLT Immediate recall [13.0(5.0) vs. 14.7(5.0)] and Delayed Recall [4.3(2.5) vs. 3.8(2.4)] were numerically lower in participants above the cut-off. As reported previously, in the overall population there were no differences between placebo and NFMD treated patients in the ISLT measures. However, in participants with baseline plasma ptau181<2.2 pg/mL (i.e., those without medial temporal lobe tau pathology by PET) at 40mg TID vs. placebo there was a positive trend for ISLT Immediate Recall [p=0.053, difference=+2.1 words (95% CI: -0.03, 4.17), Cohen’s d effect size=0.28] and a significant positive difference for ISLT recognition [p=0.024, difference=+1.4 words, 95%CI=0.2, 2.5, d=1.0)}. No differences were seen for ISLT delayed recall, nor on any of the ISLT measures in participants with plasma ptau181≥2.2. Conclusion: Neflamapimod may improve verbal learning, as assessed by the ISLT, particularly with respect to recognition. This potential effect is consistent with an effect of neflamapimod on the cholinergic system and a conceptual model in which a treatment that acts on the cholinergic input to the hippocampus is able to improve verbal learning, but only in the context of an intact hippocampus, and is not able to do so in the presence of significant neurodegeneration in the hippocampus. Longer duration studies would be required to assess the impact of such a therapy on the progression of hippocampal neurodegeneration. Conflict of Interest: JJA, JC and KB are employees of EIP Pharma Inc, the sponsor of the AscenD-LB clinical trial.
LP26- FINAL 4 YEARS RESULTS OF THE CLINICAL TRIAL ASCOMALVA. A. Carotenuto1, A. Fasanaro1, E. Traini1, F. Amenta1(1. University of Camerino — Camerino (Italy))
Background: Cholinesterase inhibitors (ChE-Is) are used for symptomatic treatment of mild-to-moderate Alzheimer’s disease (AD), but long-term effects of these compounds are mild and not always obvious. Preclinical studies have shown that combination of ChE-Is and the cholinergic precursor choline alphoscerate is more effective than single compounds alone in rising brain acetylcholine levels. Objective: The study Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in AD associated with cerebrovascular injury (ASCOMALVA) is a double-blind trial that has investigated the efficacy of the combined treatment donepezil + choline alphoscerate versus donepezil alone. Methods: This 4 years trial has recruited 210 AD patients with associated ischemic brain damage documented by neuroimaging. Patients were randomly assigned to an active treatment group [donepezil (10 mg/day) + choline alphoscerate (1,200 mg/day), D+CA] or to a reference group [donepezil (10 mg/day) + placebo, D+P]. The 48.6 % of patients recruited have completed 4 years of observation. Cognitive functions were assessed by the Mini-Mental State Evaluation and Alzheimer’s Disease Assessment Scale Cognitive subscale. Daily activity was evaluated by the basic and instrumental activities of daily living tests. Behavioral symptoms were assessed by the Neuropsychiatric Inventory. Among patients who underwent annual Magnetic Resonance Imaging (MRI), 56 patients were selected (27 treated with D+P; 29 treated with D+CA). The selection was made to allow the comparability of the data, electing resonances obtained with similar and new generation equipment. Data from magnetic resonance were used for the voxel morphometric cerebral volume analysis. Results: After 4 years of observation, patients of the reference group (D+P) showed a time-dependent worsening in all parameters investigated. Treatment with D+CA significantly slowed changes of the different items analyzed. The volume analysis of hippocampus and amygdala grey matter has shown a progressive reduction in the volume of these two areas noticeable along the course of the study. These reductions were more pronounced in the D+P group than in the D+CA group. The reduction of the volumes of grey and white matter was compensated by a significant increase in cerebrospinal fluid volume. Conclusions: These findings suggest that the combination of choline alphoscerate and donepezil counters to some extent the loss in volume occurring in some brain areas of AD patients. Cognitive, functional and behavioral parameters tested suggests that morphological changes observed may have clinical relevance and that the combination of the cholinergic precursor choline alphoscerate with a ChE-I may prolong/increase the effectiveness of cholinergic therapies in AD associated with cerebrovascular injury. Key words: Alzheimer’s disease, cerebrovascular injury, choline alphoscerate, donepezil, association
LP27- AGE-DEPENDENT EFFECTS OF THE P75 MODULATOR LM11A–31 ON ALZHEIMER’S DISEASE BIOMARKERS IN A 26-WEEK SAFETY AND EXPLORATORY ENDPOINT TRIAL. H. Shanks1, S. Massa2,3, M. Windisch4, A. Borjesson-Hanson5, F. Longo6, T. Schmitz1(1. Western University — London (Canada), 2. University of California San Francisco — San Francisco (United States), 3. SFVAHCS — San Francisco (United States), 4. Neuroscios — Graz (Austria), 5. Karolinska University Hospital — Stockholm (Sweden), 6. PharmatrophiX — Menlo Park (United States))
Background: The p75 neurotrophin receptor (p75NTR) modulates degenerative signaling networks active in Alzheimer’s disease and mitigates amyloid- and pathological tau-induced synaptic degeneration in preclinical models. LM11A–31 is a first-in-class, small molecule modulator of p75NTR that downregulates degenerative signaling. Because p75NTR is highly expressed on neuronal populations vulnerable to both ‘pure’ AD pathology and other heterogeneous age-related risk factors, we hypothesized that the potential disease-modifying effects of LM11A-31 on a cohort of AD patients would be additionally moderated by their age. Indeed, we noted that age range of our cohort at baseline spanned multiple decades (50–84 years). We therefore examined the potential age effects of LM11A-31 on our predefined endpoint biomarkers of disease progression. Methods: A safety and exploratory endpoint phase 2a trial was conducted by PharmatrophiX in five countries in Europe with each site led by a site principal investigator. The study included three arms: placebo, 200mg bid and 400mg bid LM11A-31 administered by oral capsules for a duration of 26-weeks. Enrollment criteria included a diagnosis of mild to moderate AD according to McKhann (2011) criteria and assessment of CSF amyloid-beta. Given the short treatment interval of this trial (26-weeks) and thus limited degree of progression of cognitive decline, we prioritized age-effect analysis of potential disease-modifying effects of drug on biomarkers of pathological progression. Biomarkers included CSF assays of amyloid, tau and synaptic degeneration; and structural magnetic resonance imaging (sMRI) assays of gray matter volume which serve as a surrogate marker for neuronal/synaptic integrity. For the study population, age groups were defined using a median-split: younger (<72 years) and older (>=72 years). Results: Significant attenuating effects of drug on multiple longitudinal biomarkers of disease progression were detected. Age moderated many of the drug’s attenuating effects. Results outlining age-group specific effects of LM11A-31 on longitudinal CSF and sMRI biomarkers will be presented. Conclusions: This investigation points to the possibility that certain biomarkers can demonstrate age-dependency in response to therapeutic interventions in the context of mild-moderate AD. Because increasing age tends to increase the heterogeneity of brain pathophysiology, the disease modifying effects of LM11A-31 on biomarkers of neuronal and synaptic degeneration may be impacted by the age of the patient sample, in line with prior theoretical modeling work (Bernick et al., 2012). Our results thus inform biomarker selection and age stratification of future studies of LM11A-31 in human AD. Acknowledgments: We thank the participating subjects and families as well as the site teams. Funding: NIA Pilot AD Trial Program. Conflict of Interest: FL has equity interest, is a board member and has a consulting relationship with PharmatrophiX. FL and SM are listed as inventors of LM11A-31 and hence entitled to royalties and related payments. References: Yang et al. Small molecule modulation of the p75 receptor inhibits multiple amyloid beta-induced tau pathologies. Sci Reports 2020a; Yang et al. Small-molecule modulation of the p75 receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice. Acta Neuropath Comm 2020b.
LP28- CLINICAL PHASE IB DATA OF THE ORALLY AVAILABLE ANTI-PRIONIC COMPOUND RD2 THAT DISASSEMBLES AB OLIGOMERS INTO AB MONOMERS. D. Willbold1,2,3, N.C. Cosma4, J. Kutzsche1, O. Peters4(1. Institute of Biological Information Processing (IBI-7), Forschungszentrum Jülich — Jülich (Germany), 2. Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf — Düsseldorf (Germany), 3. Priavoid GmbH — Düsseldorf (Germany), 4. Department of Psychiatry and Psychotherapy, CampusBenjamin Franklin, Charité Berlin — Berlin (Germany))
Background: We have developed the anti-prionic mode of action to disassemble toxic protein assemblies, like oligomers and amyloids, into functional monomeric building blocks. This mode of action is realized by all-D-enantiomeric peptide ligands that stabilize the respective monomers in their native conformations, mostly intrinsically disordered proteins (IDP). This is a purely thermodynamic mode of action, which does not require inhibition of enzymes or ion channels, and is therefore not prone to show side effects. RD2 is an all-D-enantiomeric peptide developed to stabilize Aβ monomers in their IDP conformation. RD2 has been demonstrated to disassemble Aβ oligomers into Aβ monomers in vitro, in vivo and ex vivo, only recently. There, RD2 disassembled Aβ oligomers from brain tissue of former AD patients into Aβ monomers by ex vivo treatment. RD2 has been previously shown to reverse cognition deficits and decelerate neurodegeneration in four different transgenic and non-transgenic animal models. RD2 has also demonstrated safety and tolerability in healthy young volunteers. Objectives: To investigate safety and tolerability in the target age group, we carried out a randomized, placebo-controlled, double-blind, Phase 1b study to evaluate the safety, tolerability and pharmacodynamics of RD2 in patients suffering from MCI due to AD and mild AD. Methods: 20 AD patients in early disease stages fulfilling all three ATN-criteria were recruited to participate in a single center, randomized, placebo -controlled, double-blind study. Patients received once daily oral doses of 300 mg RD2 or placebo for 28 days. Safety and efficacy assessments were executed at baseline, day 28 and day 56 (follow up). Blood sampling was carried out at each time point, EEG and CSF measurements before and at the end of treatment (day 1 and day 28). Imaging (MRI) and functional tests (CERAD, CDR) were performed in parallel to EEG/CSF and additionally at follow up. Results: 10 patients (age 76.9±3.4, MMSE 28±1.6) received placebo and 9 patients RD2 (72.4±6.9, 27.2±2.9). One patient withdraw informed consent before treatment was started. 13 patients reported in total 27 adverse events while no serious adverse event was noted. There was no statistical difference regarding adverse events between treatment and placebo. In contrast to reported anti-Aβ-antibody-treatments, no ARIA events have been observed. EEG and MRI revealed no changes after treatment. While no significant changes were detected in p-TAU, Aβ1–42 and Aβ oligomers in CSF before and after treatment, patients receiving RD2 significantly performed better than those receiving placebo in the CERAD word list at follow up (p≤0.05). Each single dosed patient increased his/her word list score, whereas the patients of the placebo group behaved heterogeneously and did not change significantly as a group. Oral uptake of RD2 was inter-individually very heterogeneous. This allowed pseudo-dose-response correlation analysis. Although changes in Aβ oligomer concentrations in CSF between day 28 and day 1 were not significant between the groups or between time points, there was a significant inverse correlation between changes in Aβ oligomers in CSF (between day 28 and day 1) and the blood plasma concentrations of RD2 in the dosed patients. Conclusions: RD2 showed an excellent safety profile in MCI and mild AD patients. While no significant biomarker changes were detected after 4 weeks of treatment interestingly, a significant improvement of memory function was noted at follow up. To be very conservative and cautious, due to the low number of patients, we do not claim this as a target engagement, nor do we claim the results of the CERAD word list result as a proof of concept. Anyway, despite the small number of patients, we feel that this phase Ib study results deserve reporting to the scientific community. A phase 2 study is scheduled.
LP29- LATE-LIFE DEPRESSION, SUBJECTIVE COGNITIVE DECLINE, AND THEIR ADDITIVE RISK IN INCIDENCE OF DEMENTIA: A NATIONWIDE LONGITUDINAL STUDY. S.Y. Park1, W.M. Bahk2, S.M. Wang2, H.K. Lim2, Y.J. Kwon3, B.H. Yoon4, K.H. Lee5, S.Y. Lee6, M.D. Kim7, B.W. Nam8, E.S. Lim9(1. Keyo hospital — Uiwang-Si (Korea, Republic of), 2. Yeouido St. Mary’s Hospital — Seoul (Korea, Republic of), 3. Soonchunhyang University Cheonan Hospital — Cheonan (Korea, Republic of), 4. Naju National Hospital — Naju (Korea, Republic of), 5. College of Medicine, Dongguk University — Gyeongju (Korea, Republic of), 6. Wonkwang University Hospital — Iksan (Korea, Republic of), 7. Jeju National University School of Medicine — Jeju (Korea, Republic of), 8. Dr. Nam’s Psychiatric Clinic — Chungju (Korea, Republic of), 9. Shinsegae Hyo Hospital — Kimje (Korea, Republic of))
Background: Late-life depression, subjective cognitive decline, and their additive risk in incidence of dementia: A nationwide longitudinal study. Objective: Late-life depression and subjective cognitive decline (SCD) are significant risk factors for dementia. However, studies with a large sample size are needed to clarify their independent and combined risks for subsequent dementia. Methods: This nationwide population-based cohort study included all individuals aged 66 years who participated in the National Screening Program between 2009 and 2013 (N = 939,099). Subjects were followed from the day they underwent screening to the diagnosis of dementia, death, or the last follow-up day (December 31, 2017). Results: Depressive symptom presentation, recent depressive disorder, and SCD independently increased dementia incidence with adjusted hazard ratio (aHR) of 1.286 (95% CI:1.255–1.318), 1.697 (95% CI:1.621–1.776), and 1.748 (95% CI: 689–1.808) respectively. Subjects having both SCD and depression had a higher risk (aHR = 2.466, 95% CI:2.383–2.551) of dementia than having depression (aHR = 1.402, 95% CI:1.364–1.441) or SCD (aHR =1.748, 95% CI:1.689–1.808) alone. Conclusions: Depressive symptoms, depressive disorder, and SCD are independent risk factors for dementia. Co-occurring depression and SCD have an additive effect on the risk of dementia; thus, early intervention and close follow up are necessary for patients with co-occurring SCD and depression.
LP31- EFFICACY AND SAFETY OF BENFOTIAMINE PLUS DONEPEZIL FOR THE TREATMENT OF PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE IN A PHASE 2 CLINICAL TRIAL. X. Pan1, Q. Zhao2, S. Sang1, C. Zhong1(1. Zhongshan Hospital, Fudan University — Shanghai (China), 2. Huashan Hospital, Fudan University — Shanghai (China))
Background: Pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase (KGDH), and transketolase are three important enzymes involved in intracellular glucose metabolism. The reduction in the activities of these enzymes has been well demonstrated in patients with Alzheimer’s disease (AD) (1, 2). Thiamine diphosphate (TDP) is the common coenzyme of these enzymes. Our previous studies have demonstrated that TDP reduction is AD-specific (3) and contributes to cerebral glucose hypometabolism of the disease (4). Benfotiamine, a thiamine derivative able to elevate in vivo TDP level (5–7), has showed the beneficial effect on delaying cognitive decline of patients with mild cognitive impairment and dementia due to AD defined by positive amyloid PET scan and the Mini Mental Status Examination (MMSE) scores > 21 in a phase IIa trial (8). The results suggest that benfotiamine is an effective drug candidate and TDP reduction is a potential target for AD treatment. Objective: To assess the efficacy and safety of benfotiamine treating mild-to-moderate AD delimited by the MMSE scores of 11 to 24 (inclusive). Methods: A randomized, double-blind, placebo-controlled, multicenter trial was conducted in China from Mar 10, 2018 to Apr 28, 2020. Individuals aged between 50 to 80 years (inclusive) who took donepezil (5 mg daily) over six months (inclusive) were screened, enrolled, and randomly assigned (1:1:1 allocation) to high-dose benfotiamine(600 mg daily), low-dose benfotiamine (300 mg daily) or placebo groups. All participants continued to take donepezil (Eisai, Suzhou, China) after the enrollment. The blinded study and treatment period was 52 weeks. The cognitive abilities were measured at weeks 0 (baseline), 12, 24, 36, and 52. The safety evaluation, including adverse events and vital signs, were performed every 4 weeks. The primary endpoint outcome was the change of Assessment Scale-Cognitive Subscale 11(ADAS-cog) score at week 52 from baseline. The secondary endpoint outcomes included the changes of MMSE, Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL), Neuropsychiatric Inventory—Nursing Home version (NPI—NH), NPI caregiver distress scale (NPI-D), and Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) scores at week 52 from baseline. The missing data of the ADAS-cog, MMSE, and ADCS-ADL scores were imputed using the last observation carried forward (LOCF). The other indicators, NPI-NH, NPI-D, and CIBIC-plus scores, were analyzed using the data without imputation. The ADAS-cog scores at baseline were adjusted using mixed methods for repeated measures (MMRM) model and the gate-keeping strategy was utilized for inter-group comparison. The differences between high-dose and placebo groups were first compared. If p value is less than 0.05 (inclusive) between high-dose benfotiamine and placebo groups (α = 0.05), then the differences between benfotiamine treatment group (combining high-dose with low-dose groups) and placebo group were compared. If that p value is also less than 0.05 (inclusive), the differences between low-dose and placebo groups were compared (α = 0.05). Results: Three hundred two subjects were enrolled and divided into high-dose benfotiasmine (99), low-dose benfotiamine (104), and placebo (99) groups. In the overall population, the mean changes of ADAS-cog scores at week 52 from baseline did not reach significant difference between high-dose benfotiamine or benfotiamine treatment and placebo groups. This result drove us to perform a further ad-hoc analysis to examine the changes of ADAS-cog scores at week 52 from baseline in the placebo group based on the severity of the disease assayed by MMSE scoring at baseline. The results showed that the changes of ADAS-cog scores were not significant in patients with the MMSE scores of 20 to 24 but exhibited obvious increases in patients with the MMSE scores of 11 to 19 in placebo group. Therefore, we divided the participants into two subgroups: mild subgroup delimited by the MMSE scores of 20 to 24 and moderate subgroup with the MMSE scores of 11 to 19 at baseline. Post hoc analyses indicated that the increases of ADAS-cog scores at week 52 from baseline were the least in high-dose subgroup of moderate cases (-3.07, p = 0.027) and the second least in low-dose subgroup (-1.49, p > 0.05) as compared with that in placebo subgroup in the full analysis set. The significant differences in ADAS-cog scores of patients with moderate AD between high-dose benfotiamine and placebo groups were further verified using the imputation methods of the copy-reference multiple-imputation and the worst observation carried forward (the worst values from individual self during the treatment). Changes in all secondary outcomes at week 52 from baseline did not exhibit statistical differences. The incidences of adverse events had no significant differences among three groups. Conclusions: Benfotiamine is effective in delaying cognitive decline of AD patients with excellent safety, preliminarily demonstrating the concept of TDP reduction as a therapeutic target for AD. Further large-sample clinical trials should be performed. Donepezil treatment seriously interferes with the efficacy observation of new drugs in the treatment of mild AD, which should be paid attention to in the future studies. Disclosure: Chunjiu Zhong holds shares of Shanghai Rixin Bitech Co., Ltd., which is dedicated to developing drugs for the prevention and treatment of AD. The other authors declare that they have no competing interests. References: 1. Gibson GE, Sheu KF, Blass JP, et al. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol 1988; 45(8):836–840. 2. Butterworth RF, Besnard AM. Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer’s disease. Metab Brain Dis 1990; 5(4):179–184. 3. Pan X, Fei G, Lu J, et al. Measurement of blood thiamine metabolites for Alzheimer’s disease diagnosis. EBioMedicine 2016; 3:155–162. 4. Sang S, Pan X, Chen Z, et al. Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer’s disease, whereas amyloid deposition does not. Alzheimers Res Ther 2018; 10(1):26. 5. Xie F, Cheng Z, Li S, et al. Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride. J Clinic pharmacol 2014; 54(6):688–695. 6. Park WS, Lee J, Hong T, et al. Comparative pharmacokinetic analysis of thiamine and its phosphorylated metabolites administered as multivitamin preparations. Clin Ther 2016; 38(10):2277–2285. 7. Sheng L, Cao W, Lin P, et al. Safety, tolerability and pharmacokinetics of single and multiple ascending doses of benfotiamine in healthy subjects. Drug Des Devel Ther 2021; 15:1101–1110. 8. Gibson GE, Luchsinger JA, Cirio R, et al. Benfotiamine and cognitive decline in Alzheimer’s disease: Results of a randomized placebo-controlled phase IIa clinical trial. J Alzheimers dis 2020; 78(3):989–1010.
LP32- VIVIAD, A PHASE 2B STUDY INVESTIGATING VAROGLUTAMSTAT IN PATIENTS WITH MCI AND MILD AD: UPDATE ON DOSE SELECTION AND INTERIM BLINDED SAFETY RESULTS. F. Weber1, M. Schaeffer2(1. CMO Vivoryon Therapeutics N.V. — München (Germany), 2. CBO Vivoryon Therapeutics N.V. — München (Germany))
Background: Varoglutamstat (PQ912), a small molecule glutaminyl cyclase (QPCT) inhibitor, reduces the brain levels of pyroglutamate-3-Abeta (N3pE-Abeta), a toxic Abeta variant shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). A prior Phase 2a study (NCT02389413) reported encouraging first evidence of the disease-modifying activity of varoglutamstat, most importantly with statistically significant change from baseline in working memory after only 12 weeks of treatment. Thus, showing a positive effect on a hallmark feature of AD. While varoglutamstat was generally well tolerated, a maximum tolerated dose (MTD) was reached at 800 mg twice daily (BID). These results led to the initiation of a state-of-the-art Phase 2b trial investigating multiple cognitive, safety and biomarker endpoints. Safety data reported to date show no on-target toxicity and no clinical signs of amyloid-related imaging abnormalities (ARIA), a severe side effect reported for antibody-based AD therapies. Objectives: To evaluate the safety and efficacy of Varoglutamstat in patients with early AD and mild cognitive impairment (MCI). To convey and update on the status of the Phase 2b study. Methods: VP/LAD (NCT04498650) is a multicenter randomized, placebo-controlled, double-blind, parallel group dose finding Phase 2b study in patients with early Alzheimer’s disease (MCI due to AD and mild AD). The treatment duration varies between 48 and 96 weeks depending on the time of inclusion. Efficacy is assessed by the Cogstate NTB and the Amsterdam Quality of Life Questionnaire. Secondary endpoints include functional read-outs by EEG and assessment of functional and inflammatory biomarkers. In June 2022, an independent Data Safety Monitoring Board (DSMB) decided that the highest dose tested, 600 mg BID, a dose known to result in a target occupancy of close to 90%, was well tolerated and safe to be carried forward for the second part of the study. Patients previously randomized to 300 mg BID have been blindly up-titrated to 600 mg BID. All data remain blinded outside the DSMB. Interim Results: As of September 6, 2022, the study has enrolled 224 patients with a planned total of 250 participants. Per September 6th, 376 patients were screen failures. Of the 224 patients randomized, 114 were female and 110 male, with a mean age of 68 years. As recommended by the DSMB, all patients are dosed with either 600 mg BID varoglutamstat or placebo. As of September 6, 175 patients had reached week 12, 66 patients had reached week 48 and 17 patients had reached week 84 of treatment. The occurrence of adverse events normalized per 100 visits continues to be stable around 31, indicating that up-titration from 300 to 600 mg twice daily did not result in an increased frequency of adverse events. Overall, 4 treatment emergent adverse events have led to discontinuation. Further updates on the safety data and the baseline characteristics of the patients enrolled into the trial so far will be reported at CTAD 2022. Conclusion: The state-of-the-art Phase 2b study VIVIAD aims to yield important results in early AD for Varoglutamstat, the first small molecule and only project in clinical development selectively targeting the de novoproduction of neurotoxic N3pE-Abeta. Through a carefully crafted study design, the study was able to achieve improved tolerability for Varoglutamstat compared to a prior Phase 2a study (NCT02389413), without significantly sacrificing target engagement. The study continues as planned, with participants receiving 600 mg active treatment BID or placebo for at least 48 weeks.
LP33- QUANTITATIVE EEG RESULTS FROM A MULTIPLE ASCENDING DOSE STUDY IN HEALTHY VOLUNTEERS WITH NEURORESTORE ACD856, A POSITIVE MODULATOR OF NEUROTROPHIN TRK-RECEPTORS. K. Önnestam1, B. Nilsson1, M. Rother1, E. Rein-Hedin2, P. Anderer3, M. Kemethofer3, M. Halldin1, P. Forsell1, G. Nordvall1, J. Sandin1, M. Segerdahl1(1. AlzeCure Pharma AB — Huddinge (Sweden), 2. CTC Clinical Trial Consultants AB — Uppsala (Sweden), 3. The Siesta Group Schlafanalyse GmbH — Vienna (Austria))
Background: Quantitative EEG results from a multiple ascending dose study in healthy volunteers with NeuroRestoreÒ ACD856 is a novel positive allosteric modulator of Trk-receptors in clinical development for the treatment of Alzheimer’s disease (AD) and other disorders where cognition is impaired. Neurotrophin signalling pathways, such as those mediated by NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor), have in numerous studies been shown to be important for neuronal cell function, communication, and cell survival in brain areas vital for cognitive function, such as the hippocampus and basal forebrain. BDNF and NGF mediate their effects by binding to their Trk- receptors; TrkA or TrkB, respectively. A large body of pathological and mechanistic evidence suggests that loss of NGF signaling contributes significantly to the dysfunction of basal forebrain cholinergic neurons during the course of AD. Several studies have also shown a decrease of BDNF in the hippocampus and in cerebrospinal fluid (CSF) in disease states with cognitive decline, including AD. This suggests that decreased BDNF signalling may contribute to the progression of hippocampal dysfunction. Increased NGF and BDNF signalling could potentially enhance cholinergic function, synaptic plasticity and improve cognition. This supports the development of stimulators of NGF and BDNF signalling, such as ACD856, as cognitive enhancers for the treatment of Alzheimer’s disease. Objectives: The aim of the multiple ascending dose (MAD) study was to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple ascending doses of ACD856. As part of this study, quantitative electroencephalography (qEEG) was included to allow for an exploratory analysis of pharmacodynamic effects of ACD856 on CNS activity and target engagement. Methods: ACD856 was administered once daily over a treatment period of 7 days in 3 ascending dose cohorts. Subjects in each cohort were randomised to receive either ACD856 (n=6) or placebo (n=2). qEEG was recorded for the two last study cohorts. This resulted in 6 subjects treated with 30 mg ACD856, 6 subjects with 90 mg ACD856, and 4 placebo subjects. EEG recordings were performed at baseline, 1.5, 6 and 24 hours following the first dose, and at 1.5 hours following the last dose of ACD856. Results: The qEEG results show that treatment with ACD856 significantly increases the relative theta power and decreases fast alpha and beta power which leads to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio (TBR). These effects are seen both in comparison to placebo (TBR: p<0.05) and when analysing intraindividual treatment induced EEG changes (TBR: p<0.01). These effects are most evident in the vigilance-controlled EEG recordings with eyes closed as opposed to resting EEG recordings with eyes closed or open and are most pronounced at 24 hours post 1st dose and 1.5 hours after dose on day 7. Conclusion: NeuroRestore ACD856 has a pharmacodynamic effect on EEG activity in healthy volunteers suggestive of target engagement. The qEEG results are in line with previously reported exposure of ACD856 in the cerebrospinal fluid, with relevant concentrations reaching CNS. The new data shows that ACD856 not only passes the blood brain barrier but also has an effect on neuronal pathways in the CNS. In the next step, ACD856 will be evaluated in a patient population to better understand the clinical relevance of these results.
LP34- A RANDOMIZED DOUBLE-BLIND STUDY TO ASSESS THE SKIN IRRITATION AND SENSITIZATION POTENTIAL OF ONCE-WEEKLY DONEPEZIL TRANSDERMAL DELIVERY SYSTEM. M. Sabbagh1, P. Mathew2, A. Blau3(1. Barrow Neurological Institute — Phoenix (United States), 2. Novum Pharmaceutical Research Services — Toronto (Canada), 3. Corium Inc — Grand Rapids (United States))
Background: Oral donepezil, a reversible acetylcholinesterase inhibitor, is the most used treatment for dementia of the Alzheimer’s type. Once-weekly donepezil TDS (Adlarity®) was approved in 2022 by the US Food and Drug Administration for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type. Previous study results showed that 10-mg/d and dose-normalized 5-mg/d donepezil TDSs are bioequivalent to 10 mg/d of oral donepezil, with an acceptable skin adhesion and safety profile (Tariot PN, et al. J Alzheimers Dis. 2022;9:doi:10.3233/JAD-220530). Objective: This study’s aim was to assess the skin irritation and sensitization potential of once-weekly 5-mg/d donepezil TDS. Methods: In this placebo (vehicle) TDS-controlled, randomized, double-blind phase 1 trial (NCT03397862), healthy volunteers aged ≥40 years with Fitzpatrick skin type of I, II, or III and without a history of severe allergies to medical adhesive tapes and dressings were evaluated for the primary end points of skin irritation and sensitization potential. There was a 30-day screening phase before TDS application. During a 21-day induction phase, participants received weekly both the 5-mg/d donepezil TDS and a placebo TDS, without donepezil, to opposite sides of their back. Participants were randomized to receive applications of donepezil TDS on one side of the back and placebo TDS on the opposite side, or vice-versa, with 3 consecutive weekly TDS applications to the same skin site. After completion of the induction phase, participants entered a ∼14-day rest period, followed by a challenge phase for skin sensitization assessments. During this challenge phase, donepezil TDS and placebo TDS were applied to naïve skin sites on opposite sides of the back in a randomized manner for 48 hours followed by a 3-day observation period. After a 4–8-week rest phase some participants also underwent a 48-hour rechallenge phase if the participant was designated as potentially sensitized to one or both TDSs. The combined skin irritation score was based on the sum of the dermal response scale score (range, 0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) and other effects scale score (range, 0 [none observed or slight glazed appearance] to 3 [glazing with fissures, dried serous exudate film covering all or part of the patch site, or small petechial erosions and/or scabs]). Skin irritation scoring was performed 30 minutes after TDS removal on days 8, 15, and 22 in the induction phase. Results: Among the 256 participants who were randomized and received ≥1 dose of any treatment, the mean (SD) age was 54.3 years (9.4 years); 48% were aged 50–64 years, 16% were aged ≥65 years, and 59.4% were women. After the first weekly TDS application (day 8) in the induction phase, the incidence of combined irritation scores of 0 (no evidence of skin irritation) and 1 (minimal irritation) were similar between donepezil (189/195 TDSs [96.9%]) and placebo (186/194 TDSs [95.9%]). Two donepezil TDSs (1%) had a score of 4 (definite edema), and there were no scores ≥5 (erythema, edema, and papules). There were no scores >2 for the placebo TDSs. At the third weekly TDS application (day 22) in the induction phase, irritation scores were higher for donepezil TDS versus the placebo TDS. For donepezil (n = 195 TDSs), 76 TDSs (39.0%) had a skin irritation score of 0 and 72 TDSs (36.9%) had a score of 1; 39 TDSs (20.0%) had a score of 2, 3 TDSs (1.5%) had a score of 3, and 2 TDSs (1.0%) had a score of 4. For placebo (n = 193 TDSs), most scores were 0 (164 TDSs [85.0%]) and 1 (25 TDS [13.0%]); 4 TDSs (2.1%) had a score of 2, and there were no placebo TDSs with scores ≥3. The average of the mean combined irritation score was 0.55 out of a possible maximum 7, indicating none to minimal skin irritation for donepezil TDS, and 0.19, indicating no skin irritation for placebo TDS (treatment difference, −34 [95% CI, −0.43 to −0.25]). TDS skin irritation scores during the induction phase appeared to be independent of age, ethnicity, or sex, although there was a slight numerical trend of better skin tolerability in the ≥65-year-old versus the <65-year-old age group. In total, 4 of 198 participants (2.0%) were considered potentially sensitized to donepezil TDS treatment, and no participants were potentially sensitized to placebo TDS. Conclusion: Once-weekly 5-mg donepezil TDS demonstrated acceptable skin tolerability, with minimal skin irritation under conditions of use of 3 consecutive weekly patch applications to the same skin site and minimal sensitization potential, supporting its use as treatment for dementia of the Alzheimer’s type.
LP36- ABVAC40 ELICITS A PREDOMINANTLY TH2 IMMUNE RESPONSE THAT SUPPORTS ITS EXCELLENT SAFETY PROFILE. M. Montañés1, C. Martín-Fortún1, S. Castillo1, E. Molina1, J. Terencio1, M. Sarasa1(1. Araclon Biotech-Grifols — Zaragoza (Spain))
Background: The balance between Th1 (cell-mediated) and Th2 (humoral) immune pathways is a key factor in determining the safety of a vaccine. AN1792, the first Alzheimer’s disease (AD) vaccine entered clinical trials, was terminated due to meningoencephalitis attributed to a cell-mediated immflamatory response (1, 2). Subsequent to the experience gained from AN1792 vaccine, immunotherapies for AD that predominantly activate Th2 cells would be strongly recommended. ABvac40, was designed as the first active immunotherapy against the C-terminal end of amyloid β 1–40 (Aβ40) in order to avoid antibody binding to the unprocessed amyloid precursor protein (APP) inserted in the cell membrane. This vaccine has shown a great safety and tolerability profile in a phase I clinical trial as well as in the preliminary data from a currently ongoing phase II clinical trial. Confirmation of a Th2 biased immune response would suggest that ABvac40 does not induce a proinflammatory response, in agreement with the safety results reported. Objective: The aim of this study is to determine whether the drug substance, i.e., the hapten Aβ33–40 coupled to the carrier protein, induces a Th1 or Th2 polarized immune response in patients from phase II clinical trial AB1601, since aluminum hydroxide used as an adjuvant in ABvac40 is known to have a Th2-polarizing activity. Methods: Peripheral blood mononuclear cells (PBMCs) obtained from verum (n=37) and placebo (n=12) treated patients recruited to ABvac40 phase II study were stimulated in vitro by the drug substance of the vaccine. The frequency of IFN-γ or IL-4-secreting T cells as prototypic Th1 and Th2 cytokines, respectively, were determined, at both the preimmune visit and after-five vaccine inoculations employing a commercially available IFN-γ/IL-4 dual FluoroSpot kit. Number of spot forming units (SFUs) in negative controls (non-stimulated PBMCs) were subtracted from stimulated samples to account for background responses. All differences in SFUs between groups were examined using Mann Whitney test, except for preimmune versus after-five inoculations time points that were analyzed using Wilcoxon’s test. Results: A significantly higher frequency of IL-4 SFUs was found in ABvac40 treated samples compared to IFN-γ (p < 0.0001) while no placebo response was observed with any cytokine. To be noted that, among patients samples receiving ABvac40, 35 out of 37 developed a polarized Th2 response. The frequency of IFN-γ and IL-4 secreting cells increased significantly after five immunizations (p < 0.0001 in both cases) compared to the basal time point in the verum group. In the placebo samples, no significant changes were found in any case. As expected, since the patients at the preimmune timepoint were not in contact with the vaccine, no significant changes between the stimulated and non-stimulated samples in the preimmune group were detected. Observed: SFUs were specific to the cells stimulated by the ABvac40 drug substance, since in the verum group a significant increase of both cytokines was observed in response to ABvac40 stimulation (p<0.0001). Conclusion: ABvac40 drug substance induces a Th2 polarized T-helper immune response that promotes a humoral response and minimizes a proinflammatory effect, which is consistent with the excellent safety profile shown by ABvac40 in phase I and phase II studies. References: Pride M et al., Neurodegener Dis. 2008; 5(3–4):194–6. Mantile F and Prisco A. Biology (Basel). 2020 Nov 27;9(12):425. M. Montañés, C. Martín-Fortún, S. Castillo, E. Molina, J. Terencio and M. Sarasa are full-time employees at Araclon Biotech-Grifols.
LP37- CY6463 ADMINISTRATION IN HEALTHY PARTICIPANTS WAS ASSOCIATED WITH IMPROVEMENTS IN ALZHEIMER’S DISEASE-RELEVANT BIOMARKERS BASED ON A SYSTEMATIC ANALYSIS OF MULTIPLE PHASE 1 CLINICAL TRIALS USING KEM® EXPLAINABLE AI. M. Kindermans1, H. Chakroun1, J. Chickering2, C. Glasser2, P. Iriso1, F. Parmentier1, T. Milne2, P. Wilson2, M. Afshar1(1. Ariana Pharma — Paris (France), 2. Cyclerion — Cambridge (United States))
Background: CY6463 is a first-in-class, CNS-penetrant, soluble guanylate cyclase (sGC) stimulator that modulates a key node in a fundamental signaling pathway. CY6463 has been evaluated in two Phase 1 studies (NCT03856827, NCT04240158) and is in clinical development for the treatment of CNS diseases including Alzheimer’s disease (AD). A total of 134 healthy participants were enrolled across 2 randomized, placebo-controlled, Phase 1 studies in which single ascending doses, multiple ascending doses, food effect (crossover design), and the pharmacology of CY6463 (crossover design) were evaluated. In each study, safety, pharmacokinetic, and pharmacodynamic assessments were collected at baseline and at the end of dosing. Safety assessments included adverse event collection, clinical laboratory values, vital signs, and electrocardiography. Pharmacodynamic assessments included electroencephalography (EEG) measures, cognitive performance tests, saccadic eye movement (SEM) evaluations, and cerebrospinal fluid (CSF) biomarkers. KEM (Knowledge Extraction and Management) explainable Artificial Intelligence (xAI) is a tool that systematically extracts and evaluates all associations between all variables in a database. An objective of such an analysis is the identification of potential subgroups with higher chances of treatment response, paving the way to the development of a precision-medicine approach and potentially increasing chances of clinical success. Objectives: The goal of this post hoc analysis was to use KEM xAI to characterize CY6463 impact on a range of endpoints and to identify characteristics of subgroups that had a greater pharmacodynamic response. Methods: All data were integrated into a single, consolidated meta-database totaling 134 subjects and 48,300 variables. Data across the 4 different study designs were integrated into a common data-driven framework with doses and plasma concentrations binned into three different levels — low, medium, and high. The analysis was divided into two steps: first, the impact of CY6463 on all pharmacodynamic outcomes was assessed to identify changes associated with CY6463 treatment; second, subgroups of subjects with a further improved response were characterized. In the first step, KEM explored the associations between pharmacokinetic and pharmacodynamic variables in the meta-database. Filtering the associations using metrics such as Support (number of examples), Confidence (conditional probability), Lift (relative probability) and Fisher’s p-value (unadjusted for multiplicity), identified the associations with the greatest support for future hypothesis testing. In total, 1015 theoretical associations between all variables were explored by KEM, extracting a subset of 20,860,826 associations that were further reduced to a subset of 67 using the filtering metrics. In a second step, KEM was used to identify biomarkers that stratified the patients within the identified associations. Results: On safety, our analysis showed that headache was the only adverse event associated with CY6463 treatment, with transient headache occurring more often in subjects with high total dose of CY6463. Headaches were generally mild and did not lead to discontinuation. No other associations among safety variables were identified. On pharmacodynamics, our analysis showed that faster speed and better accuracy in the Milner Maze Test (MMT) was associated with a high total dose of CY6463 (nominal p=0.004 for speed and nominal p=0.045 for accuracy). Increase in alpha power (Pz-O1) as measured by EEG during eyes closed resting state was also associated with high total CY6463 dose (nominal p=0.003). Additionally, decrease in CSF levels of matrix metalloproteinase 3 (MMP3; nominal p=0.008) and increase in CSF levels of cyclic guanosine monophosphate (cGMP; nominal p=0.013) were associated with CY6463 treatment. In the second step of the analysis, baseline age, blood pressure, and certain neurophysiological measures were found to be associated with greater pharmacodynamic response on some endpoints. For example, greater CY6463 treatment-associated improvement in MMT (Cohen’s d increase by respectively 39% and 157% for respectively the speed and the accuracy) was seen in participants with high baseline systolic blood pressure (≥121mmHg). Similarly, greater CY6463 treatment-associated improvements in MMT were seen in those with higher age (≥49y): Cohen’s increase by respectively 40% and 120%. Focusing on subjects with higher age also enables the identification of additional signals such as the decrease in EEG theta power Pz-O2 eyes closed (nominal p = 0.005). Conclusion: Results for safety endpoint associations were consistent with the favorable safety profile of CY6463 previously reported. On pharmacodynamics, this analysis identified CY6463 treatment-associated, positive effects on endpoints that have been linked with AD. For example, AD patients have been described in previous studies as showing increased theta and decreased alpha power by EEG as well as increased MMP3 and decreased cGMP levels. Demonstration of improvement on these AD-associated endpoints as well as identification of candidate patient-selection criteria lay a promising foundation for the design of hypothesis-testing, next-phase studies. This analysis of Phase 1 data in healthy participants demonstrates the ability of explainable AI tools, such as KEM, to integrate and analyze broad and heterogeneous sources of data from different trials, to provide insight into a drug’s mechanism of action, to generate testable hypotheses, and to guide optimal design of clinical development next steps.
LP38- A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO ASSESS TOLERABILITY, SAFETY, PHARMACOKINETICS AND EFFECT OF AZP2006 ON CEREBROSPINAL FLUID BIOMARKERS IN 36 PATIENTS WITH PROGRESSIVE SUPRANUCLEAR PALSY. P. Verwaerde1, N. Callizot1, S. Del Signore1, A. Blondel1, C. Estrella1(1. Alzprotect — Loos (France))
Background: Progressive Supranuclear Palsy (PSP) is a rare, rapidly progressing, neurodegenerative 4-repeat tauopathy. Currently, no medications are approved for treatment of PSP. AZP2006 (EZEPROGIND) is a first-in-class disease-modifying small molecule that modulates the release of progranulin (PGRN). In vitro, AZP2006 promotes neuron survival, enhances synaptic function, decreases Tau hyperphosphorylation and reduces neuroinflammation via PGRN. The chronic oral administration (3mg/kg/day) to rodent models of Tauopathy, AD and PD, showed to prevent and reverse both cognitive and motor deficits. Phase-1 studies (SAD and MAD) demonstrated that oral administration of AZP2006 (liquid formulation) to healthy adults was well tolerated, had a good safety profile and no side effects were observed. Orphan drug designation has been granted to AZP2006 by the EMA and the FDA. Objectives: Primary objectives are to determine safety and tolerability of AZP2006 12-week oral administration in patients suffering from PSP, and the pharmacokinetic profile in plasma, blood, and CSF. Secondary objectives are to determine the effect of AZP2006 on up to 21 CSF biomarkers including PGRN, Tau, P-Tau, NfL, and amyloid peptides at baseline and after 12-week treatment with 2 different doses of AZP2006 or placebo, and to evaluate the exposure-response relationship (PK/PD) of AZP2006 on CSF and plasma putative pharmacodynamic biomarkers. Exploratory objectives are to evaluate the effects on clinical endpoints including SPS-RC rating scale. Methods: AZP2006C04 (NCT04008355) is a phase-2a study conducted in 3 French clinical centers. It is a randomized, double-blind, placebo-controlled, parallel group study, comparing 2 doses of AZP2006 (60 mg once daily during the 12-week treatment period and 80 mg once daily for 10 days followed by 50 mg once daily), versus placebo in 36 patients with PSP (men and women aged ≥40 years and ≤80 years). Lumbar punctures were performed on D1 and D84. PK blood sampling was performed 36 times throughout the treatment and a further 12-week follow-up period. Randomized patients underwent a comprehensive clinical evaluation at Day-1, Day 84 (end of treatment) and Day 180. Results: AZP2006C04 successfully completed the enrollment of 36 patients in January 2022. Last patient visit occurred in July 2022. Database lock and unblinding was performed in September 2022 followed by data analysis. Both AZP2006 60 mg/day and 80mg/50mg/day 12-week administration were well tolerated, no product related SAEs was reported. Baseline clinical characteristics of the enrollees, baseline and changes of CSF and plasma biomarkers upon 12-week treatment will be presented. In addition, selected disease characteristics evolution (including PSP-RS and MDS-UPDRS Part II) will be revealed. Conclusion: AZP2006C04 represents an original approach based on Progranulin modulation to treat PSP. AZP2006 12-week administration was well tolerated by patients and safety was overall satisfactory. Final validated unblinded results will be discussed. AZP2006 will be followed by AZP2006C05 which is designed as a pivotal Phase 2/3 study for the treatment of PSP and should take place in Europe and the USA. Reference: Callizot, N., Estrella, C., Burlet, S. et al. AZP2006, a new promising treatment for Alzheimer’s and related diseases. Sci Rep 11, 16806 (2021). 10.1038/s41598-021-94708-1
LP39- THREE-YEAR OMEGA-3 PUFA TRIAL TARGETING CEREBRAL WHITE MATTER LESIONS AND INTEGRITY BREAKDOWN IN OLDER ADULTS: APOE STRATIFIED AND EXPLORATORY RESULTS. G. Bowman1, C. Murchison2, L. Silbert3, H. Dodge4, K. Hagen4, D. Lahna4, H. William5, J. Kaye3, J. Quinn3, L. Shinto4(1. McCance Center for Brain Health, Department of Neurology, Massachusetts General Brigham and Harvard Medical School — Boston (United States), 2. Department of Biostatistics, University of Alabama at Birmingham — Birmingham (United States), 3. Department of Neurology, Oregon Health & Science University and Veterans Affairs Portland Health Care System — Portland (United States), 4. Department of Neurology, Oregon Health & Science University — Portland (United States), 5. Department of Internal Medicine, University of South Dakota School of Medicine and Fatty Acid Research Institute — Sioux Falls (United States))
Background: Intake and blood n-3 PUFA [20:5 and 22:6] are lower in people with MRI derived white matter lesions (WML) suggesting that these fatty acids with known anti-inflammatory and neuroprotective properties have a role in the prevention of a major vascular contribution to cognitive impairment and dementia. Objective: This trial was designed to examine whether n-3 slows total WML progression and sustains white matter integrity in older adults with baseline enrollment evidence of WML and suboptimum blood n-3. Methods: Double-blind, placebo-controlled trial in non-demented adults with plasma n-3 < 110 ug/mL and total WML ≥ 5 cm3. Participants randomized to 1.65 g of n-3 or placebo. Primary outcome was annual WML change. Diffusion tensor imaging fractional anisotropy (DTI-FA) was a secondary outcome. Treatment stratification by apoE genotype was pre-specified. Linear mixed-effects models used for hypothesis testing. Results: 102 participants were randomized (51 per group; 75–96 years old; 60% female, 28% apoE4 positive). 78 completed the 3-year visit (39 per group). ITT showed annual WML increase of 1.34 cm3 (95%CI: 0.80–1.88) vs 1.19 (0.64–1.74)(p=0.303) and annual DTI-FA change was -0.002718 vs -0.001352 (p=0.069) in the placebo and active, respectively. ApoE4 carriers on placebo had annual DTI-FA decline of -0.005 vs -0.002 in n-3 treatment group (p=0.037). An exploratory comparison of participants with study exit plasma n–3 ≤ 110 ug/mL vs >110 ug/mL exhibited annual WML increases of 1.71 vs. 0.99 cm3 (p=0.026). Conclusion: N-3 PUFA failed to slow total WML progression in all randomized participants; however, those that superseded plasma n-3 >110 ug/mL by study exit had a 50% reduction in annual total WML increase. ApoE4 carriers with accelerated white matter integrity breakdown may benefit from n-3 PUFA. A more extensive, well-powered trial to confirm or refute these results are necessary.
LP40- ACCOUNTING FOR DISEASE MODIFICATION IN MODELS OF COST EFFECTIVENESS OF MABS SUCH AS LECANEMAB AND DONANEMAB. S. Hendrix1, C. Mallincrodt1, S. Dickson1(1. Pentara Corporation — Millcreek (United States))
Objectives: The first treatment for Alzheimer’s disease was approved nearly 30 years ago and most treatments on the market today are considered primarily symptomatic. In the past 20 years, dozens of companies have tested treatments thought to be disease modifying with minimal or no success. Only recently have disease modifying therapies achieved success in clinical trials. The distinction between disease modification and symptomatic therapies is critical and can be based on clinical patterns of treatment response as well as biomarker outcomes. The distinction between symptomatic and disease modifying effects results in striking differences in the cost effectiveness modeling associated with each type of treatment. Methods: We define disease modification as a treatment benefit that is maintained if treatment is discontinued, but continues to accrue over the time during treatment, and can be modeled as a slowing of progression time. A symptomatic benefit is one that achieves benefit only when the treatment is in the body and is lost with clearance of treatment. Disease modifying effects are expected to be larger in early stages of disease (pre-dementia AD) and smaller in later stages of disease, when measured in terms of time savings, although point benefits may be larger in later stages due to ceiling effects in early disease. Symptomatic treatments work best in later disease stages when symptoms are prominent. Results: Combining these definitions and expected patterns of treatment response results in implicit models of economic cost savings. Both lecanemab and donanemab have shown slowing in the range of 30% during 1–1.5 years of treatment. A 30% slowing of progression results in a 5 month time savings with 1 year of treatment, calculated as (0.3*12)/(1-.3). With this rate of slowing, 2 years and 4 months of treatment would postpone all AD costs for 1 year over the course of disease. If direct annual costs associated with dementia are in the range of $27,000 (USD), and additional indirect costs are also considered, such as lost work for caregivers, then a cost per year in the range of $20–30K could be justified. If treatment is started earlier, and the treatment effect is larger in early disease as expected, then these cost savings could be much larger and maintaining patients in a very mild stage of disease could allow this larger effect to be self-aggregating. Conclusion: Disease modifying treatments require a different approach for analysis than symptomatic treatments. Focusing on point benefits at a single time point is appropriate for symptomatic treatments, but not for disease modification. The permanent benefit achieved with disease modifying treatments translates into a benefit across the remaining lifespan of a treated patient and should be taken into consideration when evaluating cost effectiveness of new therapies.
LP41- EFFECTIVENESS OF DIGITAL-BASED MULTIDOMAIN INTERVENTION FOR MILD COGNITIVE IMPAIRMENT. M.D. Patterson1, J. Leonardo1, S.B. Jabar1, Y.G. Rykov1, B.A. Gangwar1, J. Yee1, N. Kandiah2, K.P. Ng3(1. Neuroglee Therapeutics — Singapore (Singapore), 2. Lee Kong Chian School of Medicine — Singapore (Singapore), 3. National Neuroscience Institute — Singapore (Singapore))
Background: Pharmacological treatments for Alzheimer’s Disease (AD) have had little success at slowing its progressive development. This may be because treatments began too late, after brain damage was already irreversible. However, more recent research has targeted a prodromal stage of AD, Mild Cognitive Impairment (MCI) (Petersen, 2016). Targeting modifiable lifestyle risk factors is a non-pharmacological approach to treating MCI since up to 40% of AD cases may be preventable by modifying lifestyle factors if treatment occurs at an early enough stage (Livingston et al., 2020). The most successful previous attempt at modifying lifestyle factors was a multidomain intervention, the FINGER study which demonstrated that diet, exercise, and cognitive training could significantly improve cognitive scores and reduce the risk of cognitive decline (Ngandu et al., 2015). Thus, multidomain lifestyle interventions hold much promise in preserving cognition. However, this approach does not scale well, is expensive, and is difficult to monitor individuals’ progress and to tailor the interventions for greatest individual benefit. Digital therapeutics offers an approach to overcome these issues, making treatment more accessible, allows monitoring of each individual, and allows improved health outcomes on a larger scale. Objectives: The objective of this study was to evaluate the effectiveness and safety of a 12-week multidomain intervention delivered using a digital platform, NG-001, on cognitive function, mental health, and quality of life of older adults (50–70 years old) diagnosed with MCI. Participants were tested at week 1 and week 12 of the study. The primary outcome measures were changes in processing speed and executive function, as measured by the Neuropsychological Test Battery (NTB), and changes in depression, anxiety, and stress as measured by the Depression Anxiety Stress Scale (DASS-21). The secondary outcome measures were changes for overall cognition from the NTB, and Quality of Life (QOL), as measured by a subset of the QOL-AD questionnaire. The exploratory outcome measures were changes in memory measures from the NTB in MCI patients, and changes on the Zarit Burden Interview for care partners. Methods: A 12-week open-label clinical trial was conducted in older adults diagnosed with amnestic MCI (n=27). Participants undertook 10 roughly 1-hour long sessions delivered weekly via a digital tablet at their own convenience consisting of: 1) health literacy education; 2) physical and mindfulness exercises; 3) reminiscence therapy; 4) cognitive games. Participants completed the Neuropsychological Test Battery (NTB), Depression Anxiety Stress Scale (DASS), and Quality of Life in Alzheimer’s Disease (QoL-AD) surveys at baseline and at the end of the trial. The NTB was similar to that used in the FINGER Study. Results were adjusted for the participants’ age and education levels using normative data, before being converted to composite scores representing overall cognition, processing speed, executive function, overall memory, immediate memory, and delayed memory. Fifteen of the MCI patients were enrolled with care partners who installed a care partner app on their own mobile phones where they were able to monitor their partner’s progress on completing the therapy. The care partner app included articles that provided information about MCI and compensatory strategies for their partner’s cognitive decline. Care partners completed the Zarit Burden Interview before and after the trial. Changes in NTB, DASS, QoL-AD, and Zarit Burden Interview scores were assessed using paired Wilcoxon signed ranked tests (two-tailed) to determine if differences between baseline and post-intervention scores were significant at a statistical significance of p<.05. Hedge’s g was calculated for effect size. Results: Significant cognitive improvements were seen across MCI participants, whose compliance with the therapies was over 96%. For our primary outcome measures, there were no significant changes in Executive Functioning (mean z-score of -0.491 vs -0.424) or Processing Speed (0.153 vs. 0.178), (both p>.05). MCI participants showed improvements in mood as measured by DASS. Depression (4.643 vs. 3.214, g = 0.228), Anxiety (6.357 vs. 3.786, g = 0.440) and Stress (7.786 vs. 5.429, g = 0.356) scores all decreased significantly (all p<.05). Secondary outcome measures of NTB Overall Cognition (-0.440 to -0.213) were significantly (p<.001, g = 0.352) improved, but QoL-AD scores were not significantly affected by the intervention (p>.05). Other exploratory outcome measures, Overall Memory (-0.587 to -0.132, g = 0.407), as well Immediate (-0.549 to -0.030, g = 0.512) and Delayed memory (-0.626 to -0.233, g = 0.305) were significantly improved from baseline to post-intervention (all p<.001). Zarit Burden scores given by caregivers were not significantly changed (p>.05). Conclusions: This study demonstrated that older adults with MCI who underwent the NG-001 digital multidomain intervention experienced statistically significant improvements in overall cognition, memory (overall, immediate, and delayed), depression, anxiety, and stress levels, improved cognition and mental health. Further research should be conducted to investigate larger populations and with a matched control group of MCI patients.
LP42- THE SENSE-COG TRIAL: A EUROPE-WIDE RANDOMISED CONTROLLED TRIAL OF HEARING AND VISION AUGMENTATION IN DEMENTIA. I. Leroi1, E. Camacho2, N. Chaghil-Boissier3, A.P. Charalambous4, J.P. Connelly1, F. Constantinidou5, R. David6, R.A. Elliott2, E. Frison3, M. Hann2, A. Holden2, S.P. Kennelly1, B.A. Lawlor1, J. Longobardi3, A.M. Politis7(1. Trinity College Dublin — Dublin (Ireland), 2. University of Manchester — Manchester (United Kingdom), 3. University of Bordeaux — Bordeaux (France), 4. European University of Cyprus — Nicosia (Cyprus), 5. University of Cyprus — Nicosia (Cyprus), 6. University of Nice Sophia Antipolis — Nice (France), 7. National and Kapodistrian University — Athens (Greece))
Background: Hearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia-related outcomes. Intervening to optimise sensory impairment and support sensory function may be a means of improving dementia-related outcomes. The SENSE-cog Trial evaluated whether a home-based multi-part ‘sensory support’ intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their companions. Methods: This was a pan-European, multi-centre, observer blind, randomised controlled trial (RCT), of PwD with hearing and/or vision impairment and their companions. We evaluated a multi-part complex intervention of hearing and vision rehabilitation tailored to each participant dyad, compared to care as usual (CAU). The intervention included at a minimum: assessment and correction of hearing and/or vision impairments; home-based, therapist-delivered sensory support (i.e., adherence with devices; improving the sensory environment (i.e., lighting), communication training, and signposting to other support agencies. Results: Across 7 centres in the UK, Ireland, Greece, France and Cyprus, 291 participants with dementia were randomised from May 2018 to May 2021 to receive either ‘care as usual’, or a multi-component sensory intervention (10 visits over 18 weeks). Mitigating strategies to adapt study procedure to the COVID-19 pandemic were implemented. No significant difference in Quality of Life at 36 weeks was found. Average DEMQoL scores at week 36, adjusted for model covariates, were lower (poorer quality-of-life) in the CAU group but, at most, by 0.3 units/ points. A significant difference was observed in Quality of Life at 18 weeks. The average DEMQoL scores at week 18, adjusted for model covariates, were lower in the CAU group by between 2.6 and 2.7 units/ points. There were no Significant differences in care burden, activities of daily living or hearing impairment at 36 weeks, as assessed by the care companion were also not observed. No serious adverse effects were related to the intervention; low grade adverse effects related to the intervention were reported by five participants only. Conclusions: Hearing and vision support and rehabilitation in PwD living at home is a potentially important means of improving the lived experience of dementia and may represent a critical step in the diagnostic and post-diagnostic care pathway. However, effects may not be sustained over the longer term. Trial registration: ISRCTN (Trial ID: ISRCTN17056211)
LP43- MRI CHANGES FOLLOWING TREATMENT OF GLP-1 ANALOGUE, LIRAGLUTIDE, IN PATIENTS WITH ALZHEIMER’S DISEASE (ELAD STUDY). P. Edison1, G.D. Femminella1, C. Craig2, J. Joseph2, N. Nicholas1, Z. Walker3, B. Basil4, H. Hilary5, S. Salman6, G. George7, K. Paul7, C. Christian8, R. Rainer9, P. Peter10, B. Clive11(1. Imperial College London — London (United Kingdom), 2. The university of Edinburgh — Edinburgh (United Kingdom), 3. University College London — London (United Kingdom), 4. Brighton and Sussex University Hospitals NHS Trust — Brighton (United Kingdom), 5. University of Bristol — University Of Bristol (United Kingdom), 6. Lancashire NHS Trust—Lancashire (United Kingdom), 7. Birmingham University Hospital—Birmingham (United Kingdom), 8. Henan University of Chinese Medicine — Henan (China), 9. University of Manchester — Manchester (United Kingdom), 10. Queens University — Belfast (United Kingdom), 11. University of Exeter — Exeter (United Kingdom))
Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue licensed for the treatment of type 2 diabetes mellitus (T2DM). Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild to moderate Alzheimer’s dementia), conducted at several centres in the UK. As a part of this study, MRI brain scans of all patients were performed at baseline and after 12 months treatment with liraglutide or matching placebo, along with neuropsychometric evaluation and [18F]FDG PET. A total of 204 Alzheimer’s participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. All subjects underwent volumetric MRI scans at baseline, and repeat scans were performed in all subjects who completed 52 weeks of treatment. Volumetric changes from baseline to follow-up MRI scans were evaluated using both regional volume analysis and voxel-based morphometric analysis. MRI analysis demonstrated that temporal lobe volume (p<0.001), total grey matter volume (p<0.002) and frontoparietal volume were higher in liraglutide treated patients compared to the placebo group. Voxel-based morphometry (VBM) analysis demonstrated that liraglutide-treated participants showed that whole cortical grey matter, frontal, temporal and parietal lobe volume was higher in participants treated with liraglutide compared to placebo. This was associated with better cognitive function (ADAS-EXEC) (p=0.01) in patients treated with liraglutide compared to the placebo. However, there was no difference in glucose metabolism between the two groups. These findings highlight the potential of GLP-1 analogues in the treatment of Alzheimer’s disease.
LP44- THE EFFECTS OF POMEGRANATE SEED OIL ON MILD COGNITIVE IMPAIRMENT. T. Chatzikostopoulos1, M. Tsolaki1(1. Greek Association of Alzheimer’s Disease and Related Disorders — Thessaloniki (Greece))
Background: In recent years, there has been a growing interest, supported by a large number of experimental, epidemiological and clinical studies, about the beneficial effects of pomegranate in preventing various pathologic conditions, including brain neurodegeneration. The Pomegranate Seed Oil (PSO) contains high level phytosterols and vitamin C. Its antioxidant and antiapoptotic properties are helpful in the treatment of neuroinflammation. Specifically, it increases the the levels of Interleukin-17 and Interferon-γ, modulates mucosal immune responses and reduces the expression of TNf-α and Interleukin–6. Methods: The Greek Association of Alzheimer’s Disease and Related Disorders is conducting randomized clinical trial on the effects of PSO on cognition and mental health of patients with Mild Cognitive Impairment (MCI). The rigor methodological plan of the present randomized clinical trial will cover every aspect of the disease and eliminate possible limitations with careful selection of inclusion and exclusion criteria, with randomization of the sample and with the use of all the contemporary means and measures, such as neuropsychological assessment, MRI and analysis of blood biomarkers. The effects of PSO (experimental group) will be compared with the effects of Mediterranean Diet (control group) and the participants will be divided further into Apolipoprotein ε3 carriers and Apolipoprotein ε4 carriers in order to clarify the role of this specific allele in the treatment. Objectives: So, the present study is going to be the first in vivo clinical trial internationally which will examine thoroughly the effects of PSO on MCI patients. However, this study is ongoing and almost completes one year of treatment. For this reason, the results after six months and one year of treatment will be presented with evidence from the neuropsychological assessment. Results: The statistical analysis using Wilcoxon Signed-Ranks test and indempendent samples T-Test have shown statistically significant improvement of the experimental group in processing speed and working memory meausured by Trail Making Test B (p<.01) and verbal episodic memory measured by Rey Auditory Verbal Learning Test (p<.05). Discussion: The results of the present study confirmed the findings of previous studies on laboratory animals supporting that PSO has positive effects on memory. Besides that, due to the use of an extensive neuropychological assessment exact types of memory were identified that they can benefit from PSO. Conclusions: The PSO can be beneficial for MCI patients leading to prevention of dementia. As far as it is a natural product that does not burden the human body, it can be used by MCI patients and be a significant and promising part of holistic treatments for dementia.
BEYOND AMYLOID AND TAU: EMERGING SOLUTIONS
P50- MITOCHONDRIAL METHYLCYTOSINES AS NOVEL BLOOD-BASED BIOMARKERS FOR PREDICTING PROGRESSION TO ALZHEIMER’S DISEASE DEMENTIA AT THE MILD COGNITIVE IMPAIRMENT STAGE: A MACHINE LEARNING APPROACH. J.L. Mosquera1, M. Blanch1, N. Rojo2, I. Rico2, J. Campdelacreu2, B. Fontal1, P. Ferrer1, C. Fowler3, S. Laws4, A. Tort-Merino5, R. Sanchez-Valle5, R. Rene-Ramirez2, J. Gascon2, M. Barrachina1(1. ADmit Therapeutics SL — Barcelona (Spain), 2. Functional Unit of Dementia, Service of Neurology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute, IDIBELL — Barcelona (Spain), 3. The Florey Institute, The University of Melbourne — Melbourne (Australia), 4. Collaborative Genomics and Translation Group, Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University — Joondalup (Australia), 5. Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona — Barcelona (Spain))
Background: The prediction of progression to Alzheimer’s disease dementia (ADD) at the Mild Cognitive Impairment (MCI) stage is an unmet medical need. The current inclusion criteria for clinical trials destinated to AD drug development is MCI patients with CDR=0.5, and a positive bA-PET scan. However, the Sensitivity and Specificity of bA-PET scan for the progression of MCI stage to AD show variability depending on the clinical study. In addition, the inclusion of false positives is impairing the success rate of clinical trials. Several studies have reported mitochondrial dysfunction in AD at cerebral and systemic level. Our proof of concept was obtained from human post-mortem brains, showing and altered mtDNA methylation pattern along AD disease progression (Blanch et al. 2016). Interestingly, similar results have recently been described in blood samples from MCI patients (Stoccoro et al. 2022). ADmit has developed a cutting-edge epigenetic technology based on next-generation sequencing. It identifies differential mtDNA methylation patterns in blood samples from MCI patients providing a percentage of progression to ADD using a machine learning approach. Objectives: Our main objective is to develop a model to classify patients diagnosed with MCI susceptible of progressing to ADD. Methods: A total of 211 subjects recruited from three logitudinal prospective clinical studies were studied: Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL, 129 subjects), ADmit (74 subjects recruited in Bellvitge University Hospital), and Hospital Clínic de Barcelona (8 subjects). In our prototype, two clinical variables were examined: (1) Group (response variable) consists of three levels which are Controls, MCI Non-progressed to ADD, and MCI Progressed to ADD; (2) bA-PET scan measurement to detect positive or negative levels of cerebral b-amyloid. In addition, more than 200 mitochondrial cytosines were analyzed using MiSeq platform (Illumina). Each of these variables indicates the percentage of methylation for a single specific cytosine in CpG and non-CpG sites for D-Loop region and ND1 gene. Only blood samples from the baseline visit for control (CDR=0) and MCI subjects (CDR=0.5) were epigenetically analyzed. An MCI patient was considered to have progressed to ADD when one of the following criteria was met: CDR change from 0.5 to 1, or ≥2-point deterioration in CDR-SOB from baseline, or ≥1-point deterioration in at least four instrumental activities of daily living measured by the FAQ adaptation questionnaire. The Random Forest, a supervised learning method, was applied to build our prototype, which was run using a 3 repeated 10-fold Cross-Validation, and the total number of parameter combinations evaluated was 5. To measure the performance of the classification predictions a confusion matrix was built to show a cross-tabulation of the observed and predicted classes. Results: Three groups of individuals were considered: Control subjects (n=68, CDR=0, MMSE=29.21 ± 1.10, 68.85 ± 5.34 years old; 16% E4 carriers; 0% positive bA-PET scan) with clinical follow-up greater than 10 years; MCI patients Non-progressed to ADD (n=58, CDR=0.5, MMSE=27.19 ± 2.02, 70.76 ± 7.80 years old; 29% E4 carriers; 19% positive bA-PET scan) and a clinical follow-up greater than 36 months without showing progression symptoms; and MCI patients progressed to ADD (n=85; CDR=0.5, MMSE=25.69 ± 2.53, 74.69 ± 6.62 years old; 56% E4 carriers; 79% positive bA-PET scan). Control subjects were only available on the AIBL cohort, however MCI patients were recruited from all three cohorts. Sex showed a balanced number, 52.4% were females and 47.6% were males. The time frame of ADD progression was between 1 and 5 years. Data splitting generated a first subset of 170 subjects for the training model process and a second subset of 41 individuals for testing the classification model. Results of the model training indicated that the best performance was the Random Forest, with an average Accuracy of 0.760 and an average Kappa value of 0.636. The model predictions on the testing data results in an overall Accuracy score of 0.756 with a 95% Confidence Interval of 0.597 to 0.876, and a Kappa value of 0.63. Sensitivity and Specificity of the model to classify a subject as an MCI progressed to ADD is 0.76 and 0.92, respectively. The precision of the model is 0.87, and the F1-score is 0.81. The Positive Predictive Value is 0.87, and the Negative Predictive Value is 0.85. The ROC curve showing the performance of the classification model for the MCI progressed versus MCI non-progressed patients has an AUC=0.791. Conclusion: Our classification model performs a good classification of ADD at MCI stage CDR=0.5 up to 5 years before the appearance of dementia. These novel blood-based biomarkers could support bA-PET scan-based patients’ stratification in clinical trials. This protoype is currently under review with a higher sample size in order to improve the tuning process during the model training. This fact, might cause that estimates provided in this study as well as its associated metrics to evaluate the performance of the classification could be slightly modified.
P51- IMPROVEMENT OF COGNITIVE DYSFUNCTION FOLLOWING REPEATED INFUSION OF ADIPOSE TISSUE-DERIVED STEM CELLS. K. Shigematu1, M. Ideno2, N. Komori3, H. Yamagishi4(1. Minami Kyoto Hospital — Joyo (Japan), 2. Takara Bio Inc. — Kyoto (Japan), 3. Nagitsuji Hospital — Kyoto (Japan), 4. Kyoto Prefectural University Of Medicine — Kyoto (Japan))
Background: Adipose tissue-derived stem cells (ADSCs) secrete neprilysin, an enzyme that degrades amyloid associated with Alzheimer’s disease, and secrete nerve cell growth factors and cytokines, which may be effective in cognitive dysfunction. Objectives: To investigate whether repeated infusion of ADSCs improves cognitive function. ADSCs has been suggested to be useful in several neurological disorders. Cognitive function is supported by neurons in the broad cerebral cortex, so administration of ADSCs may have a positive effect on those neurons, resulting in improved cognitive function. Methods: First, we confirmed the presence of neprilysin activity in ADSCs. We examined 15 ADSCs-treated patients who had some cognitive dysfunction to see if there were any changes in cognitive function. Approximately 100 million ADSCs were administered intravenously six times at approximately one-month intervals. Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA). The patient and caregiver were asked monthly about the effects or any adverse events from before administration to about 1 month after the 6 doses. As part of the questionnaire, the respondents were asked to select «improved,» «unchanged,» or «worsened» as their final overall evaluation. If the neurologist judged that the patient had difficulty answering a question on the MoCA test because he or she did not understand it, the score was zero with no educational history correction. The patient was accompanied by his/her physician during the administration of ADSCs infusion to ensure safety. After the observation period, i.e., one month after the end of the administration, the safety and efficacy of the ADSCs are being monitored for as long as possible. Results: Underlying diseases of the patients in this study who had cognitive changes were Alzheimer’s disease (9 patients), Parkinson’s disease (4 patients), amyotrophic lateral sclerosis (1 patient), and chronic obstructive pulmonary disease (1 patient), for a total of 15 patients. MoCA scores before ADSCs administration were 17, 15, 13, 10, 9, 9, 3, 3, 0, 24, 19, 17, 9, 13, 12 (mean 11.5, standard deviation 6.5), respectively, and those after 6 doses were 22, 23, 19, 19, 19, 17, 14, 10, 8, 0, 29, 28, 28, 28, 28, 23, 28 (mean 19.7, standard deviation 8.7). The change in MoCA scores before and after the last dose was an improvement of 7.6 (95% confidence interval 5.2–10.1, p < 0.01; t-test). In the post-treatment assessment by patient caregivers (family members), all selected «no deterioration» or «improved» for patient cognitive function after treatment, and none selected «worsened. No changes in vital signs, abnormal bloodchemistry tests, or any suspected side effects, including subjective or objective symptoms, were observed. Discussion: The results suggest that administration of ADSCs may improve cognitive dysfunction. Since neprilysin activity was identified in the administered ADSCs, amyloid removal was a possible mechanism of action for the effect. It is noteworthy that the improvement was not limited to Alzheimer’s disease. It is possible that neprilysin activity worked other than in Alzheimer’s disease, since amyloid is deposited with aging. ADSCs secrete several nerve growth factors as well as other factors that may be useful for neuronal repair and activation, which may have contributed to the improvement in cognitive function. In neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and ALS, inflammatory responses are known to occur at lesion sites, which may have two implications for the actions of ADSCs: ADSCs secrete several cytokines to control inflammation, and inflammation may facilitate ADSC accumulation in the brain parenchyma, especially at lesion sites. Although ADSCs have the ability to differentiate into neurons, the actual strength of their regenerative potential in the brain is unknown; however, it is possible that they work to regenerate nerves at the site of brain damage, and it will be a challenge to determine how long this takes and how long the effect lasts. This ADSCs treatment study has limitations, first of all, it is not a double-blind controlled trial. The placebo effect cannot be completely ruled out. However, the improvement in generally progressive cognitive impairment, along with the lack of side effects associated with this treatment, supports further study as a promising treatment modality for dementia in the future. Conclusion: The results suggest that intravenous administration of ADSCs may improve cognitive dysfunction independent of the underlying disease, i.e., cognitive dysfunction associated with lung disease in addition to several neurodegenerative diseases. This also suggests that ADSCs administered into the bloodstream can reach and act on the cerebral cortex. The possible mechanisms of action include neuroregeneration, neuroprotection/repair, anti-inflammation, improvement of blood flow, and removal of abnormal proteins.
P52- NOVEL APPLICATION OF DEEP CANONICAL CORRELATION ANALYSIS IDENTIFIES REGIONAL BRAIN ATROPHY LINKED TO PROINFLAMMATORY GUT MICROBIAL GENERA BEFORE COGNITIVE DECLINE. M.B. Heston1,2, Z. Meng3, A. Kohli1,2, A. González4, S.C. Johnson1,2,5, R. Knight4,6,7,8, R.F. Kaddurah-Daouk9,10,11,12, F.E. Rey13, V. Singh3,14,15, B.B. Bendlin1,2,5(1. Wisconsin Alzheimer’s Disease Research Center — Madison (United States), 2. Division of Geriatrics, Department of Medicine, University of Wisconsin School of Medicine and Public Health — Madison (United States), 3. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison — Madison (United States), 4. Department of Pediatrics, University of California, San Diego — La Jolla (United States), 5. Wisconsin Alzheimer’s Institute — Madison (United States), 6. Department of Bioengineering, University of California, San Diego — La Jolla (United States), 7. Department of Computer Science & Engineering, University of California, San Diego — La Jolla (United States), 8. Center for Microbiome Innovation, University of California, San Diego — La Jolla (United States), 9. Department of Psychiatry and Behavioral Sciences, Duke University — Durham (United States), 10. Department of Medicine, Duke University — Durham (United States), 11. Duke Institute of Brain Sciences, Duke University — Durham (United States), 12. Duke University Medical Center — Durham (United States), 13. Department of Bacteriology, University of Wisconsin- — Madison (United States), 14. Department of Computer Sciences, University of Wisconsin-Madison — Madison (United States), 15. Department of Statistics, University of Wisconsin-Madison — Madison (United States))
Background: The gut microbiome modulates neurodegeneration through proposed pathways including inflammation and epigenetic modifications. We published the first human study linking the gut microbiome to Alzheimer’s disease (AD) pathology; this and subsequent studies identified trends between proinflammatory taxa and greater amyloid and tau burden. A recent study also linked gut microbiome composition and cognition in midlife, suggesting the microbiome plays a role in preclinical AD development. However, it remains unknown whether the associations with cognition and AD pathology are reflected in preclinical brain atrophy. Objectives: This study tested the hypothesis that a proinflammatory microbial profile is linked to greater cortical atrophy before AD dementia onset. To accomplish this, we used deep canonical correlation analysis (DCCA), which employs neural networks to develop a sparse representation of high-dimensional data, then performs CCA to correlate bacterial taxa and regional volumes. DCCA enables estimation of unknown nonlinear relationships, which frequently occur among microbiome data. This is the first recorded use of DCCA to link gut microbiome composition and neuroimaging data. Methods: 157 cognitively unimpaired participants provided fecal samples and T1-weighted neuroimaging through the Microbiome in Alzheimer’s Risk Study (NIA R01AG070973), Wisconsin Alzheimer’s Disease Research Center (WADRC), and Wisconsin Registry for Alzheimer’s Prevention (WRAP). These mid- to late-life cohorts are enriched for participants at risk for developing AD. T1-weighted images were collected using published methods; CAT12 was used to preprocess images and quantify regional gray matter volumes with the Automatic Anatomically Labeled Atlas 3. Fecal samples were collected at home, returned chilled, and subsequently weighed, scored using the Bristol scale, and frozen at -80°C. Using published methods, 16S rRNA V4 sequencing was performed on previously frozen samples. Taxa were denoised and classified (Qiita and QIIME2), filtered to 5% prevalence, and agglomerated at the genus taxonomic rank (phyloseq). DCCA was used to identify a maximally correlated set of genera and brain regions. Multinomial regression (songbird) was used to calculate differentials, or log fold change in genus abundance, associated with increases in regional volume. Differentials were ranked (qurro), and genera ranked first and last (indicating positive and negative correlations, respectively) were used to evaluate relationships with gray matter volume. Regression covariates included age at fecal sample and sex. Results: Participants were demographically representative of the WADRC and WRAP cohorts. Age at fecal sample was 66.25±6.73 years (mean±SD), and imaging was obtained within 0.66±0.48 years of fecal samples. 104 (66%) participants were female, and 52 (33%) were APOE e4 allele carriers. Average body mass index was 28.71±5.64 kg/m2, and average fecal sample Bristol score was 3.89±1.23. Microbiome processing resulted in 86 genera present in 5% of samples. DCCA identified 7 genera (Akkermansia, Anaerostipes, Bacteroides, Clostridium, Coprococcus, Ruminococcus, unidentified Lachnospiraceae genus) correlated with 18 regions (bilateral (b): cerebellar crus I (CERCRU1), cerebellar lobule 8 (CER8), postcentral gyrus (PoCG), superior frontal gyrus (SFG); left (l): calcarine cortex (CAL), cerebellar crus II (CERCRU2), middle occipital gyrus (MOG), middle temporal gyrus (MTG), precentral gyrus (PreCG), temporal pole: superior temporal gyrus (TPOsup); right (r): cerebellar lobule 6 (CER6), supracallosal anterior cingulate cortex (ACCsup), opercular inferior frontal gyrus (IFGoperc), middle frontal gyrus (MFG)). The rACCsup, lTPOsup, rCER6, and lCERCRU1 had strongest genus associations; magnitudes of their differentials ranged from 0.53 (rACCsup) to 0.22 (lCERCRU1). Anaerostipes negatively correlated with volumes of bCERCRU1, bSFG, lTPOsup, lMTG, lPreCG, rPoCG, lCERCRU2, rCER6, lCER8, and lCAL. Bacteroides positively correlated with lTPOsup, rACCsup, rCERCRU1, bSFG, lMOG, and rIFGoperc. Clostridium correlated negatively with lPoCG, rMFG, and rIFGoperc, and positively with lCERCRU2. Ruminococcus positively correlated with lCERCRU1, bCER8, and lMTG. The Lachnospiraceae genus positively correlated with rPoCG, lPreCG, and rMFG. Coprococcus positively correlated with lCAL and rCER8, while Akkermansia negatively correlated with rACCsup and lMOG. Conclusions: This study further implicates the microbiome in preclinical AD, and demonstrates the potential clinical utility of fecal samples as a low-cost, noninvasive source of biomarkers early in AD development. Selected brain regions included temporal and frontal regions susceptible to AD pathology, as well as several cerebellar regions that exhibit reduced connectivity with cerebral regions early in AD. Higher gray matter volume was linked to more abundant genera with short chain fatty acid-producing species, and less abundant Clostridium, a genus with several opportunistic pathogens. Interestingly, Akkermansia and Anaerostipes, two genera with known anti-inflammatory species, were less abundant with higher volumes. Akkermansia has been identified as elevated in untreated multiple sclerosis, and Anaerostipes supplementation aggravated intestinal lesions in a colitis mice model, suggesting variable roles in modulating inflammation. To determine whether the microbiome-brain correlations vary with AD severity, future analyses will evaluate the moderating effect of amyloid burden on the present relationships. Further, to identify effects on the earliest AD-related changes in neuroarchitecture, microbiome composition will be evaluated against gray matter microstructure captured via multishell diffusion-weighted imaging.
P53- BEYOND TARGETING AB AND TAU: NOVEL FORMULATIONS OF ALPHA-CYCLODEXTRINS FOR THE SAFE (NOT OTOTOXIC) AND CONVENIENT (ORAL) PREVENTION AND TREATMENT OF ALZHEIMER’S DISEASE. K. Wittkowski1(1. Asdera Llc — New York (United States))
Introduction: More than 6M US people are living with Alzheimer’s disease (AD). This number is projected to double by 2050, when dementias will cost the nation >$1T/yr. Still, few, if any, early interventions or disease-modifying drugs (DMTs) are available to prevent or treat AD and other dementias. Most AD drugs are cholinesterase inhibitor (donepezil), glutamate regulator (memantine), or directly targeting beta-amyloid (aducanumab) or tau-protein. HP-beta-cyclodextrin (HPβCD), which was shown to be active across the blood-brain barrier (BBB), has also shown effectiveness against the inherited childhood disease Niemann-Pick type C, which shows parallels with AD in cellular pathology. However, HPβCD has consistently caused cholesterol-related hearing loss, often permanent, both in animal models (Davidson CD, 2016, Ann Clin Transl Neurol 3: 366) and in clinical trials. Methods: Since Ohdner’s 1900 mechanical calculator, each advance in computer technology has made more statistical methods available. After 2001, a computational biostatistics approach to the analysis of GWAS data, developed over 20 years at The Rockefeller University (Wittkowski KM, 2018, PLoS One 13: e0199012), yielded insights about high levels of endocytosis during accelerated age-related (AR) decline of lysosomal function as a key component in the etiology of AD. A review of AD-related publications investigated the role of (1) Ab and tau as causative vs reflective of the etiology of AD and (2) cholesterol vs phospholipids as the lipids involved in the etiology of AD. ASDERA developed interventions to improve AR health by addressing two common components in the etiology of AR conditions at a fraction of the cost for society: garb-aging and inflamm-aging. ASD-IFM (as a nutraceutical) and ASD-005 (as a drug for treatment) lowered serum phospholipids (PLs) to mimic the benefits of intermittent fasting: less activity of PLA2s reduces inflammation and also reduced endocytosis, which prevents aging lysosomes from becoming overloaded and, in turn, disrupts autophagy (causing accumulation of substrates, incl. Ab and tau). Results: Studies of HPbCD have often assumed that it acted by “depleting cholesterol” (Simons M, 1998, PNAS 95: 6460), rather than other lipids, including phospholipids, even though this was not fullly supported by evidence. For instance, an official name of “ABCA1, a membrane cholesterol transporter” (Yao J, 2012, J Exp Med 209: 2501) is “Phospholipid-Transporting ATPase” (genecards). Unfortunately, HPβCD also causes cholesterol-related permanent hearing loss. Animal studies have shown HPαCD (6 sugars, too small to fit cholesterol) to be more effective than HPβCD (7 sugars) in breast cancer (reducing endocytosis and inflammation) and also effective in movement disorders, incl. HD and ALS, by improving weight gain, as a DMT, the opposite effect of reducing body weight in wild type animals and human trials (Wittkowski KM (2019) WO 2019/067269 A2). αCD was more effective than HPβCD in vitro against various lysosomal storage diseases (McKew 2014 US 201715620753 A). In the absence of dietary milkfat (eg, with animal chow), αCD is not excreted into urine, but βCD was absorbed in pre-weaned rats (De Schaepdrijver L, 2015, Reprod Toxicol 56: 87). In human trials (Wittkowski KM (2019) l.c.), no αCD was excreted into urine in the absence of dietary milkfat, some αCD and small increases in PLs were seen in urine when milk or capric acid (C10) added, and much more when αCDs and C10 were formulated as a non-covalently bound clathrate. The nutraceutical ASD-IFM and the drug ASD-005 are formulated with GRAS αCD or the drug HPαCD, respectively. Oral ASD-IFM and -005 (related US claims accepted, PCT pat. pend.) are absorbed from the intestine. Hence, CDs can now be administered orally, avoiding the need of overnight iv infusion. Discussion: Intermittent fasting (IF) and the IF mimetics HPαCD (too small to fit cholesterol) were previously shown to be more effective than HPβCD in LSDs, NDDs and cancer, diseases characterized by different manifestations of dysfunctions along the endocytosis/lysosome/autophagy (ELA) axis. With the new results showing that: • the MoA of HPbCD is via PLs, not cholesterol, • the clathrates ASD-005/IFM of aCDs and C10 are intestinally absorbed and safe, • αCDs have systemic effects in various cardiometabolic conditions and diseases involving ELA axis dysregulation, • the FDA has accepted HP-CDs as drugs with activity across the BBB, several barriers against a more convenient, safer, and potentially more effective prevention and DMT for ND diseases have been overcome. Most of the benefits of aCD have been demonstrated in clinical trials and health claims are already approved (US) or authorized (EU) for use with nutraceuticals and supplements. HP-CDs were recently accepted by the FDA as drugs, so the more water-soluble HPaCD can undergo clinical trials as a DMT (mono- or adjuvant therapy) against AD and other ND diseases.
P55- ESTABLISHING FLUID BIOMARKERS ASSOCIATED WITH CELLULAR SENESCENCE IN ALZHEIMER’S DISEASE. B. Ng1, A. Heslegrave1,2, N. Fox1,3, H. Zetterberg1,2(1. Dementia Research Institute, University College London — London (United Kingdom), 2. Department of Neurodegenerative Disease, University College London — London (United Kingdom), 3. Dementia Research Centre, Queen Square Institute of Neurology, University College London — London (United Kingdom), 4. Department of Psychiatry and Neurochemistry, University of Gothenburg — Molndal (Sweden))
Background: Chronological age is the biggest non-genetic risk factor of Alzheimer’s disease (AD). However, there is a wide range in age at onset (AAO) such that chronological age itself is a poor predictor of risk or AAO. Biological age may offer a more precise molecular measure of ageing, but it is currently unclear how biological ageing is associated with AD. Recently, pathological hallmarks of AD have been reported to be alleviated by removing senescent glial cells in the brains of AD mouse models. We therefore hypothesise that biomarkers of biological ageing measured in cerebrospinal fluid (CSF), specifically linked to the process of cellular senescence, can serve as biomarkers of AD. Objectives: We set out to measure fluid biomarkers of biological ageing specifically linked to cellular senescence and selected based on their implication in AD, and compare their associations with CSF biomarkers of AD. Methods: Using CSF samples from a biomarker discovery cohort in Sweden, we quantified the levels of multiple candidate biomarkers associated with ageing and cellular senescence with various immunoassays. The levels of biological ageing markers were then analysed with clinical and pathological data from the sample donors. Results: The levels of Growth differentiation factor-15 (GDF-15), Interleukin-6 (IL-6), Osteopontin and Klotho in human CSF were measured (n = 67) to assess their relevance in the context of existing CSF biomarkers of AD. The levels of all four candidate biomarkers change with chronological age (increase, except decrease for Klotho), and both GDF-15 and Osteopontin levels can differentiate individuals with high level of CSF amyloid-β1–42 (Aβ1–42) from those with low levels of Aβ1–42. In addition, the levels of Osteopontin correlate positively with those of phosphorylated tau-181 while the levels of IL-6 correlate positively with both GDF-15 and Osteopontin. Conclusion: Our data support the relevance of biological ageing in the context of AD and the need for further investigation. The abovementioned candidate biomarkers, among others in consideration, will be quantified in clinically characterised AD cohorts to result in a consolidated molecular signature for biological ageing.
P56- THE GUT-PRO STUDY: A PILOT PROBIOTIC INTERVENTION STUDY IN ALZHEIMER’S DISEASE. J.W. Kang1, S.J. Harding1, M. Heston1, A.E. Braceros1, N. Davenport-Sis1, N. Chin1, H. Zetterberg2, F. Rey1, B. Bendlin1(1. University of Wisconsin-Madison — Madison (United States), 2. University of Gothenburg, Sahlgrenska University Hospital — Mölndal (Sweden))
Background: Recently, gut microbiome has emerged as a potentially modifiable factor that may contribute to exacerbate development of Alzheimer’s disease (AD) pathology. Our research group previously found altered gut microbiome composition among individuals with AD and abundance of specific microbiota was associated with AD pathology; however, no studies have tested whether restoring the relative abundance of gut bacteria that are depleted in AD, i.e., Bifidobacterium and Lactobacillus impacts AD or related pathology. Objectives: The primary objective of this study is to assess the safety and feasibility of an oral probiotic intervention in humans with or at risk for dementia due to AD. The secondary objective is to test the effects of a probiotic intervention on the composition and function of the gut microbiota in humans with or at risk for dementia due to AD as well as collect preliminary biomarker and cognitive data to estimate sample size and other critical parameters for a larger study. Methods: A randomized, double blind, and placebo-controlled clinical study will be conducted in 40 participants, including 20 participants with mild cognitive impairment (MCI) or early AD dementia and 20 cognitively unimpaired enriched for elevated amyloid (CU-EA). An equal number (ten) of MCI/AD dementia and CU-EA participants will be randomly assigned to intervention (probiotic) and ten participants in each group will be assigned to placebo control. The probiotic group will receive probiotic capsules comprising a custom formulation of probiotics for 6 months, and the placebo group will receive placebo capsules for 6 months. Study participants will be followed for 1 year, and will participate in stool collection, cognitive and functional assessments, actigraphy, and blood draw for plasma biomarkers of AD. Discussion: Probiotics, including those that impact abundance of Bifidobacterium and Lactobacillus, have previously been shown to impact digestive and immune function, as well as lower symptoms associated with digestive disorders, reduce inflammatory markers, and improve cognitive function. Gut microbiota and their secondary metabolites, including short chain fatty acids, indoles, and bile acid profiles, have the potential to modulate the central nervous system via the gut-brain axis. Ongoing human and animal studies in our lab are testing the pathways by which gut microbiome may impact AD, including via gut permeability, gut microbial metabolites, and immune-related mechanisms. Given few effective treatment options to support maintained cognition and function in the context of AD, modulating the composition of the gut microbiota deserves further testing. Conflict of interests: Authors declare that they have no competing interests.
P57- THE POTENTIAL OF FLAVONOIDS TO ENHANCE MITOCHONDRIAL FUNCTION AND PROTECT NEURONS FROM DEGENERATION IN ALZHEIMER’S DISEASE. M. Ankarcrona1, L. Naia1, G. Dentoni1, M. Shimozawa1, E. Bereczki1, X. Li2, J. Liu3, N. Santos Leal3, B. Portal4, M. Lindskog4, P. Nilsson1, M. Gaetani1(1. Karolinska Institutet (KI) — Solna (Sweden), 2. Tsinghua University — Tsinghua (China), 3. Karolinska Institutet (KI) — Huddinge (Sweden), 4. Uppsala University — Uppsala (Sweden))
Background: Mitochondrial dysfunction and decreased energy production occur early in the Alzheimer’s disease (AD) process. Hence, mitotherapeutics may be valuable disease modifiers for AD. We have previously identified the flavonoid luteolin as a mitochondrial enhancer in primary neurons (Naia et al 2021). We revealed a novel mechanism showing that luteolin increase mitochondria-endoplasmic reticulum (ER) contact, ER to mitochondria Ca2+-transfer and ATP production. We believe that flavonoids have the potential to enhance mitochondrial function, support synaptic activity and halt the progression of AD. To validate our findings with luteolin and other flavonoids and to understand the molecular mechanism in depth we have here identified appropriate disease models and performed target identification. Objectives: -to characterize AD-mouse models in terms of mitochondrial function; -to perform target analysis for flavonoids using the Proteome Integral Solubility Alteration (PISA) Assay. Methods: RNA sequencing was performed on hippocampal tissue isolated from knock-in AppNL-F (6, 12, 18 months old animals) and AppNL-G-F (2, 6, 12 months old animals) AD-mouse models and wild-type (WT) mice where APP is expressed at physiological levels under its endogenous promoter with a humanized amyloid β-peptide (Aβ) sequence and familial AD mutations. AppNL-F and AppNL-G-F mice display an increased Aβ42/40 ratio and accumulate amyloid plaques (Saito et al 2014). Data were analyzed by gene ontology enrichment analysis, pathway analysis and unsupervised genome-wide clustering. Primary cortical neurons were derived from mouse embryos at embryonic day 16–17, WT embryos were generated from inbred C57B6/J parent and AppNL-F embryos from homozygous C57B6/J AppNL-F parents. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) evaluation was performed using a XFe96 SeaHorse Analyzer. Calcium (Ca2+) uptake by mitochondria (AppNL-G-F and WT) was measured using the Ca2+-sensitive probe Calcium Green-5N and Ca2+-retention capacity calculated. Patch-clamp recording spontaneous activity of neurons was recorded and miniature EPSCs were recorded in the presence of 0,5µM of tetrodotoxin (TTX) in the extracellular solution to block action potentials. Mitochondrial movement MitoDsRed-transfected neurons were washed and imaged at 37 °C in Na+ medium using a 63x objective with NA=1.4 in the LSM710 confocal microscope (Zeiss). Mitochondrial movement analysis was done using the Kymograph Macro in Fiji. Mitochondria-ER contacts (MERCS) were analyzed by electron microscopy and confocal microscopy using split-GFP-based contact site sensor (SPLICS) analysis. Proteome Integral Solubility Alteration (PISA) Assay a high throughput method based on protein solubility/stability upon thermal treatment was used for target analysis of flavonoids in cortical primary WT neurons. Results: Energy metabolism emerged as one of the most significantly altered pathways in young AppNL-F and AppNL-G-F knock-in (KI) mice. Functional experiments in brain mitochondria isolated from two months old AppNL-G-F mice subsequently identified upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, combined with higher susceptibility to Ca2+-overload. Consequently, mitochondrial function was impaired in 12 months old AppNL-G-F mice as reflected in the transcriptome analysis. In AppNL-F primary neurons derived from mouse embryos, also displaying an increased Aβ42/40 ratio, we detected an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL-F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which account for increased transfer of Ca2+ from ER to mitochondria and upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function. PISA analysis with several flavonoids revealed cytosolic and mitochondrial targets which are now further analyzed in silico, in vitro and in vivo. Conclusion: We report for the first time an upregulation of brain mitochondrial function in young AppNL-G-F mice which was subsequently impaired in old animals. Interestingly, mitochondria from young AppNL-G-F mice had impaired Ca2+-buffering capacity. AppNL-F primary cortical neurons show a similar phenotype with upregulated mitochondrial function, increased ECAR (reflecting a lower glycolytic reserve) and impaired mitochondrial Ca2+-buffering capacity. We have previously shown that WT cortical neurons exposed to Aβ42 display increased oxygen consumption rate (OCR) and increased juxtaposition between ER and mitochondria (Leal et al 2020). Even though Aβ accumulates in AppNL-F and AppNL-G-F mice, we cannot exclude other triggers of mitochondrial alterations. However, we show here that these App KI animal models are appropriate for studies with molecules boosting mitochondrial function. Therefore, we are now performing target validation and proof-of-concept studies of the potential protective effect of flavonoids in these AD-models. We report no conflicts of interest.
P58- AN ONLINE DEMENTIA PREVENTION USING THE COGSTIM MODEL: A PILOT STUDY. R. Ownby1,2(1. Nova Southeastern University — Fort Lauderdale Fl (United States), 2. Enalan Communications, Inc. — Fort Lauderdale Fl (United States))
Background: Given limited progress in creating treatments for dementia, interest has increased in the possibility of dementia prevention through lifestyle interventions. A large number of factors that have been related to risk and protection from dementia, however, and patients may not be able to choose among confusing claims to develop their own brain health plans, and may have difficulty initiating and maintaining behavior change. We developed the Cogstim shared decision-making model to help patients and clinicians to address these issues. The model organizes brain health activities according to the putative mechanisms through which they affect brain health, lays out evidence-based criteria for activity choices, and integrates both with behavior change techniques. Further, during the COVID-19 pandemic it was difficult to do in-person education or support patients’ behavior change efforts, making the development of an online intervention desirable. Objectives: The purpose of this study was to carry out a test of the Cogstim model for dementia prevention delivered completely online. Persons receiving the model-based intervention were compared to a group receiving an educational intervention without structured goal setting and behavior change techniques. Methods: Individuals 50 years of age and older were recruited from local organizations for older adults and by word of mouth from other participants. They completed baseline cognitive assessments and a series of self-report inventories evaluating mood, stress, and knowledge of dementia risk and protective factors. The primary outcome measure was score on the Alzheimer’s Disease Risk Inventory (ADRI) with secondary outcomes designated as self-reports on the Memory Self-Efficacy scale (MSE) and the Dementia Knowledge Scale, Risk subscale (DKAS). Acceptability of the intervention was assessed with a questionnaire based on the Technology Acceptance Model. Participants also completed exit and three-month follow-up interviews. Participants were randomly assigned to 12 weekly videoconference sessions of either (1) the Cogstim (CS) intervention, comprising structured goal setting, weekly review of goals, and problem-solving of behavior change strategies or (2) treatment as usual (TAU), comprising the same educational sessions without structured goal setting and support for behavior change. As part of the study, we tested a brain health tracking tool that asked participants to report daily brain health activities. Participants completed these logs for 7 consecutive days during weeks 1, 6, and 12 of the study. Change over time for outcome measures was assessed with mixed effects models in R, and group differences in report of brain health activities were evaluated using interrupted time series analyses (ITSA) completed in Stata. This study was registered on ClinicalTrials. gov (NCT04822129). Results: Eighteen individuals (6 men 12 women, 2 blacks and 16 whites, average age 72.7 years, average years of education 17.9) were enrolled; 16 completed the study. Twelve completed all follow-up self-report questionnaires (5 in the TAU and 7 in the CS groups). For the primary outcome measure (ADRI), persons in the CS group showed larger increases than those in the TAU group, and although the difference did not reach statistical significance (t = 1.72, p = 0.11) it represented a large effect size (d > 1.00). Analyses for the two secondary measures (MSE, DKAS) showed no between-group differences (all ps > 0.20). The ITSA models for the composite Cogstim index of brain health activities showed a positive effect over time in both groups, suggesting that persons in both groups increased their brain health activities over time, but no between-group difference existed (linear trend for TAU: t = 2.73, p = 0.01, for CS: t = 3.12, p = 0.004; between group difference: t = 0.25, p = 0.81. On the Technology Acceptance Model (TAM) questionnaire, participants rated the intervention positively for both its usefulness (mean rating 5.38, SD 0.68, on a scale from 0 to 6, with 6 indicating a positive rating) and ease of use (mean 5.33, SD 0.91). Test of group differences in TAM ratings did not suggest that group membership affected ratings (all ps > 0.10). All 16 completers provided interview data at immediate and three-month follow-up. Interviews showed that the intervention was viewed positively by participants. All 16 participants felt the program was helpful to them in developing better brain health, while 15 indicated they enjoyed the program. All stated they would to the program again. Conclusions: This pilot study shows that an online dementia prevention intervention based in the Cogstim model is feasible and acceptable to older persons. The Cogstim daily index may be useful to support self-monitoring persons developing a brain health plan. The Cogstim model provided a useful framework that supported participants’ efforts at change, and this pilot study provides preliminary evidence of the intervention’s a positive effect on participants’ behavior. Conflicts: Dr. Ownby is a major stockholder in Enalan Communications, Inc., a company that develops digital health interventions.
P59- EFFECTS OF NON-INVASIVE BRAIN STIMULATION ON INDIVIDUAL ALPHA POWER. O.A. Onur1, R. Fassbender1(1. Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany — Cologne (Germany))
Background: In Germany, more than one million people suffer from dementia. Due to the steadily increasing life expectancy in our society, the number of dementia patients with all the resulting social and economic consequences will continue to increase in the future. However, the pharmacological therapies established in the treatment of Alzheimer’s disease (AD) show only a limited effect on mnestic deficits, which are the leading symptom of Alzheimer’s dementia. In recent years, non-invasive brain stimulation has revealed promising findings for modulating cognitive functioning in AD patients, although some of these effects have not been replicated. One reason for these contradictory findings could be a variable reactivity of each individual to stimulation, so that personalized stimulation protocols hold great potential in the therapy of cognitive and mnestic deficits in these patients. Objectives: The aim of this study was to evaluate non-invasive brain stimulation as a therapeutic tool in Alzheimer’s disease by individually adapting stimulation protocols. Methods: 17 MCI patients based on Alzheimer’s disease with a typical cerebrospinal fluid profile (amyloid- and pTau-positivity) were recruited via the memory clinic of the University Hospital Cologne and 19 age-matched healthy control via public announcement. All subjects were examined with regard to the effectiveness of non-invasive brain stimulation. Data collection was successfully completed in September 2020 after a pandemic-related break in data collection. Study participants first underwent a detailed neuropsychological assessment to evaluate cognitive status. Subsequently, two sessions took place in which non-invasive brain stimulation was performed simultaneously with EEG measurements (rTMS-EEG). For rTMS four circular coils for low-intensity (<10 mT) and high-frequency stimulation were placed in a cushion (CERTIS, ABNeurotech). Subjects were asked to lay their head in the cushion sitting in an upright position. The head was positioned in a way that the coils targeted parietal and occipital areas on both hemispheres. In one of the two sessions, sham stimulation was performed in randomized order as a control condition. At the beginning of the rTMS-EEG sessions, a baseline EEG resting state measurement was performed. This was followed by real time quantitative electroencephalography (qEEG) in parallel to the application of four different stimulation protocols to determine the optimal stimulation pattern for each subject. The stimulation protocols differed in the design of the stimulation trains. For the rest of the experiment the stimulation protocol resulting the highest power spectral density (PSD) of the alpha frequency band (alpha power) in parietal and occipital areas was chosen. Stimulation or sham stimulation occurred throughout the duration of the item-memory object-location paradigm performed, consisting of encoding, immediate recall, consolidation (10 minutes), and delayed recall. The memory task under stimulation or sham stimulation was followed by another resting state EEG measurement. Behavioral measures, relative PSD and individual alpha peak level (iAPL) were analyzed using SPSS and EEGlab. Results: The stimulation was well tolerated, subjects could not determine whether stimulation took place or not (stimulation vs sham). PSD analysis in the resting state before the stimulation revealed a decrease of alpha power and an increase in theta power in the group of AD patients as described before. Relative PSD yielded no stimulation effect. However, during stimulation, in contrast to sham stimulation, increased iAPL was detected at the occipital electrodes in the group of AD patients. In contrast, no effect of stimulation on memory performance during the paradigm was found. Conclusion: In this study, we were able to demonstrate that a single session of low-intensity and high-frequency rTMS is capable to increase iAPL in AD patients. It remains to be determined in which stage of the learning process stimulation could have the most beneficial behavioral effect. In addition, it is yet unclear if repetitive stimulation over a certain period of time reveals stronger effects. However, this rTMS-system is a promising approach as it could be easily applied also in out-of-hospital settings due to the small coils and the low-intensity of the magnetic field.
P60- A PRAGMATIC ASSESSMENT OF ULTRA-FAST MRI IN REAL-LIFE CLINICAL AND RESEARCH COGNITIVE PRACTICE. M. Rosa-Grilo1, E. Mulroy1, M. Beament1, H. Chughtai2, D. Thomas1, G. Parker2, N. Fox1, C. Mummery1(1. UK Dementia Research Centre at University College London (UCL) — London (United Kingdom), 2. Centre for Medical Image Computing, Department of Medical Physics & Biomedical Engineering and Department of Neuroinflammation at University College London (UCL) — London (United Kingdom))
Background: Structural brain imaging is an essential component of the diagnostic workup for cognitive disorders, enabling the exclusion of reversible causes and assisting dementia subtype diagnosis. Further, with the emergence of disease-modifying therapies for neurodegenerative disease, demand for MRI imaging is likely to increase, both to facilitate early diagnosis, and safety monitoring, particularly for amyloid-related imaging abnormalities (ARIA). MRI has several advantages over other imaging techniques, including its lack of ionizing radiation and excellent soft-tissue contrast. However, MRI scans are time-consuming, costly, and less widely available than their closest alternative, CT scans. Together, these factors contribute to variability in availability and quality of MRI access leading to inequality in diagnosis. Reducing MRI scan time is a critical step in increasing efficiency, reducing cost, and enabling more widespread adoption of MRI as the first-line imaging modality for neurodegenerative diseases. Objectives: Current conventional MRI protocols typically require patients to stay in the MRI scanner for 20–30 minutes. Recent developments in accelerated MRI acquisition techniques have enabled us to design a protocol greatly reducing this time to below 10 minutes whilst retaining good image quality. The performance of this novel protocol will be compared against a conventional 3T MRI protocol in a pilot cohort of patients with varied diagnoses recruited from cognitive disorders outpatient clinics and research studies. Our primary aim is to demonstrate that, by using a new ultra-fast MRI protocol, we will be able to reduce barriers to the widespread use of MRI. To do so, we aim to evaluate the non-inferiority of this rapid scanning protocol, providing equivalent diagnostic utility to current conventional scanning protocols. Secondary objectives include the assessment of qualitative and quantitative scan metrics (image resolution, motion artefacts, signal-to-noise ratio, tissue volumes). Methods: For the pilot study, 40 individuals will be consecutively recruited from a single UK centre (National Hospital for Neurology and Neurosurgery, London). Eligible participants are individuals who are having a conventional 3T MRI scan as a part of their diagnostic workup. Recruiting in this way ensures that individuals are representative of the population of interest in a real-life environment. We aim to compare the conventional MRI protocol to the pilot rapid protocol, which uses wave-controlled aliasing in parallel imaging (Wave-CAIPI) work-in-progress sequences implemented on a Siemens 3T Prisma system. The rapid Wave-CAIPI protocol includes sequences widely used clinically and in clinical trials (3D MPRAGE, 3D FLAIR, 3D T2, and 3DT2*) and has been optimized to achieve a balance between acquisition speed and image resolution/quality. We will perform a head-to-head comparison of the images using a predefined 5-point Likert-scale from -2 to +2, with 0 being equivalent. Each sequence will be rated for utility in making a radiological diagnosis and assessed for qualitative and quantitative scan metrics. Quantitative analysis will involve calculation, and comparison of key structural measurements (e.g. cortical grey matter, deep grey matter, white matter, and hippocampal volumes) for the two protocols using tools such as FreeSurfer. Results: Recruitment began in March 2022 and is projected to take five months. We will test for noninferiority of the accelerated sequences compared to standard sequences in the head-to-head analysis and agreement of quantitative measures will be assessed through Bland-Altman analysis to evaluate any differences between the two protocols. Conclusion: Worldwide population ageing brings with it an ever-increasing incidence of dementia and augments demands on our healthcare systems. Rapid and accurate structural brain imaging is key to meeting such demands. This ultra-fast MRI protocol, investigated in real-life clinical and research cognitive practice, holds the potential to significantly increase efficiency, reduce costs and enhance diagnostic yield, all while affording patients greater convenience and comfort. In addition to the enhanced diagnostic capabilities, rapid imaging holds many other uses in neurodegenerative diseases. With the advent of disease-modifying therapies for Alzheimer’s disease, rapid brain imaging will also be invaluable for the management of clinical trials by enabling earlier diagnosis, optimizing the efficacy of therapeutics, improving drug safety, and reducing patient burden. The results of this study will provide crucial insights into the utility of rapidly acquired MRI sequences in a real-world cohort of people with suspected cognitive decline, informing the set-up of larger research studies on the topic. Acknowledgments: This study has been funded by Biogen Idec UK. No conflicts of interest.
P61- OPTIMAL CONDITIONS FOR ENTRAINING GAMMA WAVES USING SENSORY STIMULATION IN OLDER ADULTS. Y. Park1, E. Yoon1, K.W. Kim1(1. Seoul National University — Seoul (Korea, Republic of))
Objective: Although light flickering at 40 Hz reduced Alzheimer’s disease (AD) pathologies in mice by entraining gamma waves, it failed to reduce cerebral amyloid burden in patients with AD or mild cognitive impairment. We investigated the optimal parameters of the flickering light stimulus for entraining gamma waves in older adults with aging in eyes and brain. Methods: We measured electroencephalography (EEG) during the FLS presented. We compared the event-related synchronization (ERS) and spectral Granger causality (sGC) of entrained gamma rhythm in 26 cognitively normal older adults between different colors, luminance intensities and flickering frequencies of lights. We investigated the relationship between white matter integrity and entrainment and propagation using fractional anisotropy (FA).Results: Entrained gamma activity started after the FLS onset, lasted during the FLS, and diminished after the FLS offset which was observed most highly at parietal area and steadily decreased from the parietal to the frontal area. In human, FLS entrained significantly higher event related synchronization (ERS) at the lower frequencies than 40 Hz. In addition, the stronger FLS entrained higher ERS with stronger parietooccipital to frontotemporal connectivities. Adverse effects were tolerable and comparable between FLS conditions in older adults. Lower WM microstructural integrity was related to weaker gamma entrainment and propagation. Conclusion: Optimal FLS did work, but lower white matter integrity was related to less gamma entrainment and propagation.
P62- SERUM LEVELS OF GLYCAN EPITOPE CORRELATE WITH TAU AND PREDICT PROGRESSION TO DEMENTIA IN COMBINATION WITH APOE4 ALLELE STATUS. R.Z. Zhou1, D.L. Vetrano2, G. Grande2, B. Winblad1, L. Tjernberg1, S. Schedin-Weiss1(1. Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet — Solna (Sweden), 2. Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University — Stockholm (Sweden))
Background: Identifying early biomarkers for Alzheimer’s disease (AD) is crucial for starting potential treatments at the right time. Recent investigations with high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS) have shown alternations in N-glycosylation patterns in cerebrospinal fluid of AD patients (1). Therefore, glycan biomarkers may prove to be useful, novel alternatives or complements to existing AD biomarkers. As serum samples are more available and easier to obtain than CSF samples, a glycan biomarker in blood would be preferrable. One type of N-glycosylation pattern of interest is the “Bisecting GlcNAc” epitope, which is highly expressed in brain and thus more likely to be altered in cerebral disease (2). Bisecting GlcNAc is synthesized by the enzyme N-acetylglucosaminyltransferase-III (GnT-III) and has been shown to be linked to AD by regulating β-site APP-cleaving enzyme-1 (BACE1) (2). Using an assay based on Phaseolus vulgaris erythroagglutinin (PHA-E), which binds specifically to the “Bisecting GlcNAc” epitope, we found elevated levels of this epitope in CSF of AD patients compared to control subjects (3). Thus, we were interested in evaluating this potential biomarker in blood. Objectives: To evaluate Bisecting GlcNAc levels in serum as a glycan biomarker for early detection of dementia. Methods: We developed a plate-based enzyme-linked lectin assay (ELLA) with PHA-E coupled to biotin functioning as an epitope-binding lectin (3). We optimized sample dilutions for serum analysis and used a final dilution of 1:100000. In a pilot study, we analyzed baseline and 6-year follow-up serum samples from 233 individuals enrolled in the Swedish National study on Aging and Care in Kungsholmen (SNAC-K). The average age at baseline was 77.6 years (SD = 10.1, range 60.2 — 96.6), with 62 % females. Cognitive status of patients was followed for up to 15 years, during which 52 of 233 individuals developed dementia. The serum samples were also analyzed for several proteins, including total tau, with a R&D Luminex© biomarker assay. Results: At baseline, serum PHA-E fluorescence correlated with tau levels in individuals who later developed dementia (r2 = 0.30). The correlation was much weaker in individuals who did not develop dementia (r2 = 0.07). At 6-year follow-up, the individuals who already developed dementia exhibited an even stronger PHA-E to tau correlation (r2 = 0.63). Individuals were then stratified into three groups according to their relative baseline tau/PHA-E ratio: high, intermediate, or low. Intermediate tau/PHA-E ratio was identified as a predictor for future dementia diagnosis (AUC = 0.61, 95 % CI: 0.52 — 0.70, p < 0.05). Thus, in our cohort, intermediate tau/PHA-E levels in an individual more accurately predicted future dementia diagnosis than having at least one APOE4 allele (AUC = 0.58, 95 % CI: 0.49 – 0.67, p > 0.05). Progression to dementia diagnosis was significantly more common in individuals with intermediate tau/PHA-E ratio compared to individuals with low/high tau/PHA-E ratio (p < 0.05). In subjects with one or two APOE4 alleles, the risk of progression to dementia compared with subjects with no E4 alleles was even higher if they also had intermediate tau/PHA-E levels (p < 0.05). Conclusion: Serum PHA-E correlates with total plasma tau in individuals who later develop dementia. An intermediate PHA-E/tau ratio was a risk factor in dementia development and added predictive value to other known risk predictors such as heterozygous or homozygous APOE4 status. Interestingly, the PHA-E to total tau correlation has been previously shown in cerebrospinal fluid of patients with Subjective Cognitive Impairment (SCI) (3). Our results support the usefulness of glycan biomarkers in blood for prediction of dementia. References: 1. Gaunitz S, Tjernberg LO, Schedin-Weiss S. What Can N-glycomics and N-glycoproteomics of Cerebrospinal Fluid Tell Us about Alzheimer Disease? Biomolecules. 2021 Jun 9;11(6):858. 2. Kizuka Y, Taniguchi N. Neural functions of bisecting GlcNAc. Glycoconjugate Journal. 2018 Aug 16;35(4):345–51. 3. Schedin-Weiss S, Gaunitz S, Sui P, Chen Q, Haslam SM, Blennow K, et al. Glycan biomarkers for Alzheimer disease correlate with T-tau and P-tau in cerebrospinal fluid in subjective cognitive impairment. The FEBS Journal. 2020 Aug 14;287(15):3221–34.
P63- SERUM PROBDNF PREDICTS MEMORY GAINS AFTER LIFESTYLE CHANGES IN ELDERLY PERSONS — A SUBGROUP ANALYSIS AMONG ADHERENT PARTICIPANTS IN THE FINGER STUDY. A. Matton1, K. Håkansson1, J. Goicolea1, M. Daniilidou1, T. Ngandu2, G. Gerenu1, A. Solomon3, H. Soininen3, T. Laatikainen2, M. Kivipelto1(1. Karolinska Institutet — Solna (Sweden), 2. Finnish Institute on Health and Welfare — Helsinki (Finland), 3. University of Eastern Finland — Kuopio (Finland))
Background: Brain-derived neurotrophic factor (BDNF), including the mature form (mBDNF) and its precursor (proBDNF), has an important role in brain plasticity, and is possibly also involved in neuroprotective mechanisms against development of dementia. Objective: In this study we relate, for the first time, serum levels of both mBDNF and proBDNF with cognitive changes in elderly persons at risk of dementia during a comprehensive life-style intervention. Methods: A sub-sample of 151 participants from the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER), aged between 60 and 79 years, and with high adherence to the intervention protocol were included in the analysis. The multidomain intervention combined several lifestyle changes in parallel (diet, exercise, cognitive training, social stimulation, and vascular risk management) over 24 months. Serum mBDNF and proBDNF levels were measured at baseline and after after 24 months, and were related to changes in cognitive performance using multiple linear regression models. Results: We found a positive association between proBDNF levels at baseline and improved memory performance over the 24-month intervention period. This association was especially strong for changes in complex memory performance. In addition, participants with larger increases in their proBDNF levels over the intervention period also had larger gains in memory performance. We found no associations between levels of mBDNF, or changes in mBDNF levels, and performance changes in any cognitive domain. Conclusion: These results suggest that proBDNF may have a key role in molecular processes underlying memory improvement, and that proBDNF availability can serve as a predictor of memory benefits from comprehensive lifestyle changes in elderly persons.
P64- EVALUATION OF LONG-TERM SAFETY AND COMPLIANCE TO A MULTINUTRIENT INTERVENTION FOR UP TO 8 YEARS IN MILD COGNITIVE IMPAIRMENT / PRODROMAL ALZHEIMER’S DISEASE: DATA FROM THE RANDOMISED CONTROLLED LIPIDIDIET TRIAL. T. Hartmann1,2, A. Solomon3,4,5, P. Visser6,7, K. Blennow8,9, M. Kivipelto5,10,11, H. Soininen10,12(1. Deutsches Institut fur Demenzpravention, Saarland University — Homburg (Germany), 2. Experimental Neurology — Homburg (Germany), 3. Neurology, Institute of Clinical Medicine, University of Eastern Finland — Kuopio (Finland), 4. Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute — Stockholm (Sweden), 5. Clinical Trials Unit, Theme Aging, Karolinska University Hospital — Huddinge (Sweden), 6. Department of Neurology, Alzheimer Center, VU University Medical Center — Amsterdam (Netherlands), 7. Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht — Maastricht (Netherlands), 8. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg — Mölndal (Sweden), 9. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, — Mölndal (Sweden), 10. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland — Kuopio (Finland), 11. Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute — Stockholm (Sweden), 12.Neurocenter, Department of Neurology, Kuopio University Hospital — Kuopio (Finland))
Background: Lifestyle factors such as nutrition and diet are increasingly recognized as modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Previous studies with the multinutrient combination Fortasyn Connect (Souvenaid) have shown benefits on memory and functional connectivity in mild AD dementia (1, 2). The LipiDiDiet (3, 4) study was designed to investigate the effects of Fortasyn Connect in individuals with prodromal AD. With up to 6 years of randomised, double-blind, placebo-controlled (RCT) intervention and an additional 2 years of open-label intervention, LipiDiDiet is a unique long-running RCT with a nutritional intervention in prodromal AD/MCIAD. Results over the first 2 and 3 years of intervention showed that Fortasyn Connect slowed cognitive decline and reduced brain atrophy (5, 6). Objectives: Here we report on compliance and long-term safety of the use of Fortasyn Connect compared to control over a maximum of 8 years of intervention. Methods: LipiDiDiet was a double-blind, parallel-group, multi-center randomized controlled clinical trial conducted between 2009 and 2013 in 11 sites across Finland, Germany, the Netherlands, and Sweden. A total of 311 participants with prodromal AD, defined according to the International Working Group (IWG)-1 criteria, were enrolled and randomized (1:1) to the active product (125ml once-a-day drink; Fortasyn Connect) or a calorie-matched placebo control. Following the first 2 years of intervention, participants could opt in for annual extensions up to a maximum of 6-year double-blind and 2-year open-label intervention. When participants started the trial, they were not taking any pharmaceutical AD drugs. Once individual participants progressed to mild dementia during the double-blind intervention period, they were provided with AD drugs and/or open-label Souvenaid (together referred to as open-label medication) and could continue in the trial. Main efficacy outcomes included measures of cognition, function, brain atrophy, and disease progression. Safety assessments included (serious) adverse events, concomitant medication use, vital signs, and clinical safety laboratory tests, analysed in all participants who received at least one dose of study product. To allow for separate evaluation of safety data collected before and after a switch to open-label Souvenaid, analyses were done in two safety phases: the double-blind treatment phase and the open-label treatment phase. Product compliance was assessed by participants’ recording of product use in a daily dairy and calculated as the percentage of study product used throughout the study period compared with the prescribed dosage, both over the entire intervention period and separately for each year of double-blind or open-label intervention. Results: From the 311 participants randomized at baseline, n=245, 162, 84, 49, 29, 17, 8 participants completed respectively the 24-, 36-, 48-, 60-, 72-, 84-, and 96-month intervention periods. The frequency, severity and types of recorded adverse events were consistent with the studied population and none of the serious adverse events was related to the study product as assessed by the investigators. The overall incidences of (serious) adverse events were comparable between groups, both while on double-blind treatment over the first 6 years and while on open-label treatment from dementia diagnosis or start open-label intervention onwards. Self-reported compliance to the study product was high throughout the entire intervention period, ranging from 85% to 98% across the different intervention years. Conclusion: Inherent to long-term follow-up studies like LipiDiDiet, interpretability of the safety and compliance data is complicated by several factors like decreasing sample size, treatment switching, potential non-compliance, differential attrition, and gradual underreporting of events. Despite that, the current results showed that participants’ compliance to the study product remains high over a long-term intervention period and there was no indication for a health concern related to the use of Fortasyn Connect for up to 8 years in a prodromal AD/MCIAD population. References: 1. Scheltens P, et al. Alzheimers Dement. 2010;6:1–10 e1. 2. Scheltens P, et al. J Alzheimers Dis. 2012;31:225–236. 3. Dutch Trial Register: NL1620 (NTR1705). 4. Funding by EU-FP7 211696, EU JPND EURO-FINGERS. 5. Soininen H, et al. Lancet Neurol. 2017;16:965–975. 6. Soininen H, et al. Alz Dementia. 2021;17:29–40.
P66- CLINICAL UTILITY OF NON-INVASIVE WHOLE TRANSCRIPTOMIC PROFILING OF ALZHEIMER’S DISEASE. S. Toden1, J. Zhuang1, S. Quake2, R. Rissman3, J. Brewer3, J. Sninsky1(1. Molecular Stethoscope — South San Francsico (United States), 2. Stanford University — Stanford (United States), 3. University of California, San Diego — San Diego (United States))
Background: Histological analysis and gene expression profiling studies using post-mortem human brain tissues have provided insight into the disrupted pathological networks of Alzheimer’s disease (AD). The resulting insights, however, are qualified because only end stage disease is surveyed, patient selection bias occurs due to informed consent, tissue sampling bias needs to be considered and pathology review introduces subjectivity. Recently, blood-based liquid biopsies assessing circulating nucleic acids have emerged as an alternative for non-invasive examination of molecular alterations in multiple diseases. Although quantification of cell-free messenger RNA (cf-mRNA) was considered challenging due to low abundance in the circulation, we have developed a next generation sequencing (NGS) based platform that enables hypothesis-independent transcriptome characterization of the cf-mRNA secretome from low volume plasma/sera. Noninvasive testing provides the opportunity to collect information along the disease continuum, may provide differential diagnosis for dementias and identify potential additional therapeutic targets that trigger later stages of disease pathology. Objectives: Using a cf-mRNA RNA-Sequencing AI/Machine learning platform, we evaluated plasma cf-mRNA profiles of AD subjects with a range of severity and non-cognitively impaired (NCI) individuals. We examined genes and associated pathways that are dysregulated in cf-mRNA transcriptome of AD subjects. Furthermore, we evaluated whether these dysregulated genes in AD subjects could be used to build an AD diagnostic classifier. Finally, we assessed the contribution of brain cell type-specific transcripts in cf-mRNA transcriptome of AD and NCI subjects. Methods: Plasma samples were collected from 126 AD and 116 NCI subjects with a similar age distribution from five independent institutions. Subsequently, cell free RNA was isolated from plasma samples and sequencing libraries were generated. Sequencing was performed using Illumina NextSeq 500 platform. Differential expression analysis was conducted with DESeq 2 using read counts for each gene as input. Pathway analysis was conducted using Ingenuity Pathway Analysis software. Samples were split into “training” and “testing” cohorts and an AD diagnostic classifier was built using training cohort with logistic regression with L2 regularization. Classifier performance was evaluated using the independent “testing’ cohort. The Tabula Sapiens single cell datasets were used to estimate the abundance of brain cell type-specific transcripts. Results: We identified 2,591 dysregulated genes in the cf-mRNA of AD patients. These identified genes recapitulated biological processes associated with AD, such as synaptic dysfunction, mitochondrial dysfunction and inflammation. Unsupervised decomposition analysis using differentially expressed genes resulted in identification of 6 gene clusters and a subset of these clusters were associated with the processes known to be involved in AD onset and progression. The AD diagnostic classifier derived from the training cohort was able to discriminate AD from NCI subjects in the testing cohort. Quantification of the brain cell type-specific genes indicated that a subset of brain cell types such as Bergmann glia cells were less abundant in cf-mRNA of AD subjects compared to those of NCI. Conclusion: Collectively, our study highlights cf-mRNA profiling as a potential tool to non-invasively characterize neurological diseases such as AD. Pathway and cell type analyses revealed potential diagnostic and therapeutic targets of AD beyond the ATN framework.
P67- DEVELOPMENT OF A SELECTIVE ESTROGEN B-RECEPTOR PHYTOESTROGEN FORMULATION — PHYTOSERM — FOR IMPROVING COGNITIVE HEALTH TO REDUCE ALZHEIMER’S RISK AND MENOPAUSAL SYMPTOMS: A PHASE 2 RANDOMIZED CLINICAL TRIAL. C. Lopez1, M. Drew1, G. Hernandez1, R. Brinton1(1. University of Arizona — Tucson (United States))
Background: Accumulating evidence points to life-time estrogen exposure as a protective factor against cognitive decline and Alzheimer’s disease (AD) in women, and to the menopause transition as a trigger for an existing AD predisposition. If estrogen therapy is effective for sustaining neurological health and preventing AD, why are women reluctant to use this therapy? Fear of breast cancer is the principal reason menopausal women report for rejecting estrogen replacement therapy. While women forego pharmaceutical hormone therapy, they extensively, utilize over the counter products labeled natural and considered to be safer. Thus, to attain brain protection, we also had to address breast protection. To achieve this goal, we developed a rationally designed combination of select ERβ-selective phytoestrogens that promote brain health to reduce AD risk while also reducing breast cell proliferation. The greatest risk factors for AD are age, APO ε4 allele and female sex. Close to two thirds of the Alzheimer population are women and women bear the greatest burden of the disease. The estimated lifetime risk for AD is 19.5% for women compared to 10.3% in men. Multiple conditions that emerge during menopause, such as cognitive decline, dysregulated glucose metabolism, insomnia, depression, are associated with increased AD risk. Adverse outcomes of ovarian hormone loss, especially estrogen, in midlife (average age 51) can initiate a 15–20-year prodromal phase between menopause and AD onset. While the clinical definition of menopause focuses on reproductive function, the symptoms of this midlife aging transition are largely neurological1. Although about 20% of women transition through menopause without symptoms, 80% of women experience symptoms and over 70% of these experience multiple symptoms associated with risk of Alzheimer’s disease. Previous phase 1b/2a trial outcomes demonstrated that the PhytoSERM formulation was safe, well-tolerated, and had an adequate pharmacokinetic profile. An optimal dose of 50mg was established. Based on such outcomes, we designed a phase 2 efficacy trial to further assess PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flashes and cognitive decline. Objectives: To conduct a phase 2 clinical trial to determine the effect of oral PhytoSERM (50mg) for 24 weeks in regional brain glucose metabolism standardized uptake value ratio (SUVR) by FDG PET. To assess change in cognitive function, vasomotor symptoms, and sleep. To measure single-dose pharmacokinetics of PhytoSERM in a subset of 12 participants. To evaluate the effect of PhytoSERM on exploratory MRI imaging outcomes and blood-based biomarkers. Methods: This is a single-center, double-blind, parallel-group, randomized-controlled phase 2 clinical trial. A total of 100 participants, 50 per treatment arm, will be enrolled. Eligible participants are female, age 45 to 60 years old, peri or post-menopausal (last menstrual period completed ≥ 60 days and ≤ 4 years), cognitively normal (MMSE ≥27) and experiencing ≥7 hot flashes per day. Participants will be randomized to 50 mg of PhytoSERM (administered orally, once per day) or matching placebo, 1:1 allocation, for a 24-week period. FDG-PET scans to evaluate the primary endpoint will be conducted at baseline and 24 weeks. Cognitive endpoints and clinical ratings will be assessed at baseline, 12 and 24 weeks. Hot flashes will be measured both subjectively with a diary and objectively with a digital wristband measuring electrodermal activity. Results: Primary Endpoints: Change from baseline to 24 weeks in regional brain glucose metabolism standardized uptake value ratio (SUVR) by FDG PET. Secondary Endpoints: Mean rate of change in cognitive outcomes: Verbal Paired Associates score, List Sorting Working Memory Test score, WAIS digit symbol test score, and Selective Reminding Task score. Mean rate of change in frequency of hot flashes and menopause rating scale score. Mean rate of change in affect score and sleep quality index score. Pharmacokinetic parameters (Cmax, tmax, t1/2, AUC). Exploratory Endpoints: Mean change from baseline in regional brain volumes (mm3). Mean change from baseline in fractional anisotropy (FA). Mean change from baseline in quantitative anisotropy (QA). Mean change from baseline in functional connectivity (Hedges’ g). Mean change from baseline in cerebral blood perfusion (perfusion clusters) on arterial spin labeling (ASL). Conclusion: Herein we present a phase 2 proof-of-concept framework to assess the efficacy of PhytoSERM as a non-pharmacologic therapeutic to improve cognitive health and reduce menopausal symptoms. Results from this study will validate previous findings that indicate that PhytoSERM is safe alternative to hormone therapy and has the potential to sustain neurological health and preventing AD during the menopausal transition.
LP45- PHYLUM FIRMICUTES ABUNDANCE IS ASSOCIATED WITH BRAIN VOLUMES IN A COGNITIVELY UNIMPAIRED COHORT ENRICHED FOR ALZHEIMER’S DISEASE RISK. M. Ibrahim1, H. Margo1, J.W. Kang1, G. Ennis1, S. Harding1, S. Johnson1, S. Asthana1, B. Bendlin1, A. González2, F. Rey1, R. Knight2, R. Kaddurah-Daouk3(1. University of Wisconsin school of Medicine and Public Health — Madison (United States), 2. department of pediatrics, university of california, san diego — la jolla — La Jolla (United States), 3. Department of Psychiatry and Behavioral Sciences, Duke — Durham (United States))
Background: The gut microbiome has recently received attention as a potential modifiable risk factor for Alzheimer’s disease (AD). To understand how the gut microbiome may affect AD pathology, our research group previously compared the gut microbiome compositions of people with AD dementia to those of healthy controls, finding that gut microbiome composition is altered in AD. We also found associations between microbial abundance and amyloid and tau pathology, even among cognitively unimpaired individuals. However, the microbiome’s preclinical relationships with measures of neurodegeneration, such as gray and white brain matter volume require further examination. Objectives: The primary objective of this study was to evaluate the extent to which abundances of gut microbial phyla were associated with brain tissue volumes. We hypothesized that lower relative abundances of Bacteroidetes and Actinobacteria phyla would be associated with lower white and gray matter volumes. Methods: 157 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center (WADRC) and Wisconsin Registry for Alzheimer’s Prevention (WRAP) study provided fecal samples and underwent T1-weighted neuroimaging through the Microbiome in Alzheimer’s Risk Study (NIA R01AG070973). The sample was enriched for participants in the preclinical stage of AD and presence of the APOE ε4 genotype. Fecal samples were typically collected at home, returned chilled, and subsequently weighed, scored using the Bristol scale, and frozen at -80°C. CAT12 software implemented in SPM12 was used to process and quantify brain images with the Automatic Anatomically Labeled Atlas 3. 16S ribosomal RNA V4 bacterial genome sequencing was performed on the frozen fecal samples using published methods. Taxa were denoised, classified (Qiita and QIIME2), and agglomerated at the phylum taxonomic rank. Multiple regressions were run to ascertain associations of each bacterial phylum with gray and white matter individually, as well as combined brain volume (calculated as the sum of gray and white matter). Covariates included age, sex, APOE ε4, and total intracranial volume. Results: Participants demographically represented the WADRC and WRAP cohorts. Age at fecal sample was 66.25±6.73 years (mean±SD), and imaging was obtained within 0.66±0.48 years of fecal samples. 104 (66%) participants were female, and 52 (33%) were APOE ε4 allele carriers. Average body mass index was 28.71±5.64 kg/m2, and average fecal sample Bristol Stool Scale score was 3.89±1.23. Seven different phyla were observed in the samples, namely: Actinobacteria, Bacteroidetes, Cyanobacteria, Firmicutes, Proteobacteria, Tenericutes, and Verrucomicrobia. All seven phyla showed no significant relationships with gray and white matter volumes individually, and six of the seven showed no significant relationships with combined brain volume (p>0.1). Firmicutes, however, showed a significant positive correlation with total brain volume (p=0.04) and a positive correlation with white matter, although the latter relationship did not meet the threshold for significance (p=0.07). Conclusions: These results further validate the association of the gut microbiome and brain in the context of AD risk by showing that lower Firmicutes relative abundance is associated with smaller total brain volume. The results are also consistent with a previously published finding from our lab that showed reduced Firmicutes in AD in a smaller sample. Firmicutes has been implicated in Parkinson’s disease pursuant to its association with several microbiota-associated epitopes that play significant roles in inflammatory responses. Further analysis of Firmicutes may help elucidate how chronic inflammation and gut microbiome alterations are associated with cognitive decline in Alzheimer’s disease. Determining a role for gut microbiome in the etiopathogenesis of AD or related dementias may provide a potentially modifiable target, as well as contributing to the development of therapeutics that may mitigate the development and progression of the disease. Future analyses will extrapolate the genera or species of bacteria from phylum Firmicutesthat are absent in people with AD. With that, probiotic options could be explored to ameliorate AD pathology or neurodegeneration in AD.
LP46- OPTIMIZING DETECTION OF PRODROMAL ALZHEIMER DISEASE IN MILD COGNITIVE IMPAIRMENT — A 4-YEAR CEREBROSPINAL FLUID STUDY OF MILD BEHAVIORAL IMPAIRMENT IN ADNI AND MEMENTO. Z. Ismail1, R. Leon2, B. Creese3, C. Ballard3, P. Robert4, E.E. Smith1(1. University of Calgary — Calgary (Canada), 2. Hotchkiss Brain Institute — Calgary (Canada), 3. University of Exeter — Exeter (United Kingdom), 4. Université Côte d’Azur — Nice (France))
Background: Recruitment inefficiencies and even failures in the Alzheimer’s disease (AD) modifying drug clinical trial program can be attributed to suboptimal detection of early phase illness. Imprecise case ascertainment of prodromal AD based on standard clinical assessment necessitates further investigations such as detailed neuropsychological testing and biomarker confirmation with cerebrospinal fluid (CSF) or positron emission tomography (PET), which are time consuming and expensive. Further, high screen-failure rates contribute to cost inflation, prohibitive for some drug developers, rendering some trials infeasible. Simple, inexpensive, and scalable proxy markers that improve AD detection in participants with MCI are required, to recruit into trials more efficiently and reduce screen failures. Neuropsychiatric symptoms (NPS) can emerge early in the disease course; 30% of AD cases present with NPS in advance of a cognitive diagnosis. Mild Behavioral Impairment (MBI) is a syndrome that exploits this early manifestation of NPS to identify a high-risk group for incident cognitive decline and dementia. The ISTAART-AA criteria for MBI stipulate that NPS must emerge de novo in later life and persist for at least 6 months to qualify, echoed in descriptions of pre-dementia NPS in the NIA-AA research framework for AD. Using these criteria, epidemiological studies have demonstrated a significantly higher incidence rate of cognitive decline and dementia in participants with MBI compared to participants with no NPS or with NPS not meeting MBI criteria (NPSnotMBI). Specific to MCI, a recent study found that when participants were stratified by NPS status (i.e., noNPS, NPSnotMBI, or MBI), MBI was associated with a higher progression rate to dementia, and a lower reversion rate to normal cognition. These findings demonstrate the utility of behavioral-risk stratification (represented by MBI) in conjunction with cognitive-risk stratification (represented by MCI) to improve specificity, and highlight the advantage of the MBI framework over conventional models of NPS for dementia prognostication. However, biomarker confirmation of AD status in the MCI progressors is required to move this approach forward into clinical trial recruitment. Preliminary evidence using plasma, CSF, and PET data has demonstrated mostly cross-sectional associations between MBI and amyloid and p-tau. Definitive studies are still required. Here, in MCI participants in two independent studies (ADNI and MEMENTO), we explore cross-sectional and longitudinal associations between MBI and CSF biomarkers (Aβ42, Aβ40, t-tau, p-tau, Aβ42/40, t-tau/Aβ42, and p-tau/Aβ42), and conduct survival analyses for incident AD over 4 years. Objectives: In MCI participants, to assess cross-sectional associations between MBI, NPSnotMBI, and no NPS and AD biomarkers measured in CSF. To assess 4-year longitudinal changes in AD biomarkers comparing persistent (MBI) and transient (NPSnotMBI) NPS. To determine relative rates of incident dementia in MBI and NPSnotMBI compared to no NPS. Methods: The primary dataset comprised 352 ADNI participants and the validation dataset 158 MEMENTO participants. MCI was defined by standard criteria. MBI was defined in accordance with the ISTAART-AA MBI criteria, in comparison to NPSnotMBI and noNPS. In the ADNI analyses, the Roche Elecsys assay was used for Aβ42, p-tau, and t-tau levels, and mass spectrometry method was used for Aβ42/40 levels. In MEMENTO, Innotest was used for all biomarkers. Linear regressions were fitted to determine cross-sectional associations between NPS status as independent variable, and CSF biomarkers (Aβ42, Aβ40, t-tau, p-tau, Aβ42/40, t-tau/Aβ42, and p-tau/Aβ42) as continuous dependent variables. Hierarchical linear mixed-effects models were implemented to assess the longitudinal relationship between NPS profile (MBI vs NPSnotMBI) and repeated measures of CSF biomarkers over 4-years. Kaplan-Meier and Cox proportional hazards models determined NPS group differences in dementia-free survival time and rates of incident AD. Results: ADNI participants had a mean age of 72 (43.5% female, median MMSE=28); MEMENTO participants had a mean age of 69 (46.2% female, MMSE=28). In ADNI, cross-sectional linear regressions showed that compared to noNPS, MBI was associated with lower CSF Aβ42 level and Aβ42/40 ratio, higher CSF p-tau and t-tau levels, and higher t-tau/Aβ42 and p-tau/Aβ42 ratios. NPS-not-MBI was associated only with lower Aβ42/40 ratio. Linear mixed effects models revealed this same AD-specific biomarker profile over 4 years in association with MBI, whereas NPS-not-MBI was associated with higher tau levels. Survival analyses revealed lower AD-free survival and greater rate of incident dementia in MBI (Hazard Ratio (HR) 3.5) relative to comparator groups. ADNI and MEMENTO findings were consistent. MEMENTO, a memory clinic study, demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater MBI-associated reduction in Aβ40; HR for incident dementia was 3.93 in MBI and 1.83 in NPS-not-MBI. Conclusion: We have demonstrated the utility of applying the MBI criteria to MCI to improve the specificity for detection of prevalent AD, and prediction of incident AD dementia. These results are congruent with the a priori goals in development of the MBI criteria, and have implications for research methodology, clinical trial recruitment, drug development, clinical care, and public health efforts. Disclosures: All authors report no relevant disclosures.
LP47- COMPARISON OF CYTOKINE PROFILE IN OLDER ADULTS WITH POSITIVE AND NEGATIVE PROTEIN BIOMARKERS AB42, P-TAU, T-TAU AND P-TAU /AB42 RATIO. I.C. Bolaños Burgos1,2,3,4, G.T. Oliveira Engelmann4,5,6, E. Oliveira Hansen7, N. Silva Dias2,8, A. Teixeira Carvalho9, D. Valadão4,10, D. Miranda2,10,11, M.A. Romano-Silva2,4,10, B. Mattos Viana2,8,12, M.A. Camargos Bicalho1,2,4,5(1. Adult Health Sciences Applied Program — Belo Horizonte (Brazil), 2. Hospital das Clinicas — Belo Horizonte (Brazil), 3. National Institute of Science and Technology of Molecular Medicine (INCT-MM), Faculdade de Medicina, Universidade Federal de Minas Gerais — Belo Horizonte (Brazil), 4. Universidade Federal de Minas Gerias — Belo Horizonte (Brazil), 5. Molecular Medicine Program — Belo Horizonte (Brazil), 6. Jenny de Andrade Faria Institute- Reference Center for the ElderlyHospital das Clinicas — Belo Horizonte (Brazil), 7. Jenny de Andrade Faria Institute- Reference Center for the Elderly, Hospital das Clinicas — Belo Horizonte (Brazil), 8. Older Adult Psychiatry and Psychology Extension Program (PROEPSI) — Belo Horizonte (Brazil), 9. René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz) — Belo Horizonte (Brazil), 10. National Institute of Science and Technology of Molecular Medicine (INCT-MM)Faculdade de Medicina, Universidade Federal de Minas Gerais — Belo Horizonte (Brazil), 11. Universidade Federal de Minas Gerias — Belo Horizonte (Bouvet Island), 12. Department of Mental HealthFaculdade de Medicina, Universidade Federal de Minas Gerais — Belo Horizonte (Brazil))
Background/Objectives: Cytokines are small proteins that indicate inflammatory activity and may impair cognitive function. Moreover, in Alzheimer’s disease (AD) the inflammation has been considered one of its neuropathological processes. Deposition of beta-amyloid in the brain may trigger inflammatory processes, as well as the inflammation may accelerate beta-amyloid (Aβ) deposition. Exaggerated release of pro-inflammatory cytokines and chemokines, may result in synaptic dysfunction, neurodegeneration and progression of the disease. Therefore, it’s relevant to know the inflammatory profiles of the Cerebrospinal Fluid (CSF) of patients in the AD biomarker continuum. This study aims to compare CSF cytokines levels in older adults with positive and negative biomarkers of proteins Aβ42, p-Tau, t-Tau, and p-Tau/Aβ42 ratio. Methods: We collected 80 older adults’ CSF by lumbar puncture and stored it at -80°C. Aβ42, p-Tau, t-Tau, and 27 cytokines were assessed by Luminex xMAP technique. The levels of Aβ42, p-Tau, and t-Tau were determined using the cutoff points for each protein, and made a categorical classification in groups: Aβ42+, Aβ42-, p-Tau+, p-Tau-, t-Tau+, t-Tau- and p-Tau/Aβ42+ e p-Tau/Aβ42-. Comparations of CSF’s cytokine levels between these groups were assessed with Mann-Whitney U Test. Results: Significantly lower IL–8 levels were found in Aβ42+ compared to Aβ42- groups [U=473,0, p=.029]. The granulocyte colony-stimulating factor (G-CSF) was significantly higher in p-Tau+ [U=625,0, p=.014] and p-Tau/Aβ42+ [U=752,0, p=.033] groups. No significant differences were found between the groups in t-Tau+, and t-Tau-. Conclusion: Elevated levels of IL-8 in patients with negative Aβ42 may be related to cell recruitment in response to damage caused by the accumulation of β-amyloid plaques. Increases in G-CSF levels in the p-Tau/Aβ42+ group could be associated with decreased Aβ plaques and greater disease severity. The authors declare that they have no competing interests.
LP48- EARLY DETECTION OF ALZHEIMER’S DISEASE USING MICRORNAS. B. Steinkraus1, M. Heuvelman1, J.L. Cummings2, J. Manson3, C. Ritchie3(1. Hummingbird Diagnostics — Heidelberg (Germany), 2. Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas — Las Vegas (United States), 3. Centre for Clinical Brain Sciences, The University of Edinburgh — Edinburgh (United Kingdom))
Background: MicroRNAs (miRNAs) represent a class of ∼22nt short non-coding RNAs that have been identified as a sophisticated layer of post-transcriptional regulation, governing many cellular, inflammatory and vascular processes. This characteristic, together with the observation that miRNAs are frequently secreted into the extracellular space and stable in blood and other body fluids, make them specific, robust and above all non-invasive biomarkers that could qualify to augment the amyloid and tau framework. miRNAs have been used for the detection of Alzheimer’s disease (AD) in its early forms (e.g., mild cognitive impairment (MCI) due to AD) and to distinguish AD from other dementias. However, to date no miRNA panel has been translated into a clinical test. Objectives: With funding from the Alzheimer’s Drug Discovery Foundation (ADDF) Hummingbird Diagnostics (HBDx) is developing a blood-based microRNA (miRNA) biomarker intended to inform the diagnosis and prognosis of Alzheimer’s disease (AD). The project objective is two-fold: a) to evaluate the diagnostic performance of a miRNA panel in the following deeply phenotyped cohorts: i) amyloid-positive MCI due to AD subjects (prodromal AD), ii) amyloid-negative cognitively unimpaired control subjects, iii) amyloid-positive cognitively unimpaired subjects (preclinical AD), iv) amyloid-negative MCI (due to non-AD conditions) subjects. And, b) to compare baseline small RNA profiles with longitudinal profiles (≥2 years) and clinical outcome data. HBDx seeks to explore biomarkers that can be utilized to characterize clinicopathologic heterogeneity and could lead to the discovery of identifiers of disease prognosis (e.g. rapidly progressive AD). Methods: Through collaboration with the European Prevention of Alzheimer’s Dementia (EPAD) consortium, we have analyzed 3,302 blood samples of 1,895 patients from over 20 European sites. To ensure a simple, robust, and reproducible platform, the IVD-certified PAXgene Blood RNA System (PAXgene) was used for the collection, lysis, and subsequent RNA stabilization of whole blood samples to enable “pipetting- and cell sorting-free” sample collection in the clinic. Analytical processes, including RNA extraction, library preparation, and next-generation sequencing (NGS) were optimized to measure a whole blood, immune enriched, small RNA expression profile. We analyzed 1,895 prospectively enrolled individuals ≥50 years of age, 1540 were amyloid negative (81%) and 355 were amyloid positive (19%). Abeta_1_42/P-tau–181 > 0.024 was used as the threshold. We deployed 100-fold cross validation of a linear regression classifier to construct and validate small RNA feature models to evaluate their utility as biomarkers for amyloid positivity as well as for MCI with or without amyloid positivity. Results: We generated small RNA feature models and report a median diagnostic receiver operating area under the curve (AUC) of 0.64 for amyloid positivity (Abeta_1_42/P-tau-181 > 0.024). Amyloid positive MCI (CDR 0.5) individuals could be discerned from cognitively unimpaired (CDR 0) amyloid negative individuals with an AUC of 0.75. In a cross-sectional analysis of amyloid positive individuals, we could predict MCI (CDR 0.5) with an AUC of 0.76. Deconvolving the signature into its blood cell and plasma origin, revealed that ∼38% of features used for the analysis were found in plasma whilst ∼62% originated from circulating immune cells. Conclusion: These data suggest the potential of a small RNA-based blood test as a viable complement to the AT(N) framework for the management of individuals at risk for AD.
CLINICAL TRIALS IMAGING
P69- DO THE RADIOMICS OR STRUCTURAL AND FUNCTIONAL MAGNETIC RESONANCE IMAGING GIVE ADDITIONAL INFORMATION TO PREDICT BRAIN AMYLOID POSITIVITY? Y. Lee1, S. Jo1, J. Lee1(1. Asan Medical Center — Seoul (Korea, Republic of))
Background: Cerebral beta amyloid deposition is a characteristic pathological change in Alzheimer’s disease (AD) and precedes the emergence of dementia symptoms by a couple of decades. Current methods to measure amyloid deposition include cerebrospinal fluid study or positron emission tomography (PET). However, these methods are difficult to be used in a large number of population because they are invasive or expensive in nature. Objectives: We aimed to predict amyloid positivity using conventional T1 image, radiomics and functional magnetic resonance image (MRI). Methods: We included 186 patients with mild cognitive impairment (MCI) who underwent florbetaben positron emission tomography (PET), MRI (3D T1 and diffusion tensor image), neuropsychological tests, and APOE genotyping at Asan Medical Center. We developed separate machine learning algorithm using each MRI feature (T1 volume, cortical thickness, and radiomics, and fractional anisotropy (FA) from diffusion tensor image) in addition to demographics, neuropsychological tests, and APOE genotype to predict amyloid positivity on florbetaben PET. We used 5-fold cross-validation scheme and the procedure were repeated 20 times. We compared the performance of each algorithm based on the MRI features used. Results: Study population included 72 patients with MCI in Aβ- group, and 114 patients with MCI in Aβ+ group. The median (IQR) age was 74.0 (65.0–77.5) in Aβ- group and 72.0 (64.0–77.0) in Aβ+ group. The machine learning algorithm using T1 volume performed better than that using only clinical information (0.770 vs. 0.757, p=0.01). The machine learning algorithm using T1 volume showed better performance than that using cortical thickness (mean AUC 0.770 vs. 0.738, p<0.001) or texture (mean AUC 0.770 vs. 0.754, p<0.001). The performance of machine learning algorithm using FA in addition to T1 volume was worse than that using T1 volume only (0.76 vs. 0.77, p<0.01). Conclusion: Among MRI features, T1 volume could be used for the prediction of amyloid PET positivity, but radiomics or diffusion tensor image might not have additional benefit.
P70- DIFFERENTIAL EFFECTS OF CARDIOMETABOLIC SYNDROME ON BRAIN AGE IN RELATION TO SEX AND ETHNICITY. S.H. Kang1, M. Liu2, S.W. Seo3, H. Kim2(1. Department Of Neurology, Korea University Guro Hospital, Korea University College Of Medicine — Seoul (Korea, Republic of), 2. Usc Steven Neuroimaging And Informatics Institute, Keck School Of Medicine Of University Of Southern California — Los Angeles (United States), 3. Departments Of Neurology, Samsung Medical Center, Sungkyunkwan University School Of Medicine — Seoul (Korea, Republic of))
Background: The incidence of cardiometabolic syndrome (CMS) and the effect of CMS on dementia were different among sex and ethnicity. Although there were growing evidence that CMS exerts on cortical atrophy, the differential effect of CMS on brain age remains unclear. Deep learning approach enable to compute the exact difference between the predicted brain age by the algorithm and the chronological age, called the brain age index (BAI). Objectives: To investigate the possible differential effects of CMS on aging based on different ethnicity/race and sex, we firstly estimated the BAIs of both populations without CMS components and analyzed them in relation to sex and ethnicity. Then, we tested whether the association of each CMS component and BAI is modified by either sex or ethnicity. Methods: We retrospectively recruited 5,541 cognitively unimpaired participants at Samsung medical center in Korea, and 9,903 participants from UK biobank. We developed BAI prediction model using graph-convolutional networks. We analyzed the associations of CMS and BAI using generalized linear models and three-way interactions with sex and ethnicity. Results: The BAI of healthy populations was lower in women than in men regardless of ethnicity (UK, p = 0.006, Cohen’s d = 0.12; Korean, p < 0.001, Cohen’s d = 0.39). Particularly, the difference in BAI between men and women was more prominent in the Korean compared to the UK metabolically healthy population (p for interaction = 0.002). Diabetes was associated with a higher BAI regardless of sex or ethnicity (p < 0.001 in all groups), and hypertension significantly increased BAI for all participants except the Korean men (p < 0.001 in UK men, UK women and Korean women; p = 0.390 in Korean men). Furthermore, the effects of diabetes and hypertension on BAI showed significantly interactive effects between sex and ethnicity (diabetes, p for interaction < 0.001; hypertension, p for interaction = 0.005). Specifically, diabetes and hypertension had more deleterious effects on brain aging in Korean women compared to that in Korean men, whereas they had more deleterious effects on brain aging in UK men than that in UK women. Conclusions: Our findings suggest that metabolically healthy women may have a lower brain age than men regardless of ethnicity. However, cardiometabolic risk factors may exert differential effects on brain age in relation to sex and ethnicity. Consequently, ethnic- and sex-specific prevention strategies are recommended to protect against accelerated brain aging.
P71- GENOME-WIDE ASSOCIATION STUDY OF THE FUNCTIONAL BRAIN NETWORK FOR ALZHEIMER’S DISEASE. M. Kim1, J.M. Lee2(1. Department Of Electronic Engineering, Hanyang University — Seoul (Korea, Republic of), 2. Department Of Biomedical Engineering, Hanyang University — Seoul (Korea, Republic of))
Background: Genome-Wide Association Study (GWAS) with neuroimaging-derived endophenotypes can serve as a screening tool to analyze the association between genetic variants and disease-associated brain traits to elucidate the genetic basis of the disease. Objectives: The goal of this study was to identify genetic risk loci significantly associated with functional brain network properties in AD. Methods: Data were downloaded from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The subjects who had both resting-state functional MRI (rs-fMRI) and single nucleotide polymorphism (SNP) genotype data were selected from the ADNI2. The sample consisted of 137 individuals with 5 groups including CN (n = 31), SMC (n = 21), EMCI (n = 28), LMCI (n = 29) and AD (n = 28). For genetic data, un-genotyped SNPs were imputed and quality-control procedures for samples and SNPs were performed using PLINK v1.9 software. Finally, 7,618,009 bi-allelic SNPs in autosomal chromosomes remained. The rs-fMRI preprocessing was conducted using Statistical Parametric Mapping (SPM12) software and Data Processing Assistant for Resting-State fMRI Advanced edition (DPARSFA). After removing the first 5 time points, the images were slice timing corrected, realigned, spatially normalized into the MNI space and resampled. Time-series data were smoothed and filtered with 0.01 ∼ 0.1 Hz. The cerebrospinal fluid and the white matter signals were removed as nuisance covariates. In the process of preparing endophenotypes for GWAS, the static functional brain network was constructed using Graph thEoreTical Network Analysis (GRETNA) toolbox. After mean time series were computed in each of the functional ROIs based on the Dosenbach-160 atlas, a connectivity matrix per subject was constructed. Binary networks were obtained by thresholding with a wide range of sparsity (5% to 50%) with intervals of 0.05. Finally, the following 7 global network metrics were calculated as AUC values: clustering coefficient, characteristic path length, normalized clustering coefficient, normalized characteristic path length, small-worldness, global efficiency and local efficiency. To measure the allelic effects of all SNPs on the 7 global network properties as phenotypes, we performed GWAS using PLINK software. As our phenotypes showed skewed distributions, the values were quantile normalized. Linear additive models considering age, sex, education level and ApoE4 genotype as covariates were used. SNPs that passed the genome-wide significance threshold of p < 5e-08 were considered statistically significant. The less stringent threshold was set at p < 1e-07. Subsequently, we calculated gene-based p-values from SNP p-values using KGG4 software and conducted a gene-based association analysis. The ideal statistical threshold was p < 2.5e-06 considering 20,000 genes. The suggestive threshold was set at p < 2.5e-05. As a post-GWAS, we conducted an expression quantitative trait locus (eQTL) analysis to figure out the functional effect of identified candidate genetic variants. Data were downloaded from the Brain eQTL Almanac (Braineac) database and gene expression levels were investigated in 10 brain regions. The significance threshold was p < 0.05. Results: From GWAS, no SNP passed the genome-wide significance threshold (p < 5e-08). As a result, all genetic variants that exceeded the less stringent threshold (p < 1e-07) were regarded as candidate genetic variants and two SNPs were identified. The rs7140236 on chromosome 14 showed a negative correlation with global efficiency (p = 5.328e-08) and the rs59143542 on chromosome 7 showed a positive correlation with local efficiency (p = 9.269e-08). In the gene-based association analysis, genes that satisfied the suggestive significance (p < 2.5e-05) were chosen for further analysis. LOC101928575 on chromosome 14 was detected for the global efficiency metric (p = 6.03e-06). Characteristic path length property was affected by the TTC9 gene on chromosome 14 (p = 2.48e-05). The peak SNP in the previous analysis with the same metric was rs7140236. In the eQTL procedure, the LOC101928575 was not found in the database. Expression levels of the gene TTC9 were stratified by rs7140236 in the hippocampus (p = 0.0041), substantia nigra (p = 0.044), temporal cortex (p = 0.0047), frontal cortex (p = 0.035) and putamen (p = 0.046). Conclusion: In this study, we performed GWAS, gene-based association study, and eQTL analysis of the whole-brain functional network properties to identify genetic risk loci for AD. We found that rs7140236 in TTC9 on chromosome 14 and rs59143542 on chromosome 7 are associated with global efficiency and local efficiency, respectively. Especially, the rs7140236 was repeatedly detected as a candidate genetic locus in further analyses. This result suggests that rs7140236 can be a candidate genetic risk locus for AD in that it negatively affects the global efficiency of the brain and regulates the expression level of the protein-coding gene in AD-related brain regions.
P72- CLINICAL AND RADIOMIC FEATURES FOR PREDICTING THE TREATMENT RESPONSE OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION IN MAJOR NEUROCOGNITIVE DISORDER. H. Lu1, S.S.M. Chan1, S.L. Ma1, V.C.T. Mok1, L. Shi1, A.D.P. Mak1, L.C.W. Lam1(1. The Chinese University of Hong Kong — Hong Kong (Hong Kong))
Background: Image-guided repetitive transcranial magnetic stimulation (rTMS) has shown clinical effectiveness in senior adults with co-occurring depression and cognitive impairment, yet the imaging markers for predicting the treatment response are less investigated. In this clinical trial, we examined the efficacy and sustainability of 10 Hz rTMS for the treatment of depression and cognitive impairment in major neurocognitive disorder (NCD) patients and tested the predictive values of imaging-informed radiomic features in response to rTMS treatment. Methods: Fifty-five major NCD patients with depression were randomly assigned to receive a 3-week rTMS treatment of either active 10 Hz rTMS (n=27) or sham rTMS (n=28). Left dorsolateral prefrontal cortex (DLPFC) was the predefined treatment target. Based on individual structural magnetic resonance imaging scans, surface-based analysis was conducted to quantitatively measure the baseline radiomic features of left DLPFC. Severity of depression, global cognition and the serum brain-derived neurotrophic factor (BDNF) level were evaluated at baseline, 3-week, 6-week and 12-week follow-ups. Results: Logistic regression analysis revealed that advanced age, higher baseline cognition and randomized group were associated with the remission of depression. Increased cortical thickness and gyrification in left DLPFC were the significant predictors of clinical remission and cognitive enhancement. Conclusions: A 3-week course of 10 Hz rTMS is an effective adjuvant treatment for rapid ameliorating depressive symptoms and enhancing cognitive function. Pre-treatment radiomic features of the stimulation target can predict the response to rTMS treatment in major NCD. Cortical thickness and folding of treatment target may serve as imaging markers to detect the responders. Trial registration: ChiCTR-IOR-16008191, registered on March 30, 2016. The authors have no conflicts of interest.
P73- ASSOCIATION OF REGIONAL AMYLOID BURDEN AND BRAIN VOLUME WITH COGNITIVE PERFORMANCES AMONG INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE. C. Lee1, D.W. Yang1, Y.J. Hong2, S. Ho3, J.H. Jeong4, K.H. Park5, S. Kim6, M.J. Wang7, S.H. Choi8, S. Lee9(1. Neurology, Catholic University Of Korea, Seoul St. Mary’s Hospital — Seoul (Korea, Republic of), 2. Neurology, Catholic University Of Korea, Seoul St. Mary’s Hospital — Uijeongbu (Korea, Republic of), 3. Neurology, Changwon Hanmaeum Hospital — Changwon (Korea, Republic of), 4. Neurology, Womans University School Of Medicine, Ewha Womans University Seoul Hospital — Seoul (Korea, Republic of), 5. Neurology, Gachon University Gil Hospital — Incheon (Korea, Republic of), 6. Neurology, Seoul National University College Of Medicine, Seoul National University Bundang Hospital — Seongnam (Korea, Republic of), 7. Neurology, Roa Clinic — Seongnam (Korea, Republic of), 8. Neurology, Inha University School Of Medicine, Inha University Hospital — Incheon (Korea, Republic of), 9. Neolab Convergence Inc. — Seoul (Korea, Republic of))
Background: Subjective cognitive decline (SCD) is now regarded as the first preclinical stage of Alzheimer’s disease (AD) spectrum disorders. Previous studies showed neurodegeneration and amyloid deposition in SCD are similar to those in AD, suggesting the possible relationship between SCD and AD pathology. Objectives: In this study, we aimed to evaluate associations between regional amyloid burden and volume changes with cognitive performances among individuals with SCD. Methods: This cross-sectional study examined baseline automatic regional brain magnetic resonance imaging (MRI) volumetric data, visual and SUVR analysis of 18F-Florbetaben brain amyloid Positron Emission Tomography (PET), demographics and cognitive data from the cohort of the CoSCo study in republic of Korea from July 2018 to December 2020. A subset of this sample, 87 amyloid-negative and 20 amyloid-positive individuals included in this study. Considering Alzheimer’s disease pathology, we mainly analyzed volume of hippocampus and entorhinal cortex (z-scores adjusted for age, sex and intracranial volume) and SUVR of precuneus, inferior temporal, superior orbitofrontal, middle orbitofrontal and post cingulate cortex in amyloid PET. All patients underwent the standardized neuropsychological test battery of the Seoul Neuropsychological Screening Battery (SNSB) that assesses five cognitive domains (attention, language, visuospatial function, memory and frontal/executive function). Correlations between both regional brain volume, SUVR and neuropsychological test percentile scores were determined using Pearson’s or Spearman’s correlation tests according to the variable distribution in each amyloid group. Results: Of the 107 patients (mean (SD) age, 70.7 (6.2) years); 59 were women (55.1%). Amyloid PET results were positive for 20 patients (18.7%). Amyloid-positive patients were older and more educated than amyloid-negative patients (p ≤ 0.05). Seoul Verbal Learning Test: 20 minutes delayed recall scores in amyloid positive group were significantly lower than amyloid negative group (p=0.005). In amyloid positive group, partial correlation analysis controlled for education showed significant positive correlation between Korean-Color Word Stroop Test : color reading and both left entorhinal cortex (r=0.534, p=0.019) and left hippocampal (r=0.593, p=0.009) volume. In amyloid negative group, left hippocampal volume was significantly and negatively correlated with Digit Span Forwards test (r=-0.226, p=0.036). Right hippocampal volume was positively correlated with Rey Complex Figure Test : 20 minutes delayed recall (r=0.250, p=0.020). Korean-Boston Naming Test showed negative correlation with regional SUVR values of 4 areas (precuneus, inferior temporal cortex, middle orbitofrontal cortex and post cingulate cortex) in amyloid positive group. In amyloid negative group, both precuneus and post cingulate cortex SUVR were positively correlated with Korean Trail Making Test B. Inferior temporal cortex SUVR was positively correlated with both Digit Span Forwards and Korean-Color Word Stroop Test : color reading. Conclusions: Our study showed distinctive correlation pattern between both structural changes, amyloid burden and cognitive tests scores in each SCD group with or without amyloid. Amyloid positive SCD showed higher correlation between regional brain volume and cognitive subtest scores. These findings may be helpful for the screening of SCD population at risk of conversion to MCI or dementia. CoSCo study was supported by a grant from the Ministry of Health and Welfare, HI18C0530
P74- THE ROLE OF SUBTHRESHOLD LEVELS OF AMYLOID DEPOSITION ON DEMENTIA CONVERSION-VALIDATED WITH ADNI. H.J. Kim1, J.H. Lee2(1. Uijeongbu Eulji Medical Center — Uijeongbu-Si (Korea, Republic of), 2. Asan Medical Center — Seoul (Korea, Republic of))
Background: About 40–50% of patients with amnestic mild cognitive impairment (MCI) are found to have no significant Alzheimer’s pathology based on amyloid PET positivity. Notably, conversion to dementia in this population is known to occur much less often than in amyloid-positive MCI. However, the relationship between MCI and brain amyloid deposition remains largely unknown. Object: We investigated the influence of subthreshold levels of amyloid deposition on conversion to dementia in amnestic MCI patients with negative amyloid PET scans. Methods: This study was a retrospective cohort study of patients with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain magnetic resonance imaging, and [18F]-florbetaben (FBB) positron emission tomography scan (PET). Conversion to dementia was determined by a neurologist based on a clinical interview with detailed neuropsychological test or a decline in the Korean version of Mini-Mental State Examination score of more than 4 points per year combined with impaired activities of daily living. Regional cortical amyloid levels were calculated and a receiver operating characteristic (ROC) curve for conversion to dementia was obtained. To increase the reliability of the results of the study, we analyzed Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset together. Results: During the follow-up period, 36% (39/107) of patients converted to dementia from amnestic MCI. The dementia converter group displayed increased standardized uptake value ratio (SUVR) values of FBB on PET in the bilateral temporal, parietal, posterior cingulate, occipital, and left precuneus cortices as well as increased global SUVR. Among volume-of-interests, the left parietal SUVR predicted conversion to dementia with the highest accuracy in the ROC analysis (area under the curve [AUC] = 0.762, P < 0.001). The combination of precuneus, parietal cortex, and FBB composite SUVRs also showed a higher accuracy in predicting conversion to dementia than other models (AUC = 0.763). Of the results of ADNI data, the SUVR of the left precuneus SUVR showed the highest AUC (AUC = 0.596, P = 0.006). Conclusion: Our findings suggest that subthreshold amyloid levels may contribute to conversion to dementia in patients with amyloid-negative amnestic MCI. The authors declare no competing interests.
P75- EVALUATION OF A CLINICALLY VALIDATED DIGITAL PLATFORM TO PROVIDE DIFFUSION MRI BIOMARKERS IN ALZHEIMER’S DISEASE. E. Bories1, A. Bezie1, D. Cassereau1, J. Rachline1, I. Trimeche1, J.B. Martini1, V. Perlbarg1(1. BRAINTALE SAS — Strasbourg (France))
Background: White matter alterations are observed at a very early stage of Alzheimer’s disease (1), including demyelination, axonal loss and abnormalities of oligodendrocyte lineage cells (2). Research studies in Alzheimer’s disease showed that diffusion tensor imaging (DTI) allows to detect white matter alterations (3). The translation into the clinic of meaningful biomarkers developed or used in research framework remains a major challenge, especially to monitor the efficacy of new therapeutics in real life conditions and ultimately to monitor disease and enable efficient follow up of patients. brainTale-care, a recently CE-marked platform, overcomes this issue by providing standardized DTI parameters and designing fit-for-purpose digital biomarkers. These biomarkers are relevant for several purposes, such as predicting the outcome of comatose patients in ICU settings with extensive clinical validation (4) or monitoring the efficacy of drug candidates in clinical development settings notably in adrenoleukodystrophy (5). Objectives: The main objective of this study was to test whether standardized DTI biomarkers, activable in clinical routine through a clinically validated CE-marked platform, can discriminate between patients with Alzheimer’s disease from age-matched normal controls and subjects with mild cognitive impairments (MCI). Methods: MRI data, including diffusion weighted imaging sequences, were obtained from 113 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu) : 66 healthy controls (HC), 34 patients with MCI and 13 diagnosed with dementia (DEM). These subjects have been selected from 5 different centers for which the same MRI diffusion weighted sequence have been acquired in HC than in patients to ensure proper calibration of DTI parameters required for multicentric data comparisons. The brainQuant module of brainTale-care v2.2 was used to extract standardized DTI parameters (Fractional Anisotropy: FA, Mean Diffusivity: MD, Axial Diffusivity: AD, Radial Diffusivity: RD) from deep white matter consisting in 20 regions of interest covering the main cerebral white-matter tracts (6). Kruskal-Wallis H-tests were used for group comparisons following post-hoc Mann-Whitney tests in case of significant (p<0.05) group effects. Results: Significative group effects were found for all DTI parameters. Post-hoc test for group comparison showed significant differences between DEM and HC groups as well as between MCI and HC groups. Decrease FA and increase MD, AD and RD were observed in pathological conditions. In more details, MD, AD and RD significantly increase for DEM and MCI in comparison to controls as well as FA decrease in MCI compared to controls. Conclusions: This study shows that global alterations within the main cerebral white-matter tracts from brainQuant module of Braintale care- platform enabling analysis are relevant biomarkers of disease severity. The access to these biomarkers in a CE-marked medical device opens the potential of this approach to be transferred in the clinic for diagnosis, disease monitoring decision-making and also potentially clinical trials recruitment and management. References: 1. Lee et al. White matter hyperintensities are a core feature of Alzheimer’s disease: Evidence from the dominantly inherited Alzheimer network. Ann Neurol. 2016; 2. Nasrabady et al. White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes. Acta Neuropath Comm. 2018; 3. Mayo et al., Alzheimer’s Disease Neuroimaging Initiative. Longitudinal changes in microstructural white matter metrics in Alzheimer’s disease. Neuroim Clin. 2016; 4. Velly L et al. Use of brain diffusion tensor imaging for the prediction of long-term neurological outcomes in patients after cardiac arrest: a multicentre, international, prospective, observational, cohort study. Lancet Neurol. 2018; 5. Vincent Perlbarg et al. Myelin content monitoring by diffusion biomarkers in a therapeutic trial with leriglitazone in men with adrenomyeloneuropathy (P1-1.Virtual). Neurology May 2022, 98 (18 Supplement); 6. Van der Eerden et al. White matter changes in comatose survivors of anoxic ischemic encephalopathy and traumatic brain injury: comparative diffusion-tensor imaging study. Radiology. 2014. Disclosures: EB, AB, IT, JB and VP are employees of BrainTale, inc. in Paris, France; VP is co-founder of BrainTale, inc. in Paris, France; DC and JR are consultants of BrainTale, inc. in Paris, France.
P76- INCREASE IN WHITE MATTER VOLUME AND MYELINATION AFTER 6 MONTHS. X. Da1, E. Hempel1, H. Mrozak1, Z. Malchano1, B. Vaughan1, J.T. Megerian1, M. Hajos1,2, A. Cimenser1(1. Cognito Therapeutics — Cambridge, Ma (United States), 2. Yale University School of Medicine — New Haven, Ct (United States))
Background: Alzheimer’s Disease (AD) is characterized by the pathological changes in the brain gray matter, however recent studies have also demonstrated pathologies in white matter, including significant volume loss. Since white matter comprises axons, microglia, oligodendrocyte precursor cells and myelin-producing oligodendrocytes, degeneration in this region ultimately affects the neuronal network connectivity and function. Advanced imaging techniques have further revealed micro- and macro- structural abnormalities of the white matter in AD, and significant differences between AD patients and age-matched healthy controls. Furthermore, enhancing myelination has been suggested as a therapeutic strategy for improving cognition in AD (Chen et al., 2021). Gamma sensory stimulation has been proposed as a potential treatment of AD, and multiple studies have showed positive effects of 40Hz gamma sensory stimulation in AD transgenic mouse models (for review, see Adaikkan & Tsai, 2020), and more recently, in AD patients (He et al., 2021, Cimenser et al., 2021). However, potential impact of this therapy on white matter and myelination has not been studied. Objectives: The present study evaluated whether gamma sensory stimulation could impact white matter atrophy and myelination in patients on AD spectrum who received gamma stimulation therapy for a 6-month period. Changes in entorhinal region was measured since this region is a key structure providing connections for transferring bidirectional information between cortical and hippocampal networks. Furthermore, both histological and neuroimaging studies have shown that the entorhinal region is one of the brain regions impacted in early stage of the AD. Methods: Neuroimaging data collected in Cognito Therapeutics’ Overture clinical trial is used in this study. Overture is a randomized, placebo-controlled feasibility study (NCT03556280) in patients (MMSE 14–26) on AD spectrum. In this trial, subjects in the active treatment arm received daily, at-home, 40Hz gamma sensory stimulation for a 6-month period while the placebo arm subjects received sham stimulation. Structural magnetic resonance imaging (MRI) data was obtained at baseline, month 3 and month 6 visits using 1.5 Tesla MRI scanner. FreeSurfer and SPM12 plugin toolbox, MRTool, were used to study multiple white matter structures for 38 participants (66% Treatment, 34% Placebo). Volume assessments were done using T1 MRI. Myelination assessments were done using T1w/T2w ratio. Due to T2w image quality, 2 patients were excluded from the myelination analysis. Bayesian linear mixed effects modeling was used to assess the changes from baseline. Changes in white matter volume and myelination were compared between treatment group and placebo group participants after 6 months of treatment. Results: With respect to baseline levels, we observed that the treatment group demonstrated 1.06±5.35 cm3 increase and the placebo group demonstrated −12.37± 6.81 cm3 decrease in total cerebral white matter volume. The difference between the treatment and the placebo groups was statistically different (p<0.036). Entorhinal white matter showed profound changes: The treatment group demonstrated 0.08±0.06 cm3 increase, while the placebo group demonstrated -0.13±0.07 cm3 decrease in volume. The difference between these two groups was statistically significant (p<0.004). Within the same region, the treatment group demonstrated 2.78±4.97 % increase and the placebo group demonstrated -10.59±5.63 % decrease in myelination. This difference was also statistically significant (p<0.003) between groups. Conclusion: We conclude that 40Hz gamma sensory stimulation led to beneficial effects on both white matter volume and myelination after 6 months of treatment. Specifically, the treatment may significantly reduce white matter atrophy and substantially prevent white matter myelin damage in the entorhinal region. Damage of this brain region is particularly relevant to AD pathology due to its afferent connections to the hippocampus and the entorhinal cortex. Further larger studies are warranted to confirm effects of gamma sensory stimulation on white matter atrophy and myelination and provide an insight to potential mechanism. References: Adaikkan C, Tsai LH. Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends Neurosci. 2020 Jan;43(1):24–41. Cimenser A, Hempel E, Travers T, Strozewski N, Martin K, Malchano Z, Hajós M. Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer’s Disease Patients. Front Syst Neurosci. 2021 Sep 24;15:746859. Chen JF, Liu K, Hu B, Li RR, Xin W, Chen H, Wang F, Chen L, Li RX, Ren SY, Xiao L, Chan JR, Mei F. Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease. Neuron. 2021 Jul 21;109(14):2292–2307.e5. He Q, Colon-Motas KM, Pybus AF, Piendel L, Seppa JK, Walker ML, Manzanares CM, Qiu D, Miocinovic S, Wood LB, Levey AI, Lah JJ, Singer AC. A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer’s disease. Alzheimer’s Dement (N Y). 2021 May 13;7(1):e12178.
P77- SUMMARY OF ACR PHANTOM MRI SITE QUALIFICATION FINDINGS OVER 7 YEARS AND RECOMMENDATIONS MOVING FORWARD. L. Bracoud1, J. Oh2, Q. Cao2, C. Conklin3, M. Ingalhalikar3, H. Pham2, D. Scott2, J. Suhy2(1. Clario (formerly Bioclinica) — Lyon (France), 2. Clario (formerly Bioclinica) — San Mateo (United States), 3. Clario (formerly Bioclinica) — Princeton (United States))
Background: As part of qualification activities for MRI sites participating in Alzheimer’s disease and related dementia type trials, where quantitative volumetric analyses are involved, it has become the norm that phantom scans be performed to verify scanner performance and MRI protocol set-up ahead of the first subject scan. Such phantom scans are also typically performed periodically as a longitudinal follow-up to monitor scanner performance. For that purpose, the American College of Radiology (ACR) phantom has been employed. It consists of a short, hollow cylinder of acrylic plastic closed on both ends. While resulting images will by no means visually compare to in-vivo data, inside the phantom are structures designed for performing several quantitative tests. Further, the phantom is filled with a solution of nickel chloride and sodium chloride to simulate a typical electric load of a human head, therefore justifying that data be reflective of future image quality. Objectives: Having accumulated multiple thousands of such scans over the past years, the objective of this retrospective analysis was to identify the types of issues commonly found in the ACR phantom scans and their frequency. After years of collecting these scans across sites globally, the impression was that actual scanner performance issues are becoming extremely uncommon, and that it may not be necessary to impose this process to all imaging sites, as this is a time-consuming procedure that adds burden to the sites, together with the cost associated with acquiring and assessing the scans. Methods: We included analysis results of ACR phantom scan submissions (N=9080) collected from 2015 to 2021 from 11 global trials in 38 countries worldwide on 1.5T and 3T scanners manufactured by GE, Philips and Siemens. MRI data consisted of the T1-weighted MRI sequences recommended in the ACR scanning guidelines, that is a single-slice Sagittal T1 Spin Echo (in-plane resolution = 0.98×0.98 mm2, slice thickness = 10 mm), and an 11-slice Axial T1 Spin Echo (same resolution, slice thickness = 5 mm, slice gap = 5 mm). Besides, all mandatory brain MRI sequences expected from study participants were also required, so that the MRI protocol settings could be automatically verified based on DICOM header information. Most of the tests recommended in the ACR guidelines were conducted per these instructions, namely a qualitative evaluation, together with tests for geometrical accuracy, high contrast spatial resolution, image intensity uniformity, low contrast object detectability and percent signal ghosting. The outcome of this Quality Control (QC) was either to pass the scan (and therefore qualify the scanner) or ask for servicing of the MRI scanner and/or adjustments of the settings used, with or without requiring a new scan to take place. Only after successful resolution of all pending issues would the scanner be qualified. Results: Of the 9080 QC results reviewed, outcome was pass in 86.5% of cases. Among the 13.5% that failed, the most common issue reported was the use of incorrect (or suboptimal) imaging parameters (85.7%), followed by poor positioning of the ACR phantom (6.6%), use of an incorrect scanner, coil or phantom (3.7%) or data format issues (1.5%). Only in 0.1% of cases was there an actual technical issue related to scanner malfunction. Such low failure rate can be explained by the fact that all MRI scanners are subjected to regular (daily or weekly) maintenance and monitoring procedures at local site level, as well as by the continuous improvement in the stability of MRI scanners. Conclusions: The first goal sought during site qualification, which is to verify proper implementation of the study MRI protocol, can be achieved without a dedicated ACR phantom scan. A regular MRI-compatible phantom or test object could be used, but this would still require time spent running the MRI protocol on the scanner. A more efficient and equally thorough method could consist of collecting a protocol export generated from the scanner and submitted electronically, for a similarly automated and effective verification of parameters used. This could lower the site burden by not having the site perform a dedicated phantom scan and shorten the start-up timeline with no impact on the quality of the site qualification process. The use of protocol exports may not catch the use of the improper coil, or the over-masking of DICOM tags. But it was found that these issues may still occur on the first subject scans irrespective of what was observed on preceding phantom scans. Therefore, the benefit-risk ratio is still highly in favor of phasing out ACR phantom scans as the means by which to qualify sites and monitor scanner performance.
P79- EFFECTS OF ALZHEIMER AND LEWY BODY DISEASE PATHOLOGIES ON BRAIN METABOLISM. B.S. Ye1, S.W. Kang2(1. MD. PhD — Seoul (Korea, Republic of), 2. MD — Seoul (Korea, Republic of))
Background: In vivo detection of mixed pathologies in patients with neurodegenerative dementia would have clinical importance for treatment and predicting prognosis. Objective: This study aimed to determine the pattern of18F-fluorodeoxyglucose positron emission tomography (FDG-PET) related to postmortem Lewy body disease (LBD) pathology in clinical Alzheimer disease (AD). Methods: FDG-PET scans were analyzed in 62 autopsy-confirmed patients and 110 controls in the Alzheimer’s DiseaseNeuroimaging Initiative. Based on neuropathologic evaluations on Braak stage for neurofibrillary tangle, Consortium to Establish a Registry for AD score for neuritic plaque, and Lewy-related pathology, subjects were classified into AD()/LBD(), AD()/LBD(+), AD(+)/LBD(), and AD(+)/LBD(+) groups. The association between postmortem LBD and ADpathologies and antemortem brain metabolism was evaluated. Results: AD and LBD pathologies had significant interaction effects to decrease metabolism in the cerebellarvermis, bilateral caudate, putamen, basal frontal cortex, and anterior cingulate cortex in addition to the left sideof the entorhinal cortex and amygdala, and significant interaction effects to increase metabolism in the bilateralparietal and occipital cortices. LBD pathology was associated with hypermetabolismin the cerebellar vermis, bilateral putamen, anterior cingulate cortex, and basal frontal cortex, corresponding to the Lewy body-relatedhypermetabolic patterns. AD pathology was associated with hypometabolism in the bilateral hippocampus,entorhinal cortex, and posterior cingulate cortex regardless of LBD pathology, whereas LBD pathology wasassociated with hypermetabolism in the bilateral putamen and anterior cingulate cortex regardless of ADpathology. Conclusion: Postmortem LBD and AD pathologies had significant interaction effects on the antemortem brainmetabolism in clinical AD patients. Specific metabolic patterns related to AD and LBD pathologies could be elucidatedwhen simultaneously considering the two pathologies.
P80- REDUCING SLEEP APNOEA FOR THE PREVENTION OF DEMENTIA (RESHAPED): THE PROTOCOL OF A MULTI-SITE FEASIBILITY RANDOMISED CONTROLLED TRIAL. S. Naismith1, C. Hoyos1, C. Phillips1, Y. Kristine2, R. Martins3, N. Marshall1, J. Lagopoulos4, M. Jackson5, L. Mowszowski1, R. Grunstein1(1. University of Sydney — Sydney (Australia), 2. University of California — San Francisco (United States), 3. University of Macquarie — Sydney (Australia), 4. University of Sunshine Coast — Sunshine Coast (Australia), 5. Monash University — Melbourne (Australia))
Background: Obstructive sleep apnoea (OSA) is a sleep disorder characterised by complete or partial cessation of breathing during sleep. The rates of OSA increases up to 70% in older adults. There is accumulating evidence that has linked OSA with increased risk of cognitive decline, increase in beta-amyloid, and dementia (Leng et al. 2017). Preliminary evidence suggests that continuous positive airway pressure (CPAP) may be beneficial for cognition. In mild cognitive impairment, a pilot study of 3-months (n=26) showed that CPAP was associated with improvements in verbal learning and memory in older adults with mild cognitive impairment (Hoyos et al., 2022). In a 1-year quasi-experimental pilot trial with older adults with MCI and were CPAP adherent (use of 4 hours or more; n=29) showed improvements in memory, attention, and daytime sleepiness compared to those who were not adherent (Richards et al., 2020). These preliminary findings suggest that CPAP for older adults with concomitant OSA and cognitive impairment may show improvement in cognitive function or slow cognitive decline. However, larger randomised controlled trials (RCT) are necessary to confirm these findings. Objectives: As defined in the UK MRC framework of complex interventions, it is critical to firstly establish feasibility of the recruitment strategy, methods, measures, and intervention before proceeding to a full-scale RCT. Here we present a national multi-site randomised controlled, parallel open-label trial which aims to evaluate the feasibility for a full-scale trial investigating the effects of treating OSA on cognitive decline in older adults at risk of dementia with OSA within memory clinic settings. The primary outcome of the study are 1) demonstrating acceptability by ≥50% of eligible participants randomised; 2) alleviating hypoxic burden by reducing OSA severity by ≥30%; 3) Determining tolerability of the outcome assessment of the planned primary outcome. Secondary outcomes include safety (the rate of participants who drop in or out of treatment, as well as rate and types of adverse events) and cognitive function (assessed using traditional and online measures) after 2-years of treatment. Methods: Participants will be randomized to either the treatment intervention group or control group for 2-years. This feasibility study aims to randomise 180 older adults aged between 50–75 years with mild-severe OSA (defined as an average ODI ≥ 10 with 3% oxygen desaturation determined by wrist oximetry over two nights) and subjective cognitive complaints or MCI. Participants will be recruited through hospital, university and private memory clinics. OSA will be diagnosed with at-home oximetry screening using a wrist-worn device with a finger sensor (WristOx, Nonin). The treatment intervention arm intends to achieve an optimal treatment response based on reducing hypoxic burden with either CPAP, mandibular advancement splint, positional therapy, or oxygen therapy. Furthermore, participants in this arm will receive up to 8 treatment sessions which involve motivational interviewing, collaborative goal setting, and behavioural sleep management. The control arm will not receive OSA treatment as part of this trial, however there will be no OSA treatment restrictions and any treatment will be documented. Data collection and assessments will occur at baseline, 6-month, and 24-month timepoints. These assessments will involve medical assessment, full cognitive battery (processing speed, executive function, learning and memory), blood collection (ApoE4, hsCRP, p-tau181, p-tau 217, Gfap, and Nfl) and brain magnetic resonance imaging scan (optional). This clinical trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621001190897). The study is funded by the National Health and Medical Research Council (NO:1171479). The sponsor is The University of Sydney. Recruitment has commenced in 2022 with an expected recruitment end date of 2026. References: Hoyos, C. M., Cross, N. E., Terpening, Z., D’Rozario, A. L., Yee, B. J., LaMonica, H., Marshall, N. S., Grunstein, R. R., & Naismith, S. L. (2022). CPAP for Cognition in Sleep Apnea and Mild Cognitive Impairment: A Pilot Randomised Cross-Over Trial. American Journal of Respiratory and Critical Care Medicine, 10.1164/rccm.202111-2646LE. Advance online publication. 10.1164/rccm.202111-2646LE. Leng, Y., McEvoy, C. T., Allen, I. E., Yaffe, K. (2017). Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis. JAMA Neurology. 74(10), 1237–1245. doi:10.1001/jamaneurol.2017.2180. Richards, K. C., Gooneratne, N., Dicicco, B., Hanlon, A., Moelter, S., Onen, F., Wang, Y., Sawyer, A., Weaver, T., Lozano, A., Carter, P., & Johnson, J. (2019). CPAP Adherence May Slow 1- Year Cognitive Decline in Older Adults with Mild Cognitive Impairment and Apnea. Journal of the American Geriatrics Society, 67(3), 558–564. 10.1111/jgs.15758.
P81- ARTERIAL STIFFNESS IS ASSOCIATED WITH CORTICAL TAU BURDEN. Y. Noh1(1. Gachon University Gil Medical Center — Incheon (Korea, Republic of))
Objectives: Previous studies have shown that vascular risk factors are also risk factors of Alzheimer’s disease frequently. However, the relationship between cerebrovascular disease and Alzheimer’s pathology remains unclear. In this study, we evaluated the relationship between arterial stiffness and cortical tau burden with consideration of β-amyloid burden. Methods: Total number of 153 participants was included (cognitively normal, 57; Alzheimer’s disease, 53; non-AD dementia and MCI, 43). They took detailed neuropsychological tests, magnetic resonance imaging (MRI), 18F-Flutemetamol [FLUTE] PET as amyloid PET, 18F-MK-6240 PET as tau PET and transcranial Doppler (TCD). We evaluated arterial stiffness with penetrating arterial pulsation using the sonographic resistance index (RI) along the M1 segment of middle cerebral artery (MCA). MRIR was defined as distal RI divided by proximal RI. We used generalized additive model (GAM) to check if there is a non-linear relationship between arterial stiffness (MRIR) and tau burden adjusted for age, gender, educational years, Framingham Heart Study cardiovascular disease (FHS-CVD) score, total metabolic equivalents (METS), and diagnosis. Multivariable linear regression was used to check if there is a linear relationship between MRIR and tau burden or amyloid burden, where MRIR >=1. Lastly, we used causal mediation analysis to check if amyloid burden mediates the association between MRIR and tau burden where MRIR >=1. Results: Between MRIR and tau burden, U-shaped relationship was statistically significant (p=0.026). Linear relationship was only shown where MRIR was 1 or greater. In the participants with 1 or greater of MRIR, as MRIR increased by 0.1, cortical SUVR of 18F-MK-6240 PET increased by 1.23 (β-coefficient, SE=0.48, p=0.014, adjusted R2=0.39). Cortical SUVR of FLUTE increased 0.21, as MRIR increased by 0.1 (β-coefficient, SE=0.10, p=0.049, adjusted R2=0.37). In the causal mediation analysis, average causal mediation effect and proportional medicated (indirect effect/total effect) were statistically significant. Conclusion: In the elderly participants with substantial arterial stiffness (MRIR >=1), arterial stiffness was associated with tau burden, where amyloid burden mediated the relationship.
P82- APPLICATION OF FULLY AUTOMATIC HIPPOCAMPAL SUB-FIELD SEGMENTATION VOLUMES TO STANDARD RESOLUTION T1 MR IMAGING IN ALZHEIMER’S DISEASE. R. Joules1, R. Wolz1(1. IXICO — London (United Kingdom))
Background: Volumetric analysis of the hippocampus is an established biomarker in the study of Alzheimer’s disease as well as other neurodegenerative diseases. The assessment of hippocampal sub-field volumes is of great interest as it may provide increased sensitivity to earlier pathological changes as well as effects of clinical interventions when compared to whole hippocampus volume. The segmentation of hippocampal sub-fields is complex, resource intensive and susceptible to variability if undertaken manually and additionally requires specialised scans. Several fully automatic methods have been proposed allowing utilisation of subfield volumes without the need for specialised manual segmentation. Hippocampal subfield segmentation is preferably performed using a combination of T1 and high-resolution (HR) T2 images. Such multi-spectral analysis permits segmentation of small hippocampal regions, not distinguishable from T1 contrast alone. However, HR T2 imaging can increase scan time and patient burden and is commonly absent from legacy datasets limiting applicability of such analysis in retrospective analysis of existing datasets or a routine clinical setting. Existing methods may be applied to standard resolution (∼1mm3) T1 MRI for segmentation of larger robustly defined sub-regions (e.g. CA1). These existing methods commonly employ multi-atlas based methodology and can be significantly influenced by the atlas prior in the absence of clear bounds and often require the generation of specific templates for the given population/therapeutic area to optimally perform. Deep learning approaches have been applied to the problem of both full hippocampal and hippocampal sub-field segmentation; while limited by availability of sufficient high quality training data, recent work has demonstrated state of the performance for multi-modal hippocampal segmentation of HR T2 and T1 data using methods based on convolutional neural networks (CNN). Here we extend such work to investigate the application of CNN approaches to segment hippocampal subfields from 1mm3 T1 MRI using publicly available data with high quality manual segmentation labels. Objectives: This work aims to develop methods for hippocampal subfield segmentation of standard resolution, 1mm3, T1 MRI using publicly available few-shot training data with T1 images and manually refined hippocampal labels. Segmentation models will be assessed in terms of segmentation accuracy and association with disease state and clinical scores for utility in clinical trials and clinical assessments. Methods: In this work we utilise a publicly available dataset of 25 subjects with manually segmented labels for a 3-part parcellation of the hippocampus (CA1-3, CA4/DG, and Subiculum) and a 3D-MPRAGE-T1 at 1mm3 aligned to MNI152 space (https://www.nitrc.org/projects/mni-hisub25). Images were pre-processed with N4 bias field correction, skull stripping and affine (12-dof) registration to MNI space. A template in label image was generated for each region of interest (ROI) in MNI space to allow approximate placement of bounding boxes centres by registration. Images are z-normalised within the brain masked area and augmentation is employed to apply random bias effects, noise, motion, sharpening, and spatial deformation. Images are cropped to bounding box cantered around the approximate position of the target ROI as estimated from non-linear registration of a ROI template to the input image. To maximise the limited dataset available, we reflect the right laterality ROIs and associated anatomical images to generate a left oriented dataset of 50 samples from 25 subjects. For the whole hippocampus and each of the 3 ROIs, we train a binary segmentation model using the popular UNET architecture. A multi-label segmentation may be generated through combination of the outputs from each model in a subsequent refinement process, permitting future flexibility for combining models from different training data and parcellation schema. Models were trained with a 5-fold cross validation where 10 samples (5 subjects) were withheld for testing and a 0.8 training (16 subjects) validation (4 subjects) split. Due to the randomness of the augmentation and shuffled train/validation split, multiple models were trained in each fold where the mean softmax can be computed across all models for each segmentation. Results: Total hippocampal and subfield segmentations were generated for all test subjects standard resolution T1 images in each cross validated loop and the DICE overlap with the ground truth label computed. Preliminary results indicate near state-of-the-art segmentation quality, comparable to using both T1 and HR T2 in combination, for the test data with mean DICE in whole Hippocampus = 0.943(std: 0.017), CA1-3 = 0.902(std:0.032), CA4/DG = 0.895(std: 0.052), and Subiculum = 0.891(std:0.041). Optimisation and testing are ongoing with final results for the optimised framework, its comparison to other methods for disease state discrimination, and segmentation agreement is expected for presentation at the CTAD conference. Conclusion: We have presented a framework and preliminary results for a CNN based segmentation of hippocampal subfields based on a deep learning approach trained with limited publicly available data. Preliminary results indicate competitive performance in terms of DICE overlap with training labels. Further optimisation and refinement are required with testing on independent data to assess sensitivity to disease state and clinical measures.
P83- AMYLOID PET CENTILOID: IMPACT OF CALIBRATION AND PROCESSING STEPS. L. Presotto1, M. Shekari2, L.E. Collij3, R. Manber1, D. Vállez Garcia3, J.D. Gispert López2, R. Wolz1(1. IXICO — London (United Kingdom), 2. Barcelonaβeta Brain Research Centre, Pasqual Maragall Foundation — Barcelona (Spain), 3. Amsterdam UMC — Amsterdam (Netherlands))
Background: Centiloids (CL) were introduced to consistently quantify amyloid load across tracers and analysis pipelines. CL linearly scale activity ratios so that in two reference groups (young healthy subjects, converted AD subjects) an average load 0 and 100 CL, respectively, is measured. Such linear scalings are unique for each combination of tracer, analysis algorithm, and reference region (1). Objectives: As part of centiloid calibration in the AMYPAD project, the impact of applying different processing steps on centiloid analysis results were compared. Here, we summarize key options considered and present the impact on centiloid analysis in two AMYPAD cohorts. Methods: As a first step, CL equations were computed using the GAAIN Flutemetamol datasets. Two linear regression strategies were compared: 1. calibrated pipeline Flutemetamol vs GAAIN PiB values, then apply GAAIN provided anchor points; 2. both PiB SUVr and anchor points estimated with the calibrated pipeline. Three approaches were compared to obtain a segmentation of the global cortical average (GCA) target region: I. registering a GCA template (1) from MNI space using NiftyReg for registration; II. like I) but using SPM for registration; III. using a subject-specific segmentation from a multi-atlas segmentation approach (LEAP) to define the GCA. Four reference regions obtained from LEAP were compared: a) whole cerebellum; b) cerebellar grey matter; c) Pons; d) white matter. The effect of the different options was evaluated on datasets independent from the calibration dataset from two cohorts in non-demented participants of at least 50 years of age: 83 datasets from the EPAD cohort and 163 datasets from the PreclinAD Twin60++ cohort. Data in the PreclinAD study was acquired on a single PET/MR scanner and data in the EPAD cohort was acquired from a range of PET/CT scanners with a separate MRI scan. Approaches were considered to be comparable if the mean CL difference were below 2 CL (within the error), and r2>0.9. Results: On both validation datasets the different linear regression options (1. / 2.) impacted average CL values by less than 1.5 CL. This is less than the statistical error on the anchor points used for CL definition. Registering the GCA region using NiftyReg (I.) or SPM (II.) resulted in no notable differences (r2>0.94, TWINS: no difference, EPAD: -2.6±0.6, whole cerebellum reference). Comparing GCA vs subject specific segmentation (III.) also shows that CL scaling is robust (r2=0.96, TWINS: no bias, EPAD: -1.5±0.5, whole cerebellum reference). Comparing alternative reference regions to the whole cerebellum has a significant impact. EPAD (TWINS) cohort mean difference: gray cerebellum: -5.5 (-5.3), pons: +17.1 (+22.1) and white matter: +7.9 (+10.3). Conclusion: The CL approach appears to be robust to different technical implementations, including definition of the target region and spatial registration algorithm. Different reference regions, however, are not comparable over multiple cohorts. Su et al previously reported that comparing different reference regions in a cohort independent from the calibration dataset can result in bias (2). Longitudinal studies (e.g. Chen et al) also showed that using different reference regions can impact data comparison (3). Additional work is required to understand the impact of the technique used to segment reference regions. References: 1. Klunk, William E., et al. «The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET.» Alzheimer’s & dementia 11.1 (2015): 1–15. 2. Su, Yi, et al. «Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies.» NeuroImage: Clinical 19 (2018): 406–416. 3. Chen, Kewei, et al. «Improved power for characterizing longitudinal amyloid-β PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region.» Journal of Nuclear Medicine 56.4 (2015): 560–566.
P84- INDEPENDENT EFFECTS OF HIPPOCAMPAL SUBFIELD VOLUMES AND P-TAU ON MEMORY PERFORMANCE IN CLINICALLY UNIMPAIRED OLDER ADULTS. T. Tran1, A. Trelle1, W. Edward1, G. Deutsch1, S. Sha1, K. Andreasson1, V. Carr1, G. Kerchner1, E. Mormino1, A. Wagner1(1. Stanford University — Stanford (United States))
Background: Prior work has demonstrated that abnormal cerebral spinal fluid (CSF) biomarkers, including p-tau181, are associated with diminished performance across several hippocampally-dependent memory tasks in clinically unimpaired (CU) older adults. It is unknown whether structural differences in medial temporal lobe (MTL) subfields are associated with (1) elevated p-tau181 and (2) poorer memory performance in CU older adults. Furthermore, it is unclear whether any relationship between structural volume and memory performance may be mediated by p-tau181. Objective: To understand how structural volumetric measures of the hippocampal subfields relate to p-tau181 and memory performance in CU older adults. Methods: The current study draws on a cohort of cognitively unimpaired older adults from the Stanford Aging and Memory Study that completed CSF, genetic, and neuropsychological testing, along with 3T fMRI and MRI and 7T MRI. In the current analysis, 147 participants completed both 3T MRI and lumbar puncture. Participants ranged from 66 — 88 years of age. To examine memory performance, participants completed two hippocampally-dependent tasks: a paired associate cued recall task and a mnemonic similarity task (MST) that examined discrimination between previously studied “old” objects, novel “foil” objects and perceptually similar “lure” objects. Lure trials were binned in five difficulty levels, ranging from low to high similarity compared to previously studied stimuli. Hippocampal subregions (CA1, CA3/DG, subiculum) and MTL cortical subregions were manually delineated following Carr et al., 2017. CSF was processed with Lumipulse to measure Ab42:Ab40 ratio and p-tau181. Linear multiple regression models were used to assess the relationship between p-tau181 and structural volume, as well as between volume and associative memory d’ from the paired associate task. Given the repeated measures design of the MST task across five similarity bins, linear mixed models were conducted to examine the association between hippocampal subfields and p-tau181 on performance as a function of similarity level (Trelle et al., 2021). Age, sex, and education level were controlled in all models. Results: P-tau181 significantly negatively correlated with reduced left CA1 volume (partial r = -0.20, p = 0.02), but not with volume in other hippocampal subfields (partial r = -0.04 to -0.13, p > 0.05), nor with the left (partial r = -0.07, p = 0.40) or right total hippocampal volume (partial r = -0.04, p = 0.61). When examining the relationship between volume and memory, increased CA1 volume positively associated with better memory performance, including higher associative memory and old-lure discrimination. However, after controlling for p-tau181, CA1 volume was no longer significantly associated with performance on the associative memory task but remained significantly correlated with old/lure discrimination. Similarly, although DG/CA3 volume was not associated with p-tau181, DG/CA3 volume significantly correlated with old/lure discrimination on the mnemonic similarity task. Notably, increased CA1 and DG/CA3 volume associated with overall discrimination for old/lure trials, independent of the difficulty level, whereas the association between p-tau181 and performance was strongest at the lower similarity level. Conclusions: Although there is a relationship between p-tau181 and CA1 volume, these biofluid biomarker and structural measures explain unique variance in predicting memory performance in CU older adults. Critically, the memory tasks utilized included an associative memory task that assayed the retrieval of episodic memory details. This task has been hypothesized to depend, in part, on hippocampal CA1, due to the role of CA1 in linking pattern completion processes in DG/CA3 with the reinstatement of event features in neocortex. In contrast, the MST task has been hypothesized to be sensitive to DG and CA3 function by taxing both pattern separation and pattern completion processes. DG is theorized to orthogonalize sensory inputs into nonoverlapping memory representations, while CA3 is hypothesized to reactivate memories (pattern completion). Memory representations are passed from CA3 to CA1, where CA1 also acts as a comparator of the match between remembered and presently-perceived representations. Consistent with these theories of hippocampal subregion function, we find that CA1 volume is related to overall performance on both the associative memory task and the MST, while DG/CA3 volume is also associated with performance on the MST task. Furthermore, the independent effects of hippocampal subfield volume and p-tau181 on memory performance suggest they capture distinct age-related changes. Hippocampal subfield volume may be impacted by multiple drivers of individual differences in MTL integrity, while p-tau181 may reflect pathological Alzheimer’s disease processes occurring in this preclinical population. Collectively, the combination of biofluid biomarkers and high-resolution MRI has the potential to further delineate mechanisms underlying age-related memory decline and preclinical Alzheimer’s disease processes in clinically unimpaired older adults.
P85- SUPPORTING THE COMMUNICATION OF MODERN ALZHEIMER’S DATA THROUGH AUGMENTED REALITY AND WEB TECHNOLOGIES. T. Ard1, B. Michael1, A. Toga1(1. USC Stevens Neuroimaging and Informatics Institute — Los Angeles (United States))
Background: Alzheimer’s disease research is based on many forms of data, from MRI scans to microscopic image stacks. Unfortunately, while throughout the course of research these types of data can be effectively digitally viewed, for publication all data is typically reduced to 2D static images. Ultimately, this leads to incomplete and suboptimal reporting, dramatically hindering our ability to effectively communicate modern data. Digital supplementary materials held some promise to address this situation, however recent metrics indicate these materials are accessed by as few as .04% of readers (1). Over the last several decades many additional attempts have also been made to modernize scientific articles and communications, however none have yet reached the adoption level necessary to displace the standard of static text and images as the major mode of communication (2, 3). However, recent technological advances such as augmented reality (AR) and web graphical integration now make it possible to merge data directly with scientific publications in a manner not previously feasible. Objectives: We aim to provide a framework that supports the inclusion of the scientific digital data directly with articles and other means of communication. We particularly aim for this platform to fluidly integrate data with articles in a manner where the data travels with the paper independent of publishers, submission status, or which technologies are supported through various submission systems. Further, we aim for the system to be highly accessible to readers, avoiding shortcomings that have contributed to low adoption rates of previous efforts to integrate data with communications. Method: We introduce a data layering approach for directly including modern digital information on top of scientific figures, enabling entire datasets to be included with scientific articles, posters, and other communications. Through this approach standard PDFs and other printable documents can incorporate modern data by layering digital augmentations ‘on top’ of figures. These augmentations can provide dynamic viewing of scientific information in an interactive manner, while requiring no changes to the format of scientific articles or to the publishing system that distributes them. This approach is supported through web and mobile applications as well as cloud infrastructure, all of which is accessible by readers and authors through our framework, termed ‘Schol-AR’. Result: Data layering facilitates communication and comprehension of data that underlies clinical trials and Alzheimer’s research by enabling accessible viewing of complex information directly with scientific articles, posters, and other formats. Authors can augment their own communications by uploading their datasets and the figures data should be ‘attached’ to. The framework then automatically renders the data readily accessible to any reader viewing those figures, regardless of where the document is hosted or published. Conclusion: Using augmented reality and web technologies we can modernize communication of Alzheimer’s research, bridging the gap between the digital basis of modern science and the natural limitations of journal articles. Incorporating augmentation into scientific publishing can support the inclusion of full datasets with publication in a manner that can be highly accessible by the general readership of the articles and communication. As such this technique can not only enhance the comprehension of scientific materials, but also the thoroughness in which data is reported, ultimately improving the state of scientific communication. 1. Flanagin, A. et al. Editorial Evaluation, Peer Review, and Publication of Research Reports With and Without Supplementary Online Content. JAMA 319, 410 (2018). 2. Sopinka, N. et al. Envisioning the scientific paper of the future. FACETS 5, 1–16 (2020). 3. Shotton, D. Semantic publishing: the coming revolution in scientific journal publishing. Learned Publishing 22, 85–94 (2009). Competing Interests: T.A. has a financial interest in Ardist Inc. No other authors have any competing interests. This report does not analyze or interpret any scientific data.
P86- LONGITUDINAL ASSESSMENT OF NOVEL IMAGING MARKERS OF NEUROINFLAMMATION, AXONAL DENSITY AND DEMYELINATION AS BIOMARKERS IN ALZHEIMER’S DISEASE. M. Roy1, M. Dumont1, J.C. Houde1, M. Descoteaux1, J.R. Bélanger1(1. Imeka — Sherbrooke (Canada))
Aims: Three recent quantitative white matter (WM) measures from diffusion MRI (dMRI) were analyzed: i- free-water, a marker of neuroinflammation ii- apparent fiber density, a marker of axonal integrity iii-tissue radial diffusivity, a marker of myelin content. Our objective was to establish the dynamics of these three markers over 2 years in ADNI. Methods: All ADNI cohorts with dMRI at 3-, 6-, 12- and 24-months were included, which resulted in 51 NC, 78 MCI and 37 AD. In the MCI group, 15 subjects converted to AD over the 24 months (MCI converters). From dMRI, free-water, apparent fiber density and tissue radial diffusivity maps were computed. Then, a composite quantitative track-specific score (AD-bundles) was calculated combining the WM bundles altered in AD (the fornix, cingulum, arcuate, uncinate, inferior fronto-occipital and inferior longitudinal fasciculi, genu and splenium of the corpus callosum). Diffusion measures were analyzed with a general linear model using age, sex, apolipoprotein E4 status, intracranial volume and total WM hyperintensities volume as covariates. Results: In AD patients, free-water in AD-bundles was increased by 5.7, 7.6, 9.6 and 14.4% at 3, 6, 12 and 24 months respectively. In AD patients, fiber density in the fornix was decreased by 1.6, 2.7, 4.5 and 8.4% at 3, 6, 12 and 24 months respectively. Fornix reductions in fiber density at 24 months were larger in AD vs NC (P< 0.001), and trending toward statistically significant in MCI vs NC (P= 0.062). At 24 months, tissue radial diffusivity increase in the arcuate fasciculus was 89% higher in AD vs NC. At baseline, MCI converters had 14% higher free-water (P< 0.001), 15% lower fiber density (P= 0.002) and 10% higher tissue radial diffusivity (P= 0.009) in the fornix compared to MCI stable. Conclusions: In MCI, the three markers in the fornix may be considered a prognostic biomarker of conversion to AD. In clinical trials, stabilizing (or reversing decline) fiber density and tissue radial diffusivity measures would suggest tissue repair, strengthened axons and potential remyelination, making the case that they may be used as a monitoring biomarker. Disclosures: MD, JCH are shareholders of Imeka Solutions Inc. MR and MD are employees of Imeka Solutions Inc.
P87- PREDICTING PET-DETERMINED ATN BIOMARKER STATUS IN ALZHEIMER’S DISEASE WITH MRI USING DEEP CONVOLUTIONAL NEURAL NETWORKS. C. Lew1, L. Zhou1, M. Mazurowski1, P.M. Doraiswamy1, S. Landau2, J. Petrella3(1. Duke Unversity Medical Center — Durham (United States), 2. University of California, Berkeley — Berkeley (United States), 3. Duke University Medical Center — Durham (United States))
Background: Pathological hallmarks of Alzheimer’s disease (AD), including amyloid, tau, and neurodegenerative pathology constitute a subject’s “ATN” status, a unique endophenotype which has been proposed as a research framework aimed at a biological, rather than clinical, definition of AD. These hallmark pathologies can be detected as ATN biomarkers on positron emission tomography (PET). However, multiple PET scans are expensive and involve ionizing radiation. On the other hand, magnetic resonance imaging (MRI) is routinely obtained in patients undergoing workup of Alzheimer’s and related dementias, though its use in characterizing AD biomarkers is limited. Deep learning techniques such as convolutional neural networks (CNN) show great potential is uncovering hidden patterns in MRI data to aid in AD diagnosis and prognosis. Although there are previous applications of deep learning techniques that utilize MRI data to determine other aspects of AD, such disease progression and diagnosis, there are no prior studies, to our knowledge, that predict ATN biomarker status. Objective: The purpose of this study was to determine the predictive efficacy of deep learning applied to MRI data and other readily available patient diagnostic data for PET-determined ATN biomarker status. Methods: MRI data from the Alzheimer’s Disease Imaging Initiative (ADNI) was paired with PET biomarker data within 30 days of MRI acquisition date, resulting in 2372 amyloid-, 557 tau-, and 2769 FDG-MRI scan pairs. MRI data was preprocessed with bias field correction, skull stripping, and intensity normalization. For each biomarker, data was split into training, validation, and testing sets with a 70%/10%/20% split. Biomarker values were thresholded into positive vs. negative labels using bimodal gaussian mixture models based on training set values. The MRI data was input into a CNN to generate 100 imaging features. These features were combined with normalized patient diagnostic data, including sex, age, APOE status, hippocampal volumes, cognitive scores, and clinical diagnosis, in a logistic regression classifier model to output a binary prediction for each of the three PET biomarkers. Model performance was evaluated for each biomarker using accuracy and area under the receiver operator characteristic curve (AUROC). In addition to the above model that combined MRI data with patient diagnostic data, we evaluated models that utilized MRI data alone and patient diagnostic data alone. Results: The deep learning method that combined MRI data and diagnostic data outperformed methods that utilized each individually. For the deep learning method that utilized patient diagnostic data alone, we found the following AUROC values for the validation/training set; amyloid: 0.67/0.71, tau: 0.70/0.54, neurodegeneration: 0.70/0.76. For the deep learning method that utilized MRI data alone, we found the following AUROC values for the validation/training set; amyloid: 0.63/0.73, tau: 0.76/0.80, neurodegeneration: 0.81/0.85. For the deep learning method that combined both MRI data and patient diagnostic data, we found the following AUROC values for the validation/training set; amyloid: 0.74/0.79, tau: 0.83/0.69, neurodegeneration: 0.84/0.86. Conclusion: Our deep learning method was able to predict amyloid and neurodegeneration biomarker status with high diagnostic efficacy and tau with moderate efficacy by utilizing MRI and other readily available patient diagnostic data. This method may reduce the need for costly PET procedures in select groups of patients needing AD biomarker evaluation. Conflicts of Interest: Dr. Doraiswamy has received grants, advisory or board fees and/or stock from several biotech companies and is a coinventor on several patents. All other authors declare that they have no conflicts of interest to disclose.
P88- EARLY [18F]-PI-2620 TAU PET SIGNAL IN THE STAGES PRECEDING AD DEMENTIA. C. Young1, H. Vossler1, E. Wilson1, A. Trelle2, K. Poston1, M. Zeineh1, M. Greicius1, G. Zaharchuk1, V. Henderson1, A. Wagner2, K. Andreasson1, G. Davidzon1, E. Mormino1(1. Stanford ADRC — Stanford (United States), 2. Stanford Department of Psychology — Stanford (United States))
Background: Although [18F]-PI-2620 has shown promise in visualizing tau aggregates in Alzheimer’s disease (AD), no studies have examined how signal of this novel second generation tracer is impacted by methodological considerations or how it relates to amyloid burden and CSF pTau early in the AD pathological cascade. Objectives: To determine whether methodological considerations including timing acquisition and reference region selection impact PI2620 signal, and to evaluate this tracer in stages preceding AD dementia. Methods: We scanned a total of 61 participants with PI2620 Tau PET who were either clinically unimpaired (CU, N=52) or had Mild Cognitive Impairment (MCI, N=9), recruited from either the Stanford Aging and Memory Study (SAMS) or the Stanford Alzheimer’s Disease Research Center (ADRC). Of the 61 total participants, 39 CU had CSF AB42:40 and pTau-181 available measured by Lumipulse immunoassay. The remaining 22 had amyloid PET with Florbetaben. Using z-scored tau PET SUVRs that were standardized in reference to amyloid negative CU participants, we examined the impact of acquisition time (45 – 75 min vs. 60 – 90 min) and reference region (inferior cerebellum vs. white matter) on regional tau PET in the medial temporal lobe (entorhinal, hippocampus, amygdala), inferior temporal (IT) cortex, and striatum. We then examined associations of regional tau with age, amyloid status, continuous amyloid burden, and pTau-181. Results: Across all 61 participants, a 45–75 min or 60–90 min acquisition time did not significantly affect regional tau PET signal (all ps > 0.05) except in IT when a white matter reference region was used [B (SE) = 1.319 (0.295), p < 0.001]. As expected, age was not associated with regional tau PET (all ps > 0.300) except in striatum where off-target binding is expected [inferior cerebellum reference region: B (SE) = 0.074 (0.019), p < 0.001; white matter reference region: B(SE) = 0.077 (0.018), p < 0.001] and in IT with a white matter reference region [B (SE) = -0.045 (0.019), p = 0.020]. Amyloid positive individuals had significantly higher SUVRs than amyloid negative individuals in entorhinal, amygdala, and IT using either reference region (all ps < 0.05), as well as in hippocampus using an inferior cerebellum reference region [B (SE) = 0.923 (0.430), p = 0.036] when controlling for diagnostic status; there were no significant differences based on amyloid status in striatum (all ps > 0.100). Within the 39 CU participants with tau PET and CSF, regional tau PET was related to CSF AB42:40 in entorhinal, amygdala, and IT using either reference region (all ps < 0.05), but not in hippocampus (all ps > 0.05). Regional tau PET was also related to CSF pTau181 in entorhinal, hippocampus, amygdala, and IT using either reference region (all ps < 0.01) except for IT when a white matter reference region was used (p>0.05). Within the subset of 22 CU and MCI participants with amyloid PET, global amyloid SUVRs were associated with regional tau PET in amygdala [B (SE) = 5.003 (2.083), p = 0.027] and IT [B (SE) = 5.362 (1.474), p = 0.002] when using an inferior cerebellum reference region, but these associations were not present when using a white matter reference region (all ps > 0.140); global amyloid SUVR was also not significantly related to entorhinal or hippocampal tau using either reference region (all ps>0.130). Conclusion: Methodological considerations of acquisition time and reference region selection had minimal impact on tau associations with amyloid status, continuous amyloid, and pTau181 in medial temporal lobe regions, whereas reference region did impact some associations in IT. How reference region influences PI2620 signal in cortical regions warrants further investigation. Additionally, our results show that amyloid-related regional PI2620 tau elevations are present in individuals without dementia. Future studies with larger samples and longitudinal follow up are needed to evaluate the regionally specificity of early PI2620 tau PET signatures in preclinical and prodromal AD.
P89- AMYLOID AND TAU BURDEN IN AN AT-RISK, COGNITIVELY UNIMPAIRED CLINICAL TRIAL COHORT: NEUROIMAGING DATA FROM THE U.S. POINTER TRIAL. A.E. Murphy1, T.M. Harrison1, T.J. Ward1, P. Vemuri2, R. Koeppe3, S.N. Lockhart4, M.A. Espeland4, D.J. Harvey5, J. Masdeu6, H. Oh7, D. Gitelman8, N.T. Aggarwal9, L.D. Baker4, C. Decarli5, S.M. Landau1(1. U.C. Berkeley (United States), 2. Mayo Clinic (United States), 3. University of Michigan (United States), 4. Wake Forest School of Medicine (United States), 5. U.C. Davis (United States), 6. Houston Methodist (United States), 7. Brown University (United States), 8. Advocate Lutheran General Hospital (United States), 9. Rush University Medical Center (United States))
Background: Measurement of beta-amyloid (Aß) and tau in a clinical trial setting makes it possible to identify individuals on the Alzheimer’s disease (AD) pathway and determine whether a therapeutic intervention targets these pathologies. The neuroimaging substudy of the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial is examining Aß and tau PET and cerebrovascular biomarkers measured with MRI in older individuals (60–79 years), in order to determine whether lifestyle-based interventions are associated with changes in these biomarkers. AD and cerebrovascular biomarkers assessed prior to intervention could also help determine which biomarker characteristics predict a beneficial cognitive response to lifestyle changes. All POINTER imaging substudy participants are enrolled in the U.S. POINTER parent trial, which will test whether random assignment to either of two multidomain lifestyle interventions (nutrition, exercise, cognitive stimulation, health coaching) that differ in intensity and format affects cognitive outcomes. POINTER participants lack significant memory impairment, but are sedentary, have a suboptimal diet, and are at risk for future cognitive decline based on family history of memory impairment, race/ethnicity, and/or other risk factors. Enrollment into the U.S. POINTER Trial and the POINTER imaging substudy is ongoing. Objectives: The primary aim of this work is to examine the demographic characteristics, hippocampal volume (HCV), white matter hyperintensities (WMH) and prevalence of elevated Aß and tau in currently enrolled POINTER imaging participants (N=481, approximately 50% of the anticipated total sample with 18F florbetaben and 18F MK-6240 scans; 60–79 years) in relation to a comparable subset of ADNI participants (N=524, cognitively normal and early MCI individuals with a Clinical Dementia Rating (CDR)<2, 18F florbetaben or 18F florbetapir, and 18F flortaucipir (FTP) scans; 55–90 years). This comparison was used to examine the influence of the at-risk characteristics of the POINTER sample on AD and cerebrovascular biomarkers. All individuals have contemporaneous Aß PET, tau PET, and structural MRI scans, measured at the baseline visit for POINTER imaging participants. A secondary aim is to examine MK-6240 tau PET (POINTER) and FTP tau PET (ADNI) in relation to Aß PET (florbetaben or florbetapir) in order to determine if the tau PET tracers differ in terms of sensitivity to early tau (entorhinal cortex) deposition. Methods: To quantify PET SUVrs and MRI structural data, we segmented MRIs with Freesurfer, coregistered PET to MRI, and sampled PET means within AD-related regions of interest (Aß: cortical summary; tau: entorhinal cortex, temporal composite) relative to established tracer-specific reference regions. WMH were calculated from T1 and FLAIR images using a Bayesian estimation approach that integrates likelihood estimates, spatial priors, and tissue class information, and subsequently log-transformed and adjusted for head size. We categorized subjects into Aß+/- and tau +/- groups using previously-validated positivity thresholds for cortical Aß burden (florbetapir: 1.11, florbetaben: 1.08) and, for tau, the upper 90th percentile of Aß-negative normals in ADNI (FTP: 1.25) and POINTER (MK-6240: 1.20). We compared cohort data with two-sample t-tests and chi-square tests. Effect sizes of Aß +/- group differences in tau SUVrs were evaluated using Cohen’s d. Linear regression was used to measure the relationships between PET and age, WMH, and HCV. Results were considered statistically significant at α=0.05. Results: POINTER imaging participants were younger (POINTER: 70.0±5.0 vs. ADNI: 73.0±7.5 years) and had fewer years of education (11.3±2.0 vs. 16.7±2.4 years), higher BMIs (29.8±5.1 vs. 28.0±5.8), a higher proportion of females (66% vs. 57%), more individuals with smoking history (45% vs. 16%), a higher proportion from underrepresented racial/ethnic groups (27% vs. 15%), and more participants with a global CDR greater than zero (22% vs. 10%). The samples did not differ on Aß status (POINTER: 32% vs ADNI: 36%), WMH, or HCV; but POINTER had fewer individuals with elevated temporal tau (9% vs. 19%). In addition, POINTER entorhinal (1.12±0.29) MK-6240 SUVrs had a broader dynamic range compared to ADNI entorhinal (1.15±0.14) FTP SUVrs, but the temporal dynamic ranges were similar. However, effect sizes reflecting Aß status group differences were larger for entorhinal and temporal FTP/ADNI than MK-6240/POINTER. Entorhinal tau was correlated with older age in both samples, but age explained a greater amount (5%) of entorhinal tau variance in POINTER than in ADNI (3%), suggesting that MK-6240 variability may reflect sensitivity to early tau accumulation. Conclusions: Despite worse cognition and other at-risk characteristics of the POINTER imaging sample, ADNI and POINTER individuals had similar Aß, WMH burden, and HCV. The ADNI subsample had a greater proportion of individuals with elevated tau, perhaps due to older age and/or differences in the tau tracers used in these studies. Longitudinal data and head-to-head comparisons of the two tau tracers will be critical for determining whether the broader dynamic range of entorhinal tau observed with MK-6240 reflects greater sensitivity to early tau accumulation compared with FTP.
LP50- FIRST MICROTUBULE-BASED PET IMAGING STUDIES IN COGNITIVELY NORMAL AND IMPAIRED OLDER ADULT SUBJECTS— A PILOT STUDY. N. Damuka1, B. Bhoopal1, M. Miller1, I. Krizan1, S. Lockhart1, M. Rundle1, A. Mintz2, S. Craft1, K.K. Solingapuram1(1. Wake Forest School of Medicine — Winston Salem (United States), 2. Columbia University Medical Center — New York (United States))
Introduction: Disruption of the structural integrity of microtubule (MT) network and impairment of MT function are critical for pathophysiology of Alzheimer’s disease (AD) and related disorders (ADRDs). Additionally, MT-based pathophysiology is commonly associated with tauopathies. Our lab reported the first brain-penetrant PET radiotracer [11C]MPC-6827 to image MTs in vivo in both rodent and non-human primate models of AD. Our mechanistic studies demonstrated that [11C]MPC-6827 uptake is elevated with destabilized tubulins. We reported the dosimetry of [11C] MPC-6827 in healthy adults (WMIC 2021). Here we report the first clinical [11C]MPC-6827 PET imaging study in age-matched cognitively normal and impaired male older adult subjects from Wake Forest ADRC clinical cohort (Craft, PI). Methods: Two cognitively normal (both [11C]PiB Aβ and [18F]flortaucipir [FTP] tau-PET negative) and two cognitively impaired (both Aβ-PET and FTP positive) male subjects (79–85 y) with brain MRI brain scans were recruited from Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Cohort. [11C]MPC-6827 was produced from the corresponding phenol precursor following our reported methods. Dynamic 0–60 min brain PET imaging was obtained with an intravenous injection of [11C]MPC-6822 (9±0.5 mCi, <10 µg) using the GE Discovery PET/CT scanner. ROIs were drawn on whole brain, cortex, thalamus, putamen, cerebellum, hypothalamus, and hippocampus from the fused PET/MR DICOM images using the PMOD software. Time activity curves (TACs), standard uptake values (SUV) were determined and correlated closely with FTP tau, PiB Aβ PET, and age. As FTP primarily measures phosphor-tau expression in AD brains, we closely correlated its uptake with our destabilized MT tracking radiotracer, [11C] MPC-6827. Results: [11C]MPC-6827 was produced with high radiochemical purity (>99.8%) and specific activity (3960 ± 100 mCi/µmol). Based on the SUV analysis, uptake of radiotracer was higher in the cognitively impaired subjects compared to the controls in all the studied brain regions. Radiotracer uptake was positively correlated with their age, Aβ, and tau uptake—validating its relevance with existing AD biomarkers. When examined with the Braak-based analyses (tau staging scheme) with SUVRs from both FTP (80–100 min post injection) and [11C]MPC-6827 (28–60 min post injection) with inferior cerebellar reference for both radiotracers, [11C]MPC-6827 and FTP SUVR values were positively correlated (*p=0.077) and the scatterplot exhibited an L-shaped association, such that elevated FTP (phosphor-tau) uptake was present only when [11C]MPC-6827 (MT destabilization) uptake was already present. Conclusion: Our preliminary results here suggest that MT destabilization precedes paired helical filaments of tau in neurofibrillary tangles. We are currently collecting data on more subjects to exploit the clinical significance of the MT-based PET in AD imaging.
LP51- COMPARATIVE STUDY ON THE PREDICTIVE VALUE OF DIFFERENT RESTING-STATE FUNCTIONAL MAGNETIC RESONANCE IMAGING PARAMETERS IN PRECLINICAL ALZHEIMER’S DISEASESE. W.M. Bahk1, Y.J. Kwon2, B.H. Yoon3, K. Lee4, S.Y. Lee5, M.D. Kim6, B. Nam7, S.Y. Park8, E. Lim9, S.M. Wang1, H.Y. Lim1(1. The Catholic University of Korea — Seoul (Korea, Republic of), 2. Soonchunhyang University — Cheonan (Korea, Republic of), 3. Naju National Hospital — Naju (Korea, Republic of), 4. Dongguk University — Gyeongju (Korea, Republic of), 5. Wonkwang University — Iksan (Korea, Republic of), 6. Jeju National University — Jeju (Korea, Republic of), 7. Dr. Nam’s Psychiatric Clinic — Chungju (Korea, Republic of), 8. Keyo Hospital — Uiwang (Korea, Republic of), 9. Shinsegae Hyo Hospital — Kimje (Korea, Republic of))
Objective: Diverse resting-state functional magnetic resonance imaging (rs-fMRI) studies showed that rs-fMRI might be able to reflect the earliest detrimental effect of cerebral beta-amyloid (Ab) pathology. However, no previous studies specifically compared the predictive value of different rs-fMRI parameters in preclinical AD. Methods: A total of 106 cognitively normal adults (Ab+group=66 and Ab-group=40) were included. Three different rs-fMRI parameter maps including functional connectivity (FC), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity(ReHo) were calculated. Receiver operating characteristic (ROC) curve analyses were utilized to compare classification performance of the three rs-fMRI parameters. Results: FC maps showed the best classifying performance in ROC curve analysis(AUC, 0.915, p < 0.001). Good but weaker performance was achieved by using ReHo maps (AUC, 0.836, p < 0.001) and fALFF maps (AUC, 0.804, p < 0.001). The brain regions showing the greatest discriminative power included the left angular gyrus for FC, left anterior cingulate for ReHo, and left middle frontal gyrus for fALFF. However, among the three measurements, ROI-based FC was the only measure showing group difference in voxel-wise analysis. Conclusion: Our results strengthen the idea that rs-fMRI might be sensitive to earlier changes in spontaneous brain activity and FC in response to cerebral Ab retention. However, further longitudinal studies with larger sample sizes are needed to confirm their utility in predicting the risk of AD. Key words: magnetic resonance imaging, Alzheimer’s disease, amyloid.
LP52- DEVELOPMENT OF RANDOM FOREST ALGORITHM BASED PREDICTION MODEL OF ALZHEIMER’S DISEASE USING NEURODEGENERATION PATTERN. K.H. Lee1, W.M. Bahk2, Y.J. Kwon3, B.H. Yoon4, S.Y. Lee5, M.D. Kim6, B.W. Nam7, S.Y. Park8, E.S. Lim9, S.M. Wang2, H.K. Lim2(1. Department of Psychiatry Dongguk University Hospital — Gyeongju (Korea, Republic of), 2. Department of Psychiatry, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea — Seoul (Korea, Republic of), 3. Department of Psychiatry, Soonchunhyang University Cheonan Hospital, Soonchunhyang University, — Cheonan (Korea, Republic of), 4. Department of Psychiatry, Naju National Hospital, — Naju (Korea, Republic of), 5. Department of Psychiatry, Wonkwang University Hospital, Wonkwang University School of Medicine, — Iksan (Korea, Republic of), 6. Department of Psychiatry, Jeju National University School of Medicine, — Jeju (Korea, Republic of), 7. Dr. Nam’s Psychiatric Clinic — Chungju (Korea, Republic of), 8. Department of Psychiatry, Keyo Hospital, — Uiwang (Korea, Republic of), 9. Department of Psychiatry, Shinsegae Hyo Hospital — Kimje (Korea, Republic of))
Objective: Alzheimer’s disease (AD) is the most common type of dementia and the prevalence rapidly increased as the elderly population increased worldwide. In the contemporary model of AD, it is regarded as a disease continuum involving preclinical stage to severe dementia. For accurate diagnosis and disease monitoring, objective index reflecting structural change of brain is needed to correctly assess a patient’s severity of neurodegeneration independent from the patient’s clinical symptoms. The main aim of this paper is to develop a random forest (RF) algorithm-based prediction model of AD using structural magnetic resonance imaging (MRI). Methods: We evaluated diagnostic accuracy and performance of our RF based prediction model using newly developed brain segmentation method compared with the Freesurfer’s which is a commonly used segmentation software. Results: Our RF model showed high diagnostic accuracy for differentiating healthy controls from AD and mild cognitive impairment (MCI) using structural MRI, patient characteristics, and cognitive function (HC vs. AD 93.5%, AUC 0.99; HC vs. MCI 80.8%, AUC 0.88). Moreover, segmentation processing time of our algorithm (<5 minutes) was much shorter than of Freesurfer’s (6–8 hours). Conclusion: Our RF model might be an effective automatic brain segmentation tool which can be easily applied in real clinical practice.
LP53- ASSOCIATION BETWEEN WHITE MATTER HYPERINTENSITIES (WMH) VOLUME AND COGNITIVE FUNCTION IN ALZHEIMER’S DISEASE. Y. Bo-Hyun1, B. Won-Myong2, K. Young-Joon3, L. Kwanghun4, L. Sang-Yeol5, K. Moon-Doo6, N. Beomwoo7, P. Sung-Yong8, L. Eunsung9(1. Department of Psychiatry, Naju National Hospital — Naju (Korea, Republic of), 2. Department of Psychiatry, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea — Seoul (Korea, Republic of), 3. Department of Psychiatry, Soonchunhyang University Cheonan Hospital, Soonchunhyang University — Cheonan (Korea, Republic of), 4. Department of Psychiatry, College of Medicine, Dongguk University — Gyeongju (Korea, Republic of), 5. Department of Psychiatry, Wonkwang University Hospital, Wonkwang University School of Medicine — Iksan (Korea, Republic of), 6. Department of Psychiatry, Jeju National University School of Medicine — Jeju (Korea, Republic of), 7. Dr. Nam’s Psychiatric Clinic — Chugnju (Korea, Republic of), 8. Department of Psychiatry, Keyo Hospital — Uiwang (Korea, Republic of), 9. Department of Psychiatry, Shinsegae Hyo Hospital — Kimju (Korea, Republic of))
Background: WMH in MRI are common among the elderly. WMH are associated with increased cognitive impairment and risk of Alzheimer’s disease (AD). Although WMH contribute to AD pathology, their clinical implications are not fully understood. This study aimed to assess whether WMH predict AD and investigate the association between WMH (including subclassified WMH volume) and cognitive function in AD. Method: This study enrolled 171 patients with AD. All participants underwent clinical evaluations including brain MRI study and neuropsychological tests using the CERAD-K neuropsychological assessment battery. In addition, Charlson comorbidity index, the Korean version of the Geriatric Depression Scale short from were administered. WMH volume was calculated using automated quantification method with SPM and MATLAB image processing software. WMH were classified according to the distance from the ventricular surface. WMH located in juxtaventricular areas, within 3 mm from the ventricular surface, were classified as juxtaventricular with matter hyperintensities (JVWMH). WMH located within 3–13 mm or farther than 13 mm from the ventricular surface were classified as periventricular white matter hyperintensities (PVWMH) or deep white matter hyperintensities (DWMH), respectively. WMH volume data were right-skewed. Consequently, WMH volume data were logarithmic transformed. Result: The AD group had a higher mean WMH volume(20.7 ± 18.2 ml). Multivariate linear regression analysis showed that total WMH volume in AD was associated with poor performance in categorical verbal fluency test (p = 0.008) and word list memory test (p = 0.023). JVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.013) and digit span test forward (p = 0.037). PVWMH volume in AD was associated with poor performance on categorical verbal fluency test (p = 0.011) and word list memory test (p = 0.021), whereas DWMH volume showed no association with cognitive dysfunction in AD. Conclusion: Total WMH, JVWMH and PVWMH were associated specifically with executive function, immediate memory, and working memory, independently of hippocampal atrophy in AD. WMH were associated with AD risk and cognitive dysfunction differentially according to the distance from the ventricular surface. Key words: Alzheimer’s disease, cognition and white matter disease
LP53A- CROSS SECTIONAL ASSOCIATION BETWEEN FRAILTY AND WHITE MATTER HYPERINTENSITY AMONG ALZHEIMER’S DISEASE. K. Moon-Doo1, B. Won-Myong Bahk2, K. Young-Joon3, Y. Bo-Hyun4, L. Kwanghun5, L. Sang-Yeol6, N. Beomwoo7, P. Sung-Yong8, L. Eunsung9(1. Department of Psychiatry, Jeju National University School of Medicine — Jeju (Korea, Republic of), 2. Department of Psychiatry, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea — Seoul (Korea, Republic of), 3. Department of Psychiatry, Soonchunhyang University Cheonan Hospital, Soonchunhyang University — Cheonan (Korea, Republic of), 4. Department of Psychiatry, Naju National Hospital — Naju (Korea, Republic of), 5. Department of Psychiatry, College of Medicine, Dongguk University — Gyeongju (Korea, Republic of), 6. Department of Psychiatry, Wonkwang University Hospital, Wonkwang University School of Medicine — Iksan (Korea, Republic of), 7. Dr. Nam’s Psychiatric Clinic — Chugnju (Korea, Republic of), 8. Department of Psychiatry, Keyo Hospital — Uiwang (Korea, Republic of), 9. Department of Psychiatry, Shinsegae Hyo Hospital — Kimje (Korea, Republic of))
Purpose: With an aging global population, recent years have seen rapid expansion in the attention of the frailty. Thus, understanding, and determinant the potentially modifiable risk factor for frailty is a major concern for health care policy and provision. Material and method: Subjects were recruited for the study from the dementia clinic of Jeju National University Hospital between January 2018 and January 2020. All of the subjects were evaluated by using CERAD-K and diagnosed probable AD and possible AD by a panel of two experienced dementia research neuropsychiatrists. WMH volume was calculated using automated segmentation analysis and further partitioned into three categories (Kim, BIOL PSYCHIATRY 2008). Frailty evaluated by Korean Frailty Index (KFI) and classified into three categories according to the cutpoints. Other physical performances such as BMI, muscle mass index, grip strength, and gait speed measures were performed by experienced researchers specialized in geriatric assessment. comorbidity status using the Charlson comorbidity index, and depressive symptoms using GDS was examined. Results: In total, 34 subjects (23.6 %) were classified as frail 47 subjects (32.6 %) were classified as prefrail, and 63 subjects (43.8 %) were classified as a non-frail group. The frail group had higher WMH volume compared to the non-frail group (p=0.002), and these trends remained significant after linear regression analyses. According to the new subclassification of WMH, using the non-frail group as a reference, total WMH volume (OR=6.297, p=0.013), JVWMH volume (OR=12.955, p=0.014), and PVWMH (OR=3.382, p=0.025) were associated with frail. Furthermore, according to the path model, only the gait speed mediated the association between WMH and frailty. Conclusion: In our study provides evidence of a cross-sectional relationship between WMH and frailty, and there is a difference in the association between the subclassification of WMH volume and frailty. Furthermore, we suggest that gait speed could be a useful biomarker for assessment of the frailty.
LP54- CLINICAL AND BIOMARKER CHARACTERISTICS OF SUBJECTIVE COGNITIVE DECLINE WHO PROGRESSED TO MCI WITHIN 24-MONTHS FOLLOW-UP. D.W. Yang1, C.H. Lee1, Y.J. Hong2, S. Ho3, J.H. Jeong4, K.H. Park5, S.Y. Kim6, M.J. Wang7, S.H. Choi8, S.G. Lee9(1. Department Of Neurology, College Of Medicine, The Catholic University Of Korea — Seoul (Korea, Republic of), 2. Department of Neurology, The Catholic University of Korea Uijeongbu St. Mary’s Hospital, Uijeongbu, Republic of Korea — Uijeongbu (Korea, Republic of), 3. Department of Neurology, Changwon Hanmaeum Hospitaljeongbu, Republic of Korea — Changwon (Korea, Republic of), 4. Department of Neurology, Womans University School of Medicine, Ewha Womans University Seoul HospitalChangwon Hanmaeum Hospitaljeongbu, Republic of Korea — Seoul (Korea, Republic of), 5. Department of Neurology, Gachon University Gil Hospital — Inchon (Korea, Republic of), 6. Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital — Bundang (Korea, Republic of), 7. Neurology, ROA Clinic — Bundang (Korea, Republic of), 8. Department of Neurology, Inha University School of Medicine, Inha University Hospital — Inchon (Korea, Republic of), 9. NeoLAB convergence Inc — Seoul (Korea, Republic of))
Background: Subjective cognitive decline (SCD) refers to the status concerning the self-experienced memory decline but preserving cognitive function on the standardized neuropsychological tests. Finding risk factors associated with progression from SCD to mild cognitive impairment (MCI) became important for disease modifying treatment. Objectives: We investigated the characteristics of SCD patients who progressed to MCI or dementia during 24-months follow-up. Methods: 120 patients with SCD were enrolled in this prospective study. All participants were recruited as part of the multicenter cohort study to identify predictors for the clinical progression to MCI or dementia from subjective cognitive decline (CoSCo study). Demographics and clinical information were collected at baseline. Participants were assessed by using neuropsychological tests annually. At baseline, all subjects underwent 18F-florbetaben PET and 3T MRI. At the 24-months follow-up we compared the clinical, neuroanatomical, and biomarker characteristics of the SCD who progressed to MCI. Results: From the 120 subjects 107 participants were followed-up and nine progressed to MCI during 24 months. The conversion rate to MCI was 8.41% (9/107). The SCD patients who progressed to MCI showed significantly lower frequency of alcohol consumption (0/9 (0.0%) vs. 41/98 (41.8%), p=0.012) compared to the stable SCD patients. There were no significant differences in the frequency of APOE e4 carriers, various leisure and physical activities, and accompanying psychiatric symptoms between the two groups. The neuropsychological tests at baseline showed significantly poorer performance in the digit span forward test (-0.4111 ± 1.1135 vs. 0.6521 ± 1.1077 in percentile, p=0.004) and global cognition, the Mini-Mental State Examination (MMSE) score (25.22 ± 2.539 vs. 27.39 ± 1.826, p=0.009) in the SCD patients with conversion to MCI. The frequency of amyloid PET positivity was significantly higher in the SCD subjects with progression (5/9 (55.6%) vs. 20/98 (20.4%), p=0.031). In volumetric analysis the converters to MCI showed significantly lower regional volume in the left inferior parietal, left inferior temporal, right paracentral cortical areas, left pallidum, and putamen. Conclusion: At the 24-month follow-up, the subjects who progressed to MCI showed significantly decreased function in attention and global cognition at baseline. Considering the significantly higher frequency of positive amyloid PET scans and lower regional brain volume in the progression group, the most critical condition associated with progression to MCI might be having the Alzheimer’s pathology and atrophic changes of brain thereafter. We need additional follow-up period for detailed investigation of the biomarker profiles, underlying risk factors, and cognitive status that could tell us the prognosis of SCD. This study was supported by the Ministry of Health and Welfare, HI18C0530
LP55- IN VIVO HEAD-TO-HEAD COMPARISON OF [18F] GTP1 AND [18F]MK6240 IN ALZHEIMER’S DISEASE. M. Tonietto1, C. Constantinescu2, S. Sanabria Bohorquez3, R. Gunn4, D. Russell5, E. Teng3, D. Abramzon3, K. Pickthorn3, G. Klein1(1. Hoffmann-La Roche, Ltd. — Basel (Switzerland), 2. Invicro, LLC — Needham (United States), 3. Genentech, Inc. — South San Francisco (United States), 4. Invicro, LLC — London (United Kingdom), 5. Invicro, LLC — Needham (United Kingdom))
Background: In participants with Alzheimer’s disease (AD), tau Positron Emission Tomography (PET) signal is closely related to cognitive status and subsequent rates of disease progression. Tau PET is increasingly being used in clinical trials as a downstream pharmacodynamic biomarker and to select participants at higher risk for clinical decline. Several radiotracers targeting tau tangles have been examined in human studies. Although abundant data exist for individual tracers, there is only limited in-vivo data from head-to-head tracer comparisons. Head-to-head comparisons are important for the contextualization of tau PET data from clinical trials using different tracers and will enable the simultaneous use of multiple tau tracers in future observational and therapeutic studies. While a harmonized scale like the amyloid centiloid has not yet been developed for tau PET, the slope of regional linear regressions from head-to-head tau PET studies as reported here will help to better understand treatment effects observed using different tau PET tracers. Objectives: This study compared in vivo the characteristics of two second generation tau PET tracers, [18F]GTP1 and [18F]MK6240, in a cohort of participants ranging from cognitively unimpaired to moderate AD. Methods: To date, 9 participants (age 69±4 years; 5F) have completed imaging with both [18F]GTP1 and [18F]MK6240: 5 cognitively unimpaired (MMSE=[29,30], CDR=0), 1 prodromal AD (MMSE=29; CDR=0.5), 2 mild AD (MMSE=[21,22]; CDR=0.5), and 1 moderate (MMSE=17; CDR=0.5) AD. All cognitively unimpaired participants were beta-amyloid negative while all AD participants were beta-amyloid positive, as assessed by amyloid PET. [18F]GTP1 images were acquired from 60 to 90 min post injection of 259±9 MBq of [18F]GTP1. [18F]MK6240 images were acquired from 90 to 110 min post injection of 190±6 MBq of [18F]MK6240. Tracer scan order was balanced, with a mean interval between the two exams of 10±12 days. All PET images were acquired on a Siemens Biograph 6 PET-CT and reconstructed with an iterative reconstruction algorithm (OSEM four iterations, 16 subsets) and a post hoc 5-mm Gaussian filter. A structural three-dimensional sagittal T1-weighted MR image was also acquired for all participants. Image processing was performed using the PNEURO module within PMOD and included the following steps: motion correction of PET images, alignment of time-averaged PET to the corresponding T1-weighted image, normalization of the T1-weighted image to MNI space and the associated transformation of PET data into MNI space, application of the Hammers Atlas to calculate regional Standardized Uptake Value (SUV) and SUV Ratio (SUVR) values from the PET data. The inferior cerebellar cortex was used as reference region, and two sets of regions of interest (ROIs) were defined: one based on the six Braak stages, the other on the brain lobes: medial temporal, lateral temporal, frontal, parietal, and occipital cortex. Pearson correlation coefficient and linear regression analyses were used to compare SUVR values in different ROIs between tracers. Linear regression coefficients (slope and intercept) were computed using a total least square approach and expressed with [18F]GTP1 as the independent variable (i.e., SUVR_MK6240 = slope * SUVR_GTP1 + intercept). Results: [18F]MK6240 had significantly higher SUV values in the inferior cerebellar cortex compared to [18F]GTP1 (mean difference =-0.23±0.16 SUV; p=0.0025). SUVRs values were highly correlated in all Braak ROIs except for Braak II (i.e., hippocampus). Excluding Braak II, correlation coefficients ranged from r=0.96 in Braak III to r=0.996 in Braak IV. In Braak II, SUVRs between tracers were not significantly correlated (r=0.21, p=0.59). In the lobar ROIs, correlation coefficients ranged between r=0.88 in the medial temporal lobe to r=0.998 in the occipital lobe. After removing the hippocampus from the medial temporal lobe, the correlation coefficient in this ROI increased to r=0.94. The average regression slope across the Braak ROIs (Braak II excluded) was 2.9±0.4 and the average intercept was -2.3±0.5. Similar results were found using the lobe ROIs, with an average slope of 2.9±0.7, and an average intercept of -2.2±0.8. Conclusion: [18F]GTP1 and [18F]MK6240 SUVR values were highly correlated in all the ROIs considered with exception of Braak II/hippocampus. The reasons behind the divergent results in this latter region are currently being investigated. The linear regression analysis showed that [18F]MK6240 had a wider SUVR range compared to [18F] GTP1 in all regions considered (slope greater than 1). This study is currently ongoing and additional data analyses are pending. These preliminary results support the development of categorical and standardized quantification scales for bridging existing data sets and enabling the use of both tracers in future studies.
LP56- EVALUATING THE IMPACT OF CAROTID ENDARTERECTOMY ON COGNITION AND HIPPOCAMPAL FRACTIONAL ANISOTROPY. A. Bernstein1, J. Arias1, C. Weinkauf1, T. Trouar1(1. University of Arizona — Tucson (United States))
Background: Vascular contributions to cognitive impairment and dementia (VCID) have growing relevance in understanding Alzheimer’s disease (AD). However, in the absence of acute ischemic events such as stroke and/or TIA, whether large vessel disease of the carotid artery, asymptomatic extracranial carotid atherosclerotic disease (aECAD), and its treatment with carotid endarterectomy (CEA) affect AD risk is poorly understood. Objectives: This work seeks to investigate the changes in brain structure and function that occur in presence of untreated aECAD and following carotid endarterectomy using a battery of neurocognitive tests and diffusion MRI. Methods: This prospective, non-randomized study enrolled a total of twenty-six patients with aECAD and various ethnic backgrounds recruited from Vascular Surgery clinics in Tucson, Arizona. Thirteen subjects had high grade ≥ 70% stenosis in at least one carotid artery and received CEA). Thirteen had <70% stenosis, therefore not qualifying for revascularization. Participants underwent cognitive evaluation using the Montreal Cognitive Assessment (MoCA) test and multi-shell, high angular resolution diffusion magnetic imaging (dMRI) of the brain at two different timepoint visits, baseline and six months follow-up. MoCA scores and fractional anisotropy (FA) along the hippocampal tracks were used for analysis. Results: Baseline results showed that FA was statistically lower along the ipsilateral hippocampus in subjects with severe aECAD compared to subjects without severe aECAD. MoCA scores were lower in these individuals, but this did not reach statistical significance. At follow-up, MoCA scores increased significantly in subjects who received CEA and remained equal in control subjects that did not have CEA. FA remained unchanged in the CEA group and decreased in the control group. Conclusions: These results indicate that there may be detrimental changes in the microscopic structure of hippocampal white matter in the presence of aECAD and that surgical treatment with CEA may prevent further deterioration of brain structure. These findings have important clinical implications because they question the diagnosis of “asymptomatic” ECAD, suggesting that aECAD may contribute to cognitive dysfunction.
LP57- NEW INSIGHTS INTO THE CONTRIBUTION OF TAU PET IMAGING IN AD THERAPEUTIC TRIALS. J. Lagarde1,2,3, P. Olivieri1, M. Tonietto3,4, P. Gervais3, F. Caillé3, M. Moussion5, M. Bottlaender3,6, M. Sarazin1,7,8(1. Department of Neurology of Memory and Language, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France — Paris (France), 2. Université Paris Cité, F-75006 Paris, France — Paris (France), 3. Université Paris-Saclay, BioMaps, Service Hospitalier Frédéric Joliot CEA, CNRS, Inserm, F-91401, Orsay, France — Orsay (France), 4. Research and Early Development (pRED), Hoffmann-La Roche, Basel, CH — Basel (Switzerland), 5. Centre d’Evaluation Troubles Psychiques et Vieillissement, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France — Paris (France), 6. Université Paris-Saclay, UNIACT, Neurospin, Joliot Institute, CEA, F–91140, Gif sur Yvette, France — Gif Sur Yvette (France), 7. Université Paris Cité, F-75006 Paris, France — Paris, 8. Université Paris-Saclay, BioMaps, Service Hospitalier Frédéric Joliot CEA, CNRS, Inserm, F–91401, Orsay, France — Orsay)
Background: Alzheimer’s disease (AD) is a complex and heterogeneous disease, both in terms of clinical presentation and rapidity of cognitive impairment. Molecular imaging by positron emission tomography (PET) enables the in vivo detection of amyloid and tau pathologies, the latter being closely associated with clinical symptoms. To optimize the design of therapeutic trials, it is necessary to predict cognitive and functional decline by developing surrogate markers that accurately reflect the clinical course of the disease. Tau-PET imaging is a sensitive tool to measure the extent of tau pathology (that precedes neurodegeneration), which should be considered as a potential predictor of neurodegeneration and of subsequent cognitive decline as well as a longitudinal biomarker of disease progression. Objectives: We aimed at exploring whether regional tau binding measured at baseline was associated with the rapidity of AD progression after 2 years of follow-up assessed in terms of both (a) cognitive decline in specified cognitive domains, and (b) the progression of regional brain atrophy. We also explored the longitudinal progression of the tau radiotracer binding by performing a second tau-PET at 2 years, and the progression of cortical atrophy in a cohort of well-characterized prodromal and mild AD patients compared with controls, and their relationships with (a) baseline regional tau load, and (b) clinical decline in the same cognitive domains. Methods: Thirty-six AD patients (positive CSF biomarkers and amyloid-PET) and fifteen controls underwent a complete neuropsychological assessment, 3T brain MRI, [11C]-PiB and [18F]-flortaucipir PET imaging (Tau1), and were monitored annually over 2 years, with a second brain MRI after 2 years. We used mixed effects models to explore the relations between tau-PET, amyloid-PET, CSF biomarkers and MRI at baseline and cognitive decline and the progression of brain atrophy over 2 years in AD patients. Among these subjects, twenty-seven AD patients and twelve amyloid-negative controls also underwent a second tau PET imaging (Tau2) performed after 2 years. We studied the longitudinal progression of tau radiotracer binding (Tau2-Tau1) in AD patients compared with controls and its association with baseline tau load. We used mixed effects models to explore the relations between the progression of tau radiotracer binding or cortical atrophy and cognitive decline over 2 years. Results: Tau tracer binding at baseline was associated with the subsequent cognitive decline in various brain areas depending on each cognitive component. In contrast, no significant relationship was observed between cognitive decline and initial amyloid load, regional cortical atrophy or CSF biomarker levels. We also found associations between tau tracer binding and subsequent cortical atrophy in the superior temporal, parietal and frontal association cortices. In the tau-PET longitudinal study, we found an average longitudinal increase in tau radiotracer binding, especially in frontal regions, in contrast with an average decrease in the lateral temporoparietal cortex. In this region, individual analyses revealed two distinct evolutions of tau radiotracer binding according to Tau1 uptake. Specifically, low Tau1 patients (SUVr < 1.6) demonstrated an increase in tau radiotracer uptake over time and a slow clinical progression, whereas high Tau1 patients demonstrated a paradoxical plateauing or decrease of tau tracer uptake over time and a faster clinical progression. This decreased tau binding may be explained by a lower affinity of the tracer during the transition to ghost tangles, which leads to a predominance of 3R tau. Cognitive decline was weakly associated with Tau2-Tau1. A strong association was noted between regional cortical atrophy progression and cognitive decline predominating in regions based on the cognitive component considered. Conclusion: Beyond the utility of tau-PET for determining AD diagnosis, especially when CSF biomarkers are equivocal, our results suggest that tau tracer binding is predictive of cognitive decline in AD in domain-specific brain areas, particularly in the temporo-parietal and frontal cortices. This may be used to refine the selection of patients for inclusion in clinical trials in order to include patients in the prodromal stage of the disease who are at high risk of rapid cognitive decline. On the other hand, selecting AD patients with higher tau load, may lead to a misinterpretation of the progression of tracer binding over time due to the possible transition to ghost tangles. To avoid such difficulties, the choice of PET as well as MRI neuroimaging outcomes deserves to be discussed on the basis of studies with larger numbers of patients in the early stages of the disease and by using different methods for the analysis of the longitudinal data, which raises important methodological issues. Conflicts of interest: none declared.
LP58- METHODS TO DECREASE SAMPLE SIZE NEEDED FOR LONGITUDINAL FLORTAUCIPIR TAU PET. S. Baker1, P. Aguilar Dominguez1, S. Landau2, T. Harrison2, R. Lajoie3, T. Ward2, K. Zhuang2, G. Rabinovici3, W. Jagust2(1. Lawrence Berkeley National Lab — Berkeley (United States), 2. University of California, Berkeley — Berkeley (United States), 3. University of California, San Francisco — San Francisco (United States))
Background: Tau PET is highly correlated with cognition (1), making tau an attractive target for intervention. Flortaucipir (FTP) is the most widely used radiotracer for tau PET imaging. Although this tracer can differentiate between healthy controls and subjects with Alzheimer’s disease, it is well known that FTP images have focal areas of off-target signal (ie basal ganglia) (2). However, less well known is that the cortex also suffers from off-target signal (3), and cortical FTP in the absence of tau correlates with thalamus and putamen off-target signal explaining 64% of the variability in the cortical signal in a cross-sectional cohort of amyloid negative (Aβ-) cognitively unimpaired (CU) subjects (4). Objectives: In this study, we explored the impact of partial volume correction (PVC), reference region, and regressing out the thalamic signal (as defined in an Aβ-CU cross-sectional cohort) on longitudinal meta temporal FTP PET effect size and sample size in Aβ- and Aβ+CU and Aβ- cognitively impaired (CI) subjects. Methods: Data from the Alzheimer’s Disease Neuroimaging Initiative and Lawrence Berkeley National Lab were combined to create a cross-sectional cohort of Aβ-CU (n=245), and a longitudinal cohort of Aβ-CU (n=103), Aβ+CU (n=119), and Aβ+CI (n=137). The FTP tau PET scans were averaged, coregistered to an MPRAGE which was segmented using Freesurfer7. Two possible reference regions were explored, inferior cerebellar gray (ICG) and eroded white matter (WM), and quantification was done with and without a FTP-tailored geometric transfer matrix PVC (5, 6). The equation for regressing out the thalamus was defined in the cross-sectional Aβ-CU cohort and then applied to the individual scans in the longitudinal cohorts. The annual change was calculated in the longitudinal cohorts in the meta temporal region (7) with and without thalamic regression, with and without PVC, and with the two reference regions. The impact was quantified by calculating Hedges’ Effect Size (ES) and sample size (power = 0.80 and significance level = 0.05) needed to differentiate between Aβ+CI > Aβ-CU, Aβ+CI > Aβ+CU, and Aβ+CU > Aβ-CU. Results: There was no statistically significant difference between cross-sectional Aβ-CU thalamus and baseline thalamus in the longitudinal groups or change in thalamus between the longitudinal groups for all quantification methods. We then compared annual change between groups across different analyses and calculated the ES and sample size. Alone, regressing out the thalamus or performing PVC both resulted in modest increases in effect size. However, when comparing ES between no thalamic regression+no PVC to thalamic regression+PVC, the effect size increased from 0.60 to 0.71 (Aβ+CI > Aβ-CU), 0.40 to 0.53 (Aβ+CI > Aβ+CU), and 0.46 to 0.58 (Aβ+CU > Aβ-CU), translating to a decrease in sample size to 72% (Aβ+CI > Aβ-CU), 55% (Aβ+CI > Aβ+CU) and 63% (Aβ+CU > Aβ-CU) of the sample size needed in the no thalamic regression+no PVC analysis. For WM reference region, when comparing ES between no thalamic regression+no PVC to thalamic regression+PVC, the effect size increased from 0.69 to 1.13 (Aβ+CI>Aβ-CU), 0.44 to 0.84 (Aβ+CI > Aβ+CU), and from 0.38 to 0.42 (Aβ+CU>Aβ-CU), translating to a decrease in sample size to 37% (Aβ+CI > Aβ-CU), 28% (Aβ+CI > Aβ+CU) and 82% (Aβ+CU > Aβ-CU) of the sample size needed in the no thalamic regression+no PVC analysis. Conclusion: There are many difficulties when measuring annual change in tau PET such as low amounts of change expected especially at earlier stages in the disease when treatment is most likely to be effective. Any improvement that can be made in increasing the signal and decreasing the noise can result in lower sample sizes. We have shown that PVC+thalamic regression results in an average of 63% decrease from the original sample size for ICG reference region and 49% for WM reference region. References: 1. Pontecorvo, M.J., et al., A multicentre longitudinal study of flortaucipir (18F) in normal ageing, mild cognitive impairment and Alzheimer’s disease dementia. Brain, 2019. 142(6): p. 1723–1735. 2. Marquie, M., et al., Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case. Acta Neuropathol Commun, 2017. 5(1): p. 75. 3. Lowe, V.J., et al., Tau-positron emission tomography correlates with neuropathology findings. Alzheimers Dement, 2020. 16(3): p. 561–571. 4. Baker, S.L., et al., Effect of Off-Target Binding on (18)F-Flortaucipir Variability in Healthy Controls Across the Life Span. J Nucl Med, 2019. 60(10): p. 1444–1451. 5. Baker, S.L., A. Maass, and W.J. Jagust, Considerations and code for partial volume correcting [18F]-AV-1451 tau PET data. Neuroimage Data Brief, 2017. 15: p. 648–657. 6. Rousset OG, M.Y., Evans AC., Correction for partial volume effects in PET: principle and validation. J Nucl Med, 1998. 39(5): p. 904–911. 7. Jack, C.R., Jr., et al., Defining imaging biomarker cut points for brain aging and Alzheimer’s disease. Alzheimers Dement, 2017. 13(3): p. 205–216. Suzanne Baker consults for Genentech.
LP59- PREVALENCE OF MICROHEMORRHAGES, SUPERFICIAL SIDEROSIS AND OTHER MRI ABNORMALITIES IN A POPULATION OF COGNITIVELY UNIMPAIRED OLDER ADULTS FROM THE CHARIOT-PRO STUDY. L. Bracoud1, C. Udeh-Momoh2, Z. Saad3, D. Kafetsouli4, E. Daly4, O. Okoye4, P. Giannakopoulou4, D. Scott5, J. Suhy5, S. Baker6, G. Novak6, C. Ritchie7, L. Middleton2, L. Middleton8(1. Clario — Lyon (France), 2. AGE Research, School of Public Health, Imperial College of London — London (United Kingdom) — London (United Kingdom), 3. Janssen Research and Development — La Jolla (United States), 4. AGE Research, School of Public Health, Imperial College of London — London (United Kingdom), 5. Clario — San Mateo (United States), 6. Janssen Research and Development — Titusville (United States), 7. University of Edinburgh — Edinburgh (United Kingdom), 8. Imperial College Healthcare NHS Trust — London (United Kingdom))
Background: Hemosiderin deposits, including microhemorrhages (MH) and superficial siderosis (SS), have been termed as Alzheimer’s Related Imaging Abnormalities — Hemosiderin (ARIA-H) in anti-amyloid drug trials. MH and SS have also been observed in asymptomatic older adults, in contrast to ARIA-E (edema/effusion) abnormalities that have never been reported outside the context of such trials. Objectives: With the expected increased availability of disease-modifying therapies targeting Alzheimer’s disease in its preclinical and early clinical stages, we aimed at evaluating the prevalence of MH and SS in asymptomatic older adults, from the CHARIOT PRO prospective, biomarker enriched study at Imperial College London and Edinburgh University, and also assess the presence of white matter hyperintense lesions (WML) and other brain pathologies, based on structural MRI, at screening. Methods: We included 1414 cognitively unimpaired men and women, aged 60 to 85 years, through population-based regional registries, in years 2015–2018. Each participant was scanned on Siemens 3T scanners, using a standardized MRI protocol, including 2D axial FLAIR and T2* Gradient Echo sequences (5 mm slices, 0.5 mm interslice gap, 0.94×0.94 mm2 in-plane resolution). FLAIR and T2* data were reviewed by blinded neuroradiologist as part of central eligibility reading activities, in order to report the number, shape and size of hemosiderin deposits. MH were defined as punctate T2* hypointensities of <10 mm in diameter. SS were defined as linear/curvilinear T2* hypointensities, irrespective of size. WML extent was reported using the Wahlund Age Related White Matter Changes (ARWMC) scale. WML volume was, also, automatically estimated using FreeSurfer WM hypointensities category, to benefit from a rough quantitative estimate. Among these subjects, 1076 subjects also underwent Amyloid PET imaging, using one of three approved 18F tracers (Florbetapir n=170, Florbetaben n=602 or Flutemetamol n=304). PET positivity was determined using a hybrid approach taking visual and quantitative (SUVR) results into account. APOE E4 carrier status was available in 613 of the cohort participants. Relationship between age, sex, APOE4 carrier status, quantitative PET values and positivity status, hypercholesterolemia/hyperlipidemia, hypertension, Type 2 diabetes, and each of the variables of interest (MH, SS and WML) was studied by fitting linear models. Results: The presence of MH ranged from 5.8% in the younger group (60–65 years old) to 16.3% in the older group (80–85). Overall, only 1.3% had ≥4 MH. Similarly, the presence of SS ranged from 0.6% in the younger group to 2.2% in the older group. Overall, 0.9% had one area of SS and 0.4% had more than one. 4.2% of subjects with MH had SS. The presence of WMH increased from 47.1% in the 60–65 age group to 79.3% in the oldest (80–85) age group. Average ARWMC severity ranged from 1.0 (SD=1.3) in younger participants to 3.0 (2.8) in the older group and lesion volume (in mL) from 1.9 (1.3) to 6.7 (6.3). Linear models confirmed that older age was significantly associated (p<0.001) with the presence of MH, irrespective of sex, PET status (either dichotomized as positive or negative, or using SUVR value) and APOE4 carrier status. In the entire cohort, the number of MH was significantly associated with male sex and older age (p<0.05). Only age remained significantly associated (p<0.05) in the sample where PET was available (n=1076). In the sample where APOE4 status was available (n=613), age and hypercholesterolemia/hyperlipidemia were significantly associated (p<0.05) with the number of MH, and hypercholesterolemia/hyperlipidemia was significantly associated (p=0.04) with the presence of ≥4 MH. In the entire cohort, the presence of SS was positively associated with male sex and older age and the presence of Type 2 diabetes (p<0.05). This association was no longer seen in the smaller cohorts where PET or APOE4 status were available. Severity of WML was associated with age (p<0.001), sex (p<0.01) and hypertension (p<0.001). There was no evidence of ARIA-E in this study. Other MRI abnormalities, including infarcts, vascular malformations/aneurysms, meningiomas and other space occupying lesions and encephalomalacia, were found in 4% of participants, with no category exceeding 1%. Conclusions: The CHARIOT-PRO data provide valuable insights into the prevalence of microhemorrhages, superficial siderosis and white matter lesions in a large sample of cognitively asymptomatic older adults. Microhemorrhages may be present in up to 16.3% and superficial siderosis up to 2.2%, in the older old adults, with age being the main predictor. Further research should elucidate their potential role in subsequent cognitive trajectories and on risk for ARIA-H and ARIA-E, as adverse occurrences of therapeutic trials.
LP60- PREDICTION OF LONGITUDINAL CHANGE IN CDR SUM OF BOXES USING A CORTICAL MICROSTRUCTURAL AD SIGNATURE FROM BASELINE DIFFUSION MRI. G. Ridgway1, M. Torso1, D. Tzaferou1, M. Valotti1, I. Hardingham1, S. Chance1, & Alzheimer’s Disease Neuroimaging Initiative2(1. Oxford Brain Diagnostics Ltd — Oxford (United Kingdom), 2. Alzheimer’s Disease Neuroimaging Initiative (United States))
Background: The Clinical Dementia Rating (CDR; PMID:9447441) is widely used in the staging of Alzheimer’s disease; it comprises 6 domains, each rated on a 5-point scale (0, 0.5, 1, 2, 3), combined to give the global CDR on the same scale. CDR Sum of Boxes (CDR-SB) adds the scores on the 6 domains to give a more granular score from 0 to 18, and is a very common endpoint in clinical trials, for example being the primary endpoint in the recently reported phase 3 Clarity AD trial of Lecanemab. There can be substantial inter-individual variation in annualised change in CDR-SB, and the ability to predict CDR-SB change from screening or baseline data could inform patient selection or stratification, and might have clinical utility. Diffusion MRI can be used to assess the microstructure of the cerebral cortex, and has been shown to relate to microstructural measures from histology (PMID:31355989). In past work, we have shown the utility of novel cortical diffusivity measures to detect neurodegeneration in AD (PMID:33174658) and to predict subsequent macrostructural atrophy (DOI:10.14283/jpad.2022.59). Objectives: Prior work has investigated the prediction of CDR-SB change using MRI measures including AD signature regional summaries of cortical thickness (Hibar et al., 2021, CTAD). Here, we develop a novel cortical microstructural AD signature using diffusion MRI, and evaluate its ability to predict subsequent longitudinal progression in CDR-SB. Methods: Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative, including T1-weighted and diffusion MRI, CDR, and Elecsys CSF biomarkers of amyloid beta 42 and p-tau 181. Subjects were selected to have CSF samples within 180 days of MRI. Diffusion MRI and T1-weighted MRI were processed using FSL, FreeSurfer, and proprietary algorithms, to produce three novel cortical diffusivity measures (AngleR — the angle between the principal diffusion direction and the radial minicolumnar direction within the cortex; ParlPD — the principal diffusion component parallel to the minicolumnar direction; and PerpPD+ — the components of diffusion perpendicular to the minicolumnar direction; PMID:31355989). Imaging metrics were summarised by region using the Desikan-Killiany parcellation (PMID:16530430). To derive regional AD signatures, a conservatively low threshold (0.0198) for the ptau181/Abeta42 ratio was applied to define a restricted group of biomarker-negative cognitively normal (CN-) participants (n=158), and a conservatively high threshold (0.028) was applied to define a confidently biomarker-positive AD+ group (n=66). These groups were contrasted, adjusting for age, gender, total intracranial volume (TIV), diffusion MRI head movement, scanner model, number of diffusion volumes, and diffusion TE/TR ratio. Effect-sizes from left and right hemispheres were averaged, and the top 8 regions for each metric (AngleR, ParlPD, PerpPD+ and cortical thickness) were used to define AD signatures. Average values of the metrics within their signature regions were calculated at baseline, together with hippocampal volume as a fraction of TIV as a comparator. Annualised change in CDR-SB was calculated for a subset of 201 participants with longitudinal CDR-SB available over a nominal 12m or 24m interval. Delta CDR-SB was related to the five baseline metrics, adjusting for age, gender, scanner model, number of diffusion directions and the diffusion voxel volume. The 201 participants were categorised using an intermediate ptau181/Abeta42 threshold of 0.021 into 80 CN-, 32 CN+, 31 MCI-, 36 MCI+, 4 AD- and 18 AD+. Results: The cortical thickness signature comprised entorhinal, superior temporal, parahippocampal, middle temporal, inferior parietal, inferior temporal, fusiform, and precuneus. Compared to a previously published six-region AD signature from the Mayo Clinic (PMID:28050342), five regions overlap, the present signature adds superior temporal and precuneus, and replaces the angular gyrus with the broader inferior parietal region. The original AD signature for cortical thickness (PMID:18632739) differs more substantially, but still contains multiple temporal lobe regions, precuneus and angular gyrus. Considering the four sets of eight regions across the different signatures, 19 unique regions are featured, with the following regions present in three of the four signatures: entorhinal, fusiform, inferior temporal. Across the 201 participants with longitudinal CDR-SB, partial correlations of CDR-SB changes with all considered metrics were significant; in ascending order of magnitude: ParlPD (r = 0.145, p = 0.042), AngleR (r = 0.299, p < 0.001), cortical thickness (r = -0.457, p < 0.001), hippocampal volume fraction (r = -0.461, p < 0.001), and PerpPD+ (r = 0.475, p < 0.001). In the 67 MCI participants, PerpPD+ was again the most strongly correlated (r = 0.39, p = 0.002) followed by cortical thickness (r = -0.365, p = 0.004) and hippocampal volume fraction (r = -0.312, p = 0.014), with the other metrics nonsignificant. In the 36 MCI+ individuals, only PerpPD+ was able to predict CDR-SB change with statistical significance (r = 0.438, p = 0.014). Conclusion: A cortical microstructural measure — PerpPD+ — calculated from baseline diffusion MRI and summarised over bespoke microstructural AD signature regions, predicts subsequent progression in the widely used outcome measure CDR-SB, more strongly than an equivalently-derived cortical thickness signature or hippocampal volume fraction.
LP61- CORTICAL MICROSTRUCTURAL MEASURES FROM DIFFUSION MRI CORRELATE WITH COGNITIVE COMPOSITE SCORES AND PREDICT THEIR LONGITUDINAL CHANGES. M. Torso1, G. Ridgway1, M. Valotti1, I. Hardingham1, S. Chance1, & Alzheimer’s Disease Neuroimaging Initiative2(1. Oxford Brain Diagnostics Ltd — Oxford (United Kingdom), 2. Alzheimer’s Disease Neuroimaging Initiative (United States))
Background: Neuropsychological assessment contributes greatly to characterizing dementia forms associated with neurodegenerative processes, identifying the most salient and earliest cognitive deficits, and suggesting the underlying neuropathology. In individuals with suspected Alzheimer’s Disease, the neuropsychological assessment is crucial to assessing the presence and severity of memory deficits associated with a memory complaint, assessing the presence of cognitive deficits that involve other cognitive domains (e.g. executive functions, language, visual-spatial), and contributing to staging and monitoring the progression using standardized tests. As shown by previous lines of evidence, neuropsychological batteries can differ across studies and cohorts, and for valid and reliable diagnostic procedures, harmonized composite scores are necessary to allow the comparison of participants’ performances acquired in different centres. Some MRI measures focused on cortical changes at macrostructural level (e.g. cortical volume, cortical thickness) have been proposed to investigate the cortical alterations underlying memory deficits in Alzheimer’s patients, while the measures of cortical microstructural changes are still largely unexplored. Objectives: The main goal of the present study was to explore the ability of a novel set of cortical diffusivity metrics to detect the cortical microstructural changes underlying memory deficits and to predict longitudinal changes in Memory scores. Methods: Data of 113 participants (46 cognitively normal, 44 Mild Cognitive Impairment and 23 AD) with T1-weighted, diffusion MRI and memory composite scores, were obtained from the Alzheimer’s Disease Neuroimaging Initiative. For each participant, the memory composite score (1) was used as a measure of memory deficit. Structural T1-weighted and diffusion MRI (dMRI) were used to calculate three novel cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+) (2). Cortical mean diffusivity (MD) was also assessed. Whole-brain and regional cortical values were calculated using the Desikan-Killiany parcellation (3). The memory composite scores and diffusivity measures (whole brain and regional) at baseline were used to investigate the association between cortical macrostructural changes and memory deficits. To test the hypothesis that baseline cortical diffusivity values can predict change in memory composite scores over approximately 24 months, the annual change in composite memory score was computed as Δ = (follow up value — baseline value) / (time-interval). Associations between the memory composite scores and the cortical diffusivity measures were evaluated with partial correlation analysis, adjusting for age, sex, scanner model, number of diffusion directions and dMRI voxel volume. Only results surviving False Discovery Rate (FDR) correction were reported. Results: At baseline, across all participants, statistical analysis showed significant associations between all whole-brain cortical diffusivity measures and memory composite scores (AngleR: pFDR= 0.036, η2= 0.045; ParlPD: pFDR= 0.027, η2= 0.053; MD: pFDR= 0.005, η2= 0.085) with PerpPD+ showing the strongest association (pFDR <0.001, η2= 0.138). Regional analysis showed a significant bilateral pattern of association between PerpPD+ values and baseline composite score values that include the main cortical regions involved in memory processes, such as entorhinal (left: pFDR <0.001, η2= 0.401; right: pFDR= 0.003, η2= 0.313), fusiform (left: pFDR <0.001, η2= 0.477; right: pFDR <0.001, η2= 0.424), inferior temporal (left: pFDR <0.001, η2= 0.401; right: pFDR <0.001, η2= 0.387), middle temporal (left: pFDR <0.001, η2= 0.405; right: pFDR= 0.005, η2= 0.303), parahippocampal (left: pFDR <0.001, η2= 0.479; right: pFDR= 0.014, η2= 0.248), precuneus (left: pFDR <0.001, η2= 0.481; right: pFDR= 0.004, η2= 0.301) and superior temporal (left: pFDR= 0.002, η2= 0.326; right: pFDR= 0.027, η2= 0.220). Investigating the prediction of longitudinal changes in memory composite using baseline regional cortical diffusivity measures revealed a significant PerpPD+ bilateral temporal pattern. The most significant regions associated with longitudinal memory changes were: bilateral banks of the superior temporal sulcus (left: pFDR <0.001, η2= 0.403; right: pFDR= 0.005, η2= 0.312), entorhinal (left: pFDR= 0.001, η2= 0.352; right: pFDR= 0.005, η2= 0.319), fusiform (left: pFDR <0.001, η2= 0.385; right: pFDR <0.001, η2= 0.383), inferior temporal (left: pFDR <0.001, η2= 0.428; right: pFDR <0.001, η2= 0.485), insula (left: pFDR <0.001, η2= 0.357; right: pFDR= 0.019, η2= 0.263) and parahippocampal (left: pFDR <0.001, η2= 0.344; right: pFDR= 0.032, η2= 0.229). Conclusion: Novel cortical diffusivity measures can detect microstructural alterations underlying memory deficits across the Alzheimer’s continuum. Baseline cortical diffusivity predicts subsequent decline in memory, with potential utility for clinical trial stratification or subgrouping, as well as potential utility in clinical practice. References: 1; Crane, P., Carle, A., Gibbons, … & Mungas, D. (2012). Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Brain Imaging and Behavior, 6:502–516. 2. McKavanagh, R., Torso, M., Jenkinson, M., … & Chance, S. (2019). Relating diffusion tensor imaging measurements to microstructural quantities in the cerebral cortex in multiple sclerosis. Human Brain Mapping, 40:4417–4431. 3. Desikan, R., Ségonne, F., Fischl, B., … & Killiany, R. (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage, 31:968–980.
LP62- APOEΕ4 CARRIERSHIP AND AB POSITIVITY FOR THE POPULATIONAL ENRICHMENT OF CLINICAL TRIALS TESTING DRUG EFFECTS ON TAU TANGLES. J.P. Ferrari-Souza1, P. Ferreira1, B. Bellaver1, G. Povala1, F. Lussier1, D. Leffa1, C. Tissot2, J. Therriault2, T. Karikari3, J.P. Soucy2, S. Gauthier2, E. Zimmer4, P. Rosa-Neto2, T. Pascoal1(1. University of Pittsburgh — Pittsburgh (United States), 2. McGill University — Montreal (Canada), 3. University of Gothenburg — Mölndal (Sweden), 4. Universidade Federal do Rio Grande do Sul — Porto Alegre (Brazil))
Background: Tau tangles deposition is a potential secondary outcome for clinical trials in Alzheimer’s disease (AD). The use of enrichment strategies is of paramount importance in selecting the individuals with the highest probability of AD-related progression in typical clinical trial time frames. Although both amyloid-β (Aβ) pathology and the apolipoprotein E ε4 (APOEε4) genotype have been shown to accelerate tau accumulation, it is still not clear whether assessing both APOEε4 carriership and Aβ positivity statuses is a useful strategy to enrich AD clinical trials using tau positron emission tomography (PET) as an outcome. Objective: Here, we investigated whether APOEε4 carriership is associated with higher longitudinal rates of tau tangles accumulation in a group of Aβ positive cognitively impaired (CI) individuals. Methods: We studied 63 CI (Clinical Dementia Rating ≥ 0.5) individuals across the AD continuum from the McGill Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, PET for Aβ ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as an additional follow-up tau-PET scan. All included participants were Aβ positive, which was determined as global [18F]AZD4694 SUVR ≥ 1.55 (24 Centiloid units). We assessed [18F]MK6240 SUVR in the temporal meta-ROI, a common summary measure of tau-PET. We calculated the annual rate of change in tau-PET SUVR between baseline and follow-up as follows: (follow-upSUVR — baselineSUVR) / Δtime. We compared biomarker changes between APOEε4 carriers and noncarriers using regression models adjusted for age, sex, and clinical status. Additionally, we estimated the sample sizes needed for trials testing a 25% drug effect with 80% power at alpha level 0.05 on reducing tau-PET accumulation by using Aβ-PET alone or Aβ-PET in combination with APOEε4 genotype for participant selection. Results: The mean (standard deviation [SD]) age of participants was 68.9 (8.1) years, and the mean (SD) follow-up time was 2.0 (0.6) years. We found that APOEε4 carriers had significantly higher rates of tau-PET SUVR increase in the temporal meta-ROI compared to APOEε4 carriers (fold change = 6.4, P = 0.005). The use of Aβ positivity alone for population enrichment of a clinical trial focusing on CI individuals would require a sample size of 1,175 individuals per study arm to test a 25% drug effect on tau-PET accumulation. Notably, a similar clinical trial with a population enrichment strategy using Aβ positivity plus APOEε4 carriership would require a sample size of as few as 367 individuals per study arm (reduction of 69% in relation to using only Aβ positivity) to test the same drug effect. Conclusion: Our results reveal that APOEε4 carriership is associated with higher rates of tau tangles accumulation in CI individuals who are Aβ positive. Clinical trials testing drug effects on tau tangles deposition may benefit from assessing both APOEε4 carriership and Aβ positivity statuses as enrollment criteria to select individuals at higher risk of fast tau accumulation, resulting in a more cost-effective clinical trial.
CLINICAL TRIALS: BIOMARKERS INCLUDING PLASMA
P90- IMPACTS OF AMYLOID BURDEN ON LONGITUDINAL COGNITIVE DECLINES IN SUBJECTIVE COGNITIVE DECLINE: A PROSPECTIVE COHORT STUDY. Y.J. Hong1, D.W. Yang2, S. Ho2, K. Park3, J.H. Jeong4, K.H. Park5, S. Kim6, M.J. Wang6, S.H. Choi7, S. Lee8(1. Uijeongbu St. Mary’s Hospital — Uijeongbu (Korea, Republic of), 2. Seoul St. Mary’s Hospital — Seoul (Korea, Republic of), 3. Pusan National University Yangsan Hospital — Yangsan (Korea, Republic of), 4. Ewha Womans University Seoul Hospital — Seoul (Korea, Republic of), 5. Gachon University Gil Hospital — Incheon (Korea, Republic of), 6.Seoul National University College Of Medicine, Seoul National University Bundang Hospital — Seongnam (Korea, Republic of), 7.Inha University School Of Medicine — Incheon (Korea, Republic of), 8.Neolab Convergence Inc. — Seoul (Korea, Republic of))
Background: Subjective cognitive decline (SCD) is known to be a risk group of Alzheimer’s disease (AD), however, the rates of cognitive declines are variable according to underlying pathologies. We planned a longitudinal observational study to assess baseline characteristics and biomarkers related with clinical progressions in elderly participants with SCD during 24 months. Objectives: Our study aimed to assess whether SCD participants show different cognitive and biomarker trajectories according to baseline amyloid depositions. Methods: This study is a part of a prospective longitudinal cohort study named ‘CoSCo’. CoSCo study is being conducted in 6 centers in South Korea and enrolled SCD participants between May 2018 and December 2021. A total of 120 elderly participants with SCD were enrolled at baseline. Individuals who were diagnosed as SCD were eligible for the study. Inclusion criteria are as follows: 1) aged 60 years old or older, 2) complaint of persistent cognitive decline, 3) normal performance in detailed neuropsychological tests named Seoul neuropsychological screening battery (SNSB) version II, 4) performance range between 7 to 50 percentile (adjusted by age, gender, and education) of the verbal memory delayed recall test (Seoul Verbal Learning Test, SVLT). Regional volumetry, quantitative amyloid burden represented by standardized uptake value ratio (SUVR) were measured. We divided participants into 2 groups: group 1) SCD with amyloidosis (global SUVR ≥1.391) and group 2) SCD without amyloidosis (global SUVR<1.391). We compared cognitive and atrophic changes during 24 months between the two groups. Results: Finally 107 participants completed the study. Follow-up completed participants (n= 107) were not different from dropped out subjects (n= 13) in regards of baseline characteristics except the education. Baseline cognitive scores were not different between the groups except the SVLT delayed recall scores. After 24 months, SVLT delayed recall scores, a part of frontal executive tests showed more cognitive declines in Aβ-positive SCD participants. Baseline left entorhinal volumes and global SUVR values were relevant factors related with the cognitive declines. In regards of neurodegenerative changes, hippocampal and left entorhinal atrophic changes were more prominent in Aβ-positive SCD participants. Conclusion: Aβ-positive SCD participants showed more cognitive declines and medial temporal atrophic changes after 24 months. Baseline entorhinal volumes and amyloid burden were relevant factors related with cognitive declines in SCD during the study period.
P91- PREDICTIVE VALUE OF PLASMA P-TAU181 VERSUS BASELINE AMYLOID-PET FOR LONGITUDINAL AMYLOID ACCUMULATION IN ASYMPTOMATIC ALZHEIMER’S DISEASE. R. Vandenberghe1, S. De Meyer1, E. Luckett1, J.E.R.O.E. Vanbrabant2, J. Schaeverbeke1, M. Reinartz1, I. Cleyne3, E. Stoops2, E. Vanmechelen2, K. Van Laere4(1. Alzheimer Research Centre Ku Leuven, Leuven Brain Institute — Leuven (Belgium), 2. Adx Neurosciences — Zwijnaarde (Belgium), 3. Laboratory For Complex Genetics — Leuven (Belgium), 4. Nuclear Medicine Service, University Hospitals Leuven — Leuven (Belgium))
Background: The dynamic phase of asymptomatic Alzheimer’s Disease (AD), characterized by the phase of rising cortical amyloid load, is a key target for early intervention. This phase of amyloid accumulation opens perspectives for more efficacious amyloid lowering intervention. Objectives: In this study we compared the ability of baseline plasma p-tau181 and baseline amyloid-β (Aβ)-PET to predict longitudinal amyloid accumulation in community-recruited cognitively unimpaired (CU) elderly, along with age, an AD polygenic risk score and baseline cognition. Methods: Plasma p-tau181 was quantified with a novel phospho-specific Simoa assay (ADx NeuroSciences, Ghent) in a cohort of 77 CU elderly (baseline age[mean] = 70 years, 48% female, 45% APOE-ε4 carriers, 13% Aβ-PET positive at baseline) participating in the Flemish Prevent AD Cohort KU Leuven, a prospective community-recruited longitudinal observational cohort study. Plasma sampling, amyloid-β (Aβ)-PET ([18F]flutemetamol or [11C] PiB) and an episodic memory test (average Buschke Selective Reminding total retention /12) were performed at baseline and Aβ-PET was repeated on average 4.97 years later (SD: 2.01, range 0.94 – 10.46 years). The Aβ-PET rate of change was calculated by dividing the difference between baseline and follow-up tracer uptake in Centiloids (CLs) by the time interval between scans (in years). A polygenic risk score (PRS) for AD was calculated with exclusion of the APOE region (chromosome 19 45–48.8 Mb) and SNP inclusion threshold of 5x10-8 with the addition of the weighted sum of directly genotyped APOE-ε2 and -ε4 alleles. Individuals with an Aβ-PET rate of change that exceeded the median Aβ-PET rate of change of the subset (N = 41) that remained Aβ-PET negative (CL < 23.5) at both time points by at least 1.5 standard deviations, were considered to be amyloid accumulators. The ability of plasma p-tau181, baseline Aβ-PET as well as a demographic model of age and PRS to predict longitudinal amyloid accumulation was determined through ROC analyses and compared using DeLong tests. Spearman correlations between longitudinal amyloid accumulation, baseline plasma p-tau181, baseline amyloid load, baseline episodic memory, age, and PRS were calculated. Standard scores of all variables were entered into a hierarchical regression analysis in a stepwise manner based on correlation strength. Results: Fourteen (18%) subjects fulfilled the criterion of amyloid accumulators. Baseline plasma p-tau181 (AUC = 0.76) predicted longitudinal amyloid accumulation equally well as baseline Aβ-PET load (AUC = 0.74, P = 0.84). Both baseline plasma p-tau181 and baseline Aβ-PET load were better predictors of longitudinal amyloid accumulation than the combination of age and PRS (P = 0.01 for p-tau181 and P = 0.03 for Aβ-PET). However, only baseline plasma p-tau181 (Spearman’s rho = 0.27, P = 0.02) and not baseline Aβ-PET load (Spearman’s rho = 0.18, P = 0.12) correlated significantly with longitudinal amyloid accumulation. Since plasma p-tau181 demonstrated the strongest correlation with longitudinal amyloid accumulation out of all tested variables, it was used as a sole predictor of amyloid accumulation in the base regression model. This base model (F(1,75) = 7.5, P = 0.008) explained 27% of the variance (R2) in longitudinal amyloid accumulation. Stepwise addition of baseline amyloid load, baseline episodic memory score, PRS score or age did not further improve the model. Conclusion: Plasma p-tau181 measured with the novel phospho-specific Simoa assay is able to discriminate amyloid accumulators in the asymptomatic phase of AD equally well as a baseline Aβ-PET scan and superior to the combination of age and PRS. Conflicts of interest: The plasma p-tau181 assay was performed without cost by ADx Neurosciences. RV’s institution has an MTA (RV as PI) with ADx Neurosciences. The 18F flutemetamol tracer delivery for the baseline scan was delivered free of cost by GEHC. RV was PI of the 18F flutemetamol phase 1 and 2 clinical trials. RV’s institution has Clinical Trial Agreements (RV as PI) with Biogen, J&J, Novartis, NovoNordisk,Roche, and UCB.
P92- BLOOD BIOMARKERS FOR ALZHEIMER’S DISEASE TO PREDICT DEMENTIA RISK IN A LARGE CLINIC-BASED COHORT: IMPLICATIONS FOR CLINICAL TRIALS. V. Planche1, V. Bouteloup1, G. Chêne1, C. Dufouil1(1. Bordeaux University — Bordeaux (France))
Background: Blood biomarkers for Alzheimer’s disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. It is now proposed to use them to select patients for clinical trials in early AD. To achieve this goal, blood biomarkers still need to be tested in large multicentric unselected prospective clinic-based cohorts where patients present with a large spectrum of complaints or mild cognitive deficits. Methods: The MEMENTO cohort enrolled 2323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, brain MRI and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aβ42/40 ratio, total-tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period. Results: Overall, 2277 individuals had at least one baseline blood biomarker available (n=357 for CSF subsample, n=649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total-tau were mildly correlated with their equivalence in the CSF (r=0.33 to 0.46, p<0.0001) and were associated with amyloid-PET status (p<0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (AUC=0.74 [95%CI=0.69–0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aβ42/40 was less efficient than CSF Aβ42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index=0.73 [95%CI=0.69–0.77]); its accuracy was higher in patients with CDR=0 (c-index=0.83 [95% CI=0.70;0.97]) than in patients with CDR=0.5 (c-index=0.70 [95% CI=0.66;0.74]). A “clinical” reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index=0.88 [95%CI=0.86−0.91] and performance increased to 0.90 [95%CI=0.88;0.92] when adding blood p181-tau+Aβ42/40. A “research” reference model (clinical model+ApoE genotype and AD-signature on MRI) had a c-index=0.91 [95%CI=0.89–0.93] increasing to 0.92 [95%CI=0.90;0.93] when adding blood p181-tau+Aβ42/40. Conclusion: In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors. In the context of a clinical trial, they thus seem useful for easily selecting patients in the AD continuum, but do not seem suitable for selecting progressors. The authors declare that they have no competing interests related to the present work.
P93- INDEPENDENT EFFECT OF BODY MASS INDEX VARIATION ON AMYLOID-B POSITIVITY. S.H. Kang1, J.H. Kim2, K. Kim2, S.W. Seo3(1. Department Of Neurology, Korea University Guro Hospital, Korea University College Of Medicine — Seoul (Korea, Republic of), 2. Department Of Digital Health, Saihst, Sungkyunkwan University — Seoul (Korea, Republic of), 3. Department Of Neurology, Samsung Medical Center, Sungkyunkwan University School Of Medicine — Seoul (Korea, Republic of))
Background: The relationship of body mass index (BMI) changes and variability with amyloid-β (Aβ) deposition remained unclear, although there were growing evidence that BMI is associated with the risk of developing cognitive impairment or AD dementia. Objectives: To determine whether BMI changes and BMI variability affected Aβ positivity, we investigated the association of BMI changes and BMI variability with Aβ positivity, as assessed by PET in a non-demented population. Methods: We retrospectively recruited 1,035 non-demented participants ≥50 years of age who underwent Aβ PET and had at least three BMI measurements in the memory clinic at Samsung Medical Center between August 2015 and August 2020. To investigate the association between BMI change and variability with Aβ deposition, we performed multivariable logistic regression. Further distinctive underlying features of BMI subgroups were examined by employing a cluster analysis model. Results: Decreased (odds ratio [OR] = 1.68, 95% confidence interval [CI] 1.16 to 2.42) or increased BMI (OR = 1.60, 95% CI 1.11 to 2.32) was associated with a greater risk of Aβ positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI variability. A greater BMI variability (OR = 1.73, 95% CI 1.07 to 2.80) was associated with a greater risk of Aβ positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI change. We also identified BMI subgroups showing a greater risk of Aβ positivity. Conclusions: Our findings suggest that participants with BMI change, especially those with greater BMI variability, are more vulnerable to Aβ deposition regardless of baseline BMI. Furthermore, our results may contribute to the design of strategies to prevent Aβ deposition with respect to weight control.
P94- PHASE 2 STUDY REVEALS AN ADEQUATE PK/PD RELATIONSHIP OF BOSUTINIB IN DEMENTIA WITH LEWY BODIES AND CLEARS THE PATH FOR LARGER PHASE 2/3 INVESTIGATIONS. C. Moussa1, F. Pagan2, T.Y. Yasar2, H. Michaleine1, T. Raymond1, A. Jaeil1(1. Georgetown University Medical Center — Washington (United States), 2. Medstar Georgetown Hospital — Washington (United States))
Background: Bosutinib (Bosulif, Pfizer) is a potent tyrosine kinase (Abl/SRC) inhibitor that is FDA-approved at 500mg oral daily dose for leukemia. The effects of bosutinib were investigated in Dementia with Lewy Bodies (DLB). We investigated bosutinib, 100mg, which is equivalent to the lowest effective intraperitoneal daily dose (5mg/kg) in pre-clinical studies. Bosutinib was investigated in several models of neurodegeneration and it was shown to facilitate clearance of alpha-synuclein and other neurotoxic proteins via autophagy, protect dopaminergic neurons and improve motor and cognitive behavior in animals. Objectives: To investigate safety, pharmacokinetics (PK), pharmacodynamics (PD) and biomarkers effects of the lowest effective dose of Bosutinib in Dementia with Lewy Bodies (DLB). Methods: A single center, Phase 2, randomized, double-blind, placebo-controlled study primarily investigated safety and PK/PD relationship of 12-week oral treatment of bosutinib,100mg. Biomarkers and clinical outcomes were exploratory. Results: Approximately 120 subjects were approached, 39 were screened, 13 did not meet inclusion criteria and 26 were randomized and included male and female (12:1) in bosutinib and male (13) in placebo with average age 72.94±8.8 (year±SD). There was no serious adverse events (SAEs) and no difference in AEs and no dropouts. Bosutinib, 100mg, was detected in the cerebrospinal fluid (CSF) and inhibited both Abl and Src. Bosutinib significantly reduced CSF alpha-synuclein (p=0.023) and the ratio of oligomeric/total alpha-synuclein (p=0.045) compared to placebo. There was also significant decrease in plasma oligomeric alpha-synuclein (p=0.04) and ptau181/Aβ42 (p=0.03). Bosutinib significantly (p=0.034) improved activities of daily living (ADCS-ADL-MCI) compared to placebo. Conclusion: This study showed that bosutinib is safe and enters the brain. Bosutinib, 100mg, inhibited Abl/Src indicting dual target engagement, reduced brain alpha-synuclein and improved activities of daily living, suggesting that this is lowest effective dose (100mg) in DLB. This study is underpowered (by design) but the data will guide adequately powered future studies of a higher dose range of bosutinib (100–400mg) over longer time (6 months) in DLB. Funding: This work was supported by the Alzheimer’s Association Part the Cloud grant PTC-19-604235 to Charbel Moussa. Disclosures: Charbel Moussa is an inventor on a Georgetown University (GU) US and International Patent to use Bosutinib in neurodegenerative diseases, including alpha-synucleinopathies. GU exclusively licensed Bosutinib use patent to KeiffeRx. Charbel Moussa and Fernando Pagan are co-founders and shareholders of KeiferX, and Charbel Moussa and Jaeil Ahn are paid consultants to KeifeRX.
P95- BIOMARKER ASSESSMENTS FROM A PHASE 2, OPEN-LABEL STUDY OF NE3107 IN PATIENTS WITH COGNITIVE DECLINE DUE TO DEGENERATIVE DEMENTIAS. J. Haroon1, K. Mahdavi1,2, K. Jordan1, E. Rindner1, M. Zielinski1, V. Venkatraman1,2, D. Goodenowe3, K. Hofmeister3, C. Ahlem4, C. Readin4, J. Palumbo4, B. Poura5, S. Jordan1,2(1. The Regenesis Project — Santa Monica (United States), 2. Synaptec Network — Santa Monica (United States), 3. Prodrome Sciences USA LLC — Temecula (United States), 4. Biovie Inc. — Carson City (United States), 5. Pourat MD — Beverly Hills (United States))
Background: Chronic neuroinflammation and insulin resistance (IR) contribute to the pathophysiological development of Alzheimer’s disease (AD), including the accumulation of amyloid-β (Aβ) plaques and phosphorylated tau protein (P-tau). Aβ and P-tau subsequently activate pro-inflammatory pathways, including mitogen-activated protein kinase (MAPK/ERK) signaling and tumor necrosis factor-α (TNFα) release, to perpetuate inflammation and accelerate neurodegeneration. Several other cytokines, including interleukin (IL)-1β, IL-6, IL-12, and tumor growth factor β (TGFβ), have been implicated in AD pathophysiology. Additionally, brain IR lowers glucose metabolism in neurons, leading to neuronal dysfunction and death. Insulin-sensitizing and anti-inflammatory agents may be beneficial in improving brain glucose metabolism and cognitive function, but their use may be limited due to poor blood-brain permeability or safety concerns. NE3107 is an oral, blood-brain-permeable agent that is well tolerated, selectively inhibits several inflammatory mediators (via MAPK/ERK regulation), and improves insulin signaling. Across several clinical studies, NE3107 increased insulin sensitivity and restored metabolic homeostasis in patients with type 2 diabetes and inflammation, and it was also shown to alter inflammatory biomarkers that have been associated with cognitive decline. Objectives: The present Phase 2, open-label study was designed to evaluate the potential efficacy of NE3107 in patients with mild cognitive impairment (MCI) or mild dementia using AD and inflammatory biomarkers, changes in glucose metabolism, cognitive performance testing, and neuroimaging endpoints. Methods: Twenty-three participants were enrolled and received 20-mg oral NE3107 twice daily for 3 months. Participants were between 50–89 years old with MCI or mild dementia (Quick Dementia Rating Scale [QDRS] score cutoff range: 1.5–12.5; Clinical Dementia Rating [CDR] score range: 0.5–1). Primary endpoints evaluated neurophysiological health using multi-modal brain MRIs at baseline and treatment termination. Secondary endpoints evaluated changes in glucose metabolism using markers, such as hemoglobin A1c (HbA1c) and urinary glucose levels; changes in inflammatory markers, including high-sensitivity C-reactive protein, erythrocyte sedimentation rate, TGFβ, and several other cytokines, such as TNFα, IL-1β, IL-6, and IL-12; and changes in cognitive performance between baseline and treatment termination. Additionally, AD biomarkers were evaluated at baseline and treatment termination using lumbar puncture to measure Aβ42 and tau protein levels. Results: Participants had a mean age of 71.6 (SD = 9.63) years and 15 (65%) were females. At baseline, the mean QDRS score was 5.07, 18 (78%) participants had a CDR score of 0.5, and 5 (22%) participants had a CDR score of 1. Study findings related to changes in glucose metabolism and AD and inflammatory biomarkers will be presented at the conference. Conclusion: Chronic neuroinflammation and IR are thought to fuel AD progression and contribute to physiological impairment and decreased cognitive performance. Elements of AD neuropathology may then exacerbate IR and promote a perpetual state of low-grade inflammation. This study assessed key biomarkers associated with AD to provide an exclusive set of mechanistic insights into dementia and the potential therapeutic efficacy and anti-inflammatory effects associated with NE3107 treatment in patients with MCI. Funded by: BioVie Inc. Disclosures: JH, KM, KJ, ER, MZ, VV, and SJ have received grant support from BioVie Inc. DG has nothing to disclose. KH has nothing to disclose. BP has nothing to disclose. CA, CR, and JP are employees of BioVie Inc.
P96- ROBUSTNESS OF CEREBROSPINAL FLUID (CSF) AMYLOID-B 1–42/AMYLOID-B 1–40 (AB42/AB40) AND PHOSPHORYLATED TAU/AMYLOID-B 1–42 (PTAU/AB42) BIOMARKER RATIOS IN CLASSIFICATION OF AMYLOID POSITRON EMISSION TOMOGRAPHY (PET) POSITIVITY IN ROUTINE CLINICAL USE. C. Logan1, H. Schinke1, C. Rabe2, M. Simon3, O. Hansson4,5, K. Blennow6,7, E. Stomrud4,5(1. Roche Diagnostics Gmbh — Penzberg (Germany), 2. Genentech, Inc., — South San Francisco (United States), 3. Roche Diagnostics International Ltd — Rotkreuz (Switzerland), 4. Clinical Memory Research Unit, Department Of Clinical Sciences Malmö, Lund University — Malmö (Sweden), 5. Memory Clinic, Skåne University Hospital — Malmö (Sweden), 6. Department Of Psychiatry And Neurochemistry, Institute Of Neuroscience And Physiology, The Sahlgrenska Academy At The University Of Gothenburg — Mölndal (Sweden), 7. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital — Mölndal (Sweden))
Background: Cerebrospinal fluid (CSF) amyloid-β 1–42/amyloid-β 1–40 (Aβ42/Aβ40) and phosphorylated tau (pTau)/Aβ42 biomarker ratios have been shown to be highly concordant with amyloid positron emission tomography (PET) in people presenting with cognitive impairment (CI). The robustness of a biomarker assesses how variability impacts clinical decision-making; such variability is expected in a prospective routine clinical setting. In practice, there is documented inter-center variability in the measurement of CSF Aβ42 and Aβ401 that may limit utility of the Aβ42/Aβ40 ratio in routine clinical use. Previous studies suggested that the CSF pTau/Aβ42 ratio may have greater robustness than Aβ42/Aβ402, but this has not yet been investigated in the intended use population for the diagnostic test. Objective: To evaluate and compare the robustness of CSF Aβ42/Aβ40 and pTau/Aβ42 ratios in the diagnostic evaluation of Alzheimer’s disease in people with mild CI (MCI) or subjective cognitive decline (SCD), with respect to the theoretical bias that may be observed in routine clinical use (±10%). Methods: This retrospective analysis utilized biomarker measurements from the Elecsys® β-Amyloid(1–42) CSF and Phospho-Tau (181P) CSF immunoassays and the research use only β-Amyloid(1–40) CSF immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) in previously frozen samples from subjects with MCI/SCD enrolled in the BioFINDER1 cohort who had a visual amyloid PET result. Summary statistics were calculated for CSF Aβ42/Aβ40 and pTau/Aβ42 ratios across all subjects and by amyloid PET status. For each biomarker ratio, biomarker status (i.e., below or above the respective cut-off value) was compared with amyloid PET status to determine positive and negative percent agreement (PPA and NPA, respectively) for the respective optimal cut-off values (Aβ42/Aβ40: 0.050 [Youden Index]; pTau/Aβ42: 0.022 [predetermined from a prior clinical study]). To estimate robustness in routine clinical use, reclassification rates and changes in PPA and NPA were calculated with respect to the maximum theoretical bias expected in routine clinical use (based on the addition of ±10% bias to each individual biomarker). Results: The mean CSF Aβ42/Aβ40 ratio in amyloid PET-positive subjects was 0.0360 (standard deviation [SD]: 0.0084) and 0.0750 (SD: 0.0187) in amyloid PET-negative subjects. For CSF pTau/Aβ42, the mean ratio in amyloid PET-positive subjects was 0.0460 (SD: 0.0196) and 0.0145 (SD: 0.0152) in amyloid PET-negative subjects. The median ratio of CSF Aβ42/Aβ40 and pTau/Aβ42 in amyloid PET-positive subjects was 0.0350 and 0.0804, respectively and in PET-negative subjects was 0.0423 and 0.0100, respectively. When comparing the performance of the biomarker ratios with amyloid PET status, for CSF Aβ42/Aβ40 (area under the curve [AUC]: 0.94), the PPA was 0.96 and NPA was 0.88; for pTau/Aβ42 (AUC: 0.95) the PPA was 0.92 and NPA was 0.89. Following adjustment for theoretical bias, up to 10.5% of people tested using CSF Aβ42 (+10%)/Aβ40 (-10%) would be reclassified (ΔPPA: -20% and ΔNPA: +4.2%) vs. 1.4% tested using pTau (-10%)/Aβ42 (+10%; ΔPPA: +3.7% and ΔNPA: -3.6%). Conclusion: Compared with CSF Aβ42/Aβ40, pTau/Aβ42 shows greater robustness to bias (±10%); therefore, in routine clinical use, pTau/Aβ42 is likely to have greater diagnostic performance and a lower risk of misclassification for people with borderline results. 1. Hansson, O et al. Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s Disease. Alzheimers Res Ther 2019;11:34. 2. Rabe, C et al. Utility of plasma Aβ1–42/Aβ1–40 as a screening tool is limited due to lack of robustness. Poster presentation at CTAD 2021; Nov 9–12. Conflict(s) of interest: CL and HS are employees of Roche Diagnostics GmbH and hold shares in F. Hoffmann-La Roche. CR is an employee of Genentech, Inc. OH has received Institutional research support from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche and consultancy/speaker fees from Alzpath, Biogen, Cerveau, Genentech, Roche, and Siemens. KB has acted as a consultant at advisory boards and data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program and has received support from the ALF-agreement (#ALFGBG-715986), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), the Alzheimer Drug Discovery Foundation (ADDF; USA; #RDAPB-201809-2016615), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), Hjärnfonden (Sweden; #FO2017-0243), the National Institute of Health (NIH; USA; grant #1R01AG068398-01), the Swedish Alzheimer Foundation (#AF-742881), the Swedish Research Council (#2017-00915), and the Swedish state under the agreement between the Swedish government and the county councils. ES has no conflict of interest.
P97- THE BIOMARKER-BASED ETIOLOGICAL DIAGNOSIS OF NEUROCOGNITIVE DISORDERS: THE EUROPEAN INTER-SOCIETAL DELPHI CONSENSUS. S. Orini1,2, C. Festari3, F. Massa4, M. Cotta Ramosino5,6, F. Nobili7,8, G.B. Frisoni9,10, E. The European Inter-Societal Consensus On The Biomarker-Based Diagnosis Of Dement11(1. Alzheimer’s Unit-Memory Clinic, Irccs Istituto Centro San Giovanni Di Dio Fatebenefratelli — Brescia, (Italy), 2. Dipartimento di Scienze Cliniche e Sperimentali, Università degli Studi di Brescia, —Brescia (Italy), 3. Laboratory Of Alzheimer’s Neuroimaging And Epidemiology, Irccs Istituto Centro San Giovanni Di Dio Fatebenefratelli, — Brescia, (Italy), 4. Department Of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal And Child Health (dinogmi), University Of Genoa — Genoa (Italy), 5. Unit Of Behavioral Neurology, Irccs Mondino Foundation, — Pavia (Italy), 6. Department of Brain and Behavioral Sciences, University of Pavia, — Pavia, (Italy), 7. Department Of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal And Child Health (dinogmi), University Of Genoa, — Genoa (Italy), 8. IRCCS Ospedale Policlinico San Martino, —Genoa (Italy), 9. Laboratory Of Neuroimaging Of Aging (lanvie), University Of Geneva, — Geneva (Switzerland), 10. Geneva Memory Center, Department of Rehabilitation and Geriatrics, Geneva University Hospitals, G — Geneva (Switzerland), 11. The European Inter-Societal Consensus On The Biomarker-Based Diagnosis Of Dementia))
Background: In the field of neurocognitive disorders, the perspective offered by new disease-modifying therapy increases the importance of etiological diagnosis. The prescription of cerebrospinal fluid analysis (CSF) and imaging biomarkers is a common practice in the clinic but is often driven more by personal expertise and local availability of diagnostic tools than by evidence of efficacy and cost-effectiveness analysis. This leads to a widely heterogeneous dementia care across Europe. Objectives: A European initiative is currently being conducted to establish a consensus for biomarker-based diagnosis of patients with mild cognitive impairment (MCI) and mild dementia. Preliminary results will be reported here, pending final consensus, which is expected to be available in late October 2022. Methods: Since November 2020, an European multidisciplinary task force of 22 experts from eleven scientific societies have been defining a diagnostic workflow for the efficient use of biomarkers. To achieve the goal, the Delphi consensus procedure was used to bridge the gaps of incomplete scientific evidence on biomarker prioritization with expert opinion and experience. The project has been in two phases. During the preparatory phase (Phase 1), we conducted a literature review on the accuracy of imaging, CSF, neurophysiological and blood biomarkers in predicting the clinical progression or in defining the underpinning aetiology of main neurocognitive disorders. Evidence was provided to support the panelists’ decisions. In phase 2, a modified Delphi procedure was implemented, based on virtual rounds. Consensus was reached at a threshold of 70% agreement, or 50%+1 when a question required rediscussion. Results: In phase 1, 2200 papers were screened. Among them, only 167 provided validated measures of biomarker diagnostic accuracy compared with a gold/reference standard or in predicting progression or conversion of MCI to the dementia stage. Fifty studies provided accuracy values for MRI, 41 for CSF, 37 for FDG-PET, 15 for DaT-imaging, 10 for amyloid-PET, 2 for tau-PET and 6 for myocardial MIBG-scintigraphy and EEG. During phase 2, six rounds have been completed. Panelists agreed on the clinical workspace of the workflow (specialist outpatient service), the stage of application (prodromal and mild dementia), and the patient age window (biomarker use strongly encouraged below 70 years and of limited usefulness over age 85). The workflow is patient-centered and features three levels of assessment (W): W1 defines eleven clinical profiles based on integrated results of neuropsychology, MRI atrophy patterns, and blood tests; W2 describes the first-line biomarkers according to W1 versus clinical suspicion; and W3 suggests the second-line biomarkers when the results of first-line biomarkers are inconsistent with the diagnostic hypothesis, uninformative or inconclusive. More specifically, CSF biomarkers are first-line in the suspect of Alzheimer’s disease (AD) and when inconsistent neuropsychological and MRI findings hinder a clear diagnostic hypothesis; dopamine SPECT/PET for those leading to suspect Lewy body spectrum. FDG-PET is first-line for the clinical profiles leading to suspect frontotemporal lobar degeneration and motor tauopathies and is followed by CSF biomarkers in the case of atypical metabolic patterns, when an underlying AD etiology is conceivable. None of these biomarkers is indicated when clinical profiles suggest vascular cognitive impairment or other neurological disorders. Conclusions: The workflow will promote consistency in diagnosing neurocognitive disorders across countries and rational use of resources. The initiative has some limitations, mainly linked to the Delphi procedure (e.g., kick-off questions were driven by the moderators, answers are driven by the Delphi panel composition, a subtle phrasing of the questions may drive answers, and 70% threshold for convergence is conventional). However, the diagnostic workflow will be able to help clinicians achieve an early and sustainable etiological diagnosis and enable the use of disease-modifying drugs as soon as they become available. Conflict of Interest: The presenting author has no relevant disclosures regarding this abstract. Funding sources. This project received an unrestricted grant from F. Hoffmann-La Roche Ltd., Biogen International GmbH, Eisai Europe Limited, and Life Molecular Imaging GmbH. Funders had no role in the conception, design, and implementation of the project nor on data collection, data analysis, and interpretation and discussion of the results.
P98- PREDICTING AMYLOID POSITIVITY WITH BLOOD-BASED BIOMARKERS INCLUDING P-TAU181. H.S. Hyuk Sung1, E.H. Eun-Hye1, H.H. Hyun-Hee1, K. Seong-Ho1(1. Department of Neurology, Hanyang University Guri Hospital, Hanyang University College of Medicine — Guri (Korea, Republic of))
Background: Detecting amyloid pathologies has become increasingly important for selecting patients for clinical trials and diagnosing Alzheimer’s disease (AD) in clinical practice. Although amyloid beta (Aβ) positron emission tomography (PET) imaging and cerebrospinal fluid concentration of Aβ42 and/or Aβ40 reflect the presence of amyloid pathologies, these methods are expensive and/or invasive. To overcome these limitations, studies have focused on the use of blood-based biomarkers. Objectives: We aimed to determine the efficacy of combining plasma phosphorylated tau (p-tau)181, Aβ42/Aβ40, neurofilament light (NfL) and apolipoprotein E (APOE) genotypes in detecting positive amyloid positron emission tomography (PET) in a prospective cohort of individuals with and without AD. Methods: Biomarkers were measured using single-molecule array (Simoa) methods in participants who were cognitively unimpaired (CU, n=8), had mild cognitive impairment (MCI, n=53), and had dementia (n=49). All participants underwent 18F-florbetaben amyloid PET. Statistical analyses were performed to determine the best model. The significant change of area under the curve (AUC) and Akaike information criterion value were considered to find the best model. Results: In total participants, univariate analysis revealed a significant association of Aβ positivity with plasma p-tau181 (AUC=0.848, P< .001) and with APOE ε4 status (AUC=0.704, P< .001). The model that included p-tau181 alone distinguished Aβ status with high accuracy. Adding APOE ε4 or NfL improved model fitness; however, it did not significantly improve the AUCs. In each MCI or dementia group, the addition of other biomarkers to p-tau181 did not improve the performance of p-tau181 alone. Discussion: Plasma p-tau181 showed a high performance in determining Aβ-PET positivity. Adding plasma NFL and APOE ε4 status improved the model fit without significant improvement of AUC. In MCI or dementia patients, adding other biomarkers did not improve the model performance. Conflict of interest: The authors declare no competing interests.
P99- DATA-DRIVEN 18F-FLORTAUCIPIRT CUT-OFFS FOR PRECLINICAL AND EARLY AD. G. Quattrini1,2, C. Ferrari3, M. Pievani1, F. Ribaldi4, S. Tomczyk4, G.B. Frisoni4, V. Garibotto4, M. Marizzoni1(1. Laboratory Of Alzheimer’s Neuroimaging And Epidemiology (lane), Irccs Istituto Centro San Giovanni Di Dio Fatebenefratelli, Brescia, Italy — Brescia (Italy), 2. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy — Brescia (Italy), 3. Unit Of Statistics, Irccs Istituto Centro San Giovanni Di Dio Fatebenefratelli, Brescia, Italy — Brescia (Italy), 4. Memory Clinic And Lanvie-Laboratory Of Neuroimaging Of Aging, University Hospitals And University Of Geneva, Geneva, Switzerland — Geneva (Switzerland))
Background: Clinical trials for Alzheimer’s disease (AD) are starting to use tau PET positivity (T+) as eligibility criterion (e.g., the TRAILBLAZER-ALZ donanemab trial, Mintun et al., 2021). Furthermore, topographic PET staging schemes have potential for early diagnosis, predicting disease progression, and studying disease mechanism (Chen et al., 2021). Several thresholding methods have been proposed to dichotomize the tau PET uptake values and define the tau PET negativity (T-)/T+, but with considerable methodological variability (Weigand et al., 2022). Importantly, none of these previous approaches was data-driven. Here, we determined PET cutoffs for in-vivo tau PET positivity and staging in AD using a data-driven approach. The effects of potential confounders (APOE4 carriage, age, and sex) on cut-offs estimation were also explored. Methods: Amyloid negative (Aβ-) cognitively normal (CN) and amyloid positive (Aβ+) CN (preclinical AD), Aβ+ mild cognitive impairment ([MCI]; prodromal AD), and Aβ+ AD (AD dementia) subjects were included from the ADNI (n=475) and the Geneva Memory Center (GMC, n=99) cohorts. Weighted means of 18F-Flortaucipir standardized uptake value ratio (SUVr, with the inferior cerebellar gray matter as reference region) were calculated for the most commonly used regions of interest (ROI): temporal meta-ROI (as a general measure of tau positivity; Jack et al, 2017) and Braak-based stages I-VI (as a measure of disease progression; Cho et al., 2016). For each subject, the highest regional SUVr value between the left and the right hemisphere was selected. Data-driven SUVr cut-offs were estimated from the ADNI cohort applying the Gaussian mixture model (GMM) on the Aβ- CN and AD dementia subgroup (n=269), using an online application we recently developed (admodelling.org/). Cut-offs were also estimated including confounders in GMMs. Sensitivity and classification analyses were conducted by applying the GMM-based cut-offs both internally (ADNI) and externally (GMC). Previously published 18F-Flortaucipir cut-offs (Jack et al, 2017, and Maass et al., 2017, for the temporal meta-ROI; Mattsson et al., 2017, for Braak-based stages) were also applied to both cohort, to compare with GMM-based threshold. Finally, in the GMC cohort tau PET images underwent to visual rating, and the intraclass correlation coefficient (ICC2,k) was computed with the classification according to GMM-based cut-offs. Results: GMM-based SUVr cut-offs were 1.36 for temporal meta-ROI and ranged from 1.20 (stage V) to 1.39 (stage VI) for Braak-based scheme. Similar values were found when confounders were included in the GMMs. In the ADNI cohort, the sensitivity increased from Aβ- CN to preclinical, prodromal, and AD dementia for the temporal meta-ROI (2%, 13%, 49 %, 85%) and, similarly, for Braak-based stages I–VI. CNs were mainly tau negative (Aβ- : 96%, Aβ+: 76%), while the highest percentages of prodromal AD (35%) and AD dementia (38%) were classified as tau negative and stage VI, respectively. These results were confirmed in the GMC cohort. Compared to previously published values, GMMs-based cut-offs values were generally higher, denoting a more conservative threshold, and generally detected lower percentages of tau positive subjects in all subgroups. Finally, GMM-based cut-offs showed excellent (ICC=0.91, for the temporal meta-ROI) to good (ICC=0.85, for Braak-based staging) reliability with visual rating, while previously published cut-offs showed fair reliability (ICC=0.58 for the temporal meta-ROI, and ICC=0.62 for the Jack and Maass cut-offs respectively, ICC=0.56 for Mattsson’s Braak-based cut-offs). Conclusion: We provided reliable data-driven 18F-Flortaucipir SUVr cut-offs, which could be useful for study population selection in preclinical and early AD clinical trials. Lower percentages of Aβ- T+ subjects in CNs suggests less impact of type 1 error (false positive rates) than previously published cut-offs.
P100- BIOLOGICAL BRAIN AGE PREDICTION USING MACHINE LEARNING ON STRUCTURAL NEUROIMAGING DATA: MULTI-COHORT VALIDATION AGAINST BIOMARKERS OF ALZHEIMER’S DISEASE AND NEURODEGENERATION STRATIFIED BY SEX. I. Cumplido Mayoral1,2, M. Milà-Alomà1,2,3,4, L. Lorenzini5, A.M. Wink5, H.J.M.M. Mutsaerts5, S. Haller6, G. Chetelat7, F. Barkhof5,8, M. Carboni9, G. Kollmorgen10, H. Zetterberg11,12,13,14, K. Blennow11,12, M. Suárez-Calvet1,3,4,15, V. Vilaplana16, J.D. Gispert1,3,17(1. Barcelonaβeta Brain Research Center (bbrc), Pasqual Maragall Foundation — Barcelona (Spain), 2. Universitat Pompeu Fabra — Barcelona (Spain), 3. IMIM (Hospital del Mar Medical Research Institute) — Barcelona (Spain), 4. CIBER Fragilidad y Envejecimiento Saludable (CIBERFES) — Madrid (Spain), 5. Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC — Amsterdam (Netherlands), 6. CIRD Centre d’Imagerie Rive Droite — Geneva (Switzerland), 7. Imaging of Neurological Disorders», Institut Blood and Brain @ Caen-Normandie, Cyceron — Caen (France), 8. Institutes of Neurology and Healthcare Engineering, University College London — London (United Kingdom), 9. Roche Diagnostics International Ltd — Rotkreuz Zg (Switzerland), 10. Roche Diagnostics GmbH — Penzberg (Germany), 11. Institute of Neuroscience and Physiology, University of Gothenburg — Mölndal (Sweden), 12. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital — Mölndal (Sweden), 13. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology — London (United Kingdom), 14. UK Dementia Research Institute at UCL — London (United Kingdom), 15. Servei de Neurologia, Hospital del Mar — Barcelona (Spain), 16. Department of Signal Theory and Communications, Universitat Politècnica de Catalunya — Barcelona (Spain), 17. Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) — Madrid (Spain))
Background: Age is the strongest risk factor for Alzheimer’s disease (AD) and other neurodegenerative diseases. Still, the biological mechanistic links between age and AD are fundamentally unknown. A better understanding of these links is an urgent priority to develop effective strategies to deal with their rising burden amid an ageing population. Therefore, a growing amount of research is focusing on using neuroimaging techniques to develop a biomarker of biological brain aging. In this framework, the concept of brain-age has emerged as a marker that enables determining on an individual basis, the risk for age-associated brain diseases. Brain-age can be inferred from structural neuroimaging, by which individuals with a predicted brain-age higher than their chronological age may have an “older” brain than expected. Subtracting chronological age from estimated brain-age hence provides an estimate of accelerated/decelerated brain aging, namely the brain-age delta. Recent literature has shown the adequacy of using a brain-age predicted measurement in the assessment of the clinical severity of AD, but there remains a need to study the associations between brain-age delta and biomarkers of AD and neurodegeneration in preclinical stages and in independent cohorts. Moreover, given that female individuals have a higher AD prevalence compared to males and display different lifetime trajectories in the brain morphological features, it is of interest to determine the effect of sex on brain-age delta and its interaction with AD and neurodegeneration biomarkers. Objectives: We aimed to validate brain-age delta as a relevant biomarker related to AD, neurodegeneration, and cerebrovascular disease in non-demented individuals. Furthermore, we also aimed to study between-sex differences in the brain areas that better predict age, as well as to study the sex effects with these biomarkers on brain-age delta. Methods: We trained XGBoost regressor models to predict brain-age separately for cognitively unimpaired (CU) females and males using volumes and cortical thickness in regions of the Desikan-Kiliany atlas (obtained with Freesurfer 6.0) from the UKBioBank cohort (N=22,661). Using this trained model, we estimated brain-age delta (predicted brain-age — chronological age) in CU and mild cognitive impaired (MCI) individuals from four independent cohorts: ALFA+ (NCU=380), ADNI (NCU=253, NMCI=498), EPAD (NCU=653, NMCI=155) and OASIS (NCU=407). Chronological age, sex, MMSE and APOE categories were available for all subjects. ALFA+, ADNI and EPAD cohorts included data for amyloid-β (Ab) status determined by CSF Aβ42 levels according to established cutoffs (<1098pg/mL for ALFA+ and EPAD and <880pg/mL for ADNI), for AT stages determined by CSF Aβ42 and CSF p-tau (<24pg/mL) and for White Matter Hyperintensities (WMH). OASIS had data for amyloid-β status determined by amyloid-β PET (Centiloid<17). CSF and plasma neurofilament light (NfL) was available as a biomarker of neurodegeneration in ALFA+ and ADNI. Linear regression models, including chronological age and sex as covariates were used to identify associations between brain-age delta and biomarkers and, additionally, we conducted these analyses stratifying by sex. We next tested for interactions between sex and the validation variables on brain-age delta using linear regression models and including chronological age as covariate. Lastly, we studied the differences in volumes and cortical thickness between females and males in the UK BioBank for the brain regions that contributed the most to the prediction. To do so, we performed regression models for each brain region with sex as predictor variable, in which linear and quadratic expansions of age, site and total intracranial volume (only included for volumetric measurements), were included as covariates. Results: Brain-age delta was associated with abnormal amyloid-β (P<0.001), more advanced AT stages (P<0.001), APOE-β4 status (P<0.001) and increased WMH (P<0.001). Brain-age delta was positively associated with plasma neurofilament light (P=0.002), and sex differences in the brain effects of this marker were found, in which both plasma and CSF NfL were positively associated with brain-age delta in females (CSF: P=0.042, plasma: P=0.001), but not in males (CSF: P=0.959, plasma: P=0.254). Furthermore, we found between-sex differences in the most predictive brain regions: we found reduction in the superior-frontal, isthmus-cingulate and pars orbitalis regions within males and regions such as inferior-parietal, pars triangularis and paracentral within females. We also found regions that had a high impact on the prediction for both females and males, which, in addition, overlapped with regions included in the aging signature, such as the precentral sulcus, insula, superior frontal and rostral middle frontal regions. Conclusion: These results validate brain-age delta as a non-invasive marker of biological brain aging related to markers of AD, neurodegeneration, and cerebrovascular disease. Our results also indicate that there are sex differences in the development of brain aging trajectories and suggest the prevalence of different neuropathological pathways involved in brain aging within females and males. Therefore, these results show the necessity to consider different approaches for assessing aging and neurodegeneration differently for each sex.
P101- CEREBROSPINAL FLUID PLACENTAL GROWTH FACTOR IN RELATION TO CEREBROVASCULAR DISEASE AND DIABETES IN NON-DEMENTED ELDERLY. E.C. Gertje1,2, S. Janelidze1, D. Van Westen3,4, E. Stomrud1,5, S. Palmqvist1,5, O. Hansson1,5, N. Mattsson-Carlgren1,6,7(1. Clinical Memory Research Unit, Department Of Clinical Sciences Malmö, Lund University — Malmö (Sweden), 2. Department of Internal Medicine, Skåne University Hospital — Lund (Sweden), 3. Diagnostic Radiology, Department Of Clinical Sciences Lund, Lund University — Lund (Sweden), 4. Imaging and Function, Skåne University Hospital — Lund (Sweden), 5. Memory Clinic, Skåne University Hospital — Malmö (Sweden), 6. Department of Clinical Sciences Lund, Neurology, Lund University, Skåne University Hospita — Lund (Sweden), 7. Wallenberg Center for Molecular Medicine, Lund University — Lund (Sweden))
Background: Placental growth factor (PlGF) is a pro-inflammatory marker of angiogenesis, which is upregulated by hyperglycemia and involved in diabetic retinopathy. We previously found that cerebrospinal fluid (CSF) PlGF is strongly associated with white matter lesions (WML) in non-demented elderly. WML are commonly used to quantify cerebrovascular disease and correlate with cognitive decline. It is unclear to what degree CSF PlGF, and the relationship between CSF PlGF and WML, are influenced by diabetes. Objectives: To investigate associations between CSF PlGF (and the related protein vascular endothelial growth factor A, VEGF-A), WML and diabetes. Methods: 247 patients with mild cognitive impairment (MCI) and 495 cognitively unimpaired (CU) elderly from the Swedish BioFINDER study were included. CSF samples were analyzed for PlGF, VEGF-A, and β-Amyloid 40 (Aβ40) and Aβ42. 9.8% MCI and 9.1% CU subjects had diabetes. Associations between WML and CSF PlGF or CSF VEGF-A as well as their associations with diabetes were tested with linear regression models. Analyses were adjusted for age, gender, Aβ status, and intracranial volume. Results: CSF PlGF and VEGF-A correlated in both CU (β=0.36, CI 0.29 to 0.44) and MCI (β=0.56, CI 0.42 to 0.71). CSF PlGF was associated with WML in MCI (β=0.17, CI 0.11 to 0.24) and CU (β=0.16, CI 0.10 to 0.21). CSF VEGF-A was associated with WML in MCI (β=0.39, CI 0.09 to 0.69), but not in CU (β=0.06, CI -0.05 to 0.22). Participants with diabetes had significantly higher CSF PlGF, both in MCI (mean difference [MD] =-0.03, 95% confidence interval [CI] -0.07 to -0.001), and CU (MD=-0.03, CI -0.05 to -0.01), whereas CSF VEGF-A did not correlate with diabetes in any of the groups. In addition, participants with diabetes had slightly more WML compared to non-diabetes participants in MCI (MD=-0.27, CI -0.52 to -0.02), but no difference in WML was seen in CU (MD=-0.07, CI -0.03 to 0.12). The associations between CSF PlGF and WML were robust in non-diabetic subjects (MCI: β=0.19, CI 0.12–0.26; CU: β=0.18, CI 0.12–0.24), but absent in subjects with diabetes (MCI: β=-0.05, CI -0.21–0.11; CU: β=-0.03, CI -0.18–0.13). Conclusion: CSF PlGF was strongly associated with diabetes, which could indicate alterations in endothelial function, frequently seen in diabetes complications. However, the association between CSF PlGF and WML in non-demented individuals was absent in subjects with diabetes. This points out that diabetes may cause dysregulation of PlGF which attenuates associations with hallmarks of brain disease. This is relevant both for further studies of CSF PlGF as a marker of cerebrovascular disease, and for studies of CSF biomarkers in general, since biomarkers may be susceptible to confounding factors such as diabetes. The presenting author has no disclosures.
P102- PLASMA AD BIOMARKERS CAN PREDICT HIPPOCAMPAL ATROPHY. H.J. Kim1, J.H. Lee2(1. Uijeongbu Eulji Medical Center — Uijeongbu-Si (Korea, Republic of), 2. Asan Medical Center — Seoul (Korea, Republic of))
Background: Biomarkers have now become an essential component of Alzheimer’s research. Extracellular amyloid plaque and intraneuronal hyperphosphorylated tau accumulation are considered hallmarks of Alzheimer’s disease (AD). Neuroinflammation has been deemed a secondary phenomenon, but is now emerging as a central player in the development in AD. The soluble fraction of triggering receptor expressed on myeloid cells 2 (sTREM2) is regarded as a marker for microglial activation. However, the relationship of AD biomarkers, particularly plasma biomarkers with anatomical patterns of cortical atrophy has not been extensively studied. Objective: We investigated the relationship between fluid AD biomarkers including sTREM2 and anatomical patterns of cortical atrophy. Methods: This study was a single-institutional, prospective cohort study of who visited the memory clinic of Asan Medical Center aged over 40 years and under 90 years, from June 2018 to July 2020. All subjects underwent brain magnetic resonance image (MRI), detailed neuropsychological testing, [F18]-florbetaben amyloid PET, cerebrospinal fluid (CSF) and blood analysis. Subjects were stratified by their amyloid positivity and clinical status. sTREM2, amyloid-β42 (Aβ42), amyloid-β40 (Aβ40), phosphorylated tau-181 (pTau181), total tau, and neurofilament light chain (NfL) levels were measured in the plasma as well as CSF. Among 104 subjects, 42 subjects without 3-dimentional T1 image were excluded and 62 subjects were finally included in the dataset. Results: Of 62 subjects, 33 subjects were classified AD-continuum based on amyloid PET. The cortical thickness did not show a significant statistical association with fluid AD biomarkers. There was no significant association in terms of neuroinflammatory biomarkers between CSF and plasma sTREM2. However, CSF pTau181 showed significant association between bilateral CA4 (left, r = − 0.39, P = 0.003; right, r = − 0.30, P = 0.022) and whole hippocampal volume (r = − 0.31, P = 0.02). Furthermore, plasma pTau181 was significantly correlated with bilateral molecular layer (left, r = − 0.33, P = 0.011; right, r = − 0.37, P = 0.0017) and the whole hippocampal volume (r = − 0.3, P = 0.023). CSF Aβ42/Aβ40 ratio showed correlation with bilateral molecular layer (left, r = 0.37, P = 0.005; right, r = 0.27, P = 0.041). Conclusion: Higher levels of CSF and plasma pTau181 correlated well with decreased hippocampal volume. Plasma pTau181 might be a useful, promising biomarker in predicting neurodegeneration. Further research on the relationship between plasma AD biomarkers and volumetric change of the brain is warranted for each stage of AD-continuum. The authors declare no competing interests.
P103- ASSESSMENT OF PLASMA P-TAU181 IN TANGO, A PHASE 2 STUDY OF GOSURAMEMAB IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE. J. Czerkowicz1, J. Kong1, A. Racine1, C. Rubel1, J. Collins1, M. Shulman1, D. Graham1, J. Beaver1, S. Budd Haeberlein1(1. Biogen — Cambridge (United States))
Background: Gosuranemab is a humanized monoclonal antibody that binds to the N-terminus of tau with high affinity. TANGO was a Phase 2 clinical study designed to assess the safety and efficacy of gosuranemab in participants with mild cognitive impairment due to Alzheimer’s disease (AD) or with mild AD dementia with confirmed amyloid positivity (via either positron emission tomography (PET) or cerebrospinal fluid (CSF)). No treatment difference was observed between gosuranemab and placebo on the primary efficacy or exploratory efficacy endpoints. Exploratory biomarker sub-studies of TANGO included examining the effects of gosuranemab on tau protein concentrations in CSF and blood, and the effects of gosuranemab on cerebral tau changes by tau PET. Emerging data on blood-based biomarkers in AD, including phosphorylated tau (p-tau) suggest multiple potential applications to clinical trials, including patient selection and treatment response. Multiple p-tau epitopes demonstrate potential ability to discriminate AD from non-AD, and correlate to amyloid pathology, tau pathology and cognitive decline. Objectives: Our objective is to examine p-tau181 levels in plasma samples collected during the TANGO study to assess the potential use of this biomarker as a tool to identify patients with baseline pathology and predict disease progression in AD clinical trials. Methods: Plasma was collected from randomized TANGO subjects at baseline, and weeks 16, 48, 60 and 76 post-baseline. Plasma p-tau181 was measured using the Quanterix Simoa p-tau181 V2 Advantage assay. Baseline plasma p-tau181 was measured in all subjects. Due to drug interference in the assay, longitudinal (post-baseline) plasma p-tau181 was analyzed only in placebo subjects. Additional exploratory biomarker analyses included CSF and PET. CSF was collected in a sub-study of n=327 subjects, and CSF tau and p-tau181 were measured using the Lumipulse assay up to Week 76 post-baseline. Tau PET was measured in a sub-study of n=357 subjects at baseline and Weeks 52 and 78 post-baseline, using the 18F-MK-6240 tau PET tracer. Amyloid PET was only measured at screening, using 18F-florbetapir in n=322 subjects. Statistical analysis was performed using Spearman correlation coefficient. Results: CSF and plasma p-tau181 were correlated at baseline (Spearman = 0.35, p-value <0.0001). Baseline plasma p-tau181 levels were correlated with both baseline amyloid PET using SUVR in composite regions of interest (Spearman = 0.31, p-value <0.0001) and baseline Tau PET using SUVR in composite regions of interest corresponding to Braak stages I-II, III-IV, and V-VI (Spearman range = 0.380.50, p=value <0.0001). Despite this evidence of correlation between baseline plasma p-tau181 levels and baseline Tau PET, some subjects with similar plasma p-tau181 levels were observed to have considerable variability in Tau PET binding patterns. TANGO subjects with higher concentrations of plasma p-tau181 at baseline showed a statistically significant correlation with a greater rate of clinical decline at week 78, using multiple cognition assessment scales, including ADAS-Cog13 (p=0.0001), CDR-Sum of Boxes (p=0.0023), and MMSE (p=0.0001). The ADCS-ADL scale was not significantly correlated with baseline plasma p-tau181 at week 78 (p=0.2053). Conclusions: Plasma p-tau181 data from the TANGO study will help inform our understanding of plasma biomarkers in AD, and the utility of this marker as a tool for patient selection and as a biomarker of disease progression. The correlations of plasma p-tau181 with amyloid and tau PET at baseline suggests a relationship with the underlying pathological hallmarks of AD. Furthermore, the correlation of baseline plasma p-tau181 and clinical decline observed over the course of the TANGO trial supports the utility of plasma p-tau181 as a potential prognostic biomarker of disease. However, there are limitations associated with this study that prevent us from drawing conclusions on the utility of plasma p-tau181 as a standalone biomarker for patient selection and disease progression. The patient population for the TANGO study was 100% amyloid PET positive at enrollment, with approximately 85% of these subjects also tau PET positive (Racine, et al, AAIC poster, 2022), making it difficult to establish a threshold for patient selection without a well-powered negative population. Due to the interference of gosuranemab binding to tau, there is limited longitudinal plasma p-tau181 data to assess the relationship with cognitive decline over the course of the study. Assay standardization to support consistency of data and continued advancement of the p-tau methods to further optimize assay characteristics such as robustness and dynamic range will be important to increase utility of this emerging biomarker. Generation of additional datasets from AD clinical trials that include PET-imaging and CSF collections will be critical to advancing towards this goal.
P104- CORNEAL CONFOCAL MICROSCOPY AND MRI BRAIN VOLUMETRY: PROGNOSTIC BIOMARKERS FOR PROGRESSION FROM MILD COGNITIVE IMPAIRMENT TO DEMENTIA. G. Ponirakis1, R. Malik1(1. Weill Cornell Medicine in Qatar — Doha (Qatar))
Background: There is an urgent need for biomarkers that identify subjects with mild cognitive impairment (MCI) at increased risk of progression to dementia. We have previously used corneal confocal microscopy (CCM) to identify corneal nerve degeneration in subjects with MCI and dementia. Objectives: This study compared the utility of corneal nerve measures with brain volumetry for predicting progression to dementia in people with MCI. Methods: Participants with MCI underwent assessment of cognitive function, brain MRI and CCM and followed-up to identify progression to dementia. Corneal nerve fiber density (CNFD), length (CNFL) and branch density (CNBD) and the volume of different brain structures were quantified. Results: Of 107 subjects with MCI aged 68.4±7.7 years, 33 (30.8%) progressed to dementia over a mean follow-up of 2.6 years. Subjects with MCI who progressed to dementia had a significantly lower CNFD (20.6±9.3 fibers/mm2 vs 28.8±8.2 fibers/mm2, P<0.0001), CNBD (43.3±28.9 branches/mm2 vs 70.8±37.2 branches/mm2, P<0.0001), and CNFL (14.3±6.3 mm/mm2 vs 19.9±5.7 mm/mm2, P<0.0001) compared to those who did not progress. Corneal nerve measures had a higher prognostic accuracy (72–75% vs 68–69%) and specificity (78–84% vs 60–62%) and very high negative predictive value (80–84%) compared to hippocampus and whole brain volume for identifying subjects who progressed to dementia. The adjusted odds ratio for progression to dementia was 6.1 (95%CI:1.6–23.8) and 4.1 (95%CI:1.2–14.2) higher with abnormal CCM measures but was not significant for abnormal brain volume. Conclusions: Abnormal CCM measures had a higher prognostic accuracy than brain volumetry for predicting progression to dementia in people with MCI. CCM could be used to identify subjects with MCI at greater risk of progression to dementia for inclusion in clinical trials of neuroprotective or disease modifying therapies.
P105- OLIGOMER BIOMARKERS FOR PRECLINICAL AND CLINICAL DRUG DEVELOPMENT IN NEURODEGENERATIVE DISORDERS. O. Bannach1,2, L. Blömeke1,2, B. Kass1, A. Chen-Plotkin3, O. Peters4, D. Willbold1,5(1. Forschungszentrum Jülich — Jülich (Germany), 2. attyloid GmbH — Düsseldorf (Germany), 3. University of Pennsylvania — Philadelphia (United States), 4. Charité Universitätsmedizin Berlin — Berlin (Germany), 5. Heinrich-Heine-Universität Düsseldorf — Düsseldorf (Germany))
Background: The major pathological hallmark among neurodegenerative diseases is formation of toxic oligomers, comprising proteins such as amyloid-beta (Aβ) alpha-synuclein (aSyn) and Tau protein (Tau). Consequently, such oligomers are promising biomarker candidates for diagnostics and drug development. However, measuring oligomers in body liquids such as cerebrospinal fluid (CSF) or even blood is technically challenging as extreme sensitivity and selectivity is required. We have previously developed surface-based fluorescence intensity distribution analysis (sFIDA), a method featuring single particle sensitivity and absolute specificity for oligomers. Objectives: Our objective was to deliver proof-of-concept that sFIDA can be applied to quantify oligomers in preclinical and clinical samples. Methods: In brief, sFIDA combines the selectivity of an immunoassay with the digital sensitivity of fluorescence microscopy. sFIDA employs capture and probe antibodies directed against the same epitope rendering the assay selective for oligomers and insensitive for monomers. Subsequent sFIDA readout is imaging-based, capturing the number of pixels with intensity exceeding background threshold. Results: We applied sFIDA to determine aSyn and Tau oligomer titers in the CSF of different disease groups and determined elevated Tau oligomers in Progressive Supranuclear Palsy and elevated aSyn oligomers in Parkinson’s Disease and Lewy Body Dementia patients (Blömeke et al 2022). We further demonstrate that the oligomer disassembling (anti-prionic) compound RD2 indeed disassembles Aβ oligomers in AD patient-derived brain tissue homogenates (Kass et al. 2022). Finally, we will report yet unpublished data on elevated Aβ oligomers in the CSF of mild cognitively impaired (MCI) due to AD patients. Conclusion: In drug development, sFIDA is useful to validate any oligomer disassembling mechanism of action of a given drug in vitro, in animal models, and in ex vivo tissue homogenates. Further, sFIDA is a valuable biomarker assay for patient inclusion/exclusion, patient stratification, target engagement and drug effect monitoring in AD, and other protein misfolding diseases. References: Blömeke et al. (2022), Quantitative Detection of α-Synuclein and Tau Oligomers and other Aggregates by Digital Single Particle Counting”, NPJ Parkinsons Dis., 8, 68. 10.1038/s41531-022-00330-x. Kass et al. (2022), Aβ oligomer concentration in mouse and human brain and its drug induced reduction ex vivo. Cell Reports Medicine, 3, 100630 10.1016/j.xcrm.2022.100630. Competing Interests: D.W. is a founder and shareholder of the company Priavoid and member of its supervisory board. D.W. and O.B. are founders and shareholders of attyloid. D.W. is member of attyloid’s supervisory board. This had no influence on the interpretation of the presented data.
P106- EXPLORATORY STUDY ON THE PROTEOMIC AND TRANSCRIPTOMIC CONTENT OF PLASMA EXTRACELLULAR VESICLES IN AD PATIENTS. M. Solaguren-Beascoa1, A. Gámez-Valero1,2, A.M. Ortiz3, C. Minguet3, R. Gonzalo3, G. Escaramís1,2, M. Costa3, E. Martí1,2(1. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Institut of Neurociencies, Universitat de Barcelona — Barcelona (Spain), 2. Centro de Investigación Biomédica en Red sobre Epidemiología y Salud Pública (CIBERESP) — Barcelona (Spain), 3. Grifols Bioscience Research Group — Barcelona (Spain))
Background: Biomarkers for Alzheimer’s disease (AD) are important for diagnosis, patients’ stratification for inclusion in clinical trials and for treatment eligibility. Advances in the development of sensitive analytical tools have boosted biomarker discovery. Detection of beta-amyloid (Aβ42), Tau protein (Tau), neurofilament light (NfL), and/or glial fibrillar acidic protein (GFAP) proteins in plasma and other biofluids, has been successfully achieved in AD and other neurodegenerative diseases. Nevertheless, changes are very heterogeneous, and conflicting results have been reported. Most biomarkers only reflect clinical stages of the disease once the pathology has widely spread in the brain. To date, it remains unknown if other molecular changes, more sensitive and specific for AD, may be observed in blood. Specifically, early transcriptomic deregulation occurs in AD long before clinical onset, and several studies have explored the utility of plasma microRNAs and cell-free mRNA as biomarkers for AD. However, other highly abundant RNA species in plasma have been largely overlooked. In plasma, proteins and RNAs can be found as freely circulating and/or enclosed inside extracellular vesicles (EVs). EVs, which are naturally released by almost all types of cells, are known to mediate cell-to-cell communication. Proteins, nucleic acids, metabolites and lipids found inside EVs may reflect the physiological and/or pathological state of the cell/tissue of origin. In AD, EVs have been reported as important players in spreading AD pathology between brain cells. Diverse studies have found specific proteins or miRNAs deregulated in AD plasma EVs; however, the overall content of plasma EVs (proteins and small RNAs) has been scarcely explored. A detailed study of the whole vesicular content may provide new promising and more sensitive biomarkers reflecting changes occurring at different stages of AD. Objectives: The overall aim of the present proposal is to characterize the molecular content (small RNA transcriptome and proteome) of plasma EVs in AD patients in comparison to healthy individuals. We expected to identify new molecules with high biomarker potential that could be further profiled in the course of the disease and facilitate the establishment of earlier diagnosis and prognosis tools. Methods: Plasma samples from mild-to-moderate AD patients (n=10) and age matched healthy non-cognitive affected individuals (n=10) were processed by size exclusion chromatography to obtain EVs. The obtained EVs were characterized following MISEV (International Society for Extracellular Vesicles) guidelines and were further processed for transcriptomic and proteomic analyses. Vesicular RNA was extracted from half of the EV preparation and treated with T4 polynucleotide kinase; small RNA (sRNA) libraries were prepared and sequenced in an Illumina HiSeq 2500. Adapters were removed with cutadapt and reads were mapped with the STAR aligner. We used the SeqCluster tool to organize sRNAs in clusters of co-expressed sRNA consistently and non-redundantly mapping onto the same precursor. Differential expression (DE) analysis was performed via negative-binomial general linear models implemented in the R package DESeq 2. The other half of the EV preparation was used for proteomic analyses by LC-MS/MS. MaxQuant computational platform and Perseus software were used for protein identification and quantification, and DE was analyzed using a Student’s t-test. To select DE sRNAs or proteins we used a 1.3-fold change cut-off, with ratios below the low range of 0.77 considered as downregulated and those above 1.33 as upregulated. Results: Plasma EVs were successfully isolated from 1mL of plasma samples, both in AD and healthy samples (CTRL). No significant differences in EV markers CD9, CD81 and CD63 intensity were found by flow cytometry, neither in EV-size or concentration as shown by cryoTEM and nanoparticle tracking analysis between both cohorts. The proteomic profiling of EVs rendered a similar number of detected proteins, both in AD (358.3 ± 43) and CTRL (315.3 ± 69) samples, with several described as EV-enriched or exosome-related. DE analyses identified differentially deregulated proteins in AD versus CTRL; with 16 proteins downregulated and 15 proteins overexpressed (p-value<0.05). The AD upregulated proteins showed significant enrichment in proteins of the endoplasmic reticulum chaperone complex, involved in protein folding. Regarding small RNA vesicular content, similar diversity and relative abundance of the different types of sRNAs were found in both group of samples. Tissue enrichment analysis suggests that most AD-EVs enriched sRNAs mapped onto genes highly represented in the brain. DE analysis identified 56 sRNAs over-represented in AD-EVs compared to CTRL (adj p-value < 0,05), with 45 % of them mapping onto gene fragments. Specific AD-EVs overexpressed sRNAs map onto genes already described as altered in AD, and some deregulated miRNAs validated previous findings in plasma of AD patients. Conclusion: Plasma extracellular vesicles can be used for parallel analysis of the proteome and transcriptome. Current study suggests that proteomic and transcriptomic content of plasma extracellular vesicles from AD patients differ from healthy controls and deserve further investigation. Observations of the present study highlight the potential of plasma EVs molecular content (proteomic and transcriptomic) to contribute to a diagnostic blood biomarker panel. This study was supported by Grifols.
P107- TOWARDS THE DEVELOPMENT AND VALIDATION OF A GENERAL-PURPOSE REGULATORY-GRADE NEUROIMAGE ANALYSIS TOOL. N. Henscheid1, I. Pappas2, R. Cabeen2, J. Podichetty1, S. Hobel2, C. Weber3, Y. Karten1, K. Romero1, S. Sivakumaran1, A. Toga2(1. Critical Path Institute — Tucson (United States), 2. University of Southern California — Los Angeles (United States), 3. Alzheimer’s Association — Chicago (United States))
Background: The Global Alzheimer’s Association Interactive Network (GAAIN) and the Critical Path for Alzheimer’s Disease (CPAD) Consortium have undertaken a collaborative effort to develop a multimodality regulatory-grade neuroimage analysis tool, leveraging a comprehensive dataset of individual patient-level records, rich in fluid and imaging biomarkers from global clinical trials and observational studies. This effort is based on the LONI Pipeline, a tool that allows a variety of brain processing pipelines to be executed on any brain data modality, and GAAIN’s federated architecture, a system for sharing Alzheimer’s-related data stored in independently operated repositories owned by the data partners. This software tool will package previously validated image analysis pipelines with a user-friendly graphical interface allowing for rapid, automated quantification of image-derived biomarkers. It is envisioned that pipelines can be constructed and validated for any modality and analysis target, including both MRI-based and PET-based imaging. This tool will help advance the understanding of Alzheimer’s disease progression and treatment effects, in addition to answer drug development and regulatory needs, by harmonizing the quantitation of neuroimaging biomarkers and subsequent correlations with fluid markers, cognitive assessments and patient characteristics, across different cohorts, tracers and demographics. Methods: The existing LONI Pipeline software was containerized to facilitate both its incorporation into the GAAIN system, as well as its proper validation. Specifically, the GAAIN system was expanded to allow users to submit requests to initialize LONI Pipeline processes in remote brain data repositories as part of its federated architecture. A set of procedures was developed to validate both the general-purpose aspects of the Pipeline software as well as task-specific analysis pipelines. To demonstrate analytical validity for a specific task, a cohort of interest in the CPAD database was created using GAAIN’s interrogator. A brain volumetry processing request was initiated remotely, and hippocampal volumes were obtained from the brain images of that CPAD cohort. For validation, these results were tested against values calculated semi-automatically by a software-assisted human observer. The results were made available both within GAAIN as additional variables and in the CPAD database. To demonstrate clinical utility, we explored correlations of these values against blood-based biomarkers available from the CPAD database and other archives using the GAAIN system. Results: The containerized software provides a solid platform for future development of a user-friendly interface through GAAIN. Adequate correlation was found between volumetric measurements computed using the automated structural pipeline and the semi-automatic results computed by human readers. These results demonstrate the ability to provide validated regulatory-grade analyses through an existing data analytics platform. Conclusion: As novel anatomical and molecular neuroimaging techniques emerge it is essential that rigorously validated analysis software is made readily available for researchers to quickly calculate consistent results. The proposed framework will expand the existing GAAIN framework to include a regulatory-grade image analysis tool, allowing researchers to execute analysis on the GAAIN server and perform further analysis there. Expansion of the tool to include validated quantification of PET images (beta-amyloid and tau), as well as further demonstration of the scientific impact of the tool, is ongoing. Note: Nicholas Henscheid and Ioannis Pappas contributed equally to this work.
P108- COMPARATIVE PERFORMANCE OF PLASMA AB42/AB40 AND P-TAU181 FOR THE DETECTION OF EARLY BRAIN AMYLOID DEPOSITION IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE. M. Pascual-Lucas1, J.A. Allué1, L. Sarasa1, N. Fandos1, S. Castillo1, J. Terencio1, M. Sarasa1, J.P. Tartar2, Á. Sanabria2,3, L. Tárraga2,3, A. Ruiz2,3, M. Marquié2,3, M. Boada2,3(1. Araclon Biotech-Grifols — Zaragoza (Spain), 2. Ace Alzheimer Center Barcelona — Universitat Internacional de Catalunya — Barcelona (Spain), 3. CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III — Madrid (Spain))
Background: In the last years, blood-based biomarkers have shown high accuracy for the identification of early alterations of Alzheimer’s disease (AD). Among them, plasma amyloid-beta (Aβ)42/Aβ40 and phosphorylated tau 181 (p-tau181) have been proved to be reliable biomarkers of brain amyloid deposition. However, the quantification of these molecules in plasma, mainly Aβ42, presents analytical difficulties and, therefore, high reliability analytical assays are needed in order to avoid biased conclusions about the comparative performance of both biomarkers. In this study, we aim to avoid these uncertainties by the introduction of a high sensitivity assay based on HPLC-MS for the quantification of Aβ peptides in plasma. Objectives: To compare the ability of plasma Aβ42/Aβ40 ratio measured with a mass spectrometry-based assay and plasma p-tau181 measured with a high-sensitivity technology to detect early brain amyloid deposition in individuals at risk of AD. Methods: 152 subjects with subjective cognitive decline from the Fundació ACE Healthy Brain Initiative (FACEHBI) cohort(1) were included in the present study. Participants underwent comprehensive neurological evaluation and cognitive testing, APOE genotyping and 18F-florbetaben (FBB)-PET brain imaging. 16% of the participants were classified as Aβ-PET positive according to the cutoff for early amyloid deposition established at >13.5 centiloids (CL)(2). Plasma Aβ40 and Aβ42 were quantified with a high-sensitivity antibody-free mass spectrometry-based assay (ABtest-MS, Araclon Biotech) (3). Plasma p-tau181 was measured with Simoa® pTau-181 V2 Advantage Kit (Quanterix). The ability of plasma biomarkers alone, combined or after the addition of demographic covariates, to detect Aβ-PET positivity was assessed by logistic regression and ROC curve analysis. The fitting of the regression models was assessed using the Akaike’s Information Criterion (AIC) value. Area under the ROC curves (AUCs) were compared using DeLong test. Results: The regression model of plasma Aβ42/Aβ40 presented lower AIC (101.3) than the model composed of plasma p-tau181 (AIC=115.7), and discriminated Aβ-PET status with an AUC=0.86 (95% CI 0.78–0.94), compared to an AUC=0.83 (95% CI 0.76–0.90) for plasma p-tau181. At the maximum Youden index, both plasma biomarkers showed a sensitivity of 81.5%, but Aβ42/Aβ40 presented slightly superior specificity (84.0%) and overall accuracy (83.6%) than p-tau181 (80.8% and 80.9%, respectively). The combination of both plasma biomarkers yielded an AIC=94.7 and AUC=0.88 (95% CI 0.82–0.95). The inclusion of demographic covariates (age and APOE ε4 number of alleles) in the model increased the AUC up to 0.90 (95% CI 0.85–0.96), whereas the AIC was not further improved (AIC=94.4). Both Aβ42/Aβ40 and p-tau181 contributed significantly to this model (P<0.0001 and P=0.04, respectively). Moreover, the full model significantly outperformed plasma p-tau181 alone (ΔAUC=0.07, P=0.04), but did not differ from plasma Aβ42/Aβ40 (ΔAUC=0.04, P=0.09). Conclusion: The use of a high reliability method for the quantification of plasma Aβ based on HPLC-MS (ABtest-MS) suggests that plasma Aβ42/Aβ40 ratio could be a more accurate biomarker of early brain amyloid deposition than p-tau181 in the first stages of AD. 1. Rodriguez-Gomez O et al., J Prev Alzheimers Dis. 2017;4(2):100. 2. Bullich S et al., Alzheimers Res Ther. 2021;13(1):67. 3. Jang H et al., Alzheimers Res Ther. 2021; 13:179. Disclosures: M. Pascual-Lucas, J.A. Allué, L. Sarasa, N. Fandos, S. Castillo and J. Terencio are full-time employees at Araclon Biotech-Grifols. J.P. Tartari, A. Sanabria, L. Tárraga and M. Marquié report no disclosures. A. Ruiz has consulted for Grifols, Prevail Therapeuthics and Landsteiner Genenmed. He reports grants/research funding from Abbvie, Janssen, Grifols and Fundación Bancaria LaCaixa. A. Ruiz has stocks in Landsteiner Genmed. M. Boada has consulted for Araclon, Avid, Grifols, Lilly, Nutricia, Roche, Eisai and Servier. She received fees from lectures and funds for research from Araclon, Biogen, Grifols, Nutricia, Roche and Servier. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma Iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations.
P109- EVALUATION OF BLOOD-BASED PLASMA BIOMARKERS AS POTENTIAL MARKERS OF AMYLOID BURDEN IN PRECLINICAL ALZHEIMER’S DISEASE. C.N. Winston1, O. Lanford2, N. Levin1, R. Raman2, K. Yarasheski3, T. West3, S. Abdel-Latif2, M. Donohue2, A. Nakamura4, K. Toba5, C.L. Masters6, J. Doecke7, R.A. Sperling8, P.S. Aisen9, R.A. Rissman10(1. Department of Neurosciences, University of California San Diego — La Jolla (United States), 2. Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California — San Diego (United States), 3. C2N Diagnostics — St. Louis (United States), 4. Department of Biomarker Research, National Center for Geriatrics and Gerontology — Obu (Japan), 5. National Center for Geriatrics and Gerontology, Obu, Aichi, Japan, and Tokyo Metropolitan Institute of Gerontology — Obu (Japan), 6. The Florey Institute, The University of Melbourne — Parkville (Australia), 7. he Commonwealth Scientific and Industrial Research Organization — Herston Qld (Australia), 8. Harvard Medical School — Boston (United States), 9. Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California — Los Angeles (United States), 10. Department of Neurosciences, University of California San Diego and VA San Diego Healthcare System — La Jolla (United States))
Background: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given its disadvantages in accessibility and cost, blood-based biomarkers may serve as a reliable and more cost-effective screening tool for patient enrollment into preclinical AD trials. Objective: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. Methods: In this cross-sectional study, 224 A4 Study participants received an amyloid PET scan (18Florbetapir) within 90 days of blood sample collection. Approximately 38% of all participants contained at least one APOE ε4 allele while 93% of all participants identified as non-Hispanic white. Blood samples were processed within 24 hrs (Protocol 1) or 2 hrs after phlebotomy (Protocol 2). Plasma amyloid measures were quantified by Shimazdu and C2N Diagnostics using mass spectrometry-based analytical platforms under Protocol 2. A corresponding subset of blood samples (n=100) were processed under Protocol 1 and analyzed by C2N. Plasma biomarker values from Shimadzu and C2N were transferred to ATRI statisticians for analysis. Primary outcomes included plasma amyloid measures Aβ40, Aβ42 and Aβ42/Aβ40. Shimadzu provided a Composite score, generated by averaging the normalized scores of APP669711/Aβ42 and Aβ40/Aβ42. Both labs were blinded to participant demographics and metadata. Results: Plasma Aβ42/Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95% CI = 0.69, 0.82) at C2N and 0.80 (95% CI = 0.75, 0.86) at Shimadzu. Plasma Aβ42/Aβ40 diagnostic performance for a subset of 100 samples (Protocol 2) was significantly better than that for the same participants’ samples processed using Protocol 1 (AUC 0.80 vs. 0.64; p <0.001). Age, sex, and APOE ε4 carrier status did not improve the diagnostic performance of plasma Aβ42/Aβ40 to predict amyloid PET status. Conclusions: Plasma Aβ42/Aβ40 shows great promise as a reliable biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging can improve screening efficiency into clinical trials. Future studies are required to understand how sample pre-and post-processing, patient characterization variables, and amyloid tracer sensitivity impacts the biomarker performance of plasma Aβ42/Aβ40.
P110- MYOCARDIAL SYMPATHETIC DENERVATION BIOMARKERS FOR EARLY DETECTION OF PRODROMAL DLB. M.Y. Park1, D.S. Shin1(1. Neurology Yeungnam University Medical Center — Daegu (Korea, Republic of))
Background: Because of the time course of detecting DLB symptoms and signs, DLB is poorly diagnosed and hardly differentiate from AD, especially in early stage of dementia without the core clinical features of DLB. We investigated patients with a clinical diagnosis of amnestic mild cognitive impairment (MCI) and early AD whether they had cardiac sympathetic denervation, detected by cardiac 123I-MIBG scintigraphy. And we also assessed presynaptic nigrostriatal dopaminergic system by 18F FP-CIT-PET imaging to distinguish between DLB and AD. Methods: Thirty patients (72±9.0 yrs old: M:F 17:13) with a clinical diagnosis of amnestic MCI and early AD (CDR 0.5/SOB 3) who have been had visual hallucination and/or suspicious fluctuating cognition history without parkinsonism (n=20, prodromal DLB group) and who have not been had visual hallucination and/or suspicious fluctuating cognition history (n=10, eAD group) enrolled in this study. 123I-Metaiodobenzylguanidine (MIBG) uptake was assessed using the ratio of the heart to the upper mediastinum (H/M ratio), and we also assessed presynaptic nigrostriatal dopaminergic system by 18F FP-CIT-PET imaging to distinguish between prodromal DLB and eAD. Autonomic function tests and orthostatic vital signs were recorded. Results: The H/M ratio were decreased in pDLB group, and the mean H/M ratio was significantly lower (early/delayed uptake:1.72±0.61/1.65±0.63) compared with eAD group (early/delayed uptake:2.36±0.50/2.15±0.29) in 123I-MIBG scintigraphy (p<0.05). Presynaptic nigrostriatal dopaminergic deficits were founded in 18F FP CIT PET and orthostatic hypotension was evident only in pDLB group regardless of spontaneous Parkinsonism (n=17, 85%). Conclusion: Myocardial postganglionic sympathetic denervation and autonomic dysfunctions especially orthostatic hypotension can be good biomarkers to predict DLB before core clinical symptoms appear, and may useful to distinguish from AD even in early stage. This study is under long term follow up. Key words: DLB, 123I-MIBG scintigraphy, orthostatic hypotension.
P111- PTAU181 PLASMA BIOMARKER PERFORMANCE AS AN INCLUSION CRITERION IN THE RETHINK-ALZ AND REFOCUS-ALZ TRIALS IN MILD-TO-MODERATE ALZHEIMER’S DISEASE. A. Mammel1, P. Kumar2, L. Burns3, D. Biehl1, M. Encarnacion2, A. Cruz2, G.Y.R. Hsiung4, I. Mackenzie4, V. Hirsch-Reinshagen4, A. Mousavi2, R. Fortna1,5, J. Kupiec3, H. Frykman2(1. Neurocode — Bellingham, Washington (United States), 2. BC Neuroimmunology — Vancouver (Canada), 3. Cassava Sciences — Austin, Texas (United States), 4. University of British Columbia — Vancouver (Canada), 5. Northwest Pathology — Bellingham, Washington (United States))
Background: Alzheimer’s disease (AD) biomarkers have enabled more accurate, timely diagnoses and improved staging of disease, supporting clinical trials as inclusion criteria and secondary endpoints. While cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are commonly used to demonstrate AD neuropathology, these biomarkers are invasive and have limited availability and scalability. By contrast, blood-based biomarkers are non-invasive, scalable, and are increasingly used both for diagnosis and entry into clinical trials. Advances in ultrasensitive detection techniques for blood biomarkers have facilitated the development of assays to detect and quantify AD-specific phosphorylated Tau proteins, including Tau phosphorylated at threonine 181 (pTau181) (1, 2). We have established superior analytical and clinical performance of a new research use only (RUO) plasma pTau181 single molecule array (SIMOA) assay on a well-characterized clinically diagnosed AD cohort (3, 4). We evaluated the clinical performance of this RUO pTau181 assay to qualify mild-to-moderate AD patients in the RETHINK-ALZ and REFOCUS-ALZ clinical trials. Objective: To evaluate the clinical performance of a new plasma pTau181 assay to confirm AD pathology as an entry criterion for two large Phase 3 clinical trials. Methods: The University of British Columbia (UBC) biobank plasma samples from clinically diagnosed AD patients were used to establish clinical and analytical validity of the pTau181 plasma assay per CLSI guidelines (3, 4). We assessed the analytical measurement interval, clinical reportable range, linearity, intra-laboratory precision, specimen stability, interference, and clinical performance. RETHINK-ALZ and REFOCUS-ALZ subject plasma samples, along with clinical diagnosis, MMSE and PET data were also used to evaluate performance of the assay and the pTau181 biomarker. RETHINK-ALZ will randomize 750 subjects (1:1) to placebo or simufilam 100 mg and REFOCUS-ALZ will randomize 1083 subjects (1:1:1) to placebo or simufilam 50 or 100 mg. Subjects are MMSE ≥ 16 and ≤ 27, age 50–87 in both studies. Results: The clinical cut-point for this plasma pTau181 assay for clinical trial inclusion was set as ≥ 30 ng/L using the ROC curve (AUC — 0.92) and the Youden Index (34.3 ng/mL), which maximizes sensitivity and specificity, generated from a clinical validation study of clinically diagnosed AD and cognitively unimpaired control specimens (3, 4). The cut-point (≥ 30 ng/L) had 100% sensitivity and 88% specificity for AD diagnosis in 22 autopsy-confirmed samples (3). The clinical reportable range for the assay is 6.17 to 300 ng/L, with a limit of quantification ≤ 22.2 ng/L. The analytical performance of the assay meets method validation guidelines of ≤ 20% intra-laboratory variation, no detectable interference, linearity to 300 ng/L, and sample stability up to three freeze-thaw cycles. We determined the percentage of subjects screened for RETHINK-ALZ and REFOCUS-ALZ that met the ≥ 30 ng/L pTau181 plasma concentration. Current data show 83.2% (n = 321) and 89.8% (n = 333) of subjects screened for RETHINK-ALZ and REFOCUS-ALZ, respectively, meeting this criterion. Clinical sites screen subjects with an established clinical diagnosis of AD or who are suspected to have AD. 86% of the sites participating in the REFOCUS-ALZ study and 78% of sites participating in the RETHINK-ALZ had at least 70% of screened subjects meet this criterion. We also compared plasma pTau181 concentrations in RETHINK-ALZ and REFOCUS-ALZ subjects with MMSE and PET findings. The concentration of pTau181 does not correlate with MMSE score, possibly because the dynamic range of the pTau181 assay and its variability within this mild-to-moderate population is much greater than the relatively narrow range of their MMSE scores. Alternatively, the level of cognitive impairment may not correlate well with this biomarker. However, pTau181 concentrations were elevated (> 50 ng/L) in all subjects with prior Tau or amyloid-beta PET confirmation of pathology (8 of 8) enrolled in these studies, suggesting an excellent correlation of plasma pTau181 with AD neuropathology. Conclusion: This pTau181 plasma assay provides a robust and accurate biomarker approach for independent determination of AD, with an AUC of 0.92 in a validation study. This pTau181 assay appears to be performing well as a screening method for inclusion of mild-to-moderate AD subjects in two large Phase 3 clinical trials. This robust plasma biomarker measured by our RUO assay has great potential both as a diagnostic tool and to streamline clinical trials in AD. References: 1. Karikari TK, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020 May;19(5):422–433. 2. Bayoumy S, et al. Clinical and analytical comparison of six Simoa assays for plasma P-tau isoforms P-tau181, P-tau217, and P-tau231. Alzheimers Res Ther. 2021 Dec 4;13(1):198. 3. H. Frykman et al. Plasma ptau-181 concentrations accurately predict pathologically confirmed Alzheimer’s Disease cases, poster presented at Tau 2022 global conference. 4. H. Frykman et al. Analytical and clinical performance of plasma p-tau181 assay on the high-sensitivity Simoa HD-X platform, poster accepted in AAIC 2022.
P112- CRITICAL EVALUATION AND COMPARISON OF BIOMARKER VALUES IN COMMERCIAL CSF WITH LUMIPULSE® TO SUPPORT ASSAY DEVELOPMENT FOR CLINICAL TRIALS. H. Vanderstichele1, M. Rafizadeh2, E. Cline2, J. Derrick3, E. Simmons3, R. Dean2, J. Jerecic2(1. Biomarkable — Gent (Belgium), 2. Acumen Pharmaceuticals — Charlottesville (United States), 3. B2S Life sciences — Indianapolis (United States))
Background: Cerebrospinal fluid (CSF) has many applications in the study of central nervous system drug delivery and biomarker analysis. The qualification of this difficult to obtain and costly biofluid is highly dependent on the techniques and methods used to analyze, handle, and store the material. When obtained from commercial suppliers, only limited information typically is available on sample quality and collection procedures. The lack of such information can impede development timelines for assay development, validation, and ongoing quality control. Proper interpretation of CSF composition is highly dependent on test procedures used for protein analysis and directly impacts biomarker assay development. Objectives: Here we describe selection criteria for CSF research samples purchased from PrecisionMed LLC. followed by comparative quantitation of CSF biomarker profiles with the recently FDA-cleared Lumipulse®G 1200 (β-Amyloid 1–40, ß-Amyloid 1–42, total tau, pTau181) immunoassays (Fujirebio Diagnostics, Malvern, PA, US) and the qualification of the specimen collection and storage tubes that are now being used in an ongoing clinical trial, INTERCEPT-AD. Methods: The CSF research sample inventory at PrecisionMed LLC. provides a comprehensive list of clinical criteria for diagnosis, such as donor ID, age baseline, age at visit, gender, ethnicity, baseline diagnosis, visit number, Mini Mental State Examination (MMSE), sample volume, Clinical Dementia Rating (CDR), Hachinski score and a Case Report Form (CRF). Biomarker data available from PrecisionMed LLC. (e.g., AßN-42, AßN-40, AßN-38, total tau) are generated on the Mesoscale Discovery platform (MSD), using the Aß Peptide Panel Kit K15200G and Human Total Tau Kit K15AGPS. No CSF phospho Tau or plasma biomarker data were available at the time. We have applied the following selection criteria to identify samples from subjects with dementia due to Alzheimer’s disease (AD), subjects without dementia, or healthy controls. For all subjects the age group was more than 65 years and preferably first visit. For subjects with dementia due to AD, low MMSE scores, the ratio Aß42/Aß40 less than 0.06, total tau more than 600 pg/mL but not extremely high, and no extremely low values for Aß40 and Aß42, normally not detected in samples from AD or healthy control. Five control CSF samples and eight AD CSF samples were selected for further analysis. To evaluate antigen retrieval and potential loss via passive absorption when using selected tube types, we aliquoted each CSF sample in two different reagent tubes: Fujirebio (low protein binding, part of the kits), Sarstaedt tubes (Low protein-binding, Sarstedt Inc, cat 72.694.600), One series of Sarstaedt tubes was left at room temperature for 30 minutes prior to freezing to verify potential adsorption problems. Another series was pre-washed before further processing. All samples were frozen and subsequently processed for biomarker concentration batch-mode analysis in the facilities of Fujirebio Diagnostics, USA. Results: CSF analytes were measured in all selected samples (n=13) using the low-protein binding tubes from Sarstaedt. Results were compared to values obtained in low protein binding tubes from Fujirebio. First, our selection criteria applied to the Precisionmed CSF biomarker list allowed us to differentiate CSF samples with or without an AD biomarker profile and subsequently compare CSF biomarker levels quantified with the Lumipulse® immunoassays for total tau, pTau181, Aß1–42, and Aß1–40. The best separation of AD and non-AD samples was obtained using the MSD ratio of Aß42/Aß40 as described in the research databank. Secondly, samples were tested after aliquotation, after one extra serial transfer, and after pre-wetting tubes before addition of CSF. These experiments were done to simulate sample handling in the lab. Results revealed no adsorption problems for the Sarstaedt tubes for individual analytes or for a ratio of analytes. Conclusions: The applied selection criteria for identification of biomarker levels in CSF samples provided by PrecisionMed LLC. via the MSD multiplex assay identified AD and healthy control samples suitable for further analysis. Comparison of the MSD assay platform with the FDA-cleared Lumipulse® immunoassays showed a good correlation in values for all samples for AßN-42, AßN-40, and total tau. In addition, the evaluation of selected Sarsteadt tubes for levels of absorption and loss of biomarker signal further confirmed reagent suitability for use in clinical trials.
P113- DETECTION OF CSF ALPHA-SYNUCLEIN IN PATIENTS WITH PRODROMAL LEWY BODY DISEASE. M. Plastini1, C. Abdelnour1, M. Shahid1, M. Medina2, N. Kha2, H. Hovren2, J. Lamoureux2, V. Henderson1, K. Poston1(1. Stanford University — Palo Alto (United States), 2. Amprion Clinical Laboratory — San Diego (United States))
Background: Lewy body disease (LBD) is characterized by the deposit of intracytoplasmic inclusions of misfolded alpha-synuclein (αSyn) and ubiquitine named Lewy bodies and Lewy neurites. LBD is clinically classified as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and is considered the second most common cause of neurodegenerative dementia. Before the dementia stage, patients can present several prodromal presentations: mild cognitive impairment (MCI), isolated REM sleep behavior disorder (iRBD), delirium onset, among others. In addition, misfolded αSyn can co-occur with other pathologies in mixed etiology dementias, such as patients with clinical Alzheimer’s dementia (AD). Identifying underlying pathologies at the prodromal stage or in mixed etiology dementias is of particular interest when developing proteinopathy-specific therapies. Although some biomarkers like FP-CIT SPECT or PET imaging and 123iodine-MIGB myocardial scintigraphy have shown good sensitivity for LBD diagnosis, they can lack specificity and are not proteinopathy specific. A novel approach utilizing Seed Amplification Assay (SAA) technology could overcome this challenge. This new technique has been clinically validated to detect aggregates of misfolded αSyn in cerebrospinal fluid (CSF) of patients with PD and DLB demonstrating high sensitivity and specificity. However, little is known about the performance of SAA testing in patients with MCI. Objectives: Our objective was to determine whether the SAA test detects aggregates of misfolded αSyn in the CSF from patients with MCI, AD, and LBD. Our hypothesis is that the αSyn-SAA will correctly identify patients with MCI due to LBD and distinguish these from patients with MCI due to AD neuropathologic change. Methods: We studied 154 cross-sectional CSF samples from the Stanford ADRC and Pacific Udall Center. Clinical evaluation included history, physical examination, neuropsychological assessments, and general neurological examination, including detailed motor testing. Final motor and cognitive diagnosis were determined during a consensus meeting after each annual visit. CSF was collected via lumbar puncture using a 20–22 G spinal needle that was inserted in the L4-L5 or L5-S1 interspace and CSF was collected in polypropylene tubes. The tubes were immediately frozen at -80°C in a centralized freezer. Samples blinded to all clinical and demographic data were tested in Amprion’s CLIA Laboratory for the presence of misfolded αSyn aggregates using a SAA test (SYNTap® Biomarker Test). The SAA platform is based on amplification of minute levels of misfolded aggregates of αSyn present in CSF to levels that can be detected by Thioflavin T fluorescence. Chi squared test was conducted for analysis between categorical variables. The Wilson-Brown method was used to calculate the sensitivity and specificity of the αSyn-SAA test for the detection of αSyn aggregates in the CSF. Results: The final diagnostic groups included 69 LBD spectrum [34 PD-normal cognition, 21 PD-MCI, 14 PD-Dementia/DLB), 22 AD, 29 MCI and 34 sex and age-matched healthy controls. First, we compared healthy controls and PD normal cognition to determine the concordance between LBD diagnosis and αSyn-SAA testing in a cognitively normal population. CSF αSyn was detected in 88.24% of PD patients compared to 11.76% of controls (p <0.0001). We next studied participants with MCI, with and without an LBD diagnosis. Similarly, CSF αSyn was detected in 85.71% of PD-MCI patients compared to 17.24% of MCI patients (p <0.0001). Finally, we compared participants with dementia, with and without an LBD diagnosis. CSF αSyn was detected in 85.71% of PDD/DLB compared to 13.64% of AD cases (p <0.0001). Interestingly, of the 82.76% of MCI cases that had no αSyn detected, 42.31% have at least one APOE4 allele. Future studies will determine whether combining genetic and protein misfolding assay data can best predict clinical subgroups in MCI cases and give insight into possible future co-pathologies. Conclusion: Early detection of αSyn aggregates by SAA testing can help identify LBD patients prior to dementia onset and identify clinical AD patients with likely underlying mixed etiology dementia. Together, these data suggest αSyn-SAA testing can widen the therapeutic window to provide earlier interventions and personalized therapeutic options. Future studies determining whether αSyn-SAA can be used to track disease progression and determining its relationship with other CSF protein biomarkers, like amyloid and tau, is warranted. COI Disclosure: Manuel J Medina, Nelson Kha, Hanna L. Hovren, Jennifer Lamoureux are employees of Amprion and Dr. Kathleen Poston is an advisor to Amprion.
P114- EFFECT OF BUTYRYLCHOLINESTERASE GENOTYPE ON PATIENTS WITH ALZHEIMER’S DISEASE TREATED WITH RIVASTIGMINE. H. Kim1,2, S.Y. Cho3, G. Nam2, K. Kim2,4, E. Kim3, J.Y. Lee2(1. Emocog Inc. — Seoul (Korea, Republic of), 2. Department of Psychiatry, Seoul Metropolitan Government-Seoul National University Boramae Medical Center — Seoul (Korea, Republic of), 3. Department of Psychiatry, Institute of Behavioral Science in Medicine, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine — Seoul (Korea, Republic of), 4. Epi Biotech Co., Ltd. — Incheon (Korea, Republic of))
Background: Acetylcholine (Ach), a cholinergic neurotransmitter, regulates many brain processes such as memory, learning, and behavior. Acetylcholinesterase and Butyrylcholinesterase (BChE) hydrolyze Ach for normal cholinergic function. BChE gene (BCHE) is known to influence the onset and progression of Alzheimer’s disease (AD). Studies have been published on the effects of the BCHE K variant (BCHE-K), the most common BCHE polymorphism, on AD, but the results are conflicting. Objectives: In this study, we investigated how the genotype of BCHE affects the changes in cognitive function, gray matter volume, and cortical thickness in AD patients treated with rivastigmine. Methods: Blood samples were genotyped for the BCHE-K. The Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) scores and brain magnetic resonance images (MRI) of AD patients were collected before and after the rivastigmine treatment. The degree of change over time was analyzed according to BCHE genotype. Results/Conclusion: BCHE genotype significantly affected the changes in cognitive function and brain anatomy of AD patients treated with rivastigmine for 1 year. The protective effect of wild-type BCHE (BCHE-WT) on the cognitive function of AD patients was identified by measuring total score of ADAS-cog 12-item. Among 12 items, word finding, constructive praxis, and orientation were significantly correlated with BCHE genotype. However, in patients with BCHE-WT, the brain atrophy rate, particularly in frontal lobe, was higher than the patients with BCHE-K. These results suggest that BCHE-WT does not affect the spontaneous progression of brain atrophy in AD, but is sufficient to maintain the cognitive function in response to the rivastigmine treatment.
P115- IMPACT OF ALZHEIMER’S DISEASE BIOMARKER DISCLOSURE TO COGNITIVELY UNIMPAIRED INDIVIDUALS: EXPERIENCES FROM A TRUNCATED RANDOMIZED PHASE 2B/3 CLINICAL TRIAL. J. Grill1, R. Raman2, G. Miller2, K. Ernstrom2, M. Donohue2, P. Aisen2, R. Sperling3, D. Henley4, H.R. Brashear4, G. Romano4, G. Novak4(1. University of California Irvine — Irvine (United States), 2.Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, USA — San Diego (United States), 3.Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA — Boston (United States), 4. Janssen Research & Development LLC — Titusville (United States))
Background: Numerous ongoing and planned clinical trials are testing putative disease modifying therapies for Alzheimer’s disease (AD) at preclinical stages, prior to the onset of demonstrable symptoms. These studies simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals. Objectives: To report psychological safety and impact of biomarker disclosure on participants with preclinical AD in the EARLY trial (ClinicalTrials.gov Identifier: NCT02569398). Methods: We used data from a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018. Participants aged 60–85 years and deemed cognitively unimpaired (Clinical Dementia Rating Scale score of 0) were disclosed a binary AD biomarker result as having elevated or not elevated brain amyloid levels, based on amyloid PET imaging or cerebrospinal fluid (CSF) amyloid protein analyses. The study was conducted at 143 centers across 14 countries. We compared elevated and not elevated amyloid groups prior to testing and disclosure on the 15-item Geriatric Depression Scale (GDS), the six “state” items of the State-Trait Anxiety Scale (STAI), and the Columbia Suicide Severity Rating Scale (CSSRS). Additional scales assessed specific disclosure outcomes, including the Concerns for AD (higher scores associated with greater concern), Future Time Perspective (FTP, higher scores associated with greater perceived future time), and Views and Perceptions of Amyloid Imaging (higher scores associated with greater endorsement of reasons for undergoing amyloid PET). After disclosure, we assessed for differences in the Impact of Events Scale (IES) measure of intrusive thoughts and distress related to a specific event, as well as the disclosure-related measures. Comparisons between groups (elevated vs. not elevated amyloid) were performed using t-tests for continuous variables and Pearson’s Chi-Squared test for categorical variables. We used ANCOVA models to assess associations with change in scores for outcomes available pre-and post-disclosure (as the dependent variable), including amyloid group as the main independent variable and adjusting for covariates including age, sex, family history of AD, and Cognitive Function Instrument (used as a continuous measure). Results: Among 3686 screened participants, 2066 underwent amyloid PET imaging,1394 underwent CSF biomarker assessments, and 226 underwent both. Among biomarker tested participants with at least one change score on an outcome of interest (Views and Perceptions, Concerns about AD, or Future Time Perspective), 680 had an elevated brain amyloid result and 2698 had a not elevated result and were included in this analysis. We observed no differences in measures of depression (mean [SD] GDS: elevated 3.2 [3.3] vs. not elevated 3.1 [3.5]; p=0.72), anxiety (mean [SD] STAI: elevated 8.9 [2.9] vs. not elevated 8.7 [2.9]; p=0.31), or suicidality (mean [SD] CSSRS: elevated 0.25 [1.1] vs. not elevated 0.27 [1.2]; p=0.63) between the groups prior to biomarker testing. We observed slightly higher scores prior to biomarker testing among participants with elevated amyloid compared to participants with not elevated amyloid for the Concerns about AD (mean [SD]: elevated 21.1 [4.8] vs. not elevated 20.0 [4.8]; p<0.0001), Views and Perceptions of Amyloid Imaging (mean [SD]: elevated 32.4 [6.7] vs. not elevated 31.5 [6.7]; p=0.046), and Future Time Perspective (mean [SD]: elevated 44.9 [11.6] vs. not elevated 44.7 [11.1]; p=0.04). These patterns were consistent, regardless of whether participants underwent amyloid PET or CSF biomarker testing. Compared to participants learning a not elevated amyloid result (5.1 [8.4]), those disclosed an elevated amyloid result demonstrated higher scores on the IES (9.6 [10.8]) after disclosure. In an ANCOVA model that adjusted for covariates, amyloid group (elevated vs. not elevated) remained statistically significant. Younger age and female sex were also significantly associated with higher IES scores. Participants disclosed an elevated amyloid result demonstrated increased Concerns about AD scale scores overall, while those with not elevated amyloid showed decreased scores (mean change [SD], 0.61 [4.48] for elevated vs. -1.63 [4.71] for not elevated). The elevated and not elevated amyloid groups demonstrated slight increases in FTP; no difference between the amyloid groups was observed in the degree of change (mean change [SD], 1.1 [8.53] for elevated vs. 1.47 [8.14] for not elevated). Views and Perceptions of Amyloid Imaging scores increased in both the elevated (mean change [SD], 1.15 [9.75]) and not elevated amyloid groups (1.58 [9.82]), such that the difference between groups was no longer apparent after disclosure. Conclusion: AD biomarker disclosure caused greater intrusive thoughts and avoidance for participants learning an elevated compared to a not elevated result and resulted in adjustment of perceived risk for AD for all screened participants in this study.
P116- PHARMACODYNAMIC EFFECTS OF SEMORINEMAB ON PLASMA AND CSF TAU BIOMARKERS IN A PHASE 2 TRIAL IN MILD-TO-MODERATE ALZHEIMER’S DISEASE (LAURIET) S. Schauer1, J. Lee1, V. Anania1, B. Toth1, L. Honigberg1, K. Wildsmith1, V. Ramakrishnan1, M. Dolton1, S. Sanabria Bohorquez1, E. Teng1, C. Monteiro1(1. Genentech, Inc. — South San Francisco (United States))
Background: Semorinemab is a humanized anti-tau IgG4 monoclonal antibody that targets the N-terminal domain of tau and is under investigation as a treatment for Alzheimer’s disease (AD). Mild-to-moderate AD patients treated with semorinemab demonstrated a significant reduction in decline in cognition (ADAS-Cog11) relative to those treated with placebo (Lauriet study, NCT03828747). However, no treatment effects were observed on the co-primary functional endpoint (ADCS-ADL), the secondary endpoints (CDR-SB, MMSE), or on exploratory Tau PET endpoints. Longitudinal plasma and CSF samples were available from a subset of participants for fluid biomarker assessments. Objectives: To determine the effects of chronic treatment with semorinemab on plasma total Tau, plasma phospho-Tau217, CSF total Tau, CSF phospho-Tau181, phospho-Tau217, and CSF N-terminal Tau in participants with mild-to-moderate AD. Methods: Lauriet was a multicenter, double blind, placebo controlled study that enrolled 272 participants aged 50–85 years who fulfilled National Institute on Aging-Alzheimer’s Association criteria for probable AD dementia and had MMSE scores of 16–21 (inclusive) and global CDR scores of 1 or 2. Participants were initially randomized to receive monthly IV doses of either placebo or semorinemab (4500 mg) over 48 weeks, but the blinded dosing period was extended to 60 weeks for a subset of participants who experienced study disruptions attributable to the COVID-19 pandemic. CSF collection was optional; samples were obtained from 48% of participants at baseline and 20% of participants at Weeks 49 or 61. Total Tau, phospho-Tau181, and phospho-Tau217 were measured using qualified ELISAs. N-terminal Tau was measured using a targeted mass spectrometry method. Results: In participants treated with semorinemab, plasma total tau and plasma phospho-Tau217 levels increased substantially (>20-fold) compared to baseline, consistent with strong peripheral target engagement. Plasma total Tau plateaued by approximately Week 5, and plasma phospho-Tau217 peaked by Week 24. Levels for both Tau species remained elevated over the course of treatment. CSF samples were available from a subset of participants at baseline and either Week 49 or 61 (n=52) post treatment. These samples were analyzed for semorinemab exposure and four Tau indices: total Tau, pTau181, pTau217, and N-terminal Tau (amino acids 2–24; includes target epitope for semorinemab). Semorinemab pharmacokinetics in CSF and plasma were consistent with previously reported data from healthy volunteers and participants with prodromal-to-mild AD, including a mean CSF/serum ratio of 0.29% (SD 0.13). A reduction in CSF total Tau was observed with semorinemab but not placebo (change from baseline: placebo 1%, semorinemab -12%; p=0.01). Similarly, reductions in CSF pTau181 and pTau217 were observed with semorinemab but not in placebo at both Weeks 49 and 61 (pTau181 change from baseline: placebo -1%, semorinemab -14% p=0.01; pTau217 change from baseline: placebo +19%, semorinemab -27% p=0.01). No significant changes from baseline were observed for N-terminal Tau in either treatment group (change from baseline: placebo +3%, semorinemab +2%). Conclusion: In participants with mild-to-moderate AD, treatment with semorinemab resulted in increases in plasma tau levels and reductions in the levels of CSF tau species associated with AD pathology. These data provide further evidence that semorinemab engages and modulates Tau both peripherally and in the central nervous system in a manner consistent with what was previously reported from participants with prodromal-to-mild AD patients (Tauriel study, NCT03289143). The mechanistic interpretation of the observed reductions in CSF tau indices in both the Lauriet and Tauriel studies remains uncertain given that relative reductions in cognitive decline were seen with semorinemab treatment in mild-to-moderate AD (Lauriet) but not prodromal-to-mild AD (Tauriel). SS: Employee of Genentech, Inc., shareholder F. Hoffmann-La Roche, Ltd.
P117- NOVEL TECHNOLOGY PLATFORM FOR THE DIRECT AND SENSITIVE DETECTION OF CIRCULATING AD-RELATED MOLECULES IN BLOOD. C. Lim1(1. Sunbird Bio — Singapore (Singapore))
Background: Current molecular diagnostic tools of Alzheimer’s disease (AD), such as Positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) tests, are challenging to access and implement widely, impeding early detection as well as development of potential therapeutics. With the development of disease-modifying therapeutics for an exponentially growing global AD population, major efforts have been made to develop blood tests for AD as they are safe, affordable and easy to administer. However, current blood-based detection technologies under investigation are confounded by low sensitivity for the detection of brain-related molecules and poor accuracy to disease pathology. Extracellular vesicles (EVs) have recently emerged as a promising circulating biomarker for neurodegenerative diseases. Actively released by diverse cells, EVs are nanoscale membrane vesicles. They abound in blood, readily cross the blood-brain barrier, and carry diverse molecular cargoes in different organizational states. While the inherited constituents could serve as cell surrogate biomarkers, we have recently discovered that extravesicular association could reflect structural states of the bound molecules, revealing distinct subpopulations with different biophysical and/or biochemical properties. Objectives: To develop a scalable and versatile molecular detection platform for the investigation of diverse circulating EV-associated biomarkers to facilitate AD detection for disease diagnosis and monitoring. Methods: Leveraging on our discovery that prefibrillar Aβ preferentially associates with EVs, we developed a dedicated detection platform that is size-matched for the enhanced detection of exosomes directly from blood. Termed amplified plasmonic exosome (APEX) platform, it is designed to overcome numerous challenges of blood-based measurement of EV-associated biomarkers. Unlike conventional sensing technologies with limited compatibility to reveal nanoscale EV features, the highly sensitive APEX platform technology uses Transmission Surface Plasmon Resonance to enable the detection of EVs directly from biofluids, such as blood, without any pre-enrichment. The direct detection of intact EVs preserves the extra-vesicular association of EVs with molecules, thus enabling the in-depth study of different EV-associated molecules that were previously challenging to detect due to limitations in conventional technologies. Using the APEX technology, we conducted blood-based measurements of the total, unbound and EV-associated Aβ populations in a clinical cohort with subjects across the AD spectrum, as well as clinical controls with vascular dementia. Through recent developments, we have advanced the APEX platform by implementing design improvements on the platform for scalability. Not only is the newly developed platform capable of multiplexing with increased throughput, it is also highly adaptable for the detection of diverse EV-associated biomarkers in circulation. Result: We have found that the extravesicular association of Aβ proteins could reflect the aggregation states of the bound proteins, thereby enabling biophysical and biochemical subtyping of the associated biomarkers, to achieve more accurate blood-based characterization of neurodegenerative diseases. Blood-based APEX measurements of EV-associated Aβ showed a very good correlation to PET imaging measurements of amyloid deposition in the brain, unlike measurements of circulating total and unbound Aβ populations. With the recent improvements in the design and fabrication process of the sensor chips, the sensors are fabricated with standard manufacturing processes. Through partnerships with commercial foundries, the current sensor chips can robustly fabricated and scaled up to demand. The improved APEX platform is highly versatile for the detection of different disease-related and cell-origin related markers, making it highly compatible for exploring novel biomarkers as well as investigating different types of EV subpopulations in circulation. To demonstrate its capabilities, we have developed a panel of assays for the detection of a variety of EV-associated biomarkers. Conclusion: We have developed a scalable and versatile platform technology, specifically designed for the investigation of EV-associated biomarkers directly from biofluids. We have demonstrated its capability in the development of an accurate blood test for AD. Specifically, we conducted direct blood-based measurement of EV-associated Aβ in an AD clinical cohort, and showed that the APEX measurements reflect amyloid deposition in brain measured by PET imaging. With the ability to detect EVs directly from a small volume of blood, the platform has the potential to reveal new insights through the evaluation of novel subpopulations previously masked by bulk measurements. Moreover, it can be easily adapted for the detection of diverse markers of interest to investigate other features of the AD pathology, facilitating the further development of accurate and comprehensive tests that are reflective of disease pathology in AD.
P118- RECRUITMENT OF AMYLOID POSITIVE INDIVIDUALS AND EARLY ALZHEIMER’S PATIENTS IN A PRIMARY CARE SETTING — RESULTS FROM THE BIOFINDER PRIMARY CARE STUDY. S. Palmqvist1, P. Tideman1, E. Stomrud1, R. Smith1, A. Leuzy1, S.J. Jasem1, N. Mattsson-Carlgren1, A. Orduña Dolado1, S. Janelidze1, O. Hansson1(1. Lund University — Malmö (Sweden))
Background: Primary care units serve as the first point of contact for patients with cognitive impairment. From there, only a minority are referred to memory clinics and other specialist settings where tools with high diagnostic accuracy for Alzheimer’s disease (AD) are available. To improve the diagnostic accuracy of AD, facilitate correct referrals to memory clinics, and enable a broader enrolment of participants to clinical AD trials, it is of great importance to implement new tools in the diagnostic work-up of cognitive impairment in primary care. Objectives: To examine the diagnostic accuracy of plasma phosphorylated-tau217 (P-tau217) implemented in primary care as a test of β-amyloid (Aβ) positivity and AD, alone and in combination with other accessible measures. Methods: Data used in the analyses were collected from the BioFINDER Primary Care study which consecutively enrolls patients seeking care due to cognitive symptoms at 20 primary care units in Sweden. P-tau217 was measured using a Meso Scale Discovery (MSD) assay in monthly batches from plasma collected at the primary care units. Patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) or mild dementia were included. Aβ status was determined using CSF Aβ42/Aβ40 or Aβ PET. All patients underwent a full investigation at the BioFINDER Memory Clinic, including lumbar puncture or Aβ PET, neuropsychological testing and assessment by senior specialists in dementia disorders (blinded to plasma and cognitive test results from primary care). Results: 193 patients had complete Aβ and plasma P-tau217 data. The mean (range) age was 75.8 (60–90). 27% had SCD, 17% were diagnosed with MCI due to AD, 18% with dementia due to AD, 33% with MCI due to other causes, and 5% with dementia due to other causes. 56% were Aβ positive. Plasma P-tau217 discriminated Aβ positives versus negatives with an AUC of 0.88 (95% CI 0.83–0.93). Adding APOE genotype increased the AUC to 0.90 (0.86–0.94). For AD versus non-AD, plasma P-tau217 had an AUC of 0.86 (95% CI 0.80–0.91). Combined with APOE, the AUC increased to 0.88 (0.83–0.93). A predefined diagnostic AD algorithm consisting of plasma P-tau217, APOE genotype, and 10-word delayed recall (Palmqvist et al., Nature Medicine, 2021) was examined. When applied to a subset of the BioFINDER Primary Care dataset (n=132), it had an AUC of 0.92 (95% CI 0.87–0.97). Based on the individual probability for AD, it correctly identified 93% of non-AD patients as having a low risk of AD and 84% of AD patients as having a high risk. Only 6% were classified as borderline cases (of which 40% had AD). Conclusion: In this pilot analysis, we show that P-tau217 analyzed in monthly batches using plasma collected and handled in primary care has a high accuracy for Aβ status and AD in an unselected primary population. Plasma P-tau217 combined in an algorithm with cognitive testing and APOE show potential as a diagnostic decision support tool for primary care physicians. Updated results with patients recruited during the summer and fall of 2022 will be presented at the conference, including the effect of adjusting plasma analyses for body mass index, kidney function and co-morbidities.
P119- DEEP PLASMA AND CSF PROTEOMICS PROFILING OF THE AMBAR STUDY. C. Feng1, R. Gonzalo2, C. Minguet2, P. Lafuente2, A.M. Ortiz2, S. Lohr1, M. Boada3, O. López4, A. Paez2, S. Braithwaite1, M. Costa2, B. Lehallier1(1. Alkahest, a Grifols company — San Carlos (United States), 2. Grifols — Barcelona (Spain), 3. Universitat Internacional de Catalunya — Barcelona (Spain), 4. University of Pittsburgh — Pittsburgh (United States))
Background: AMBAR (Alzheimer’s Management By Albumin Replacement) is a multicenter, randomized, double-blinded, placebo-controlled, phase 2b/3 clinical trial to evaluate the efficacy of plasma exchange (PE) with albumin replacement (PE-Alb) in participants with mild-to-moderate Alzheimer’s disease (AD). Previous analyses detected significant improvement in cognitive functions in PE-treated participants compared to participants in the placebo group (Boada et al. 2020; Boada, Martinez-Lage, et al. 2021; Boada, Lopez, et al. 2021). Since PE-Alb strongly modulates proteins abundance and function, monitoring proteomics changes in plasma and CSF offer a unique opportunity to better understand molecular mechanisms of therapeutic treatment and to identify potential biomarkers for new drug target and patient selection. Here we report the results of the plasma and CSF proteomics profiling of more than 7000 unique proteins in subjects enrolled in the AMBAR trial. Objective: To identify proteomics responses and to understand molecular mechanisms of PE-Alb treatment. Methods: The AMBAR treatment consists in an intensive period comprising 6 weeks of conventional therapeutic PE (TPE: processing 1 plasma volume [≈2500- 3000 mL]) with albumin 5% replacement (1 TPE/week) followed by a maintenance period of 12 months of low volume PE (LVPE: removing approximately 1/3 plasma volume [≈690- 880 mL]) with albumin 20% replacement (1 LVPE/month) for all active arms. A total of 671 plasma samples (from 148 subjects in 5 visits) and 422 CSF samples (from 144 subjects in 3 visits) were analyzed using the aptamer-based proteomic technology SomaScan (SomaLogic, Boulder, Colorado, US). The 5 visits for plasma proteomics included baseline, immediately after the first TPE, intermediate (1–2 weeks after the intensive period), immediately after the first LVPE and end of study (EOS) (1–2 weeks after the maintenance period). The 3 visits for CSF samples covered the baseline, intermediate and EOS. Adjusted linear mixed models were used to identify proteins significantly changed after PE treatment at different times, and pathway enrichment analysis was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Results: Our analyses detected profound acute proteomic changes in the plasma proteome after PE treatment in mild-to-moderate AD. Immediately after the first TPE, 88% of plasma proteins were significantly changed and majority of them were downregulated (98%, based on BH corrected pvalue, q<0.05). On the other hand, dozens of proteins were up-regulated, part of them might be due to albumin injection and the rest reflecting acute response to PE. TPE treatment significantly down-regulated 461 proteins (log2FC < -1 and q<0.05) that were enriched for biological pathways increased in AD including humoral immune response, inflammatory response, and ion transport (Calabro et al. 2021; Seto et al. 2021; Ramachandran et al. 2021; Rayaprolu et al. 2021). TPE treatments also significantly up-regulated 39 proteins (log2FC>1 and q<0.05) that were involved in pathways decreased in AD such as Wnt signaling pathway (Ramachandran et al. 2021; Rayaprolu et al. 2021). The LVPE procedure acutely affected 27% of the plasma proteins with both down-regulation and up-regulation but with a smaller magnitude than acute TPE procedure. LVPE treatment significantly down-regulated regulatory RNA binding (based on 107 proteins with log2FC< -0.5 and q<0.05), which was found to be increased in AD patients (Rayaprolu et al. 2021) and up-regulated chromatin remodeling pathways, such as DNA methylation (based on 25 proteins increased log2FC>0.5 and q<0.05), which was decreased during AD progression and caused overexpression of AD-related genes (Yi-Ping Zhu 2015). Proteomics analysis also detected lasting effect of TPE in both plasma and CSF proteomes. There were 29 plasma proteins remaining significantly changed 1–2 weeks after the intensive period, mainly down-regulated and significantly enriched in immune response pathway. One of them was also significantly down-regulated in CSF samples after 6-week TPE period. Neither plasma proteins nor CSF proteins remained significantly changed at EOS after correction for multiple comparisons but 5 plasma proteins were strongly modulated weeks after the last PE (p.value<0.0005). Down-regulated proteins were involved in complement activation, calcium signaling, CREB, and Reelin pathways, while up-regulated were in Wnt signaling and immune response. Conclusion: Our deep proteomics profiling detected complex changes after PE-Alb treatment and demonstrated that PE-Alb-related response could last for weeks in plasma and CSF. Multiple pathways were modulated after PE-Alb, including a downregulation of the immune and inflammatory responses, supporting the multimechanistic basis of AMBAR therapeutic approach that may contribute to slowing AD progression. These results deserve further investigation and validation. Conflict of interest: CF, SL, SB, BL are employees of Alkahest, a Grifols company, RG, CM, PL, AO, AP, MS are employees of Grifols.
P120- ASSOCIATION OF NEIGHBORHOOD-LEVEL SOCIOECONOMIC. G. Ennis1, M. Zuelsdorff1, R. Powell1, T. Betthauser1, W. Buckingham1, Y. Ma1, C. Van Hulle1, M. Carboni2, G. Kollmorgen3, C. Gleason1, S. Johnson1, K. Blennow4, H. Zetterberg4, A. Kind1, B. Bendlin1(1. University of Wisconsin - Madison - Madison (United States), 2.Roche Diagnostics International Ltd - Rotkreuz (Switzerland), 3.Roche Diagnostics GmbH - Penzberg (Germany), 4. University of Gothenburg - Gothenburg (Sweden))
Background: Social determinants of health are the conditions within the environments in which people are born, live, and age that affect a wide range of health outcomes and risks. Socioeconomic disadvantage measured at the neighborhood level has been linked to cardiovascular disease and diabetes, well-known risk factors for Alzheimer’s disease (AD) and related dementias. However, there are few studies that have examined the association between neighborhood-level socioeconomic disadvantage and the development of AD pathology and subsequent neurodegeneration. A cross-sectional study of cognitively unimpaired middle-aged and older adults found that living in the most disadvantaged neighborhoods was related to lower total cerebral and hippocampal volume. A postmortem study reported that living in the most disadvantaged neighborhood at year of death was associated with increased odds of AD neuropathology. The present study sought to build upon these findings by examining the relationship between neighborhood-level disadvantage and cerebrospinal fluid (CSF) biomarkers of AD pathology (β-amyloid 42/40 and phosphorylated-tau [P-tau]), total-tau (T-tau), neurodegeneration (neurofilament light chain [NfL]), and synaptic degeneration/dysfunction (neurogranin) in a sample of predominantly nondemented middle-aged and older adults. Objective: We tested whether middle-aged and older adults living in the most (vs. least) disadvantaged neighborhoods had on average lower concentrations of CSF β-amyloid 42/40 and higher concentrations of CSF P-tau, T-tau, neurogranin, and NfL. Methods: Participants (N=622) were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or the Wisconsin Alzheimer’s Disease Research Center (WI-ADRC) Clinical Core and had 1–7 CSF samples collected as part of study participation. 33.1% had >1 CSF samples collected over an average of 4.8 years. At baseline, mean age was 63.3 years (standard deviation = 8.7), 62.2% identified as female, 8.0% had MCI, and 7.7% had dementia (n=1 converted to dementia during follow-up). 40.4% were APOE4 allele carriers and 95.5% were non-Hispanic White Americans. Neighborhood-level disadvantage was assessed using the Area Deprivation Index (ADI), a measure based on American Community Survey 5-year averages of socioeconomic disadvantage collected at the Census Block Group (i.e., neighborhood-level). ADI scores were ranked into relative deciles based on Wisconsin statewide distributions. A dichotomous ADI variable constructed from these rankings allowed comparison between the most disadvantaged (deciles 9–10) and the least disadvantaged (deciles 1–8) neighborhoods. Twenty-seven participants were in the most disadvantaged group. CSF biomarkers of AD pathology (β-amyloid 42/40 and P-tau), total-tau (T-tau), and neurodegeneration (NfL and neurogranin) were measured with the Roche NeuroToolKit panel using either the Elecsys® β-Amyloid (1–42), Total-Tau and Phospho-Tau (181P) CSF immunoassays, or robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Linear mixed-effects models tested the relationship between dichotomous ADI and average concentration of CSF biomarkers of AD pathology, total-tau, and neurodegeneration. Age, sex, APOE4 carriership and cognitive status were controlled. Follow-up linear regression sensitivity analyses were performed to test the relationship between ADI and baseline CSF biomarkers in cognitively unimpaired participants (n=518), controlling for age, sex, and APOE4 carriership. CSF P-tau, T-tau, neurogranin, and NfL were natural log-transformed to meet model assumptions. Results: The most disadvantaged group (n=27) did not significantly differ from the least disadvantaged group (n=595) in age, sex, APOE4 carriership or cognitive status. A greater proportion of participants who identified as Black Americans were in the most disadvantaged group (5/27 vs. 15/595). In linear-mixed effects models controlling for age, sex, and APOE4 carriership, ADI (0=least and 1=most disadvantaged) was not significantly associated with CSF β-amyloid 42/40 and ln(NfL) but was significantly related to higher concentrations of CSF ln(P-tau) [β= .41, p= .02], ln(T-tau) [β= .39, p = .04], and ln(neurogranin) [β= .47, p = .02]. The addition of the social construct self-identified race (Black vs non-Black) as a covariate did not change results. The pattern of relationships between ADI and CSF biomarkers was similar when testing the baseline data of cognitively unimpaired participants (n=22 in most disadvantaged group). Associations between ADI and CSF ln(P-tau), ln(T-tau), and ln(neurogranin) were not statistically significant (ps = .06 to .07) when controlling for age, sex, and APOE4 carriership but were significant when self-identified race was added as a covariate: ln(P-tau) [β= .42, p= .04], ln(T-tau) [β= .42, p = .04], and ln(neurogranin) [β= .48, p = .03]. Conclusions: In a sample of predominantly nondemented middle-aged and older adults, living in the most disadvantaged neighborhoods was related to higher concentration of CSF biomarkers of AD pathology (P-tau), total-tau (T-tau), and synaptic degeneration/dysfunction (neurogranin). These findings support previous research indicating that neighborhood-level socioeconomic disadvantage may contribute to AD pathology and neurodegeneration. Because the size of the most disadvantaged group was small and few participants in that group had >1 CSF samples, we were unable to test the relationship between ADI and longitudinal change in biomarkers. Longitudinal studies with greater sociocontextual representation are needed to investigate mechanisms accounting for associations found here and to examine whether neighborhood-level disadvantage accelerates tau and neurogranin trajectories prior to dementia onset. Conflict of interest: AK, BB: NIA (R01-AG070883); AK, BB, TB: NIA (RF1-AG057784); SJ, TB: NIA (RF1-AG027161); SJ, TB: NIA (R01-AG027161); AK, BB, SJ, TB: NIA (P30AG062715); CG: NIA (R01-AG054059); GE: Alzheimer’s Association 2019-AARF-643973; KB: Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236); HZ: Swedish Research Council (2018-02532); European Research Council (#681712); Alzheimer Drug Discovery Foundation (ADDF) (#201809-2016862); AD Strategic Fund and the Alzheimer’s Association (ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C); Olav Thon Foundation; Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor; Hjärnfonden (#FO2019-0228); European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (#860197); UK Dementia Research Institute at UCL; MZ: Alzheimer’s Association (AARF-18-562958); NIA (R03AG063303).
P121- USE OF THE PRECIVITYAD BLOOD TEST IN REGULAR CLINICAL PRACTICE: PRELIMINARY OBSERVATIONS FROM A DEMENTIA CLINIC. J. Drake1,2, L. Daiello1,2, C.K. Wu1,2(1. Rhode Island Hospital - Providence (United States), 2. Warren Alpert Medical School of Brown University - Providence (United States))
Background: Plasma biomarker assays represent a promising approach to addressing practical limitations to widespread availability of biomarker diagnosis of Alzheimer’s disease (AD); however, information on the use of these assays outside research settings is limited. We participated in a quality improvement (QI) program with C2N Diagnostics, LLC in order to assess the utility of the PrecivityAD blood test in the outpatient clinical setting. Objective: To describe clinicians’ perspective of the feasibility, patient acceptability, and diagnostic utility of PrecivityAD blood test use in routine dementia clinic practice in comparison with other available AD-specific biomarker modalities. Methods: A limited number of PrecivityAD blood test kits were provided to our neurology subspecialty dementia clinic as part of the QI program at a discounted out-of-pocket cost to patients. Diagnostically challenging patients in whom AD was etiologically possible and biomarker diagnosis had the potential to change prognosis and/or management as part of routine clinical care were offered the PrecivityAD blood test in addition to lumbar puncture (LP) and amyloid PET imaging. Potential for physician bias was minimized by equitably discussing strengths and limitations of each assay with patients as part of good clinical practice. Results: The PrecivityAD blood test was more feasible to implement and universally more acceptable to patients within the workflow of routine clinical practice, given the convenient nature of blood-based diagnostics. It should be noted that patients found the non-invasiveness of the blood test and amyloid PET similarly appealing; however, the steeply discounted cost of the blood test as part of the QI program was a clear influence versus amyloid PET, in addition to the convenience of a simple blood-based test that could be obtained the same day. Patients were able to understand the Amyloid Probability Score (APS), the main result of the PrecivityAD blood test, in the context of routine diagnosis and management in a similar manner to CSF biomarker or amyloid PET results in our hands. Analogous to routine clinical use of CSF biomarkers, strongly positive or negative APS results of the PrecivityAD blood test were the most diagnostically useful. APS results that were intermediate and/or incongruent with Aβ42/40 ratio were of limited utility in informing management. Conclusion: In our experience, the convenience and non-invasiveness of a plasma-based AD biomarker assay such as the PrecivityAD blood test offered clear advantages to LP and amyloid PET imaging in routine clinical practice. Lack of insurance coverage for plasma- and PET-based diagnostics still remains a significant barrier to more widespread biomarker diagnosis, based upon our informal observations in clinical discussions. Practically speaking, the APS value was easy to interpret, disclose to patients, and integrate into routine clinical care, analogous to use of CSF- and PET-based biomarkers. However, one general limitation in the confident use of plasma-based biomarkers for informing diagnostic and management decisions was the novelty of an indirect measure of cerebral amyloid, in contrast with CSF- or PET-based biomarkers. Another limitation specific to APS use arose in some cases where the APS and Aβ42/40 ratio were incongruent. Further validation of plasma biomarkers and use of a probability-oriented scoring system will be important for guiding evidence-based use of this modality in routine clinical practice.
P122- GENOME-WIDE ASSOCIATION STUDIES OF ARIA FROM THE ADUCANUMAB PHASE 3 ENGAGE AND EMERGE STUDIES. S. Loomis1, R. Miller1, C. Castrillo-Viguera1, K. Umans1, W. Cheng1, J. O’gorma1, R. Hughe1, S. Budd Haeberlein1, C. Whelan1(1. Biogen - Cambridge (United States))
Background: Amyloid-related imaging abnormalities (ARIA) refer to a range of findings detected on brain magnetic resonance imaging (MRI) that are associated with the use of monoclonal antibodies (mAbs) targeting amyloid beta (Aβ) in patients with Alzheimer’s disease. ARIA can manifest as brain edema or sulcal effusion (ARIA-E) or as hemosiderin deposits presenting as microhemorrhages (hemorrhages >1 cm) in the brain parenchyma and/or localized superficial siderosis (ARIA-H). ARIA was the primary adverse event in the phase 3 clinical trials of aducanumab, a human mAb that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils, which has been approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease. Analyses of clinical studies of Aβ-targeting therapies, including aducanumab, have indicated increased risk of ARIA in apolipoprotein E (APOE) ε4 carriers. However, the rest of the human genome has yet to be interrogated for additional genetic risk factors associated with ARIA. The systematic identification of genetic variants associated with ARIA among aducanumab treated patients may help predict individuals at greater risk of these adverse events, facilitating risk-benefit treatment decisions for patients, caregivers and prescribing physicians. Objectives: We sought to determine, in a hypothesis-free manner, whether genetic variation influences risk of ARIA in aducanumab-treated patients in the phase 3 clinical trials ENGAGE and EMERGE in genome- and exome-wide association studies (GWAS, EWAS). Methods: EMERGE (NCT02484547) and ENGAGE (NCT02477800) included participants aged 50 to 85 years with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia and confirmed amyloid pathology. Study participants were randomized (1:1:1) based on APOE ε4 carrier status to receive low-dose aducanumab, high-dose aducanumab, or placebo every 4 weeks over 76 weeks. Of the full study cohort, 2412 participants provided consent for genetic analysis, and had sufficient DNA samples available. These samples were genotyped on the Illumina Infinium Global Screening Array and exome sequenced using paired-end reads at the Broad Institute (Cambridge, MA). Genotyping and exome sequencing data underwent standard quality control, and genotyping data were imputed to the 1,000 Genomes reference panel, resulting in 9.5 million variants in the genotyping data and >560,000 variants in the exome data. For this genetic analysis of ARIA among aducanumab treated patients, we included all trial participants who were randomized and received at least one dose of study treatment (intent-to-treat [ITT] population) during the placebo-controlled or the long-term extension period, underwent at least one post-baseline MRI scan, and had quality controlled genetic data available (N=1691). GWAS and EWAS were performed separately for ARIA-E, ARIA-H microhemorrhage and ARIA-H superficial siderosis. Additionally, we ran secondary analyses stratified by symptomatic status and radiographic severity. Results: In the GWAS, we identified a genome-wide significant (p<5x10-8) association at the chromosome 19 locus encompassing APOE; no additional signals were observed beyond this region. The APOE association with ARIA was stronger in ε4/ε4 homozygotes than in ε3/ε4 heterozygotes across ARIA-E (ε4/ε4: OR=4.3, p< 2x10-16; ε3/ε4: OR=1.7, p=1.6x10-4), ARIA-H microhemorrhage (ε4/ε4: OR=4.6, p=2.9x10-14; ε3/ε4: OR=1.5, p=0.03) and ARIA-H superficial siderosis (ε4/ε4: OR=7.8, p=7.8x10-15; ε3/ε4: OR=3.1, p=3.2x10-6). A similar pattern of larger effect sizes with increasing number of ε4 alleles for association with ARIA was observed at all levels of radiographic severity, with a trend towards increased odds of ARIA-E and ARIA-H for severe (ε4/ ε4 OR=7.0-24.6, p 2.7x10-5) vs mild (ε4/ε4 OR=3.2-5.0, p 1.4x10-5) cases. APOE ε4 was also significantly associated with both symptomatic ARIA-E and ARIA-H (ε4/ε4 OR=3.6-9.5; p 4.2x10-3) and asymptomatic ARIA-E and ARIA-H (ε4/ε4 OR=4.2-7.9, p 1.7x10-11) cases; however, APOE genotype did not modulate symptomatic status among those with ARIA (p>0.05). The EWAS showed similar results to the GWAS, with no additional robust associations beyond the APOE region. Conclusions: We found a strong, genome-wide significant association between APOE and risk of ARIA; no other genetic risk factors associated with ARIA were identified. Participants with two copies of the APOE ε4 allele showed the highest odds of ARIA-E and ARIA-H, consistent with prior studies of anti-amyloid therapies. Future, larger-scale studies may be better powered to detect genetic associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor and the most salient genetic candidate to use for prospective ARIA risk stratification. Conflict of interest: All authors are current or former employees of Biogen and hold stock in the company.
P123- LOW PLASMA AB42/AB40 RATIO IN OLDER ADULTS WITH ENLARGED PERIVASCULAR SPACES. A. Kapoor1, A. Gaubert1, A. Nguyen1, B. Yew2, J.Y. Jang1, S. Dutt2, Y. Li1, J.P. Alitin3, J.K. Ho1, A.E. Blanken2, I.J. Sible2, A. Marshall2, A. Martini1, E. Head1, D.A. Nation1(1. University of California, Irvine - Irvine (United States), 2. University of Southern California - Los Angeles (United States), 3. University of California, Irvine - Irvine (United States) - Irvine (United States))
Background: Perivascular spaces (PVS) are fluid-filled spaces surrounding arterioles, capillaries and venules in the brain, which facilitate flow of various substances and enable clearance of waste. Dilation of PVS may indicate poor fluid drainage due to accumulation of perivascular cell debris, waste, and proteins, including amyloid-beta (Aβ). Aβ deposition is currently considered a hallmark and key pathophysiological marker of Alzheimer’s disease (AD). Novel assays now allow Aβ to be measured in plasma, and low plasma Aβ42/Aβ40 ratio has been associated with higher cortical amyloid deposition and risk of developing AD. However, to the best of our knowledge, no prior study has assessed whether lower plasma amyloid levels are related to enlargement of PVS. Objective: To examine whether plasma Aβ levels are elevated in individuals with higher number of enlarged PVS visible on MRI. We hypothesized that lower Aβ levels will be associated with higher number of enlarged PVS. Methods: Independently living older adults (N = 56, mean age = 68.2 years; SD = 6.5; age range 55–84 years; 30.4% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI, and blood draw. PVS were qualitatively scored using an existing 5-point scale in the basal ganglia, and centrum semiovale. Overall PVS score was the highest score of all anatomical regions. Scores were dichotomized to low enlarged PVS burden (scores of 0–1, none or mild) or high enlarged PVS burden (score >1, moderate-severe). Plasma was assayed using the Quanterix Simoa® Neurology 3-Plex A Advantage Kit to quantify Aβ42 and Aβ40 levels and ratio was then determined. One-way ANCOVA was conducted to compare Aβ42, Aβ40, Aβ42/Aβ40 ratio between low and high enlarged PVS burden controlling for age. Results: Thirty-seven (66.1%) participants had high burden of enlarged PVS in the centrum semiovale, 17 (30.4%) had high burden in the basal ganglia and 39 (69.6%) had high overall burden. There was a significant difference in plasma Aβ42/Aβ40 ratio between low and high overall PVS burden, controlling for age (F(1,53) = 5.59 p = 0.022, η2 = .10), with lower Aβ42/Aβ40 ratio in high PVS burden group (estimated marginal mean = .050) compared to low (estimated marginal mean = .062). This difference was driven primarily by enlarged PVS in the centrum semiovale (F(1,53) = 6.07 p = 0.017, η2 = .10). No difference in plasma Aβ42/Aβ40 ratio was observed between low versus high PVS burden in the basal ganglia. No difference was observed in Aβ42 or Aβ40 levels between groups, although the difference in Aβ42 levels between low and high overall burden of PVS was approaching significance (F(1,53) = 3.65 p = 0.064, η2 = .06). Conclusion: Prior studies have demonstrated that elimination of Aβ from the brain occurs via perivascular spaces and hypothesized that failure to eliminate Aβ may contribute to the pathogenesis of AD. Our findings suggest that lower plasma Aβ42/Aβ40 ratio, which may indicate higher cortical amyloid deposition, is associated with greater dilation of PVS. Future studies are needed to elucidate the relationship between vascular damage and the pathogenesis of AD.
P124- NADALS: AN OPEN-LABEL BASKET TRIAL EVALUATING THE JAK INHIBITOR BARICITINIB IN ALZHEIMER’S DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS. S. Daneshvari1, P. Webb1, A.M. Willsv, J. Berry1, S. Arnold1, M. Albers1(1. MGH - Boston (United States))
Background: Chronic neuroinflammation has been implicated in Alzheimer’s disease (AD) pathology. JAK kinases play a central role in innate immune signaling, often triggering an interferon response. These finding converged with our independent, laboratory study that discovered a strong interferon response in autopsied AD and ALS brains with cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions. We found that cytoplasmic inclusions of TDP-43 were associated with cytoplasmic double stranded RNA (cdsRNA), a root cause of interferon signaling and JAK kinase activation. Baricitinib, an FDA approved JAK inhibitor FDA-approved for rheumatoid arthritis, COVID-19, and alopecia, is a top hit in an orthogonal machine learning approach to repurpose drugs in Alzheimer’s disease. Baricitinib rescued differentiated human neural cell death and neuroinflammation evoked by cdsRNA in a dose dependent manner. In animal models, activation of type I interferon signaling by cdsRNA leads to propagated neurodegeneration within a neural circuit. The interferon response gene, PKR, is a biosensor for dsRNA in neurons. Elevated levels of activated PKR are associated with cognitive decline and progression of disease. Baricitinib lowered PKR levels in human neural cells and baricitinib structural analog lowers levels of PKR in an AD patient. Moreover, we further validated that baricitinib rescues neuroinflammation and neuronal death in a mouse model of cdsRNA-evoked neurodegeneration. We seek to further validate this mechanism of action in patients with AD, mild cognitive decline (MCI), or subjective cognitive decline (SCD) who have elevated markers of interferon signaling in their cerebrospinal fluid (CSF). Objectives: The primary objectives of the study are: 1. to assess whether an oral dose of baricitinib 2 mg and 4 mg per day achieves measurable levels of baricitinib in the CSF of patients with AD. 2. To determine whether an oral dose of baricitinib 2 mg or 4 mg per day decreases levels of the inflammatory biomarker chemokine ligand 2 (CCL2) in the CSF of patients with AD, MCI, or SCD. The secondary objectives of the study are: 1. to determine whether an oral doses of baricitinib 2 mg and 4 mg per day decrease levels of the inflammatory biomarkers, phospho-protein kinase R (pPKR), PKR, the pPKR / PKR ratio, C-X-C motif chemokine ligand 10 (CXCL10), and Interferon Gamma (IFNG) in the CSF of patients with AD, MCI, or SCD; 2. to determine whether the oral doses of baricitinib 2 mg and 4 mg per day decrease levels of neuronal death biomarkers of neurofilament light chain (NfL), tau, and phospho-tau in CSF and TDP-43 levels in the plasma in patients with AD, MCI, or SCD. 3. to determine whether the measured concentration of baricitinib in the CSF or blood (pharmacokinetics) correlates with the changes in CSF biomarkers (pharmacodynamics); 4. to demonstrate that baricitinib 2 mg and 4 mg by mouth daily is safe and tolerable in patients with AD, MCI, and SCD. Methods: This is a leadin, open-label, biomarker-driven trial of baricitinib in patients with AD, MCI, and SCD (NCT05189106). All participants will have a lumbar puncture (LP) at screening, and if their CSF level of CCL2 is ≥ 250 pg/mL, participants will be enrolled. After 8 weeks, a baseline LP will be performed, and each participant will treated with open-label baricitinib 2 mg by mouth daily for 8 weeks. A third LP will be performed after 8 weeks on the drug. CSF examination will be conducted to measure levels of study drug in the plasma and CSF two to four hours after dosing and levels of CCL2 (MCP1), pPKR, PKR, pPKR/PKR, CXCL10, IFNG, nNfL, Abeta, tau, and phospho-tau as well as exploratory biomarkers. Blood will be collected for safety labs, and to measure levels of TDP-43 and exploratory biomarkers in the plasma. The baricitinib dose will be increased to 4 mg by mouth daily with a fourth LP and CSF examination will be conducted at the Week 16 Visit. Clinical endpoints such as the ADAS-COG, a cognitive battery will be collected at final clinic visit at 24 weeks. Results: CCL2 levels are elevated in about 50% of patients diagnosed with AD, MCI, and SCD from the Massachusetts Alzheimer’s Disease Research Center BioBank, which is consistent with the prevalence of TDP-43 inclusions in AD brains. Conclusion: We are conducting a pilot clinical trial to determine whether baricitinib 1. significantly reduces inflammatory and/or neuronal death biomarkers in the CSF, 2. is safe and tolerable in AD, MCI, and SCD patients. Unbiased analysis of proteomics of CSF samples may refine the biomarker profile of patients that responded to baricitinib. Regardless if the clinical trial achieves its endpoints, this biomarker discovery work can be incorporated into future AD clinical trials to offer more precise eligibility criteria and deep phenotyping.
P125- EXAMINING THE TRAJECTORY OF NEURODEGENERATION BIOMARKERS AND ITS ASSOCIATION WITH COGNITIVE PROFILES AND AMYLOID IN LATE MIDDLE-AGED ADULTS: RESULTS FROM THE WISCONSIN REGISTRY FOR ALZHEIMER’S PREVENTION (WRAP). L. Du1,2, T. Betthauser1,3,4, K. Cody1,3,4, E. Jonaitis1,3,4, C. Burghy1, B. Hermann1,5, B. Larget6, R. Chappell2,3, S. Johnson1,3,4,7, R. Koscik1,3,4(1. Wisconsin Alzheimer’s Institute, University of Wisconsin-Madison School of Medicine and Public Health - Madison, Wi (United States), 2. Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison - Madison, Wi (United States), 3. Wisconsin Alzheimer’s Disease Research Center - Madison, Wi (United States), 4. Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health - Madison, Wi (United States), 5. Department of Neurology, University of Wisconsin-Madison School of Medicine and Public Health - Madison, Wi (United States), 6. Department of Statistics, University of Wisconsin-Madison - Madison, Wi (United States), 7. Madison VA GRECC, William S. Middleton Memorial Hospital - Madison, Wi (United States))
Background: Several computerized methodologies for the analysis of structural magnetic resonance imaging (MRI) have been used to assess Alzheimer’s disease (AD)-related neurodegeneration. Accumulating evidence indicates that the underlying neuropathological mechanisms associated with AD begin a decade or more before the emergence of cognitive impairment. This has led to an increasing interest in understanding the order and magnitude of biomarker changes during preclinical AD, beginning with amyloid onset. Objectives: Our objectives included: 1) characterize neurodegeneration biomarker change points (CPs, age in years) and related slope parameters in a longitudinal cohort study; 2) examine how these parameters varied across cognitive trajectory clusters derived from longitudinal WRAP cognitive data; and 3) examine whether the random effects or the within-person differences between the cognitive and neurodegeneration biomarkers’ CPs differ between those with and without amyloid as measured by PET amyloid scans. Methods: WRAP participants were included in analyses for the first two objectives (n = 581), if they had at least one structural MRI scan, were dementia-free at baseline, and had longitudinal cognitive data. Neurodegeneration measures included MRI hippocampal volume z-scores (HV, adjusted for total intracranial volume [TICV]) and global brain atrophy (GBA, CSF volume / GM + WM volume). Objective 1: Person-level posterior median-estimate CPs, slopes pre- and post-CP, and intercepts at CP for the two neurodegeneration biomarkers were extracted using Bayesian random CP mixed models (BRCPMM; age = time scale). Objective 2: In a previous analysis of a larger WRAP sample using BRCPMM, we extracted posterior median person-level CPs, slopes pre- and post-CP, and intercepts at CP using longitudinal cognitive performance on a 3-test Preclinical Alzheimer’s Cognitive Composite (PACC3; n=1068). We then used these random effects and K-means clustering to identify cognitive trajectory profiles and we identified when PACC3 CPs occurred (“CP-Timing group”; before, during or after the follow-up time period: 5 (0.9%), 63 (10.8%)) and 513 (88.3%), respectively). We then compared last observed HV and GBA across cognitive trajectory profiles and CP-Timing groups; and compared the BRCPMM HV and GBA random effects using non-parametric statistics by cognitive trajectory clusters and PACC3 CP-Timing groups. Significant omnibus tests (p < .05) were followed with pairwise comparisons. For the third objective, in the subset people with ≥1 positron emission tomography (PET) [C-11] Pittsburgh Compound B scan (PiB; n = 361), we compared the PACC3, HV, GBA CPs, slopes postCP, intercepts at CP, and within-person differences between the cognitive and neurodegeneration biomarkers’ CPs using non-parametric statistics by amyloid status (A+/-, using a previously validated global DVR threshold of > 1.19). Results: Mean(sd) last MRI scan age was 67.1(6.9) years. Posterior median random CPs estimates (corresponding 95 credible intervals from 20000 BRCPMM runs) were at 67.35 [61.05, 72.74] for HV and 69.13 [61.03, 74.65] for GBA. The three cognitive trajectory profiles identified included groups at Highest Risk of cognitive decline (relatively average PACC3 performance at CP with faster decline than the other clusters both before and after CP), Intermediate Risk (generally low-average performance at CP, later age of CP and weakly negative trajectories after CP), and Lowest Risk (high-average performance at CP and positive slopes after change point). In these analyses, 40(6.9%), 223 (38.4%) and 318 (54.7%) were in the High, Intermediate, and Low Risk groups, respectively. The Highest Risk group had lower HV and higher GBA. The “after” CP-Timing group had higher HV and lower GBA than the other CP-Timing groups (p < 0.001). The highest risk group has earlier CPs, lower HV at CPs, higher GBA at CPs and decline faster after CPs in Hippocampal volume. The “after” CP-Timing group has later CPs, lower GBA at CPs and less negative slope after CPs in HV than during group. In the subset with PiB, the A+ group had earlier CP’s and worse PACC3 and HV slopes post-CP than the A- group. Relative to PACC3 CP, the median CPs and 95% credible interval of GBA was 6.4 [4.7, 8.5] years earlier, HV was 8.1 [6.5, 9.7] years earlier. The within-person paired differences between GBA and HV CP’s was 1.7 [−0.5, 3.3] between GBA and HV CP’s. Patterns differed significantly between A+ and A- as follows: PACC3 to GBA CP median differences were 6.6 for A- and 5.7 for A+ (p = 0.006); PACC3 to HV CP median differences were 8.1 for A- and 7.5 for A+ (p = 0.04). A+ and A- groups did not differ on HV to GBA CP differences. Conclusion: The timing and rates of change in neurodegeneration biomarkers differed by cognitive trajectory profiles. In this initially non-demented sample, the overall cognitive change point occurred ∼6 years later than global atrophy and ∼8 years after hippocampal volume, and HV change points occurred 1 year later in the amyloid negative group. These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. Identifying person-level neurodegeneration biomarker trajectories and their differences in CP within cognition may provide an opportunity to find sensitive biomarkers for early intervention in a clinical trial.
LP63- RACIAL DIFFERENCES IN PREDICTING CONCURRENT AND LONGITUDINAL COGNITIVE OUTCOMES BY CSF BIOMARKERS OF ALZHEIMER DISEASE AMONG COGNITIVELY NORMAL INDIVIDUALS. C. Xiong1, J. Lah2, C. Manzanares2, A. Levey2, D. Wolk3, L. Shaw3, S. Schindler1, R. Henson1, A. Fagan1, J. Hassenstab1, T. Benzinger1, Q. Bui1, F. Agboola1, J. Gray1, J. Morris1(1. Washington University - St. Louis (United States), 2. Emory University - Atlanta (United States), 3. University of Pennsylvania - Philadelphia (United States))
Background: Molecular biomarkers of Alzheimer disease (AD) are correlated with concurrent cognitive outcomes and also predict longitudinal cognitive changes in biomarker studies of predominantly White participants. Secondary prevention trials of AD enroll cognitively normal individuals with a positive profile of biomarkers of AD at baseline in hope of establishing preventive efficacy in slowing cognitive decline. Multiple recent studies have demonstrated cross-sectional differences in concentrations of the cerebrospinal fluid (CSF) proteins Aβ42, Aβ40, total tau (t-tau), and tau phosphorylated at position 181 (p-tau181) between self-reported Blacks and Whites. The consequences of these differences in designing and analyzing secondary prevention trials of AD remain, however, poorly understood. Objectives: We first aim to examine possible racial differences in predicting concurrent and longitudinal cognition by CSF biomarkers from a multicenter observational study. Based on these data, we then aim to estimate the sample size of both Blacks and Whites necessary for a future prevention trial of AD to adequately power the test of efficacy hypothesis on a cognitive endpoint. Methods: We analyzed cross-sectional CSF biomarker data and longitudinal cognitive data from cognitively normal participants from the Washington University (WU) Knight Alzheimer Disease Research Center (ADRC), UPenn ADRC, and Emory University Goizueta ADRC. The cohort included 110 self-reported Black/ African Americans and 801 self-reported White individuals. Participants underwent a lumbar puncture (LP) and received cognitive assessment at baseline, and then longitudinally after the LP. CSF samples were centrally processed via an automated immunoassay by WU and UPenn ADRC Fluid Biomarker Cores (led by Drs. Suzanne Schindler and Les Shaw, respectively) with appropriate bridging between the labs. A cognitive composite was formed by averaging the z-scores from 12 tests in the NACC UDS. We analyzed the association of each CSF biomarker with concurrent cognitive performance and its ability to predict future cognitive decline by implementing random intercept and slope models that allowed both fixed intercept (concurrent cognition) and slope (i.e., rate of change) as functions of biomarker status and self-reported race. Racial differences in the intercept and slope were estimated and tested. Assuming a future secondary prevention trial of AD enrolls Black and White participants similar to the biomarker positive groups into the placebo arm, we further estimated the sample size of both Blacks and Whites necessary to adequately power the test of efficacy hypothesis on cognition. Results: Cognitively normal Black participants had a higher level of CSF Aβ42/40 (p=0.0022), lower level of CSF t-tau, p-tau181, and NfL (p’s<=0.0070), but similar level of CSF Aβ42 (p=0.1902). CSF Aβ42/40 was correlated with concurrent cognition in Whites (r=0.18, p<0.0001) but not Blacks (r=−0.07, p=0.4505). CSF t-tau, p-tau181, and NfL correlated with concurrent cognition in Whites (r=−0.22, p<0.0001; r=−0.24, p<0.0001; r=−0.30, p<0.0001, respectively) but not Blacks (r=−0.1, p=0.3045; r=−0.05, p=0.5940; r=−0.19, p=0.0637, respectively). However, the racial difference in these correlations was statistically significant only for CSF Aβ42/40 (p=0.0137). At baseline, lower cognitive performance was observed for Blacks, in comparison to Whites (p<0.0001), both in biomarker positive and negative groups. Regardless of self-reported race, biomarker positive participants had a faster rate of cognitive decline than those who were negative (p’s<=0.0089 for all CSF biomarkers). Further, the annual rate of cognitive decline since baseline did not differ by race among biomarker positive individuals (p’s>=0.5345 for all CSF biomarkers). Using the average annual rate of cognitive decline and the associated variance components between Aβ42/40 positive Black and White participants, and assuming a race-stratified randomization in a future 1:1 (active treatment vs. placebo) secondary prevention trial with semi-annual cognitive assessments over 2 years, a total of 2886 participants (289 Black and 2597 White participants for a ratio of 1:9, i.e., 10% Blacks) are needed to power (80%) the detection of a 50% reduction on the annual rate of cognitive decline between the active treatment and placebo arm. The sample size is reduced to 1386 (347 Black and 1039 White participants) to detect the same effect size with the same power if Black enrollment is increased to 25%. When CSF p-tau181 was used to define biomarker positivity, the sample sizes were 3550 (355 Black vs. 3195 White participants=1:9) and 1704 (426 Black vs. 1278 White participants=1:3), respectively. Conclusion: Cross-sectional racial differences in CSF biomarkers of AD and their association with concurrent and future cognition among cognitively normal Black and White individuals have consequences to the design and analysis of future secondary prevention trials of AD. The similar longitudinal rate of cognitive decline among cognitively normal and biomarker positive Black and White older adults, if confirmed, however, allows these trials to target a shared endpoint. Increased representation of Black participants in these trials improves the statistical power to detect the cognitive efficacy of interventions.
LP64- BLOOD-BASED DEMENTIA PATHOLOGY STRATIFICATION UTILIZING NEURON-DERIVED EXOSOMES. E. Eitan1, O. Volpert1, K. Elgart1(1. NeuroDex - Natick (United States))
Background: Over 50M people worldwide suffer from dementia, and the numbers are rising with the aging population. While therapeutics and diagnostics in development focused predominantly on Alzheimer’s disease (AD), most (over 80%) dementia patients display a combination of pathological features (mixed brain pathology), which include amyloidosis, tauopathy, Lewy bodies, TDP43, and vascular pathology. Recently, a few targeted therapies emerged after a long period with no available disease-modifying treatments. However, these therapies are directed against amyloidosis, and patient selection based on amyloid PET scans lacks consideration of non-amyloid pathologies that could alter treatment response. Objectives: This study aims to develop a blood test to detect divergent brain pathologies associated with or leading to dementia, including Lewy bodies (alpha-synuclein), TDP43, and tauopathy. This blood test may serve as a stand-alone assay for a detailed diagnosis of dementia pathologies to enable a precision medicine approach to neurodegeneration. Alternatively, the same test can be used as a preliminary screen to determine the need for more invasive CSF and PET tests. Methods: NeuroDex’s blood assay is based on ExoSORT™, a proprietary immunoaffinity platform for isolating and characterizing neuronal extracellular vesicles (NDEs) from blood plasma. ExoSORT technology relies on antibodies against two particular neuronal markers, GAP43 and NLGN3. The downstream measurements of alpha-synuclein, alpha-synuclein phosphorylated on serine-129 residue, TDP43, and P181-Tau. Our second approach, based on Luminex technology, allows us to characterize proteins on intact extracellular vesicles (EVs) surface. This assay, dubbed Lumin-EX, measures alpha-synuclein on the outer leaflet of plasma EVs released by neurons and oligodendrocytes, multiplex measurements. Results: ExoSORT was optimized for NDEs isolation. Its specificity for NDEs was determined by the enrichment of neuron-specific proteins Tau, SYP, proBDNF, ENO2, NFL, etc., and of neuron-specific mRNA encoding NEFL, PSD95, NRGN, etc. Unbiased proteomic and RNAseq analyses also demonstrated the enrichment of neuronal markers. Moreover, we recently published a correlation between changes observed in mice NDEs and brains. The recovery of spiked neuron-specific material was used to determine about 55% recovery, which is consistent between samples and experiments. The robust nature of the method was assessed by evaluating the day-to-day precision and reproducibility of the data between multiple operators and by independent laboratories. Next, the assays were tested on a cohort encompassing patients diagnosed with AD (N=30), PD (N=40), Multiple Systems Atrophy (N=20), Dementia with Lewy Bodies (N=20), and Amyotrophic Lateral Sclerosis (N=30), as well 40 disease-free controls. In NDEs isolated using ExoSORT, alpha-synuclein measurements showed significantly higher levels in the samples from PD and LBDs than in control (2.8-fold, AUC=0.87) or ALS samples. At the same time, AD patients were segregated into two groups, wherein 40% of AD patients presented with over 2.5-fold increase, and the other 60% were all within the range of the non-disease control samples. In contrast, synuclein levels in the NDEs from MSA and ALS patients showed no significant differences from controls; However, preliminary analysis showed significantly elevated synuclein levels in oligodendrocyte-derived EVs from MSA patients (2.2-fold, AUC=0.83). Alpha-synuclein measurements on EVs surface showed similar patterns with elevated levels in PD (3.5-fold, AUC=0.83) and DLB (2.2-fold, AUC=0.81) and separated the AD samples into two groups. Surface alpha-synuclein was also significantly higher in MSA (2.4-fold). TDP43 levels were significantly higher in NDEs isolated from plasma samples of ALS patients (1.8-fold, AUC=0.91) and correlated (R=0.32, P<0.01) with the functional/behavioral scores (ALSFRS-R slope). TDP43 was also significantly higher in approximately 70% of AD samples, generating an overall significant effect (a 2.2-fold increase of the average). Furthermore, we used the Lumin-EX assay to measure synaptic proteins on the surface of plasma EVs including NRGN, PSD95, Syntaxin-1, and GLUR2. In plasma samples from AD patients, EV-associated NRGN levels were higher, PSD95 and GLUR2 were lower compared to controls, and these changes correlated (R=0.46, P<0.002) with cognition scores (MMSE and CDR). In PD, Syntaxin-1 was elevated, and GluR2 was decreased compared to the control group. We are working on expanding the clinical cohort and validating the results with plasma samples from postmortem confirmed patients, expected results before the conference. Conclusion: The methodology we developed to isolate and characterize plasma EVs opens a new avenue for neurodegenerative diagnosis. The ability to detect different dementia-associated pathologies by a single blood test can be a game-changer for clinical trials and diagnosis. When fully developed, our blood test could provide a tool to screen the elderly population for better prognosis and treatment selection. The next test generation will include other aspects like autophagy, mitochondria, neuroinflammation, and metabolism. Conflict of interest: Dr. Eitan, Dr. Volpert, and Dr. Elgart work and receive salaries from NeuroDex. Dr. Eitan is also a shareholder in NeuroDex.
LP65- SEX-SPECIFIC DIAGNOSTIC PROPERTIES OF AD PLASMA BIOMARKERS IN COGNITIVELY UNIMPAIRED AT-RISK INDIVIDUALS. M. Mila Aloma1, N. Ashton2, T. Karikari2, A. Brugulat Serrat1, E. Vanmechelen3, J. Vanbrabant3, E. Stoops3, T.A. Day4, M.T. Ferretti5, J.L. Molinuevo1, J.L. Dage6, H. Zetterberg2, J.D. Gispert1, K. Blennow2, M. Suárez-Calvet1(1. Barcelonabeta Brain Research Center - Barcelona (Spain), 2. University of Gothenburg - Mölndal (Sweden), 3. ADx Neurosciences - Ghent (Belgium), 4. Lilly Research Laboratories, Eli Lilly and Company - Indianapolis (United States), 5. Women’s Brain Project - Guntershausen (Switzerland), 6. Stark Neurosciences Research Institute, Indiana University School of Medicine - Indianapolis (United States))
Background: Increasing evidence shows promise of plasma biomarkers indicative of Alzheimer’s disease (AD) pathology to be used in clinical trials. This can be for screening purposes and/or monitor treatment response. As AD clinical trials move towards targeting the preclinical stage of the disease, it is paramount to identify those cognitively unimpaired individuals that are at a higher risk of developing AD symptomatology. There is still very limited evidence on the factors, like sex, that may influence the levels of plasma biomarkers and their performance to detect Aβ pathology. Sex is one of the main risk factors for AD and sex differences are known in disease manifestation, biomarkers trajectories and susceptibility to risk factors. However, it remains to be elucidated whether plasma biomarkers perform differently in men than in women, particularly in the preclinical stage of AD. Answering this question will have relevant implications for the accurate use of plasma biomarkers in preventive clinical trials. Objectives: To test sex differences in AD plasma biomarker diagnostic properties in cognitively unimpaired individuals at risk for AD. Methods: We studied 397 cognitively unimpaired individuals from the ALFA+ cohort (mean age 61.1 years old, 34% CSF Aβ42/40-positive) with CSF and plasma biomarkers measurements. A subset of 337 participants also had available Aβ PET visual read (VR) assessments. We measured plasma Aβ42/40, p-tau181, p-tau231, GFAP and NfL using the Simoa HD-X (Quanterix Corp) and plasma p-tau217 and t-tau using MSD-based assay measures (Eli Lilly and Company). Sex differences in the levels of plasma biomarkers were analysed with an ANCOVA adjusted by age. We performed Receiver Operating Curve (ROC) analyses and calculated the specificity, sensitivity, negative predictive value (NPV), positive predictive value (PPV) and Youden’s index to study the performance of plasma biomarkers to discriminate Amyloid-positivity (defined by CSF Aβ42/40 or Aβ PET VR) separately in men and in women. The AUC of each biomarker alone, and when combined with risk factors (age and APOE status) were compared to the risk factors alone using DeLong tests. We also performed logistic regressions adjusted by age and APOE status to study sex differences in the capacity of each plasma biomarker to predict CSF Aβ42/40 and Aβ PET VR status. We calculated the Odds Ratio (OR) for men and women and we additionally tested the interaction term between sex and each plasma biomarker. Results: Plasma p-tau217 and GFAP were higher in women compared to men (p-tau217: Mean[SD]women =0.15 [0.08] and Mean[SD]men=0.14 [0.05]; GFAP Mean[SD] women=144.63[62.53] and Mean [SD] men=129.22[60.05]; all P<0.05). We first assessed the biomarker performance to discriminate CSF Aβ42/40 positivity. In women, plasma p-tau231 had the highest AUC (0.771), followed by plasma Aβ42/40 (0.737) and GFAP (0.736), whilst highest sensitivity and NPV were rendered by plasma GFAP (S=0.728; NPV=0.821), p-tau231 (S=0.679; NPV=0.821), Aβ42/40 (S=0.630; NPV=0.803) and NfL (S=0.709; NPV=0.791). Conversely, in men, plasma Aβ42/40 showed the highest AUC, sensitivity and NPV (AUC=0.771, S=0.796 and NPV=0.855). None of the plasma biomarkers alone improved the performance of risk factors (age and APOE status) neither in women nor in men. The addition of plasma Aβ42/40, p-tau217, p-tau231 or GFAP significantly improved the performance of risk factors in women (Padj<0.01), but in men this was only achieved by plasma Aβ42/40 (Padj=0.008). For the discrimination of Aβ PET VR positivity, plasma p-tau217 rendered the highest AUC in both sexes (AUCwomen=0.843; AUCmen=0.764). In women, plasma p-tau217 also showed the highest sensitivity and NPV (S=0.885, NPV=0.977) while in men, those were highest for Aβ42/40 (S=0.938; NPV=0.976). When combined with risk factors, both plasma p-tau217 and Aβ42/40 significantly improved the performance of risk factors alone in women (Padj<0.05), but none of the combinations improved the risk factors model performance in men. Logistic regression results showed a trend to significant interactions between sex and plasma GFAP (P=0.056) and plasma p-tau231 (P=0.099) for the prediction of CSF Aβ status. Stratified analyses revealed that these two biomarkers had a higher OR in women (plasma p-tau231 OR[CI]=3.97[2.55–6.58] and plasma GFAP OR[CI]=3.15[2.09–4.99]) than in men (plasma p-tau231 OR[CI]=2.08 [1.41–3.20] and plasma GFAP OR[CI]= 1.58[1.07–2.44]). Sex did not modify plasma biomarkers capacity to predict Aβ PET VR positivity. Conclusion: While in women p-tau231, GFAP and Aβ42/40 show similar performances, in men Aβ42/40 was shown to be the most accurate biomarker for the discrimination of CSF Aβ42/40 status. To discriminate Aβ PET VR status, plasma p-tau217 is the most accurate biomarker in both sexes. Our results suggest the sex differences might be more pronounced in the discrimination of CSF Aβ42/40 status than Aβ PET status, and therefore at the earliest stage of the preclinical AD continuum. Overall, there are sex differences in the levels and the diagnostic properties of AD plasma biomarkers that, if confirmed and replicated in further studies in comparable cohorts, can have important implications for the implementation and use of plasma biomarkers for clinical trials.
LP66- BASELINE PLASMA PTAU181 IMPROVES PREDICTION OF COGNITIVE DECLINE IN AMYLOID POSITIVE SUBJECTS WITH MILD COGNITIVE IMPAIRMENT. V. Devanarayan1, P. Sachdev1, A. Charil1, A. Koyama1, L. Reyderman1, C. Swanson1, H. Hampel1, M. Irizarry1, S. Dhadda1, L. Kramer1(1. Eisai, Inc. - Nutley (United States))
Background: Blood-based tests for screening and monitoring patients in Alzheimer’s disease (AD) clinical trials would be more convenient, faster and cost-effective. Plasma pTau181 has been shown in recent studies to be a good marker of brain amyloid burden. This research evaluated the use of baseline ptau181 as a prognostic predictor of cognitive decline (CD) in amyloid positive (A+) subjects with mild cognitive impairment (A+ MCI) over a typical 18-month duration of a clinical trial. Methods: Training cohort (TC) for constructing the signatures to predict CD comprised of 135 A+ MCI placebo subjects from two clinical trials. Two independent validation cohorts for testing the performance of these signatures included 115 and 203 A+ MCI subjects respectively from placebo arm of another clinical trial (VC-1) and from ADNI (VC-2). Plasma pTau181 was measured using Simoa assay at three different sites, and were normalized to have similar means and variances to make them comparable across cohorts. TC and VC-1 included 18-month clinical follow-up, and VC-2 included 3 to 10-year follow-up. Change in clinical dementia rating sum of boxes (CDR-SB) of at least 1 was considered as faster CD. Signatures for predicting CD were constructed using Bayesian elasticnet, regularized random forests, and gradient boosting algorithms. Additional signatures were derived for assessing the added value of ApoE4 status, cognitive function assessments and brain volumetric measures from magnetic resonance imaging (MRI). Demographics (age, gender and body mass index) were considered in all evaluated signatures. Performance of these signatures was first assessed via 10 iterations of 10-fold stratified cross-validation within TC, and then tested in VC-1 and VC-2. Results from the best performing algorithm were reported. Results: Bayesian elastic net algorithm yielded signatures with optimal prediction performance. For predicting the 18-month CD, baseline plasma pTau181 achieved similar performance as baseline cognitive function, with area under the receiver operating characteristic curve (ROC-AUC) of 64.9% and 70.9%, respectively, in VC-1 (p = 0.199) and 65.3% and 66.7%, respectively, in VC-2 (p = 0.395). Adding ApoE4 count did not improve the prediction performance. When pTau181 was added to baseline cognitive function, ROC-AUC increased significantly from 70.9% to 74.7% in VC-1 (p = 0.002) and from 66.7% to 71.1% in VC-2 (p < 0.001). When pTau181 was added to baseline cognitive function and volumetric MRI features, ROC-AUC increased marginally from 77.2% to 79.2% in VC-1 (p = 0.180) and from 76.1% to 77.2% in VC-2 (p = 0.227). For predicting 36-month clinical progression from A+ MCI to mild AD in VC-2 (ADNI), adding baseline plasma pTau181 to baseline cognitive function significantly improved the prediction performance, with ROC-AUC increasing from 72.3% to 79.1% (p < 0.0001), and similarly when added to both the baseline cognitive function and volumetric MRI features, the ROC-AUC improved from 84.7% to 87.5% (p = 0.04). Conclusions: These results demonstrate the potential of baseline plasma pTau181 as a screening marker for idenfying A+ MCI subjects with faster cognitive decline over a typical 18-month duration of a clinical trial, with the performance improving significantly when combined with baseline cognitive function. Plasma pTau181 also improves the prediction of progression of MCI subjects to AD when combined with baseline cognitive function and/or volumetric MRI features.
LP67- ASSOCIATION OF CIRCULATING BRAIN-ENRICHED MICRORNAS WITH DEMOGRAPHIC AND CLINICAL FACTORS IN A4 SCREENING PLASMA SAMPLES FROM COGNITIVELY NORMAL INDIVIDUALS. M. Keifer1, K. Sheinerman2, V. Tsivinsky3, B. Martine2, R. Rissman4, S. Umansky2(1. DiamiR Biosciences - San Francisco (United States), 2. DiamiR Biosciences - Monmouth Junction (United States), 3. DiamiR Biosciences - Boston (United States), 4. University of California San Diego School of Medicine - San Diego (United States))
Background: Reliable and minimally invasive diagnostic tools are needed to better characterize patients with early stages of cognitive impairment. DiamiR’s approach combines targeted, quantitative analysis of circulating brain-enriched and inflammation-associated microRNAs (miRNAs) with an algorithm classifier. miRNAs are small non-coding regulatory RNA molecules that modulate gene expression and whose levels change in disease. Certain miRNAs are enriched in specific organs and tissues, including different brain regions. Previously we reported differentiation between cognitively normal controls and mild cognitive impairment (MCI)/ Alzheimer’s disease (AD) study participants with a panel of 24 brain-enriched and inflammation-associated miRNAs detectable in plasma. Based on these 24 miRNAs the company is developing a molecular diagnostic assay, CogniMIR, for use in clinical trials and broader clinical practice. Objectives: The main objective of the present study was to evaluate correlations and associations between the 24 miRNAs, enriched in specific brain regions, present in synapses and detectable in blood plasma, and demographic and clinical factors known to be associated with AD, such as age, sex, amyloid status, APOE genotype, p-tau and neurofilament light (NfL), in 299 plasma samples collected during screening for the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) prevention study. Methods: The 299 plasma samples were collected from cognitively normal study participants during the screen3 of the A4 study. Specifically, blood was collected into purple-capped K2EDTA tubes (BD part#3666643) and placed on ice. Samples were centrifuged for 15 min at 2000xg using refrigerated centrifuge (4°C). Plasma supernatant was aliquoted (0.5-ml aliquots) into Sarstedt tubes (cat# 72.730.217) and frozen at −80°C. Samples with signs of hemolysis were excluded. Plasma levels of 24 pre-specified miRNAs were measured by individual quantitative RT-PCR. RNA was extracted from freshly thawed 0.5 ml aliquot of plasma using a TRIzol treatment and silica (Ambion Glass Fiber Microcolumn). Single target qRT-PCR was performed using the TaqMan® Reverse Transcription Kit and miRNA-specific stem-loop primers (Thermo Fisher Scientific). The RT step was performed in triplicate, and 2-µl plasma equivalents were present in a final PCR. The analysis was conducted with the use of the algorithms and software developed at DiamiR. Our biomarker is a ratio between two miRNAs; this “pair” approach reduces variability and enhances specificity and sensitivity of the biomarker, which is especially important when detecting gradual changes caused by a slowly developing pathology. Effective miRNA pairs are combined into classifiers. Two thresholds of determining amyloid positivity status based on PET SUVR measures were used: 1.15 as an original inclusion criteria in the A4 study, and 1.33, as more recently proposed in the literature. Plasma p-tau181 and NfL levels were measured at Quanterix with the Simoa system. Results: The analysis showed statistically significant correlations of specific miRNA biomarker pairs with markers of AD, including in amyloid-positive and APOE4-carrier high-risk, clinically relevant group. In accordance with our earlier data and literature data, the correlations are significantly improved by sex-stratification of study participants. miRNA pairs and SUVR correlation plots in amyloid positive/negative, APOE4 carriers/non-carriers, and male/female subgroups demonstrate strong correlations with r = 0.33 to 0.59; p = 0.034 to < 0.001. In amyloid positive/negative subgroup, APOE4 carriers are effectively separated from APOE4 non-carriers by select miRNA classifiers. Separation of APOE4 carriers from non-carriers is improved in subgroups stratified by sex. The best separation is observed within sex-stratified amyloid positive subgroup with AUC = 0.88 for males and AUC = 0.86 for females. Correlations between other measured parameters, including p-tau181 and NfL, with each other will be presented. Conclusion: The results generated in this study indicate that levels of cell-free miRNA biomarker candidates have a strong potential to be used in combination with other AD markers and risk factors to better characterize preclinical AD patients. A confirmatory analysis with additional well-characterized samples is underway. Acknowledgment/ Support: We thank the A4 Study Team for providing the plasma samples and associated data for this project. This project was supported by the Alzheimer’s Drug Discovery Foundation (ADDF) Diagnostics Accelerator.
LP68- AGE DEPENDENCY OF PLASMA B-AMYLOID MEASURED BY FULLY AUTOMATED AND HIGHLY SPECIFIC IMMUNOASSAYS IN A JAPANESE COHORT STUDY (SESSA). K. Ishiki1, M. Moniruzzaman2, Y. Yano2, K. Kondo2, A. Kadota2, M. Miura1, S. Iwanaga1, M. Nishimura3, H. Ueshima2, K. Miura2(1. Central Research Laboratories, Sysmex Corporation - Kobe (Japan), 2. NCD Epidemiology Research Center (NERC), Shiga University of Medical Science - Otsu (Japan), 3. Molecular Neuroscience Research Center, Shiga University of Medical Science - Otsu (Japan))
Background: In recent years, blood-based plasma β-amyloid (Aβ) has been increasingly studied as a potential biomarker of Alzheimer’s disease (AD) because it is less invasive, more cost-effective, and easily accessible. Mounting evidence shows that the ratio of plasma Aβ1–42 to Aβ1–40 (Aβ42/Aβ40) is highly concordant with amyloid PET status, suggesting that it may reflect the brain Aβ pathology. Besides amyloid pathology in the brain, other risk factors for AD development are known, most notably age. Considering the use of plasma Aβ for the enrollment of subjects for clinical trials or for diagnostic adjunct purposes, it is important to understand the association between age and plasma Aβ. Because many disease-modifying therapies currently under development target the early stages before the onset of AD, it is necessary to understand the age dependency of plasma Aβ in older adults with normal cognitive function. However, several studies have reported conflicting results regarding the age dependence of plasma Aβ levels. Aβ is known to be unstable in the blood, and various factors at the time of blood collection are known to influence levels of blood Aβ. Such factors may influence the contralateral results on age dependency so far. Currently, the technique of canceling the effect by taking the ratio as Aβ42/Aβ40 is often used. On the other hand, when trying to understand the age-dependency of Aβ40 and Aβ42 alone, the handling of samples during blood collection requires rigor. Objectives: In this study, we aimed to examine the age-dependency of plasma Aβ40 and Aβ42 in a general Japanese male population using samples collected under a uniform protocol. Methods: The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) is an ongoing epidemiological study in a general population randomly selected from Kusatsu City (Japan) residents at baseline (2006–2008). The second survey was performed between 2010 and 2014 and a total of 853 men aged 46–83 participated in medical examination. After an overnight fast of at least 12 hours, we collected blood samples by venipuncture and stored them at -80 degrees Celsius until measurement. For sample collection, blood collected in a collection tube containing EDTA was mixed by gently inverting several times, then stored on ice until centrifugation. All centrifuges were performed at 4 degrees Celsius, 3000 rpm, for 15 minutes. The time from blood collection to centrifugation was within 90 minutes. After centrifugation, plasma was rapidly stored in a freezer in 500 mL aliquots. Plasma Aβ40 and Aβ42 were measured using a fully automated immunoassay platform (HISCLTM series) in 2021. Both Aβ40 and Aβ42 were measured twice, and the average was used for analysis. We evaluated the age-dependency of Aβ40 and Aβ42 based on the measurement results of 822 participants, excluding 31 participants for whom measurements could not be performed. For this purpose, we divided participants into 5 age groups at 10 years intervals and examined the age dependency of Aβ40, Aβ42, and Aβ42/Aβ40 ratio by the Kruskal-Wallis test. Results: The mean (SD) age of the participants was 69.3±7.7 years. The mean (SD) values (in pg/mL) were 181.87±33.51, 20.47±4.28, and 0.113±0.015 for Aβ40, Aβ42, and Aβ42/Aβ40 ratio, respectively. There were significant differences in both Aβ40 and Aβ42 (p < 0.001) across the age groups, but not for Aβ42/Aβ40 ratio (p = 0.307). The change per year of age was 0.88 for Aβ40 (p<0.001) and 0.05 for Aβ42 (p=0.005), showing a significant increase by age. On the other hand, the change per year of age was −0.0002 for Aβ42/Aβ40 ratio (p<0.001), showing a significant decrease by age. Conclusion: Our results showed that plasma Aβ40 and Aβ42 increase in an age-dependent manner, while the Aβ42/ Aβ40 ratio decreases in an age-dependent manner. This age-related change in plasma Aβ levels may be due to changes in production or functional changes in the blood-brain barrier. However, compared with the age-dependent changes in Aβ40 and Aβ42, the age-dependency of Aβ42/Aβ40 ratio was more gradual, with no significant differences found in the analysis divided into 5 age groups. It may suggest that age dependence may be reduced by using the Aβ42/Aβ40 ratio. Although the present results were based only on men and limited to the Japanese population, they suggest that using appropriate sample handling protocols and measurement methods may be able to assess the relationship between plasma Aβ and other factors. To further our understanding of plasma Aβ, an assessment of the association with cognitive function and other AD risk factors, as well as in women and other races, is warranted in the future.
LP69- A FULLY-AUTOMATED AND SCALABLE PLASMA PHOSPHO-TAU181 ASSAY FOR ALZHEIMER’S DISEASE. E.N. Wilson1, C.B. Young1, M. Vandijck2, J.P. Quinn3, C.H. Van Dyck4, A. Nairn4, S. Sha1, V.W. Henderson1, F.M. Longo1, M.D. Greicius1, A.D. Wagner1, T. Wyss-Coray1, K.L. Poston1, E.C. Mormino1, K.I. Andreasson1(1. Stanford University - Stanford (United States), 2. Fujirebio NV - Ghent (Belgium), 3. Oregon Health & Science University - Portland (United States), 4. Yale University - New Haven (United States))
Background: The advent of disease modifying therapies for Alzheimer’s disease has ushered in a new era of AD treatment — highlighting the need for biomarkers for early detection and treatment monitoring. Such biomarkers should be accessible and scalable for widespread implementation. Plasma P-tau181 is an accessible blood-based biomarker sensitive to AD during the preclinical phase. However, current commercially-available and prototype plasma p-tau181 assays have limited accessibility, throughput, and/or scalability that impede widespread implementation. Objectives: Our objective was to assess the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD as determined clinically or with biomarkers. Methods: Plasma samples were obtained from the Stanford University Alzheimer’s Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS). The study cohort included clinically unimpaired individuals (CU, n = 498) and patients with mild cognitive impairment (MCI, n = 110) or AD dementia (n = 78) were. In addition to its ability to predict longitudinal cognitive and functional change, we evaluated the discriminative accuracy of the Lumipulse plasma p-tau181 assay (modified from CSF version) for clinical AD diagnosis, its association with amyloid and tau concentrations in CSF. Results: The fully-automated Lumipulse Plasma p-tau181 assay showed robust clinical performance in differentiating AD dementia from CU participants (AUC 0.959). Plasma p-tau181 levels were associated with CSF measures of amyloid and tau. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. Baseline plasma p-tau181 predicted change in MoCA and change in CDR Sum of Boxes over follow-up of up to a 5-years. In addition, our studies revealed genetic, demographic and clinical variables correlating with plasma p-tau181 that may confound its interpretation in the context of AD. Conclusion: These results demonstrate that the Lumipulse plasma p-tau181 assay is a scalable, fully-automated and commercially available plasma p-tau test for AD - features supporting its implementation in early disease detection, therapeutic monitoring, and in clinical trials.
LP70- PLASMA P-TAU181 IN THE MULTIDOMAIN ALZHEIMER PREVENTION TRIAL (MAPT). N. Coley1,2, H. Zetterberg3, S. Guyonnet1,2, P. De Souto Barreto1,2, K. Blennow3, N. Ashton3, S. Andrieu1,2, B. Vellas1,2(1. INSERM, University of Toulouse - Toulouse (France), 2. Toulouse University Hospital - Toulouse (France), 3. University of Gothenburg -Gothenburg (Sweden))
Background: Multidomain interventions may have a beneficial effect on cognitive function, especially in at risk populations, but their effects on Alzheimer’s disease (AD) biomarker trajectories have not yet been well studied. Previously, expensive and/or burdensome procedures were required to measure AD biomarkers but reliable blood-based assays have recently been developed. Like CSF p-tau, and in contrast to PET tau biomarkers, plasma p-tau is known to be elevated in early stages of AD, and fluid tau biomarkers have been suggested to be preferential for monitoring intervention effects in clinical trials. Although CSF p-tau may be a closer indicator of brain processes than peripheral measures, plasma biomarkers offer huge advantages in the clinical trial setting in terms of cost and burden, thus enabling their measurement in larger numbers of participants. To our knowledge, plasma p-tau181 has not yet been evaluated in a multidomain prevention trial setting. Objectives: Our objectives were to (1) assess the effects of a multidomain intervention, omega-3 supplementation, and both interventions combined, compared to placebo, on 3-year change in plasma p-tau 181; and (2) assess intervention effects on 3-year change in a composite cognitive score (the MAPT primary outcome) in participants with abnormal baseline p-tau181. Methods: MAPT was a 3-year randomized controlled prevention trial involving 1680 community-dwelling individuals aged 70 and older with memory complaints, a limitation in one instrumental activity of daily living (IADL) and/or slow walking speed (≤ 0.8 m/s). Participants also had to be free of dementia at baseline, with a Mini Mental State Examination (MMSE) score ≥24, and have no difficulties in basic ADL. Participants were randomized into 4 groups, receiving a multidomain lifestyle intervention (group-based cognitive training, advice and education (including personalized action plans) on physical activity and nutrition, and an annual preventive consultation), omega-3 fatty acid supplementation, both interventions combined, or placebo for 3-years. The trial’s primary outcome measure was a composite cognitive score calculated as the average of z-scores for the following tests: MMSE orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency and Digit Symbol Substitution Test. For the present analysis, we included a subsample of participants (n=527) with plasma p-tau 181 measured in stored blood samples taken at baseline and 3-years. Results: In the total sample, median (IQR) p-tau181 concentrations were similar at baseline and 3 years. Baseline p-tau181 was significantly higher in older participants (median [IQR] p-tau181 (pg/ml): 11.6 [10.4–21.9] in participants aged 85 and older; 10.1 [7.9–13.0] for age 80–84y; 9.0 [7.0–12.5] for age 75–79y; 8.3 [6.2–11.2] for age 70–74y; p<0.001), men (10.0 [7.5–12.6] versus 8.4 [6.5–11.5]; p=0.001), APOE4 carriers (9.8 [7.5–12.5] versus 8.4 [6.6–11.8]; p=0.039), those with renal dysfunction (10.1 [7.4–12.8] versus 8.6 [6.6–11.6]; p=0.039), and those with a positive PET amyloid scan (11.0 [7.7–13.0] versus 7.9 [6.0–10.9]; p<0.001), but did not differ by baseline CDR score or BMI. Amongst the 505 participants with p-tau181 data at both baseline and 3-years, there were no significant differences in baseline characteristics between randomization groups. Preliminary analyses suggested no significant change in p-tau181 between baseline and 3-year follow-up in any of the groups, and no significant between-group difference in change. Between-group differences in cognitive change by baseline p-tau status will be presented. Conclusion: In our prevention trial setting, expected associations were found between plasma measures of p-tau 181 and socio-demographic, clinical, and biological characteristics. Preliminary analyses suggested no change in p-tau181 over time, and no between-group differences in change. Full results will be presented and implications for future trials will be discussed.
LP71- THE EFFECT OF NEPRILYSIN INHIBITION ON ALZHEIMER’S DISEASE PLASMA BIOMARKERS: RESULTS FROM A RANDOMIZED CONTROLLED TRIAL EVALUATING SACUBITRIL/VALSARTAN IN COGNITIVELY UNIMPAIRED INDIVIDUALS AT RISK FOR HEART FAILURE. W.S. Brum1, K.F. Docherty2, N.J. Ashton1, S. Janelidzε3, P.S. Jhund2, O. Hansson3, H. Zetterberg1, J.J.V. Mcmurray4, K. Blennow1(1. Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg - Mölndal (Sweden), 2. BHF Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow - Glasgow (United Kingdom), 3. Clinical Memory Research Unit, Faculty of Medicine, Lund University - Lund (Sweden), 4. New British Heart Foundation Cardiovascular Research Centre, University of Glasgow - Glasgow (United Kingdom))
Background: In the amyloid cascade hypothesis, amyloid-β (Aβ) accumulation is a critical early event in the development of Alzheimer’s disease (AD), and targeting brain Aβ has long been a focus of AD clinical trials. In 2015, sacubitril/ valsartan was approved by the FDA for the treatment of heart failure (HF) with reduced ejection fraction. Sacubitril acts by inhibiting neprilysin, an enzyme responsible for degrading various vasoactive peptides including the natriuretic peptides. However, neprilysin is also involved in degrading Aβ species. Therefore, this approval raised the theoretical concern that sacubitril/valsartan treatment could potentially increase the risk of developing AD secondary to Aβ accumulation. To address this concern, the FDA ordered a trial evaluating the effect of sacubitril/valsartan on cognition and Aβ positron emission tomography (PET) in HF patients. The PERSPECTIVE trial (NCT02884206) reported no differences in cognitive function or cerebral Aβ deposition over 3 years of sacubitril/ valsartan treatment compared with valsartan alone. While this robustly supports the neurocognitive safety of long-term neprilysin inhibition, its effect on high-performing AD blood biomarkers has not been reported in PERSPECTIVE. Imaging and fluid biomarkers offer complementary information on AD pathophysiology, with studies indicating that plasma biomarkers of brain amyloidosis (Aβ42/Aβ40) and downstream tau pathology (p-tau) become abnormal several years earlier than Aβ-PET, and non-AD-specific biomarkers of neurodegeneration (neurofilament light; NfL) and glial activation (glial fibrillary acidic protein; GFAP) also provide relevant brain health information. Importantly, patients with HF often present some degree of cognitive impairment and have an increased risk of developing dementia. Thus, evaluating the effect of sacubitril/valsartan on AD blood biomarkers is needed, both for complementary neurocognitive safety information and to evaluate whether this treatment could be a potential confounding factor when interpreting AD blood tests. Objectives: To evaluate the effect of one-year treatment with sacubitril/valsartan compared with valsartan alone (i.e., the addition of neprilysin inhibition) on AD blood biomarkers in individuals with asymptomatic left ventricular systolic dysfunction late after myocardial infarction. Methods: Plasma-EDTA samples were collected at baseline, 6 months, and 12 months in a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial evaluating the effect of sacubitril/valsartan (target dose 97/103mg twice daily) compared with valsartan (target dose 160mg twice daily) on ventricular remodeling in cognitively unimpaired individuals with asymptomatic left ventricular systolic dysfunction at least 3 months following myocardial infarction (NCT03552575). With the Simoa technology, we measured Aβ42, Aβ40, Aβ42/ Aβ40, GFAP, and NfL (Quanterix Neurology-4-Plex-E kit), and p-tau231 and p-tau181 with validated in-house assays (University of Gothenburg). Measurements for p-tau217 are ongoing (Lilly; Meso-Scale Discovery). Biomarker outcomes at 12 months were analyzed using linear regression models adjusting for randomized treatment and baseline biomarker values. Results: A total of 93 patients were randomized and 92 completed the trial (sacubitril/valsartan: n=46; valsartan: n=46; mean age, 60.7±10.4 years). Sacubitril/valsartan, compared with valsartan, increased levels of Aβ42, giving an adjusted between-group difference in change from baseline of +2.3 pg/mL (95% CI 1.8 to 2.7; p<0.001), and for Aβ40, +108.4 pg/mL (95% CI 96.4 to 120.3; p<0.001), and reduced the Aβ42/Aβ40 ratio in −0.020 (95% CI −0.022 to −0.018; p<0.001). At 12 months, these corresponded to mean fold-changes, compared to valsartan, of +31% for Aβ42, +100% for Aβ40, and -35% for Aβ42/Aβ40. No significant group-differences in change from baseline were observed for p-tau231 (p=0.94), p-tau181 (p=0.48), GFAP (p=0.47), or NfL (p=0.56). Conclusion: Plasma Aβ biomarkers were substantially altered by sacubitril-valsartan treatment, with no changes observed in biomarkers of tau pathology, glial activation, or neurodegeneration. We interpret the changes in Aβ as a non-pathological pharmacodynamic effect, caused by reduced peripheral neprilysin activity. While the Aβ42/ Aβ40 ratio is low in AD patients mostly due to pathological reductions in Aβ42, the reduction in the ratio observed with sacubitril/valsartan reflected increases in both Aβ42 and Aβ40, with a greater increase in Aβ40 driving this reduction. Given the reassuring findings of the PERSPECTIVE trial and data from several studies indicating that peripherally injected Aβ42 doesn’t reach the central nervous system, it is unlikely that higher circulating Aβ levels have any deleterious effect on patients receiving sacubitril/valsartan. The absence of increases in other biomarkers, especially p-tau231 and p-tau181, further supports the neurocognitive safety of sacubitril-valsartan, since p-tau biomarkers are highly associated with Aβ pathology and anti-Aβ drug trials have reported reductions in blood p-tau levels over the same duration of our study. Importantly, our results suggest that plasma Aβ blood tests for brain amyloid risk prediction will be confounded in patients receiving sacubitril/valsartan, potentially leading to false-positive results. Furthermore, these results add to the literature that changes in plasma Aβ levels with drug treatments (e.g., BACE1 inhibitors) may not translate to a corresponding effect on brain Aβ aggregation or cognitive changes. To our knowledge, this is the first reported drug-interaction contraindication for an AD blood test, which, alongside well-described robustness issues for plasma Aβ, further supports p-tau as the most reliable AD blood biomarker.
LP72- SIMULTANEOUS MASS SPECTROMETRIC QUANTIFICATION OF MULTIPLE TAU SPECIES IN BLOOD SHOWS DIFFERENTIAL ASSOCIATION WITH AMYLOID AND TAU PATHOLOGY. L. Montoliu-Gaya1, A.L. Benedet1, A. Vrillon2, C. Tissot3, W.S. Brum1, N.J. Ashton1, J. Lantero-Rodriguez1, G. Brinkmalm1, J. Nilsson1, H. Zetterberg1, J. Gobom1, C. Paquet2, P. Rosa-Neto3, K. Blennow1(1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. - Gothenburg (Sweden), 2. Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisière Fernand Widal, Université de Paris, Paris, France. - Paris (France), 3. Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada. - Montréal (Canada))
Background: With the emergence of several immunotherapies which efficiently remove Aβ aggregates from the brain, and a very active drug development pipeline, the need for blood biomarkers to facilitate participant recruitment and monitor disease progression in Alzheimer’s disease (AD) clinical trials is even more pressing. While a single biomarker (e.g., p-tau231 or p-tau217) may work well to identify Aβ pathology for trial recruitment or AD in clinical practice, they provide little information on disease stage. Further, biomarkers are needed to better reflect key pathophysiological processes related to the drug target, or mechanisms putatively downstream of the drug target (e.g., tau pathology). Therefore, a method which systematically measures multiple p-tau and non-phospho tau species in a single-shot analysis, not dependant on antibody affinity or immunoassay platform, will give greater insight into stage-specific changes which are critical to monitor pathology changes in drug response and disease development in clinical management. Objectives: To simultaneously quantify the plasma concentration of six different phosphorylated (p-tau 181, 199, 202, 205, 217 and 231), and two non-phosphorylated, tau peptides using a targeted Mass Spectrometric (MS) method to determine disease stage-specific changes and the link of each tau specie with amyloid and tau pathologies. Methods: Tau enrichment prior to MS analysis was performed by immunoprecipitation, using a combination of several non-phospho-tau antibodies, followed by tryptic digestion. A parallel reaction monitoring method with Orbitrap MS was used to measure the levels of targeted peptides. We analysed a total of 224 samples from two centres, the BioCogBank Paris Lariboisière cohort (France) and the TRIAD cohort (Canada). In TRIAD, we tested the association of the biomarkers with Aβ and tau pathologies, indexed by [18F]AZD469 and [18F]MK-6240, respectively. Results: All p-tau, except p-tau202, and non-phospho peptides showed significantly higher levels in Aβ and tau positive (A+T+) individuals compared to A-T- participants (p<0.001), with the highest fold-changes observed for p-tau205 (4.4), p-tau217 (4.3) and p-tau231 (2.5). In addition, p-tau181, p-tau205, p-tau217 and p-tau231 showed significant changes from A+T- to A+T+ (p<0.001). Plasma p-tau217 and p-tau205 were site-specific phosphorylations that showed higher correlations with Aβ PET global SUVR (p-tau217, r=0.81, p<0.001; p-tau205, r=0.71, p<0.001), yet p-tau231 was the epitope with significantly higher levels with lower thresholds of amyloid PET signal. Voxel-based analyses were conducted to study regional brain correlations with each plasma tau peptide. No association between Aβ-PET and p-tau199, p-tau202, tau212-221 or tau195-209 was observed. P-tau205 and p-tau231 presented Aβ-PET uptake in the medial frontal and cingulate cortices, the precuneus, as well as the temporal lobes. P-tau217 showed the strongest associations with [18F]AZD4694 throughout the whole cortex (p<0.001). Plasma p-tau217, and to a lesser extent p-tau231 and p-tau205, were the site-specific phosphorylations that showed higher correlations with tau PET global SUVR (p-tau217, r=0.7, p<0.001; p-tau231, r=0.53, p<0.001; p-tau205, r=0.53, p<0.001). Correlations with tau PET uptake depending on the Braak staging, showed that p-tau205 and p-tau217 associated more with Braak stages III&IV (r=0.8, p<0.001; and r=0.81, p<0.001), while p-tau231 had higher correlations with Braak I&II (r=0.59, p<0.001) and decreased with increasing Braak. Regarding tau PET uptake, nonsignificant associations were observed with p-tau199, p-tau202 or tau212–221. P-tau181 and tau195–209 presented [18F]MK6240 retention in the precuneus, and temporal lobes and p-tau231, in the precuneus, cingulate cortex as well as the temporal lobes (p<0.001). P-tau217 and p-tau205 presented the strongest correlations with [18F]MK6240, throughout the whole cortex (p<0.001). Finally, we performed regression models, using either only amyloid PET signal (A), only tau PET signal (T), both amyloid and tau density (A+T), or both A and T including their interaction term (AxT). Plasma p-tau205, p-tau217 and p-tau231 were the phosphorylations better explained by the models. P-tau231 was similarly mediated by A alone (r=0.34, AIC=−155) and the combination A+T (r=0.36, AIC=-154). P-tau217 presented a higher correlation in the association A+T (r=0.73, AIC=−205), superior to A (r=0.67, AIC=−199) and T alone (r=0.69, AIC=−204), although not significant in the latter. Finally, p-tau205 was equally explained by T (r=0.64, AIC=−311) and the combination A+T (r=0.64, AIC=−310), and showed less association to amyloid plaque density (r=0.5, AIC=−302). Conclusion: We have developed an immunoprecipitation-mass spectrometry method to simultaneously quantify six different phosphorylated (p-tau 181, 199, 202, 205, 217 and 231), and two non-phosphorylated tau species in plasma. Our results indicate that plasma p-tau217, p-tau231 and p-tau205 are the site-specific blood phosphorylations that better reflect amyloid and tau pathologies, although with different emergence along the AD continuum. P-tau231 was more associated with Aβ pathology and might be the first to emerge, followed by p-tau217 influenced by both amyloid and tau, and finally p-tau205 increases might be weighted towards tau accumulation. A comprehensive understanding of the pathological information that each blood p-tau reflects is paramount to decide which blood biomarker to use in each stage of the disease and to guarantee a correct read-out in clinical trials for anti-Aβ and anti-tau therapies. *The presenter author declares no conflict of interest.
LP73- CEREBROSPINAL FLUID PROTEOMICS REVEAL 5 MOLECULAR SUBTYPES IN ALZHEIMER’S DISEASE: IMPLICATIONS FOR PERSONALISED TREATMENT. B. Tijms1, W. Van Der Flier1, C. Teunissen1, J. Vijverberg1, Y. Pijnenburg1, E. Birkeland2, F. Berven2, P.J. Visser1(1. Amsterdam UMC, location VUmc - Amsterdam (Netherlands), 2. University of Bergen - Bergen (Norway))
Background: Alzheimer’s disease is heterogenous in underlying pathophysiology. This may have profound implications for therapy as specific subtypes may need different treatments. We previously identified three AD subtypes based on CSF proteomics (Tijms Brain 2020). One subtype was characterized by increased amyloid metabolism and aberrant neuronal plasticity; one subtype showed evidence of innate immune activation; and one subtype had blood-brain barrier dysfunction. Aim of the present study was to discover other AD subtypes in a large independent data set of 609 individuals in which we measured 1059 proteins in CSF. Objectives: 1. To study whether the 3 subtypes in previous work could be replicated in an independent dataset; 2. To find novel subtypes by increasing sample size and number of proteins measured compared to the previous studies. Method: We selected 419 AD individuals with at least abnormal CSF abeta42 and 187 controls (normal cognition and normal AD biomarkers) from Alzheimer center Amsterdam studies. With 16-plex TMT-MS we detected 3987 proteins in CSF, of which we clustered 1059 proteins with complete observations that differed between AD and controls (all p<.05). Subtypes were compared on 2906 proteins with at least 10 observations per subgroups. Potential upstream transcription factors associated with the molecular subtypes were identified with ENRICHR. Results: We found 5 subtypes with distinct protein profiles. Three subtypes were highly concordant with our previously observed subtypes (subtype 1a, 1b and 2b). Two subtypes were new: One showed proteasome dysfunction (1c) and the other showed impaired choroid plexus functioning (2a). Subtype 1a individuals (n=137, 32%) had increased levels of 877 proteins that were associated with neuroplasticity and increased amyloid processing (as indicated by high abeta40 and BACE1 levels). REST and SUZ12 were potential upstream drivers. Subtype 1b individuals (n=124, 30%) had increased levels of 988 proteins that were associated with neuronal plasticity and inflammation with SOX2 as potential upstream driver. Subtype 1c individuals (n=24, 6%), had increased levels of 517 proteins that were associated with neuroplasticity, retromer complex and proteasome dysfunction. These proteins were associated with TAF1 and MYC as potential upstream drivers. Subtype 2a individuals (n=78, 19%,) showed increased levels of 469 proteins, of which 45% were expressed by the choroid plexus (e.g., TTR). These proteins converged on NFE2L2. Subtype 2b individuals (n=56, 13%) showed increased levels of 649 proteins that were in part associated with blood-brain barrier leakage. These proteins converged on ERG1 and ESR1 as potential upstream drivers. Conclusion: In this new dataset we replicated three AD subtypes, and detected two novel subtypes. Subtypes differed in the processes involved, including neuronal plasticity, amyloid processing, immune system activation, proteasome function, choroid plexus function and blood-brain barrier function. All these processes have previously been implicated in AD pathophysiology and our findings suggest that specifc subgroups of AD patients show dysregulation of distinct processes. This indicates that treatment may need tailoring according to AD subtype, which can be detected in the CSF. For example, BACE inhibitors may be useful in subtype 1a only. Intervention with antibodies may be in particular effective in subtype 2b (blood-brain barrier dysfunction) as the permeability of the blood-brain barrier in this subtype may allow increased Igg levels in the brain. Future studies are needed using data or samples from trials to test whether AD subtypes are associated with treatment response.
LP74- EFFECTS OF PRE-ANALYTICAL PARAMETERS ON PLASMA B-AMYLOID LEVEL. K. Ishiki1, K. Yamashita1, S. Watanabe1, M. Miura1, S. Iwanaga1, T. Sato1(1. Central Research Laboratories, Sysmex Corporation - Kobe (Japan))
Background: Blood-based biomarkers of Alzheimer’s disease (AD) are expected to be promising tools for assisting diagnosis in combination with conventional biomarkers such as neuroimaging and cerebrospinal fluid (CSF) biomarkers. In particular, the ratio of plasma β-amyloid1–42 (Aβ42) to β-amyloid1–40 (Aβ40) is known to be associated with brain Aβ pathology. Therefore, it could assist in the selection of the candidates for clinical trials of disease-modifying therapies targeting Aβ. We have developed assays that can specifically measure Aβ40 and Aβ42 in plasma using a fully automated immunoassay platform, the HISCLTM series. The assay showed high performance for predicting brain Aβ pathology defined by amyloid positron emission tomography (PET). However, it is widely recognized that plasma Aβ peptides are unstable molecules, and thus the measured values are affected by pre-analytical parameter such as external factors, measurement equipment and sample handling. Especially, blood collection and storage conditions in sample handling affect the quality of plasma Aβ levels, leading to false selection. Therefore, clarification of the influence of pre-analytical parameters on plasma Aβ levels measured by our assay is required to obtain reliable data in clinical trials. Objectives: The purpose of this study was to clarify the effect of pre-analytical parameters on plasma Aβ levels measured by HISCL series. Methods: Whole blood samples were collected in K2EDTA tubes from healthy volunteers. After centrifugation, plasma Aβ40 and Aβ42 levels were immediately measured using the HISCL series and plasma Aβ42/Aβ40 was calculated. We compared the impacts of the 11 pre-analytical parameters such as duration between blood collection and centrifugation at room temperature (RT) or 4°C, the interval between plasma storage at RT or 4°C before measurement, the number of freeze/thaw (F/T) cycles, the conditions of thawing, the length of time that the plasma was thawed before measurement, the types of tubes and manufacturers for storing plasma, the tip type using plasma separation, and the number of tube transfers on plasma Aβ42/ Aβ40. Results: Plasma Aβ42/Aβ40 levels remained unchanged after 2 hours at RT and 6 hours at 4°C after blood collection. After the plasma separation, it is unaltered even after 18 hours of storage at 4°C. Longer sample storage time and higher storage temperature after plasma separation tended to affect the reduction of the plasma Aβ42/Aβ40 ratio, but did not have an effect beyond our established criteria. The time for holding the thawed plasma at RT was also investigated, and no difference was detected until 4 hours. For the freezing samples, up to three F/T cycles did not significantly change the Aβ42/Aβ40 ratio compared to the reference value. Thawing at RT and 37°C were also used to assess the thawing state. The 37°C conditions were verified using a water bath, a dry block incubator, and an air incubator. Furthermore, neither of the thawing conditions affects the Aβ42/Aβ40 values. The Aβ42/Aβ40 values are unaffected by tube manufacturer, tip type, or tube transfer up to one time. Conclusion: In this study, we evaluated the influences of 11 pre-analytical parameters on plasma Aβ42/ Aβ40 ratio measured by HISCL series. In our evaluation, the sample storage time and temperature after plasma separation were the most influential factors in plasma Aβ42/Aβ40 ratio. These results were consistent with the previous reports of pre-analytical handling using another assay platform. This study will contribute to the determination of pre-analytical handling for plasma Aβ measurement using HISCL. By establishing pre-analytical handling based on the findings of this study, the high amyloid PET predictive performance we have shown so far could be achieved in clinical trials.
LP75- EFFECT OF A 1-YEAR NUTRITIONAL BLEND SUPPLEMENTATION ON PLASMA P-TAU181 LEVELS AMONG COMMUNITY-DWELLING OLDER ADULTS: A SECONDARY ANALYSIS OF THE NOLAN STUDY. K. Giudici1, S. Guyonnet1,2, C. Cantet1,2, P. De Souto Barreto1,2, K. Blennow3,4, H. Zetterberg3,4, C. Boschat5, J. Hudry5, S. Andrieu2,6, B. Vellas1,2, J. Schmitt5,7,8(1. Institute of Aging, Gerontopole of Toulouse, Toulouse University Hospital - Toulouse (France), 2. CERPOP UMR1295, University of Toulouse III, Inserm, UPS - Toulouse (France), 3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg - Mölndal (Sweden), 4. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital - Mölndal (Sweden), 5. Société des Produits Nestlé SA, Nestlé Research - Lausanne (Switzerland), 6. Department of Epidemiology and Public Health, Toulouse University Hospital - Toulouse (France), 7. Singapore Institute of Food and Biotechnology Innovation, Agency for Science, Technology and Research - Singapore (Singapore), 8. Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research - Singapore (Singapore))
Background: Observational studies and some randomized controlled trials have suggested that nutritional supplementation could be a possible intervention pathway to prevent cognitive decline and Alzheimer’s disease (AD). As measuring amyloid-β and tau markers in the brain and in cerebrospinal fluid (CSF) is complex, plasma versions of such biomarkers have emerged as more accessible alternatives with comparable capacity of predicting cognitive impairment. Objectives: This study aimed to evaluate the effect of a 1-year intervention with a nutritional blend on plasma p-tau181 levels (a marker of cerebral tau phosphorylation) of community-dwelling older adults. Effects were further assessed in exploratory analyses within sub-cohorts stratified according to apolipoprotein E (APOE) ε4 status. Methods: A total of 289 participants ≥70 years (56.4% female, mean 78.1 years, SD = 4.7) of the randomized, double-blind, multicenter, placebo-controlled Nolan trial had their plasma p-tau181 assessed using a Single molecule array assay, and daily took either a nutritional blend (composed of 50 mg of thiamin, 15 mg of riboflavin, 25 mg of niacin, 23 mg of pantothenic acid, 18 mg of pyridoxine, 0.15 mg of biotin, 0.4 mg of folic acid, 0.5 mg of cobalamin, 82.6 mg of vitamin E, 500 mg of vitamin C, 15 µg of vitamin D, 85 mg of choline, 80 µg of selenium, 3 g of citrulline, 700 mg of eicosapentaenoic acid - EPA and 770 mg of docosahexaenoic acid - DHA) or placebo for 1 year. The blend (or placebo) was characterized by two soft gel capsules (with 775 mg filling each) and by one powdered sachet of ∼ 15 g, to be mixed in 120 mL of cold water. Recruitment started in December 2016 and ended in January 2018. Follow-up ended in February 2019. Efficacy analyses were done on a modified intention-to-treat (mITT) basis (i.e., including all randomly assigned participants with plasma p-tau181 measured at baseline who completed at least one post-baseline visit). Linear mixed effects regression (with a random subject intercept and, if significant, a random linear slope and a random center intercept) adjusted on baseline data were performed in the mITT population in order to determine the effect of intervention, compared to placebo, on plasma p-tau181 levels. Results: At baseline, plasma p-tau181 did not differ between treatment groups at baseline (intervention: 14.1 pg/mL, SD = 6.0 vs. control: 13.3 pg/mL, SD = 5.6, p = 0.262), and was higher among subjects ≥85 years, male, APOE ε4 carriers, with CDR score 0.5 and amyloid-positive. After 1-year, both groups presented a significant increase in plasma p-tau181 values, with no effect of intervention (between-group difference: 0.27 pg/mL, 95%CI: –0.95, 1.48; p = 0.665). The allele APOE ε4 was identified among 24.7% of the sample (n = 68), and did not differ between groups (intervention: 21.9% vs. control: 27.5%; p = 0.279). Separate analyses according to APOE ε4 status mostly provided similar findings to the observed among the total studied population, with no differences in plasma p-tau181 changes between groups (difference in between-group differences over time for APOE ε4 carrier vs. non-carrier: 2.28 pg/mL, 95%CI: −0.58, 5.13; p = 0.118). Conclusions: We have shown that a 1-year supplementation with a nutritional blend composed of several vitamins and minerals was not able to mitigate the increase in plasma p-tau181 levels among community-dwelling older adults. Considering the novelty of the hypothesis tested in the present study, additional RCT with longer follow-ups and including other p-tau biomarkers are needed, and may contribute to a better understanding if (and how) nutritional supplementation may be able to protect brain health and cognitive function through impacting tau accumulation and amyloidosis. Together with other advances in the field targeting lifestyle approaches, this would enable not only setting nutritional strategies for optimizing brain health and preventing or slowing the development of neurodegenerative diseases, but also to reduce the need of drugs and expensive treatments. Conflict of interest (presenting author): None.
LP76- A NOVEL ACCESSIBLE AND SCALABLE ASSAY FOR PTAU217 IN BLOOD. S. Portbury1, I.V.E.R. Verberk2, S.S.A. Bayoumy2, W. Van Der Flier2, J.E.R.O.E. Vandrabrant3, C.T.E.U. Teunissen2, E.R.I.K. Stoops3, A. Jeromin1(1. ALZpath - Carlsbad, Ca (United States), 2. Amsterdam UMC - Amsterdam (Netherlands), 3. ADX Neurosciences - Gent (Belgium))
Background: Blood-based biomarkers that can accurately report Alzheimer’s disease (AD) pathophysiology are urgently required to aid in the diagnostic process in primary and secondary clinical care. Blood-based biomarkers are non-invasive in nature, considered to be more cost-effective compared with current assessment methods, and they do not require specialized centers. As a result, blood-based biomarkers allow for large population screening and scalability in clinical care. Plasma measures of phosphorylated tau have recently demonstrated high diagnostic accuracy in differentiating AD from non-AD neurodegenerative disorders, in several clinical trials that used neuropathological post-mortem measurements to validate AD diagnosis. Of promise is pTau217, where tau is phosphorylated at Thr217. Accordingly, ALZpath has developed a pTau217 monoclonal antibody for use in ELISA assays. The Alzpath monoclonal antibody provides the advantage of being highly scalable through expression in mammalian cells and it shows excellent lot to lot consistency. Objectives: ALZpath completed extensive fit for purpose assay development to establish an accessible, robust and scalable plasma-based ultra-sensitive assay, utilizing a proprietary monoclonal pTau217 antibody. Methods: In partnership with two independent contract research organizations (CROs), ALZpath has developed and evaluated reagents for pTau217 using various detection antibodies and calibrators across different immunoassay platforms. An ultra-sensitive blood-based ELISA assay, using a peptide calibrator, has been developed on the semi-automated single-molecule array Simoa® platform. Results: The identified clone 30H10 is highly specific to phosphorylation at residue 217 and does not bind to either phosphorylated residues 181, 231 or non-phosphorylated tau. ALZpath has successfully completed a fit for purpose validation of pTau217 assay in EDTA plasma. The Alzpath ptau217 Simoa® assay shows good precision (inter-day CVs of less than 12 %) and good sensitivity with a functional lower limit of quantification of 0.260 pg/ml. Parallelism/dilutional linearity is within the 80–120 % range. In an initial evaluation of the ALZpath pTau217 assay performance in plasma (n = 80) and CSF (n = 42), across healthy volunteer and AD participants the protein was measured in 90% of all samples with an intra-assay %CV below 10%. The ALZpath pTau217 assay demonstrated a functional (in matrix) lower limit of quantitation (LLOQ) of 0.26 pg/mL and strong linearity within 80–120% of acceptance criteria. In the subset of 40 control and 40 AD participants (70% female, 30% male), the ALZpath pTau217 assay had a 91% likelihood of accurately identifying AD (AUC = 0.91 (0.85–0.98)) with a 4.2-fold change in AD when compared with controls. The capability of the ALZPath pTau217 assay to differentiate AD exceeded the AUCs of the commercial Simoa® pTau181 based assay (abstract submitted, Bayoumy et al). Conclusion: The generated data demonstrate that the ALZpath plasma pTau217 assay is a potentially scalable reagent with high specificity for pTau217. ALZpath has established a fit-for-purpose validated Simoa® assay for pTau217 in blood with robust precision, and diagnostic accuracy in AD, compared to controls based on clinical diagnosis. ALZpath is partnering with a global network of collaborators to establish the clinical performance of the ALZpath pTau217 assay to screen and diagnose AD in both memory and primary care clinics. Cohorts selected have enrolled deeply phenotyped participants across various stages of AD and integrate multimodal biomarker assessments and evaluation of the importance of comorbidities. Based upon these results we intend to further validate the ALZpath Dx as a laboratory-developed test (LDT) for clinical use, and establish clinical evidence in different diagnostically relevant diverse populations with co-morbidities. Conflicts of interest: Andreas Jeromin PhD is an employee of Alzpath and an adviser to Quanterix. Stuart Portbury is an employee of ALZpath.
LP77- LONGITUDINAL ASSOCIATIONS OF CHANGES IN BLOOD-BASED MARKERS FOR NEURODEGENERATIVE DISEASES IN CLINICAL TRIALS ON ALZHEIMER’S DISEASE. D. Li1, M. Glittenberg1, D. Salisbury1, V.F. Lin2, F. Yu3(1. University of Minnesota - Minneapolis (United States), 2. Stanford University - San Francisco (United States), 3. Arizona State University - [email protected] (United States))
Background: Blood-based amyloid-b (Ab) 42/40 ratio, tau phosphorylated at amino acid 181 (p-tau 181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are markers for brain Aβ pathology, tau pathology, reactive astrocyte, and neurodegeneration, respectively. These blood-based markers (BBMs) are poised to revolutionize the diagnostic and prognostic work-up of Alzheimer’s disease (AD), as well as to improve the design of interventional trials as (pre)screeners to identify individuals with AD, provided the AD status is later confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. However, these BBMs are yet to be used as primary endpoints in clinical trials, because longitudinal associations between changes in these BBMs and changes in imaging measures, pathology, or cognition in AD remain unclear. Objectives: As a step toward establishing blood-based Aβ42/Aβ40, p-tau 181, GFAP and NfL as primary endpoints in clinical trials, we examined longitudinal associations of changes in these BBMs in three randomized controlled trials in AD (Active Mind Trial, ACT Trial, FIT-AD Trial). The purpose of this study was to examine (1) crosssectional associations amongst plasma Aβ42/Aβ40, p-tau 181, GFAP and NfL; (2) associations amongst longitudinal changes in plasma Aβ42/Aβ40, p-tau 181, GFAP and NfL (baseline as reference) and their baseline levels; (3) longitudinal associations amongst changes in Aβ42/Aβ40, p-tau 181, GFAP and NfL. Methods: The Active Mind Trial is an adaptive randomized controlled trial (RCT) that tests 3- month cognitive training combinations for enhancing instrumental activities of daily living among persons with mild cognitive impairment (MCI). The ACT Trial is a 2x2 factorial RCT to test the efficacy and synergistic effects of a 6-month aerobic exercise and cognitive training regimen on cognition and relevant mechanisms in older adults with amnestic MCI. The FIT-AD Trial was a 2-parallel group RCT that examined the effects of 6- month aerobic exercise on cognition and hippocampal volume in older adults with mild-to-moderate AD dementia. Active Mind Trial collected plasma samples at baseline (n=62) and 3 months (n=52); the ACT Trial at baseline (n=53), 3 (n=44), 6 (n=37), 12 (n=17), and 18 months (n=16); FIT-AD Trial at baseline (n=26), 3 (n=23) and 6 months (n=25). BBMs were measured using Quanterix SiMoA assays, except no p-tau 181 for the ACT Trial and no GFAP for the FIT-AD Trial. Because these plasma biomarker levels were not directly comparable across cohorts, we conducted linear regression models, adjusting for age and sex, within each cohort. Results: The mean (SD) age and % of female of the Active Mind, ACT, FIT-AD participants at baseline were 71.2 (5.8) years and 44%; 73.5 (5.6) and 49%; 77.6 (6.9) and 34%; respectively. None of the plasma biomarkers was significant different across time points in any of the three cohorts except p-tau 181 between baseline and 3-months in the FIT-AD Trial (mean [SD] of p-tau 181 at baseline and 3-months: 2.55 [1.37] pg/mL and 2.62 [1.29] pg/mL; p-value =0.0484). Because of this, we conducted cross-sectional association analysis by combining data of all time points within each cohort. Significant cross-sectional associations between plasma Aβ42/Aβ40 and GFAP, NfL, or p-tau 181 (standardized coefficient bs in the range of -0.38 to -0.31 and p-values 3.39′ 10–5 to 6.20′ 10–4) were generally weaker than the associations amongst plasma p-tau 181, GFAP, and NfL (b in the range of 0.60 to 0.77 and p-values 6.86′ 10–21 to 2.44′ 10–13). Significant cross-sectional association for plasma GFAP and NfL (b= 0.38 and p-value =2.36′ 10–4) and for plasma p-tau 18 and NfL (b= 0.62 and p-value =0.01) were replicated in the ACT and in the FIT-AD, respectively. Amongst the associations of all 3-month changes in plasma Aβ42/Aβ40, p-tau 181, GFAP, and NfL and their baseline levels, only greater 3-months increase in plasma Aβ42/Aβ40 was significantly associated with lower baseline Aβ42/Aβ40 in all three cohorts (bs in the range of −0.48 to 0.312 and p-values in the range of 0.023 to 0.042). When longer follow-up data were available in the ACT and FIT-AD, only 6-months increase in plasma p-tau 181 was significantly associated with lower baseline Aβ42/Aβ40 (b=0.538 and p-value=0.022) in the FIT-AD. Lastly, greater 3-month increases in plasma GFAP were significantly associated with greater 3-month increase in plasma NfL in the Active Mind (b= 0.397 and p-value 00038). The significant longitudinal association between changes in plasma GFAP and changes in plasma NfL was replicated in the ACT Trial at 3-month (b= 0.52 and p-value 0.007) but not at 6-month (b=0.409 and p-value=0.074). Conclusion: The observation that older adult with lower baseline plasma Aβ42/Aβ40 ratio had greater increase in plasma Aβ42/Aβ40 ratio at 3 months (baseline as reference) is most likely explained by regression to mean. Longitudinal associations in 3-month increases in plasma GFAP and in plasma NfL in the two independent cohorts suggests a strong coupling of neuron and astrocyte. Our study data potentially supports the use of changes in plasma GFAP and in plasma NfL as potential surrogate endpoints in clinical trials of AD, although the caveats are both changes in NfL and in GFAP are not specific for AD and can be related to other co-existing pathology (e.g., cerebrovascular pathology).
LP78- PLASMA P-TAU AND NFL POTENTIAL UTILITY AS SURROGATE BIOMARKERS IN PREVENTIVE CLINICAL TRIALS. P.L. Ferreira1, J.P. Ferrari-Souza1, C. Tissot2, B. Bellaver1, D.T. Leffa1, G. Povala1, F.Z. Lussier1, J. Therriault2, J.P. Soucy2, S. Gauthier2, V.L. Villemagne1, P. Rosa-Neto2, T.K. Karikari1, T.A. Pascoal1(1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. - Pittsburgh (United States), 2. Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC (Canada))
Background: Recently, the preclinical stage of Alzheimer’s disease (AD) has become a focus of clinical trials based on the assumption that better therapeutic outcomes can be achieved before the onset of Aβ and tau pathologies, cognitive decline and major neurodegeneration. The preclinical AD key features are the presence of abnormal markers of Aβ, and tau tangles accompanied by the absence of cognitive symptoms. While presenting an elevated risk for cognitive decline, the vast majority of these individuals will remain clinically stable during typical clinical trial periods (12- to 24-month follow-up). This challenges the use of changes in cognitive measures as a single primary outcome in therapeutical trials using cognitively unimpaired (CU) individuals. In this context, using surrogate biomarkers to evaluate disease progression is crucial. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in preventive clinical trials targeting CU individuals. However, while longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light (NfL) correlate with AD progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Objective: Here, we tested the utility of plasma p-tau181 and NfL as surrogate biomarkers for clinical trials targeting CU older individuals. Methods: We evaluated 257 CU older individuals with available Aβ-PET (18F-florbetapir uptake) at baseline and longitudinal (up to 24-months) plasma p-tau181 and NfL measures from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Aβ positivity was conferred based on Aβ-PET composite standardized uptake value ratio (SUVR) greater than 1.11, following previous validation studies. We used the SUVR value and equations previously established by the ADNI PET core to transform the Aβ-PET SUVR to the Centiloid scale. We calculated the estimated sample size needed for a clinical trial testing a hypothesized 25% drug effect on longitudinal reduction in biomarkers with 80% power at alpha level 0.05 on reducing changes in plasma biomarkers. Using data from a previous study (PMID: 29538647), we assessed changes in tau-PET (18F-flortaucipir uptake) or structural MRI (tensor-based morphology cortical volume) to calculate samples size and prices of trials using neuroimaging for surrogacy. Results: We demonstrated that longitudinal changes in plasma NfL were associated with age, whereas changes in plasma p-tau181 with progression to MCI. We found that therapeutic clinical trials using plasma biomarkers over 24 months would require 78% (n = 8,884) and 63% (n = 3,448) smaller sample sizes than 12-month trials for plasma p-tau181 and NfL, respectively. The use of Aβ positivity, in comparison to including the whole population, for population enrichment reduced the sample size of 24-month trials by 43% (n = 5,040) for p-tau181 and by 17% (n = 2,868) for NfL. Notably, using intermediate levels of Aβ (20–40 Centiloid units) as an enrichment strategy, rather than merely Aβ positivity, the sample size was reduced by 73% (n = 2,432) for p-tau181 and 59% (n = 1,396) for NfL over 24-months. The use of APOE ε4 carriership did not reduce sample sizes for p-tau181 and NfL over 24 months. We evaluated drug effects greater than 25% (used in this study), and our findings suggested that the sample size would reduce if we considered medications with larger effect sizes. For example, a ∼50% drug effect on either p-tau181 or NfL reduction would lead to the need for a total of ∼1,000 individuals for a clinical trial using plasma biomarkers as a surrogate outcome. When calculating the cost of biomarkers-only, the cost of using plasma is lower for p-tau181 (7-fold at 24 months) and similarly for NfL than the cost of using neuroimaging biomarkers for surrogacy. On the other hand, the total estimated trial cost when selecting an Aβ-positive population, considering surrogate biomarkers plus other related tests (such as costs of the definition of Aβ-PET positivity and cognitive assessment), is higher (more than 5-fold at 12 months and 2-fold at 24 months) using plasma than neuroimaging biomarkers for surrogacy. However, when we estimated the total cost of a trial including only individuals with intermediate Aβ levels, the cost was similar when using plasma and neuroimaging biomarkers for surrogacy. Conclusion: Our results suggest that plasma p-tau181 and NfL could potentially be used to monitor large-scale population interventions in CU Aβ-positive individuals. Additionally, we demonstrated that selecting individuals with intermediate levels of Aβ (20–40 Centiloid) is the most cost-effective population enrichment strategy tfor clinical trials using plasma biomarkers as surrogate marker.
LP79- FOSGONIMETON PROVIDES CONGRUENT BENEFIT ON DIVERSE BIOMARKERS OF NEURODEGENERATION, SIGNIFICANTLY CORRELATING WITH A COMPOSITE CLINICAL SCORE OF COGNITION AND FUNCTION IN ALZHEIMER’S DISEASE. H. Moebius 1, K.B. Ooi 1, M. Hale 1, S. Setti 1, K. Kleist 1, C. Bernick 2(1. Athira Pharma — Bothell (United States), 2. Cleveland Clinic Lou Ruvo Center for Brain Health — Las Vegas (United States))
Background: The pathophysiology of Alzheimer’s disease (AD) dementia is multifactorial and the resulting cognitive and functional decline debilitating. AD has been associated with oxidative stress, inflammation, vascular insufficiency, metabolic dysfunction, and specific proteotoxicity. Despite this complex mechanism of the disease, clinical research in AD has been dominated by mechanisms that target proteotoxicity alone. Additional approaches that address other, known contributory factors of AD pathophysiology may provide much-needed improvements in functional and cognitive outcomes. The MET receptor and its ligand hepatocyte growth factor (HGF), which are both expressed in neurons and glia throughout the nervous system, activate a broad range of intrinsic cellular pathways that support function and homeostasis. MET expression is markedly reduced in AD. Fosgonimeton, a small-molecule positive modulator of the HGF/MET system, was evaluated in subjects with mild-to-moderate AD in the randomized, 6-month, double-blind, placebo-controlled, phase 2 ACT-AD study (NCT04491006*). Here we present additional fluid biomarker analyses. Objectives: To evaluate changes from baseline in plasma biomarkers at Week 26 of fosgonimeton treatment compared with placebo in subjects with mild-to-moderate AD enrolled in the ACT-AD study and assess multifactorial correlations with the global statistical test (GST), a composite score informed by both ADAS-Cog11 and instrumental activities of daily living (iADL). Methods: Blood samples were drawn from subjects providing consent at baseline (before treatment start; N=77) and at visit 8 (Week 26 of treatment). Whole blood was collected into EDTA sample tubes, on ice, then plasma was isolated following centrifugation. Initial biomarkers assessed include neurofilament light chain (NfL, an indicator of ongoing neurodegeneration), glial fibrillary acidic protein (GFAP, an indicator of microglial activation), chitinase-3-like protein 1 (YKL-40, a marker of neuroinflammation), and amyloid beta 40 and 42 (Aβ40, Aβ42). All were normalized to baseline. NfL was measured using the Simoa NF-light Advantage assay (Quanterix 103186); Aβ40, Aβ42, and GFAP were measured using the Simoa Neurology 4-Plex E assay (Quanterix 103670); and YKL-40 was measured using the U-PLEX Human YKL-40 assay (MSD K151VLK). Least squares mean differences (fosgonimeton vs placebo, without background therapy) and 95% confidence intervals (CIs) were calculated for change from baseline at Week 26, and analysis of variance was performed to determine treatment impact. Effects on plasma biomarker changes were evaluated while considering several factors (eg, ApoE4 genotype) and covariates (eg, baseline age, clinical dementia rating health status, and Mini-Mental State Exam (MMSE) score). Due to the limited trial size, results are represented for pooled active arms vs. placebo, without background therapy. Results: Baseline levels of all biomarkers were similar between treatment groups, and biomarker levels indicative of AD proteinopathy were in keeping with literature data for the “probable AD” target population recruited according to McKhann et al. 2011. NfL was elevated on average at baseline (20.8 pg/mL, SE 1.6); subjects receiving fosgonimeton showed a statistically significant change from baseline compared to placebo (−7.9 pg/mL, SE 2.7, p=0.0059). Across diverse biomarkers, fosgonimeton-treated subjects consistently showed directionally favorable improvements from baseline compared with placebo: GFAP (−29.3 pg/mL, SE 28.6, p=0.312); YKL-40 (−34.9 ng/mL, SE 26.5, p=0.195); and Aβ42/40 ratio (0.0066, SE 0.0035, p=0.064). ApoE4 carrier status, MMSE at baseline, sex or age did not affect these results. To confirm the correlation of biomarkers and clinical endpoint, data from the modified intent-to-treat study population from ACT-AD were analyzed; the composite endpoint GST, a pre-specified secondary analysis, informed by both ADAS-Cog11 and iADL, proved to be highly correlated with the change in NfL (r=0.46, P=0.0011) and GFAP (r=0.30, P=0.0394). Conclusion: In this first-ever randomized, double-blind, 6-month trial of a novel small molecule positive modulator of the HGF/MET neurotrophic system, fosgonimeton, a statistically significant benefit on NfL, and descriptive, congruent GFAP and YKL-40 plasma concentration improvements were observed, which could be consistent with a neuroprotective effect of this novel intervention and the multimodal mechanism of action. These clinical findings are consistent with preclinical results of fosgonimeton-induced neuroprotection in various animal models of proteotoxicity and neurodegeneration. The significant correlation of NfL and GFAP benefit with the composite clinical endpoint, GST, informed by ADAS-Cog11 and iADL, further supports the translation and clinical relevance. *The ACT-AD trial is supported by a grant from the National Institute on Aging of the National Institutes of Health under award number R01AG06268. The information presented here is solely the responsibility of Athira and does not necessarily represent the official views of the National Institutes of Health.
LP80- IN AN OPTIMIZED CSF COLLECTION PROTOCOL THE PTAU181/AB1-42 RATIO INCREASES PREANALYTICAL VARIABILITY OVER MEASURING AB1-42 ALONE. R. Esquivel 1, S. Ho 2, J. Darrow 2, A. Calabro 1, P. Thakker 2, S. Gannon 1, F. De Simone 1, A. Moghekar 2(1. Fujirebio Diagnostics Inc — Malvern (United States), 2. Johns Hopkins School of Medicine — Baltimore (United States))
Background: Core cerebrospinal fluid (CSF) biomarker concentrations for β-amyloid1-42 (Aβ1–42) β-amyloid1–40 (Aβ1–40), and ptau181 are valuable in the diagnosis of Alzheimer’s Disease (AD). Specifically, when used in a ratio Aβl-42/Aβl-40 and ptau181/Aβ1–42 have shown high concordance with amyloid PET. However, questions remain on the robustness of these ratios when used in clinical routine due to the tendency of amyloid to adsorb to surfaces causing amyloid loss that may result in misdiagnosis. Stringent handling procedures of CSF have been proposed to reduce amyloid loss including the use of a single polypropylene tube type. The proposal of a single tube complicates CSF collection and creates doubt in results obtained from alternative tube types. Objective: In this study the effect of varying polypropylene tube type within clinical routine on amyloid concentration using Aβ1–42/Aβ1–40 and ptau181/Aβ1–42 ratios was evaluated in freshly collected CSF. The utility of the ratios to correct for pre-analytical variability and bring concentrations within +/− 5% of baseline as indicated by recently published Alzheimer’s Association International Guidelines for CSF handling was examined. Methods: Fresh CSF samples were collected in Sarstedt polypropylene tubes 72.703.600 (tube A), 62.610.018 (tube B) and 63.614.699 (tube C) from patients at the Johns Hopkins Center for CSF Disorders and subjected to laboratory specific protocols. Aβ1–42, Aβ1–40, and ptau181 concentrations were measured using the Lumipulse G1200 (Fujirebio Diagnostics Inc., Malvern, PA). Tubes were filled to 80% fill volume and CSF was analyzed post centrifugation (2000 xg, 10 minutes, 5 ± 3°C). Extended sample cap contact was evaluated by storing samples upright or upside down at 4°C for 1 week or upright or upside down at −80°C for 1 month. Tube C was also filled at 100% upright or upside down at 4°C for 1 week. Results: Amyloid concentration at 4°C did not significantly change based on tube type even when stored upside down for 1 week. Notably, at 4°C in tube C, the ptau181/Aβ1–42 ratio mean values fell outside of the acceptance criteria when stored upright (mean: 5.5% CI 3.8% — 7.2%) and upside down (mean: 7.1% CI: 4.2% — 10.0%) although individual amyloid proteins Aβ1–42 (mean: −3.3% CI: −7.0 — 0.4) and Aβ1–40 (mean: −0.1 CI −4.1%–3.9%) and ptau181 (mean: 2.3% CI −1.9% — 6.5%) did not. This was true at both 80% and 100% fill volume. The Aβ1–42/Aβ1–40 ratio remained within the acceptance criteria at 4°C for tube C upright (mean: −3.2 CI −4.6% — −1.8%) and upside down (mean: −3.0% CI −4.3% — −1.6%). At −80°C ptau181 in tube B upright (mean: −6.3% CI-12.0% — −0.5%), Aβ1–42 in tube C upright (mean: −6.6% CI −12.5% — −0.7%) and upside down (mean: −9.3% CI −18.3% — −0.3%) and Aβ1–40 upside down (mean: −5.6% CI-14.8% — 3.6%) fell outside of the acceptance criteria. The Aβ1–42/Aβ1–40 ratio compensated for the amyloid loss in tube C (upright mean: −3.2% −6.8% — 0.4%; upside down mean: −3.9% CI −8.1 — 0.3%) and remained within the acceptance criteria for tube B. Although, the ptau181/Aβ1–42 ratio remained within the acceptance criteria for tube B it fell out of the acceptance criteria for Tube A upside down (mean: 6.7% CI 1.9% — 11.5%) and Tube C upright (mean: 7.5% CI −0.3% — 15.3%) and upside down (mean: 6.6% CI −2.3% — 15.6%), despite individual proteins falling within the criteria for tube A. Conclusion: In this study no significant differences were observed between polypropylene tubes and between fresh and frozen samples when using the Aβ1–42/Aβ1–40 ratio. Individual amyloid proteins and the ptau181/Aβ1–42 ratio did have significant variability dependent on tube type and handling. Variability of ptau181/Aβ1–42 was higher in all three tubes after storage at −80°C. As Tube A had the least variability when measuring individual analytes it is recommended for −80°C storage. While it is known Aβ1–42 generally decreases in concentration due to handling, a small, and generally not significant increase in ptau181 concentration is also observed. Due to this trend, the ptau181/Aβ1–42 ratio may amplify preanalytical variability even when amyloid loss is minimal. Measuring the Aβ1–42/Aβ1–40 ratio and ptau181 as an individual analyte may provide most consistent results in studies relying on biobanked samples. In clinical routine the Aβ1–42/Aβ1–40 ratio is also preferable to minimize the impact of deviations from an optimized collection and handling protocol on patient diagnosis.
LP81- ANALYTICAL FEASIBILITY OF COMPOSITE PLASMA PHOSPHORYLATED TAU AND AB BIOMARKER FOR PREDICTING AMYLOID PET POSITIVITY. A.W. Bannon 1, W.Z. Potter 2, S. Zicha 3, L.M. Shaw 4, H. Zetterberg 5, Z.S. Saad 6, J. Dage 7, I. Dobler 8, D.L. Raunig 9, K. Ferber 10, C.E. Rubel 10, S.E. Schindler 11, M. Baratta 3, E.A. Meyers 12, E.G. Rosenbaugh 13(1. AbbVie — North Chicago (United States), 2. Subject Matter Expert (United States), 3. Takeda, Pharmaceutical Company Ltd. — Cambridge (United States), 4. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania — Philadelphia (United States), 5. Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg — Mölndal (Sweden), 6. Neuroscience Biomarkers, Janssen Research and Development LLC — La Jolla (United States), 7. Stark Neurosciences Research Institute at Indiana University School of Medicine — Indianapolis (United States), 8.Takeda, Pharmaceutical Company Ltd — Cambridge (United States), 9.Takeda, Pharmaceutical Company Ltd. — Cambridge (United States)—Cambridge (United States), 10. Biogen — Cambridge (United States), 11. Department of Neurology,Washington University School of Medicine — St. Louis (United States), 12. Alzheimer’s Association — Chicago (United States), 13. Foundation for the National Institutes of Health — North Bethesda (United States))
Background: The FNIH Biomarkers Consortium Plasma Aβ Project has recently published on the performance of six plasma Aβ amyloid assays (i.e., Aβ42/40) to predict amyloid PET status using samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Zicha et. al., 2022). Results from the study indicated that a model including age and APOE genotype predicted amyloid status with an area under the curve (AUC) of 0.75. Aβ42 and Aβ40 readouts from three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). Recent published findings have suggested that plasma phosphorylated Tau (pTau) measures perform comparably to plasma Aβ measures in predicting amyloid PET status. The current study measured pTau181 in the same ADNI plasma sample set using four different immunoassays and assessed the ability of plasma pTau181 to predict amyloid PET status alone or in combination with plasma Aβ data. Objectives: This study aimed to assess the ability of plasma pTau181 and plasma Aβ to discriminate between amyloid PET positive and negative compared to plasma Aβ, age and APOE genotype. Methods: Four plasma pTau immunoassays were selected for this study based on assay design and analytical performance criteria: ADx Neurosciences pTau181 Simoa, Fujirebo Lumipulse G pTau 181 Plasma, Quanterix Simoa® pTau 181V2 Advantage, and Roche Diagnostics Elecsys Phospho-Tau (181P) Plasma. The sample set from ADNI consisted of 121 plasma samples with corresponding amyloid PET (florbetapir, FBP) with 49.6% considered Aβ+: cognitively normal (CN) n = 49 (36.7% Aβ+), mild cognitive impairment (MCI) n = 54 (48.2% Aβ+), and Alzheimer’s Disease (AD) n = 18 (88.9% Aβ+). Laboratory personnel were blinded to the clinical data during sample testing, and the data analysis was performed with blinding to the assay platforms. Diagnostic performance for determining amyloid PET positivity was assessed using Receiver Operating Characteristic curve analysis for pTau181 or in combination with Aβ42/40. All models included age, and APOE genotype. Importantly, the study was not powered for a head-to-head comparison to determine a superior assay. Results: The plasma pTau181 concentrations positively correlated with FBP standardized uptake value ratio (SUVR) values, or in other words, elevated plasma pTau181 correlated with higher amyloid burden. The four plasma pTau181 assays predicted amyloid PET status with AUCs ranging from 70–84%. For the plasma Aβ assays alone, the AUCs in this same cohort ranged from 64–81%. The addition of pTau181 to a model using Aβ42/40, age and APOE genotype marginally improved the AUC by approximately 4%. However, the resultant AUC was comparable to that from models without the Aβ42/40 data, suggesting that the observed increase in AUC may be caused by a greater AUC for plasma pTau-181 in this dataset. Conclusion: Overall, based on this relatively small ADNI cohort, plasma pTau181 measures predicted amyloid PET status at least comparably to plasma Aβ42/40 measures. The addition of pTau181 to models including Aβ42/40, age and APOE genotype marginally improved the AUC by approximately 4%; however, validation in an independent dataset is needed to determine whether this moderate improvement is idiosyncratic to this sample set. The project team will evaluate each of the plasma pTau181 assay’s ability to predict tau positivity status from tau PET as well as CSF measures in future analyses and consider other pTau assays. Furthermore, an assessment of inter-assay correlations for pTau181 and FBP PET SUVR measures will be performed. Reference: Zicha S., Bateman R., Shaw L.M., Zetterberg H. et. al., Alzheimer’s Dement., 2022 Jul 12. doi: 10.1002/alz.12697.
LP82- THE DEVELOPMENT OF AN AUTOMATED EEG-BASED MACHINE LEARNING PIPELINE FOR THE DETECTION OF ALZHEIMER’S DISEASE, A PROOF-OF-CONCEPT STUDY FOR CLINICAL TRIAL BIOMARKERS. N. Chedid 1(1. SynapseBio Inc — New York (United States))
Background: Electroencephalography (EEG) is a promising digital biomarker modality for Alzheimer’s disease (AD) that is a non-invasive, cost-effective, repeatable, language-free, culturally fair, mobile, and brain-based screening tool that could uniquely show therapeutic target engagement in the brain at a high temporal resolution. Although EEG offers promise as a solution addressing many of the shortcomings of other diagnostic modalities for AD, EEG contain extra-cranial artifacts (most commonly eye movements and muscle contractions) that are potentially confounding and that are visually identified based on qualitative criteria. Additionally, while machine learning (ML) models have been applied to EEG to develop prediction models, many caveats exist with prior approaches, including long EEG epochs and the use of high-density EEG systems, a challenge for high throughput screening, lack of clarity around the artifact removal process, and use of computationally heavy approaches such as graph theory and ‘black box’ ML models that undermine explainability. Objectives: To develop an automated EEG-based ML pipeline for the detection of AD that solves the following problems simultaneously: (1) Lack of automation and unbiased removal of artifacts, (2) dependence on a high level of expertise in data pre-processing and ML for non-automated processes, (3) need for relatively large sample sizes and accurate EEG source localization using high density systems, (4) and reliance on black box ML approaches such as deep neural nets with unexplainable feature selection. Methods: EEGs (xx min resting state, eyes closed, xx channels) were collected from 23 healthy subjects and 18 patients with AD. EEG data was transformed from the time domain to the frequency domain. Low quality channels were removed. Our proprietary automated support-vector machine pipeline further detected and removed artifacts. Power spectral density (PSD) analysis was performed, and PSD features were selected for ML based on statistical analysis. These features were input into a logistic regression model. Results: We reached a mean accuracy of 81 % on the entire dataset for classifying subjects as healthy or with AD (AUC: 86 %, precision: 78 %, recall: 75 %). Conclusion: In summary, we developed a fully automated discrimination process for AD based on brief epochs of resting-state EEG using low-density channel montage, an end-to-end automated analysis pipeline for data preprocessing, and statistically guided feature extraction, leading to explainable ML classification with high accuracy. The novelty in our approach is twofold: 1) “transparent” ML techniques as opposed to black box deep learning methods, and 2) preprocessing EEG signals in an automated manner to remove artifacts such that our results are reproducible, rigorous, and scalable. These two novel aspects allowed us to obtain proof of concept data in a relatively small sample size. Our current and future work entails applying this automated pipeline to develop biomarkers to enhance safety, patient selection, and assessment of treatment efficacy in AD clinical trials. Disclosures: Nicholas Chedid is an employee of SynapseBio Inc.
LP83- TOWARDS IMPLEMENTATION OF PLASMA PHOSPHO-TAU 181 AS A SCREENING TOOL FOR PATIENT RECRUITMENT. A. Emersic 1, B.E. Kirsebom 2,3, W.S. Brum 4,5, M. Wettergreen 6,7, B. Winblad 8,9, K. Blennow 10,11, M. Gregoric Kramberger 1, 12, T. Fladby 6,13(1. Department of Neurology, University Medical Centre — Ljubljana (Slovenia), 2. Department of Neurology, University Hospital of North Norway—Tromsø (Norway), 3. Department of Neurology, Medical faculty, University of Ljubljana — Ljubljana (Slovenia), 4. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Clinical Neurochemistry Laboratory, The Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital — Gothenburg (Sweden), 5. Department of Psychology, Faculty of Health Sciences, UiT, The Arctic University of Norway — Tromsø (Norway), 6. Department of Neurology, Akershus University Hospital — Lørenskog (Norway), 7. Institute of Clinical Medicine, University of Oslo — Lørenskog (Norway), 8. Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics Karolinska Institutet — Stockholm (Sweden), 9. Clinical Molecular Biology (EpiGen), University of Oslo —Oslo (Norway), 10. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Clinical Neurochemistry Laboratory, The Sahlgrenska Academy at the University of Gothenburg — Gothenburg (Sweden), 11. Karolinska University Hospital — Stockholm (Sweden), 12. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital — Gothenburg (Sweden), 13. Universidade Federal do Rio Grande do Sul (UFRGS) — Porto Alegre (Brazil))
Background: Success of clinical trials in Alzheimer’s disease (AD) is largely depended on recruitment of eligible participants with underlying AD pathophysiology. Although currently available biomarkers have greatly improved the diagnostic accuracy of AD, they either require invasive lumbar puncture (LP) or costly neuroimaging procedures, which make them inconvenient for broader community screening. With the arrival of disease modifying therapies, easily available tools to facilitate early AD diagnosis are all the more needed. Plasma phospho-tau (p-tau) 181 has been shown to accurately predict AD pathology in memory-clinic cohorts, however little is known about its performance in general population settings. Objective: We aimed to evaluate plasma p-tau 181 potential to identify individuals at early asymptomatic or symptomatic stage of AD within the Precision Medicine Interventions in Alzheimer’s Disease (PMI-AD, JPND2019-466-236) project and its open house initiative for community-based screening. In line with PMI-AD objectives, further clinical evaluation and participation in early therapeutic intervention is now offered to the individuals with increased risk for developing AD dementia. Methods: Participants: Pre-screening of 147 subjects between 55–80 years was done at the Department of Neurology, University Medical Centre Ljubljana, Slovenia. The AD8 Dementia Screening Interview, as well as Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) were used to assess mental status and detect potential anxiety or depression. Individuals with cognitive complaints in recent 3–5 years, who were independent in daily activities, could undergo MRI protocol and did not fulfil any of the exclusion criteria (dementia diagnosis or treatment, psychiatric disorders, known malignancy or previous stroke) could enter the screening with blood withdrawal. Blood analysis and prediction of amyloid positivity. P-tau 181 measurements and APOE genotyping was done at the University of Oslo, Akershus University Hospital. Plasma p-tau181 concentrations were measured with the single molecule array assay on the Simoa SR-X analyzer (Quanterix). Amyloid Aβ positivity based on CSF Aβ42/40 status was predicted using previously validated cut-off (>1.628 pg/ml) within the Dementia Disease Initation (DDI) cohort. Additionally, accuracy in detection of underlying AD (CSF Aβ42/40 positivity) was assessed for a prediction model with plasma p-tau 181 and APOE status, developed in the DDI dataset. Different specificity-based thresholds of the model were evaluated in comparison with plasma p-tau 181 positivity alone as potential strategies to guide and optimize further study enrollment. CSF sampling and study enrollment. Participants with plasma p-tau 181 above the threshold underwent LP and confirmatory CSF analysis. CSF AD biomarkers, total tau, p-tau 181 and Aβ42/40 ratio were measured using the Innotest (Fujirebio) immunoassays. Amyloid β positivity as defined by CSF Aβ42/40 ratio < 0.07 (previously validated cut-off) was necessary for further study enrollment. Results: Twenty-three individuals (16%) were excluded at pre-screening and among the rest blood collection with APOE genotyping and plasma p-tau 181 measurement was so far done in 86 (57 women). Median age of already screened individuals was 71 years (range 59–80 years), their MMSE and MoCA scores were 28.6 ± 1.2 and 26.4± 1.8 (mean ± SD). Fifty-three (62%) had plasma p-tau 181 above the screening cut-off and proceeded to LP for CSF AD biomarkers evaluation. By the end of September 2022, altogether 18 LP were performed and in 9 (50%) reduced CSF Aβ42/40 ratio was confirmed. Using a prediction model with plasma p-tau 181 and APOE status, estimated probabilities of underlying AD (CSF Aβ positivity) in already screened cases (n=86) were 40%, 34% and 19 % at the 85%, 90% and 95% specificity thresholds, respectively. Based on the CSF results in a small subgroup (n=18), only the stringent 95% specificity threshold would have substantially reduced our rate of Aβ-negative CSF results. At the same time, a third who turned out to be CSF Aβ positive would not have been screened with probability cut-offs, indicating a further need for confirmatory CSF testing. Conclusions: Our preliminary results demonstrate about 50% of concordance between plasma p-tau 181 and CSF Aβ positivity in this community-based cohort. A prediction model with plasma p-tau 181 and APOE status could reduce the rate of Aβ-negative CSF results, however some of the eligible individuals would not have been able to proceed to therapeutic intervention. Further studies should address applicability of plasma p-tau 181 for screening as well as combinations of different blood-based biomarkers that might be need to reliably predict AD in general population. Acknowledgements: The project was funded by the Ministry of Education, Science and Sport, Slovenia and the Norwegian Research council, JPND/PMI-AD (NRC 311993).
LP84- LEUKOCYTE-DERIVED RATIOS ARE ASSOCIATED WITH DEMENTIA. Y.N. Kim 1,2, S. Arif 2(1. Boston University — Boston (United States), 2. DotHouse Health — Boston (United States))
Dementia is divided into late-onset (LOD) and early-onset dementia (EOD)(age <65). Studies showed that leukocyte-derived ratios could represent inflammation markers for cognitive decline in LOD. A recent study in our health center showed that they could also be markers for EOD. This study was an extension of our previous study to evaluate the relevance of these markers in EOD and LOD. We identified 86 community-dwelling patients seen at the cognitive assessment clinic in a community health center from 1/2021-4/2022 through chart review. Four patients were excluded as CBC results were unavailable. Forty-six patients were diagnosed with dementia (EOD 8 patients, LOD 38 patients), and 27 patients had MCI (early-onset 9 patients, late-onset 18 patients). Nine patients had normal results. (age < 65 2 patients, age ≥ 65 7 patients) In this study, the control group was patients who were not diagnosed with dementia (normal results and MCI diagnoses), and we divided patients into two groups based on their age(<65 or ≥ 65) and compared each group with their control groups. We collected complete blood count (CBC) and calculated lymphocyte-to-monocyte ratio(LMR), neutrophil-to-lymphocyte ratio(NLR), and platelet-to-lymphocyte ratio(PLR). In the younger population, neutrophils, monocytes, and eosinophil counts were not likely associated with EOD, but NLR, LMR, and PLR seem related to EOD. NLR and PLR again suggested this relation when comparing the EOD group with the early onset MCI group. In the older population, most markers were likely unrelated to LOD diagnosis. Still, eosinophil counts and hemoglobin levels were highly likely associated with LOD (P value: 0.0224(eosinophils), 0.005(hemoglobin)). CBC is a widely available test that can be done quickly in the outpatient setting. If CBC can predict the likelihood of developing dementia, it will tremendously help our practice for risk assessment and diagnosis of dementia. Our study suggested that low NLR, PLR, and high LMR were associated with EOD, and high eosinophil counts and high hemoglobin levels were very likely related to LOD. Because different markers were associated with dementia depending on its onset, different pathophysiology may play a role in EOD and LOD. More extensive cohort studies are needed to investigate this further.
LP84A- THREE GROUP CLASSIFICATION OF PARTICIPANTS BASED ON FULLY AUTOMATED PLASMA B-AMYLOID MEASUREMENTS TO ACHIEVE HIGH POSITIVE AND NEGATIVE PREDICTIVE VALUES. K. Yamashita 1, M. Miura 1, K. Nagai 2, D. Verbel 3, S. Iwanaga 1, T. Sato 1, T. Yoshida 4, A. Iwata 5(1. Central Research Laboratories, Sysmex Corporation — Kobe (Japan), 2. Japan and Asia Clinical Development Department, Eisai Co., Ltd — Tokyo (Japan), 3. Biostatistics, Eisai Inc. — Nutley (United States), 4. Sysmex Corporation — Kobe (Japan), 5. Department of Neurology, Tokyo Metropolitan Geriatric Hospital and Institute of gerontology — Tokyo (Japan))
Background: Blood-based biomarkers that can predict brain β-amyloid (Aβ) status are in high demand not only for the recruitment of participants into Alzheimer’s disease (AD) clinical trials but also for ensuring that appropriate AD patients can receive disease-modifying therapies in the future as they become available. Recently, we reported that plasma Aβ1–42 (Aβ42) to Aβ1–40 (Aβ40) ratio measured by our fully automated immunoassay platform (HISCLTM series) predicted brain Aβ status defined by amyloid positron emission tomography (PET) as assessed by Centiloids (CL). Area under the curves of 0.932 and 0.922 were obtained in two clinical studies (discovery and validation studies). In the previous analysis, we determined a cut-off value of 0.102 using the Youden index in the discovery study. Using this cut-off value, we achieved high negative predictive value (NPV) of 97.6% and 94.0%, and moderate positive predictive value (PPV) of 80.6% and 79.6% in the discovery and validation studies, respectively. Considering use in the screening of participants for clinical trials, higher PPV would be preferable. In this study, we combined discovery and validation studies to one dataset, and classified participants into three groups (positive, intermediate, and negative Aβ groups) depending on their plasma Aβ42/Aβ40 ratio, in order to improve PPV of our plasma Aβ assay. Objectives: To evaluate the performance of our plasma Aβ42/Aβ40 ratio in predicting amyloid PET status upon classifying participants into three groups. Methods: Plasma Aβ40 and Aβ42 were measured using a fully automated immunoassay platform in a set of plasma samples sourced from participants in the screening phase of the elenbecestat Phase 3 program. Participants were clinically diagnosed with mild cognitive impairment and mild dementia. In this analysis, we combined datasets from previously reported discovery and validation studies to make one dataset that included 172 amyloid PET positive participants and 199 negative participants. Brain Aβ status was determined by amyloid PET scans as assessed by the Centiloid method (cut-off value defined previously as 32.21 CL). Here, we determined the cut-off value of our plasma Aβ42/Aβ40 ratios that would result in a PPV of 90.0% or more. We then utilized this cut-off value and the prior reported cut-off value of 0.102 as the thresholds to divide participants into positive, intermediate, and negative Aβ groups. Results: A cut-off value of 0.092 was determined based on the criteria to achieve a PPV of at least 90.0%, and we used this cut-off value and 0.102 to classify participants into positive (≤ 0.092), intermediate (> 0.092 and ≤ 0.102), and negative (> 0.102) Aβ groups. In this analysis, PPV in positive Aβ group was 90.1% while NPV in the negative Aβ group was 95.8%. In intermediate Aβ group, 68.4% corresponded to amyloid PET positive participants. Conclusion: Our Aβ assay achieved PPV and NPV ≥ 90% by classifying participants into the three groups. Majority of participants were classified as positive or negative Aβ groups by plasma Aβ42/Aβ40 ratio, indicating that our assay may contribute to reduce amyloid PET scan or CSF Aβ testing, which could be helpful in applications such as the recruitment step of clinical trials.
CLINICAL TRIALS: COGNITIVE AND FUNCTIONAL ENDPOINTS
P126- VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY AND COGNITION IN THE SPRINT MIND TRIAL. I. Sible 1, D. Nation 2(1. USC — Los Angeles (United States), 2. Uc Irvine — Irvine (United States))
Background: Blood pressure (BP) variability (BPV) is an emerging risk factor for cognitive impairment, dementia, and cerebrovascular disease, independent of traditionally studied average BP levels, but relationships with cognition in the context of antihypertensive strategies remain unclear. Objectives: We examined whether visit-to-visit BPV is related to cognitive change based on antihypertensive treatment type. Methods: In this post hoc analysis of the SPRINT MIND trial, 2348 participants underwent 4 BP measurements over a 9-month period after treatment randomization (standard vs intensive BP lowering) and ≥ 1 neuropsychological evaluation thereafter. Participants underwent cognitive testing at study baseline and every two years during the planned 4-year follow-up. Primary outcomes for the present study were standardized composite scores for processing speed (Trail Making Test parts A and B, Digit Symbol Coding) and executive function (Trail Making Test part B minus part A, Digit Span). Linear mixed models investigated relationships between BPV, antihypertensive treatment group, and time on cognitive scores. Results: Elevated BPV was associated with the fastest decline in processing speed (ß = −.06 [95% CI −.12, −.01]; p = .03) and executive function (ß = −.09 [95% CI −.18, −.001]; p = .048) in the standard treatment group only. BPV was not significantly related to cognitive scores in the intensive treatment group. Conclusion: Elevated BPV remains a risk factor for cognitive impairment despite strictly controlled BP levels, in the standard treatment group. Declines were observed in processing speed and executive function, domains often impacted by cerebrovascular disease and may underpin risk for dementia and cerebrovascular disease associated with BPV. Additionally, BPV is easily accessible and widely available in a number of clinical settings, underscoring the utility of BPV as a vascular risk factor linked with cognitive impairment and dementia. The authors have no conflicts of interests to disclose.
P127- CLASSIFICATION AND PREDICTION OF DIFFERENT COGNITIVE TRAJECTORIES IN COGNITIVELY NORMAL ELDERLY. Y.J. Kim 1, S.E. Kim 2, A. Hahn 3, S.H. Cho 4, D.L. Na 1, J.P. Kim 1, H. Jang 1, H.J. Kim 1, J. Chin 1, S.W. Seo 1(1. Samsung Medical Center — Seoul (Korea, Republic of), 2. Haeundae Paik Hospital — Busan (Korea, Republic of), 3. Johns Hopkins Bloomberg School Of Public Health — Baltimore (Korea, Republic of), 4. Chonnam National University Hospital — Chonnam (Korea, Republic of))
Background: Aging-related health issues are receiving more spotlights as aging-related diseases are projected to be higher societal and economic burdens. In fact, Alzheimer’s disease (AD) is one of the major causes of disability and dependency of the elderly population. Therefore, early diagnosis and intervention are critical to reduce all the burdens of AD. Objectives: This study aims to investigate cognitive trajectory of cognitively normal (CN) elderly using Preclinical Alzheimer Cognitive Composite (PACC) in Alzheimer’s Disease Neuroimaging Initiative (ADNI) and explore how the risk factors impact cognitive trajectory. Methods: Data were obtained from the ADNIMERGE dataset of the ADNI database and from the Samsung Medical Center (SMC) for external validation. A total of 407 CN participants from ADNI database were included in the current study, and they had at least 2 follow-ups of cognitive assessment. We used the ADNI-modified PACC with trial-making test B time to completion (mPACCtrt) as the cognitive endpoint. We tested whether there were distinct growth patterns in cognitive trajectory of the CN elderly using the latent growth mixture modeling and developed the prediction model, a nomogram. Also, 285 CN participants from SMC were examined to check whether the trajectory modeling we built is reliable. Results: There were two latent classes in the cognitive trajectories of the CN elderly; a ‘stable group’ (86.2%) and a ‘declining group’ (13.8%) in ADNIMERGE dataset. The results of the external validation analysis also revealed similar patterns. The logistic regression model (Model 1) showed that higher age (OR = 1.092, 95% CI = 1.013–1.177), presence of APOE ε4 allele (OR = 2.692, 95% CI = 1.208–6.003), and lower hippocampal volume (HV) (OR = 0.465, 95% CI = 0.239–0.906) were predictive of cognitive decline. After adding the information of AV45 SUVR to independent variables (Model 2), higher AV45 SUVR (OR = 1.703, 95% CI = 1.374–2.111), and decreased HV (OR = 0.396, 95% CI = 0.189–0.831) predicted fast decline, but the effects of older age and APOE ε4 carrier disappeared. Finally, prediction models of cognitive decline showed fair to good discrimination and calibration capabilities (C-statistic = 0.74 for model 1, 0.84 for model 2). Conclusion: Our study provides novel insights into the different cognitive trajectories among CN participants. Furthermore, the prediction model could facilitate the classification of CN participants, which could be employed in future primary prevention trials. Competing interests: The authors declare that they have no conflict of interest.
P128- WHAT’S IN A SCORE: COMPARING AND ALIGNING SCORES BASED ON ITEM RESPONSE THEORY AND CLASSICAL TEST THEORY FOR THE AMSTERDAM INSTRUMENTAL ACTIVITIES OF DAILY LIVING QUESTIONNAIRE. M. Dubbelman 1, M. Postema 1, R. Jutten 2, J. Harrison 1, C. Ritchie 3, B. Schalet 4, C. Terwee 5, W. Van Der Flier 1, P. Scheltens 1, S. Sikkes 1(1. Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Umc Location Vumc — Amsterdam (Netherlands), 2. Department Of Neurology, Massachusetts General Hospital, Harvard Medical School — Boston (United States), 3. University Of Edinburgh — Edinburgh (United Kingdom), 4. Department Of Medical Social Sciences, Feinberg School Of Medicine, Northwestern University — Chicago (United States), 5. Amsterdam Umc Location Vumc, Epidemiology And Data Science, Amsterdam Umc — Amsterdam (Netherlands))
Background: Early along the Alzheimer’s disease continuum, individuals may develop difficulties performing cognitively complex ‘instrumental activities of daily living’ (IADLs) such as doing grocery shopping and using a computer. Performance of IADLs is a clinically relevant outcome measure often captured using patient- or observer-reported outcome measures. These outcome measures may be scored using classical test theory (CTT), which holds that an observed total score is the sum of a person’s true score (ability) and random error of measurement, regardless of ability. Item response theory (IRT) is a more advanced scoring method which assumes that measurement error varies across the scale. IRT also accounts for varying properties of items, such as discriminative ability (how well an item can distinguish between individuals with good or poor ability on the construct) and location on the scale (or, how difficult an item is). As such, IRT-based scores may provide a more precise reflection of a person’s true ability. It has been suggested that IRT-based scores may be less biased than CTT-based scores when estimating change in a construct, potentially increasing responsiveness. The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is an extensively validated functional outcome measure which was developed using IRT and has both CTT-based and IRT-based scoring available. Objective: We aimed to compare and align IRT-based with CTT-based scores of impairment in everyday functioning, as measured with the A-IADL-Q. Methods: We included 2,295 participants, 2,032 (89%) of whom were cognitively normal. Others had subjective cognitive decline (n=93, 4%), mild cognitive impairment (n=79, 3%), or dementia (n=91, 4%). A completed A-IADL-Q was available for all participants. We computed IRT-based scores, which follow a normal distribution centered around a mean of 50 with a standard deviation of 10 and with higher scores representing better functioning, as well as CTT-based scores, which range from 0 to 100 with higher scores representing more impairment. IRT-based scores are calculated using an algorithm, whereas CTT-based scores are the average of all item scores. We then compared CTT-based and IRT-based score distributions and discriminative ability between diagnostic groups using linear regressions and investigated floor and ceiling effects. We subsequently compared change over time between scoring methods using linear mixed models adjusted for age, sex, and education, in a subgroup of 1,415 individuals who had longitudinal data available (mean follow-up 1.4 ± 0.6 years). Results: IRT-based and CTT-based scores correlated strongly (Pearson’s r = −0.92, 95% confidence interval = [−0.93, −0.91]). A total of 1,622 individuals (71%) had a CTT-based score of 0, indicating no impairment, while only 54 individuals (2%) had an IRT-based score of 70, indicating no impairment. Linear mixed models showed that both CTT-based and IRT-based scores showed change in everyday functioning over time in the whole sample. IRT-based scores deteriorated modestly but significantly in cognitively normal older adults (B = −0.15, 95%CI = [−0.28, −0.03]), while CTT-based scores showed no significant change (B = 0.20, 95%CI = [−0.02, 0.41]). In the clinical groups, both CTT-based and IRT-based showed significant change over time, with similar effect size in the whole group. In more advanced disease stages, CTT-based scores showed larger effects. Mean-to-standard deviation ratios (MSDRs) were marginally larger for CTT-based scores. We aligned CTT-based and IRT-based scores using 150,000 simulated responses to the A-IADL-Q. The mean and range of IRT-based scores were computed for each unique CTT-based score and the mean was aligned with the CTT-based score. We created a crosswalk table that can be built into an electronic case report file so IRT-based scores can automatically be derived from CTT-based scores. Conclusion: IRT-based scores of the A-IADL-Q have several advantages over CTT-based scores, including the absence of a ceiling effect and slightly superior responsiveness in preclinical disease stages. With the alignment of the CTT-based and IRT-based scores, made possible by the similarities in measurement properties of the two scoring methods, IRT-based scores can be approximated using the more straightforward CTT-based scoring method. This may be useful when calculation of IRT-based scores is impractical and allows all A-IADL-Q scores to be placed on a single scale, regardless of scoring method.
P129- SLOWING OF ALZHEIMER’S DISEASE PROGRESSION WITH NEUROAID. C.L.H. Chen 1, Y. Pokharkar 2, N. Venketasubramanian 3(1. National University of Singapore — Singapore (Singapore), 2. Singapore Clinical Research Institute — Singapore (Singapore), 3. Raffles Hospital — Singapore (Singapore))
Background: Slowing disease progression in Alzheimer’s Disease (AD) remains challenging and research has focussed on targets with potential disease-modifying therapeutic effects. Moreover, drug combinations may be needed for a multifactorial approach to the treatment of AD which has complex underlying mechanisms. NeuroAiD-II (MLC901) is a formulation containing extracts from nine herbal components, which is marketed in some countries for recovery in stroke and traumatic brain injury (TBI). MLC901 has biological effects on neuroprotection and neuroregeneration as well as clinical benefits on functional and cognitive recovery in stroke and TBI. Clinical studies have been conducted in patients with mild to moderate AD, mild cognitive impairment, vascular cognitive impairments no dementia and vascular dementia (1, 2). The promising results of the ATHENE (Alzheimer’s Disease THErapy with NEuroaid) study (NCT03038035) suggested a disease slowing effect with MLC901 as an add-on treatment in subjects with mild to moderate AD. However, the full effect of MLC901 as disease-modifying treatment may have been reduced by non-compliance and missing data (1). Objectives: The objective of this exploratory analysis is to assess over 12-month period the disease modification effect of MLC901 as an add-on therapy in mild to moderate AD using an alternative linear mixed effect model. Methods: All subjects from ATHENE, a randomized double-blind placebo-controlled delayed-start clinical trial in mild to moderate AD, were included in the analysis. At study entry, subjects were stable on standard treatment (acetylcholinesterase inhibitors or memantine) which was continued throughout the study according to the treating physician’s judgement. Subjects were randomized to receive MLC901 (early-starters) or placebo (delayed-starters) for 6 months, followed by a further 6 months when all subjects received MLC901. The Alzheimer’s Disease Assessment Scale — Cognitive subscale (ADAS-Cog) scores were measured at 3, 6, 9 and 12 months. Comparison between early-starters and delayed-starters was performed using a linear mixed effect model with repeated measurements adjusted for treatment, visit, treatment by visit interaction and baseline ADAS-Cog score. The adjusted mean difference (MD) with 95% confidence interval (CI) and p-value (P) were calculated for ADAS-Cog change from baseline at months (M) 9 and 12. The analyses were conducted on both intention-to-treat (ITT) and per-protocol (PP) populations. Results: 125 subjects were included in this exploratory analysis. At baseline, mean ADAS-Cog scores were not significantly different (31±12 and 29±10) in early-starters and delayed-starters. Early-starters were significantly different compared to delayed-starters in mean change from baseline ADAS-Cog scores at M9 in both ITT (MD: −3.67 [95% CI: −6.06, −1.28]; P=0.003) and PP analyses (MD: −3.93 [95% CI: −6.99, −0.86]; P=0.013). A significant difference in change in ADAS-Cog score was also observed at M12 only in the PP analyses (MD: −4.30 [95% CI: −8.38, −0.22]; P=0.039). Conclusions: This exploratory alternative analysis confirmed a difference between early-starters and delayed-starters on ADAS-Cog suggesting either a prolonged symptomatic effect of MLC901 or slowing of disease progression in subjects on early treatment with MLC901 as an add-on to standard therapy. The treatment effect was most substantial at M12 in patients who were compliant to the study medication and study completers, as shown in PP analysis. The previously available preclinical and clinical data, along with the recent promising ATHENE study results suggest that the next step in the clinical development of MLC901 in AD should be to design a larger clinical study of a longer duration with added biomarkers to demonstrate a disease modification effect in AD. References: Chen, C., Lu, Q., Moorakonda, R. B., Kandiah, N., Tan, B. Y., Villaraza, S. G., Cano, J., & Venketasubramanian, N. (2022). Alzheimer’s Disease THErapy With NEuroaid (ATHENE): A Randomized Double-Blind Delayed-Start Trial. Journal of the American Medical Directors Association, 23(3), 379–386. e3. 10.1016/j.jamda.2021.10.018. Michel Dib, Encarnita Ampil, Hoo Fan Kee, Yakup Krespi, Akram Al Mahdawi, Shamsideen Abayomi Ogun, Hossein Pakdaman, Konrad Rejdak. (2022) A Review of NeuroAiDTMII (MLC901) Development in Alzheimer’s Disease Treatment: Promises of A Multimodal Pathway. J Neurol Res Rev Rep. 2022;4(3):1–13. SRC/JNRRR-173. DOI: 10.47363/JNRRR/2022(4)160.
P130- A MULTICENTER, PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED INVESTIGATION OF SAFETY AND EFFICACY OF NILOTINIB BE IN EARLY ALZHEIMER’S DISEASE (NILEAD). Y. Torres-Yaghi 1, M. Sabbagh 2, C. Hoyt 3, K. Guedes 3, F. Pagan 1, R. Turner 1, J. Ahn 1, C. Moussa 1(1. Georgetown — Washington, DC (United States), 2. Barrow — Phoenix, AZ (United States), 3. Keiferx — Washington, DC (United States))
Background: Nilotinib BE is a new formulation of the same active pharmaceutical ingredient (API), nilotinib (tasigna, Novartis), that has significant clinical use in over 6000 patients with Chronic Myelogenous Leukemia (CML). KeifeRx in collaboration with Sun Pharmaceuticals Research Industry will evaluate the efficacy of Nilotinib BE in individuals with Early Alzheimer’s Disease (EAD) by determining the superiority of Nilotinib BE compared with placebo on the change in the Clinical Dementia Rating—Sum of Boxes (CDR-SB) from Baseline to 18 months (Week 72) of treatment. We hypothesize that Nilotinib BE will halt cognitive decline in EAD. KeifeRx will conduct a phase 3 multicenter, placebo-controlled study that will enroll a total of approximately 1275 subjects and will include a Core Study that will enroll approximately 425 subjects who will be randomized to the placebo group (arm A) and 425 subjects to each of the Nilotinib BE, 84mg (arm B) and 112mg (arm C) groups. A Biomarker Sub-study will also enroll approximately 180 subjects (60 subjects per group), who will be randomized for the CSF biomarker sub-study at Baseline and 18 months (Week 72). Additional, approximately 164 subjects (48 per group) will be randomized to the imaging sub-studies, including amyloid PET, tau PET and vMRI, at Baseline and 18 months (week 72). Nilotinib BE is an oral drug that has significant advantages compared to intravenously administered treatments. Not only the convenience of oral administration favors Nilotinib BE, but also the known safety profile of Nilotinib in CML and in neurodegenerative diseases compared to the serious adverse effects of infusions, mainly Amyloid Related Imaging Abnormalities (ARIA).
P131- SUBJECTIVE ILLNESS REPRESENTATIONS IN AN EARLY-STAGE ALZHEIMER’S DISEASE POPULATION: PSYCHOMETRIC PROPERTIES OF THE RADIX QUESTIONNAIRE. A. Villarejo-Galende 1, E. García-Arcelay 2, G. Piñol-Ripol 3, A. Del Olmo-Rodríguez 4, F. Viñuela 5, M. Boada 6, E. Franco-Macías 7, A. Ibañez De La Peña 8, M. Riverol 9, J. Maurino 2(1. Department Of Neurology, Hospital Universitario 12 De Octubre — Madrid (Spain), 2. Medical Department, Roche Farma — Madrid (Spain), 3. Unitat Trastorns Cognitius, Hospital Universitari De Santa Maria — Lleida (Spain), 4. Department Of Neurology, Hospital Universitario Dr. Peset — Valencia (Spain), 5. Department Of Neurology, Hospital Universitario Virgen Macarena — Sevilla (Spain), 6. Ace Alzheimer Center Barcelona — Barcelona (Spain), 7. Department Of Neurology, Hospital Universitario Virgen Del Rocío — Sevilla (Spain), 8. Centro De Investigación De Parkinson, Policlínica Guipúzcoa — San Sebastián (Spain), 9. Department Of Neurology, Clínica Universidad De Navarra — Pamplona (Spain))
Background: Patients’ beliefs and expectations about a disease influence their emotional reactions and coping resources, and have been associated with quality of life and treatment adherence. Identifying and understanding patients’ representations of Alzheimer’s disease (AD) can be useful for the early implementation of individualised interventions to improve their ability to live well with their disease. The Representations and Adjustment to Dementia Index (RADIX) is a self-report instrument validated in patients with mild-to-moderate dementia to assess their understanding of the condition and its consequences in five components: identity, cause, disease course, possibilities for controlling the disease, and practical and emotional consequences. However, it has not been evaluated in patients with early-stage AD. Objectives: The aim of this study was to assess the dimensional structure and item distributions of the RADIX in early AD. Methods: A non-interventional, cross-sectional study was conducted at 21 Memory clinics in Spain. Patients aged 50–90 years, diagnosed with prodromal or mild AD (NIA/AA criteria), a Mini-mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5 or 1.0 were recruited. For practical (4 items) and emotional (5 items) consequences, responses to the RADIX questions are rated on a 4-point scale (from strongly disagree to strongly agree) and can be summed to give an overall score and then divided by 4 and 5 to give the mean score, respectively. Higher scores indicate greater negative consequences. A non-parametric item response theory procedure, Mokken analysis, was performed to assess the underlying dimensional structure and scalability of items and overall questionnaire. Each item was required to have a scalability coefficient (Hi) of ≥ 0.30 and an overall scale scalability index (H) of ≥ 0.30. A confirmatory factor analysis (CFA) was also run to check the two-dimensional structure originally described with practical and emotional consequences as latent variables underlying the RADIX measure. Associations between the RADIX and the generic Brief Illness Perception Questionnaire (B-IPQ) and Quality of Life in Alzheimer’s Disease scale (QoL-AD) were analysed using Spearman’s rank correlations. All analyses were performed with JASP (v 0.14.1) and R (v 4.0.3) using the mokken and lavaan libraries. Results: A total of 146 patients were studied. Mean (SD) age was 72.3 (7.0) years and 50.3% were female. Mean duration of AD was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1) and 87.2% had a CDR-GS score of 0.5. One hundred sixteen (79.4%) participants were aware of their condition and sixty-six (44.3%) used the term AD when asked if they knew their specific diagnosis. The most frequent causes assigned by patients as responsible for their condition were ageing and brain changes. Mean practical and emotional consequences RADIX scores were 1.8 (0.6) and 2.2 (0.8), respectively. The RADIX showed high reliability (Cronbach’s alpha = 0.86). Mokken analysis indicated its items fitted to a unidimensional scale with an overall scalability coefficient which agrees with a moderate scale (H = 0.45). Analyses also showed RADIX was consistent with the monotone homogeneity model and appropriate to order persons across the latent trait assessed. The CFA analyses were consistent with both a unidimensional model (CFI=0.96; RMSEA=0.09; SRMR=009) and the two-dimensional model previously described (CFI=1; RMSEA=0, SRMR=0.06). The linear correlation between Mokken item scalability coefficients and standardised loadings from the unidimensional CFA was 0.98 (p<0.0001), meaning that both procedures agree when ordering the items of the RADIX scale. RADIX total score correlated significantly with the emotional representation (r = 0.48, p < 0.001) and cognitive representation (r = 0.31, p < 0.001) of the B-IPQ, whereas correlation was practically null with the illness comprehensibility (r = −0.07, p = 0.43). Practical and emotional consequences RADIX scores showed a significant negative correlation with QoL-AD score (r = −0.39 and −0.41, respectively; p<0.0001). Conclusions: The RADIX showed appropriate psychometric characteristics and may constitute a valuable disease-specific addition to understand illness perceptions in earlier stages of AD.
P132- IMPACT OF DISEASE PROGRESSION ON DEPENDENCY IN PATIENTS WITH MILD AND MODERATE ALZHEIMER DISEASE. W. Ye 1, J. Chandler 1, X. Mi 2, A. Tockhorn-Heidenreich 1, J. Johnston 1, E. Doty 1(1. Eli Lilly And Company — Indianapolis (United States), 2. Techdata Services Company — King Of Prussia (United States))
Background: Dependence on others to carry out everyday activities as Alzheimer’s Disease (AD) progresses is associated with greater care partner burden, higher societal costs and lower quality of life for patient and care partner. The impact of cognitive and functional decline on dependency in early symptomatic AD has not been well characterized. Understanding progression of dependency across the disease spectrum may further support the value assessment of disease modifying treatment. Objective: We evaluated dependency in everyday activities in a sample of mild and moderate AD patients over 18 months and estimated the potential impact of a 20–30% slowing of disease progression. Methods: Participants with amyloid positivity in the placebo arms of the EXPEDITION1, 2 and 3 randomized placebo-controlled studies of solanezumab in mild and moderate AD (NCT00904683, NCT01900665 and NCT00905372) were used in these post-hoc analyses. IADRS (a composite score of Alzheimer’s Disease Assessment Scale Cognitive subscale ADAS-Cog14 and Alzheimer’s Disease Cooperative Study- instrumental Activities of Daily Living (ADCS-iADL) and Clinical Dementia Rating Scale (CDR-SB) were used to measure disease progression. Six dependence levels (DL) (0–5; 0-no care needs; 3-extensive home care services; 5-nursing home) were derived from ADCS-ADL using a previously validated algorithm. DL was dichotomized into DL =≤ 2 or > 2, where DL > 2 indicates need for extensive home care or full-time care. Mixed-model repeated measures (MMRM) analyses were conducted to estimate least squares mean change (LSMC) and standard error (SE) from baseline for measurements. A logistic regression model was used to assess the likelihood of reaching DL >2 at 18 months with IADRS or CDR-SB change from baseline as the predictor, adjusting for age, baseline dependency level, investigator, and concomitant AChEI and/or memantine use at baseline (yes/no). Separate models were fitted for mild and moderate AD. The predicted mean probability of reaching DL >2 at 18 months was estimated using prespecified values (20% and 30%) of slowing of disease progression. Odds ratios (OR) with 95% confidence interval (CI) of reaching DL>2 were estimated relative to natural disease progression. Results: 1278 study patients (1204 mild and 74 moderate AD) had mean age (Standard Deviation (SD)) 73.5 (8.06) years and 58.5% female. Moderate AD patients had greater DL than mild AD at baseline (average (SD) 2.5(0.8) and 2.1(0.9), respectively. The average (SD) IADRS and CDR-SB were 105.5 (14.21) and 3.90 (1.93) for mild AD and 85.3 (18.29) and 5.70 (2.30) for moderate AD. The mean changes in IADRS and CDR-SB from baseline to 18 months were statistically significant for both groups with IADRS and CDR-SB LSMC (SE) −14.78 (0.55) and 2.16 (0.09) for mild AD and −24.09 (2.43) and 4.26 (0.38) for moderate AD, respectively. Over 18 months, the proportion of patients reaching DL> 2 increased for both groups (from 24.8% at baseline to 41.9% at 18 months in mild AD, and from 37.8% to 68.2% in moderate AD). For mild AD, a 14.78-point worsening in IADRS led to a predicted probability of reaching DL >2 of 0.41 for progression over 18 months. Compared to the observed progression, delaying progression by 20% or 30% could lower that probability to 0.35, or 0.33 and make it 21% or 30% less likely to reach DL> 2 with OR (95% CI) 0.79 (0.76, 0.82), or 0.70 (0.66, 0.74), respectively. For moderate AD, a 24.09-point worsening in IADRS could has a predicted probability of reaching DL >2 of 0.91 over 18 months. Delaying progression by 20% or 30% could lower the probability of reaching DL >2 to 0.86 — 0.82 and make it 41–54% less likely reaching DL>2 with OR (95% CI) 0.59 (0.40, 0.88) to 0.46 (0.26, 0.82). A 2.16-point worsening for mild AD and 4.26-point for moderate AD in CDR-SB led to a predicted probability of reaching DL >2 of 0.38 and 0.81 over 18 months. Compared to the observed progression over 18 months, delaying progression by 20% or 30% could lower the predicted probability of reaching DL>2 to 0.34 or 0.32 for mild AD and 0.72 or 0.66 for moderate AD, respectively and make it 16%–24% less likely for mild AD with OR (95% CI) 0.84 (0.81, 0.86) or 0.76 (0.73, 0.80) and 40%–54% less likely for moderate AD with OR (95% CI) 0.60 (0.42, 0.86) to 0.46 (0.27, 0.80) to reach DL >2, respectively. Conclusion: Moderate AD patients had greater levels of dependency than mild AD patients and dependence levels increased over 18 months for both groups. Treatments that slow disease progression in early symptomatic AD have the potential to delay patients’ need for more extensive home care or assisted living seen in moderate AD. Full COI disclosure will be on the 2nd slide of the presentation or in the poster presentation.
P133- THE RESPONSIVENESS OF COGNITIVE AND FUNCTIONAL OUTCOME MEASURES IN PRECLINICAL ALZHEIMER’S DISEASE: IMPLICATIONS FOR TRIAL DESIGN. M. Dubbelman 1, H. Hendrikse 1, L. Ottenhof 1, E. Vijverberg 1, N. Prins 2, L. Kroeze 1, A. Van Harten 1, B. Van Berckel 1, J. Harrison 1, W. Van Der Flier 1, S. Sikkes 1(1. Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Umc Location Vumc — Amsterdam (Netherlands), 2. Brain Research Center — Amsterdam (Netherlands))
Background: Cognitive and functional outcome measures that are sensitive to the earliest cognitive changes in preclinical Alzheimer’s disease (AD) are essential for demonstrating treatment efficacy in secondary prevention trials. We hypothesized that the sensitivity of outcome measures may differ according to biomarker inclusion criteria, such as amyloid and/or tau positivity, or apolipoprotein (APOE) ε4 carriership. Objectives: To determine the sensitivity of numerous cognitive and functional outcome measures, commonly used in clinical practice, within various biomarker groups. Methods: We included 551 participants with subjective cognitive decline (61.8+8.6 years, 44% female) from the observational Amsterdam Dementia Cohort. All had longitudinal cognitive assessments and baseline biomarker data, Mini-Mental State Examination (MMSE) ≥26, and Geriatric Depression Scale <6. We created different (overlapping) target groups, based on inclusion criteria in secondary prevention trials of preclinical AD: (1) amyloid positive as determined by positron emission tomography scans or in cerebrospinal fluid (CSF) (n = 106), (2) p-tau positive as determined by CSF phosphorylated (p-)tau levels (n = 120), (3) both amyloid and p-tau positive (n = 47), (4) APOE ε4 carriers (n = 156) and (5) APOE ε4 carriers who are also amyloid positive (n = 64). Linear mixed models were used to investigate the sensitivity to change of seventeen standardized cognitive outcome measures, including the MMSE, immediate and delayed recall on word list learning and logical memory tests, the Trail Making Test, Stroop Color-Word Test, Letter Digit Substitution Test, semantic and phonetic fluency tests, digit span backwards, and the Boston Naming Test. The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) was used as a functional outcome. All test scores are presented as higher reflecting better performance. Time in years served as the main variable of interest of which we report standardized coefficients reflecting standard deviation decline per year, adjusting for sex, education, and baseline age. We also investigated composites based on the Preclinical Alzheimer Cognitive Composite (PACC5) and the Cognitive-Functional Composite (CFC). Finally, we limited study follow-up duration to a maximum of 18 months, in line with the typical minimum duration of a phase III trial. Results: Based on the full follow-up duration (mean = 3.9 ± 2.9 years, range 0.4–18.9 years), the amyloid and p-tau positive group showed the largest number of cognitive tests that show significant change over time with the largest effects (14/17, 82%) with standardized coefficients ranging from −0.70 to −0.24). The responsiveness of cognitive outcomes was lower among APOE ε4 carriers, with 9/17 responsive tests (53%; standardized coefficients ranging from −0.30 to −0.13) showing change over time. The phonetic fluency improved among APOE ε4 carriers (standardized coefficient = +0.10). In the amyloid positive group, 11/17 cognitive outcome measures (65%) were responsive to change (standardized coefficients ranging from −0.47 to −0.21) and in the p-tau positive group 10/17 cognitive tests (59%) were responsive, with standardized coefficients ranging from −0.39 to −0.14. In amyloid positive APOE ε4 carriers, 9/17 cognitive outcome measures showed significant change over time, with standardized coefficients ranging from −0.41 to −0.17. Functional impairment, as measured with the A-IADL-Q was responsive in all target groups except the p-tau only group (standardized coefficients ranging −0.16 for APOE ε4 carriers to −0.70 for amyloid and p-tau positive individuals). The PACC5 and CFC were responsive to change over time all but one group, with standardized betas ranging from −0.22 (p-tau only) to −0.60 (p-tau and amyloid) and −0.20 (p-tau only) to −0.48 (p-tau and amyloid), respectively. Both composites did not show change over time among APOE ε4 carriers. With the follow-up duration limited to a maximum of 18 months, most cognitive tests were no longer responsive to change over time. Moreover, the direction of changes reversed, indicating improvements over time. The A-IADL-Q did not show change over time in any group, nor did the CFC. The PACC5 showed improvements in the p-tau only group (standardized coefficient = 0.10) and among APOE ε4 carriers (standardized coefficient = 0.06). Discussion: We demonstrated that commonly used cognitive outcome measures, as well as a functional outcome measure, can capture cognitive decline in preclinical AD, specifically over longer follow-up times and in individuals who are included in a more advanced pathological disease stage (i.e., those who are both amyloid and tau positive). However, with a limited study duration of 18 months or shorter, as well as among APOE ε4 carriers, responsiveness was considerably lower. Our findings have important implications for trial design, to the extent that either longer study durations, more sensitive outcome measures, or more specifically targeted study populations may be required to adequately investigate potential treatment effects. We propose that outcome measures be selected to be appropriate to the target population and that trial duration be determined by the required rate of decline.
P134- THE EFFECT OF DIETARY HABIT ON THE PROGRESSION OF ALZHEIMER’S DISEASE: A CREDOS (CLINICAL RESEARCH CENTER FOR DEMENTIA OF SOUTH KOREA) STUDY. Y.K. Minn 1, S.H. Choi 2(1. Kangnam Sacred Heart Hospital, Hallym University — Seoul (Korea, Republic of), 2. Inha University Medical Center — Inchon (Korea, Republic of))
Background: The social costs associated with AD increase as dementia severity increases. Despite extensive research in the field of dementia, few drugs prevent the progression of AD. Alternative therapies, including non-pharmacological approaches, are still needed not only for the prevention of dementia but also for the stage of dementia. It is well-known that specific diet patterns, such as a Mediterranean diet, slow the development of dementia. However, dietary patterns are reflective of nations’ unique cultures and are difficult to artificially change. Both healthy and unhealthy eating habits exist even within the same culture. In addition, the effects of dietary habit on progression of on dementia patients remain unknown. Objectives: In this study, we aimed to investigate what dietary habits are associated with progression of dementia over three years from Alzheimer’s disease dementia patients enrolled in the Clinical Research Center for Dementia of South Korea (CREDOS) study (November 2005 to January 2015), a hospital based multi-center registry project (1). Methods: We selected mild to moderate Alzheimer disease patients with a Clinical Dementia Rating (CDR) scale of 2 or less from the CREDOS study. We included probable AD patients using criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Mini-Dietary Assessment Index for Koreans was initially assessed (2). A subject was asked to check, in their answers, either ‘always’, ‘usually’, or ‘rarely’, reflected by a score 5, 3, and 1 (5 means good habit, 1 means bad habit). The CDR-Sum of Box, the Caregiver-Administered Neuro Psychiatry Inventory (CGA-NPI), Seoul-Instrumental Active Daily Living(S-IADL) and a global composite score (NTB-Z) were checked for up to three years. For un-adjustment analysis, mixed model as applied, A two-way layout model with repetition was selected. ANOVA and χ2 test were used to testing the heterogeneity of well-known risk factor for dementia between each group. A mixed model analysis was performed again by correcting the disturbance variable that was found to be meaningful in the above step. Result: A total of 705 patients with mild to moderate AD were enrolled. In the un-adjustment linear mixed models, some good diet habit (Q2, eat foods made of meat, fish, eggs, beans, or tofu at least 3–4 times daily, Q7, add salt or soy sauce to food, when eating and Q10, eat all food evenly without being picky eaters) showed positive effect. In Q2, score 5 and score 3 showed lower CGA-NPI than score 1. In Q7, score 3 showed good effect on NTB-Z, CGA-NPI and S-IADL but only CGA-NPI showed good effect on score 5. In Q10, score5 showed good effect on CDR-SB and S-IADL than score 1 but score 3 did not showed good effect. Male, high education, current smoker, current drinking low GDS-15 and high MMSE participants had good dietary habits. After adjustment, Q7 and Q10 showed good effect on dementia progression. In Q7, CDR-SB, NTB-Z, S-IADL and CGA-NPI showed good effect on score 3 but only CDR-SB and CGA-NPI showed good effect on score 5. In Q10, the score5 group showed better effects than the score1 group for 3 years on CDR-SB and S-IADL. Conclusion: Good dietary habits, especially eating less salt and evenly without being picky eaters, have good effects on dementia, even after adjusting for major risk factors linked to dementia. It is important not only to find and consume special foods that are good for dementia, but eating less salty and eating the foods evenly under given environment is helpful for dementia. References: 1. Park HK, Na DL, Han S-H, et al. Clinical Characteristics of a Nationwide Hospital-based Registry of Mild-to-Moderate Alzheimer’s Disease Patients in Korea: A CREDOS (Clinical Research Center for Dementia of South Korea) Study. Journal of Korean Medical Science. 2011;26(9):1219–1226. 2. Kim W, Cho M, Lee H. Development and validation of mini dietary assesment index for Koreans. Korean J Nutr. 2003;36(1):83–92.
P135- LENGTH OF ADMINISTRATION OF ADAS-COG AND CDR ASSESSMENT IMPACTS DATA QUALITY. B. Echevarria 1, S. Negash 1, L. Wolf 1, R. Blattner 1, J. Giuffrida 1, S. Gamazo Navarro 1, V. Cimermanova 1, C. Randolph 1(1. WCG Clinical Endpoint Solutions — Hamilton (United States))
Background: Administration of both structured (ADAS-Cog) and semi-structured (CDR) clinician administered outcome assessments (COA) utilized in Alzheimer disease (AD) clinical trials can significantly vary among study sites and raters. This variability in administration of key outcome measures can undermine the detection of a treatment effect in a randomized clinical trial and may also be a contributing factor in failures and inconclusive results recently seen in AD trials. Administration time of outcome measures that is either too short or too long may be linked to poor rater performance or contribute to decreased subject performance. In this project we examined whether assessments that are duration outliers (either too short or too long) result in higher rates of scoring discrepancies and/or are deemed to not meet assessment quality expectations when reviewed by a team of highly trained and calibrated independent clinicians. Objectives: In this study we aim to evaluate whether ADAS-Cog and CDR assessments that are too short or too long result in a higher number of scoring errors and/or quality failures when they are independently reviewed by highly trained and calibrated clinicians. Methods: Aggregated data from 18 multinational clinical trials of Early Symptomatic and Mild to Moderate AD were analyzed. ADAS-Cog and CDR assessments conducted by site raters were independently reviewed via audio recording. Site raters underwent a rigorous pre-screening, qualification, and certification process prior to being added to studies. A total of 43,590 reviewed assessments were evaluated. Separate analyses were conducted for each study population and scale in four cohorts: Early Symptomatic/CDR (n = 23,536), Mild-to-Moderate/CDR (n = 5,025), Early Symptomatic/ADAS-Cog (n = 8,971), Mild-to-Moderate/ADAS-Cog (n = 6,058). Scale duration groups in each cohort were classified based on percentile rank, where assessments in the top 10 % of the cohort were classified as High Duration, bottom 10% as Low Duration, and the remaining assessments as Expected Duration. Rates of scoring discrepancies as well as quality failures were compared across Duration groups in each cohort. Results: Group differences were observed in both ADAS-Cog and CDR groups. One-way ANOVAs comparing the Duration groups in ADAS-Cog revealed significantly worse performance in High Duration group than Expected Duration for both discrepancy rates (Early Symptomatic: df = 2, F = 44.52, p < .0001; Mild-to-Moderate: df = 2, F = 10.18, p < .0001) and quality failures (Early Symptomatic: df = 2, F = 61.18, p < .0001; Mild-to-Moderate: df = 2, F = 11.61, p < .01). For the CDR, significantly worse performance was observed in Low Duration group than Expected Duration for both discrepancy rates (Early Symptomatic: df = 2, F = 47.77, p < .0001; Mild-to-Moderate: df = 2, F = 7.16, p < .0001) and quality failures (df = 2, F = 204.11, p < .0001; Mild-to-Moderate: df = 2, F = 48.68, p < .0001). Conclusion: Results indicate that unusually long duration assessments with the ADAS-Cog are associated with significantly increased score discrepancies across disease severities. Unusually short or unusually long ADAS-Cog administration times were also associated with a more modest increase in administration errors, more evident in the early symptomatic subjects than in subjects with mild-moderate dementia. For the CDR, unusually long duration of assessment was not associated with an increase in either scoring errors or administration errors, but unusually short duration of assessment was associated an increase in both scoring and administration errors, evident across disease severity.
P136- A RANDOMIZED STUDY TO EVALUATE THE EFFICACY OF DONEPEZIL IN IMPROVING VISUOSPATIAL ABILITIES IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT USING EYE-TRACKER. K. Ko Woon 1, W. Qi 2, K. Se Hee 3, S. Byoung-Soo 1(1. Department of Neurology, Jeonbuk National University Medical School and Hospital — Jeonju (Korea, Republic of), 2. Jeonbuk National University Medical School — Jeonju (Korea, Republic of), 3. Biomedical Research Institute of Jeonbuk National University Hospital — Jeonju (Korea, Republic of))
Background: Cholinesterase inhibitors (ChEIs) decrease long-term cognitive decline in patients with Alzheimer’s disease (AD); however, there is little evidence that ChEIs affect cognitive test scores in patients with mild cognitive impairment (MCI). Conventional endpoints, such as cognitive tests or clinical rating scores, may lack the sensitivity to subtle treatment effects in participants with MCI. Therefore, there is an immediate need to refocus on direct physiological assessments to detect the effects of ChEIs in patients with MCI due to AD. Methods: We propose a randomized controlled trial to evaluate the effect of donepezil, a ChEI, on patients with MCI due to AD. We plan to recruit 78 participants (39 in each arm) with MCI who had amyloid positron emission tomography (PET)-positive results for this open-label study. To evaluate subtle differences, we will measure eye-tracking metrics and digital pen data while participants perform the simplified Rey Complex Figure (RCFT) and clock drawing tests. The primary outcome is a change in the ratio of the number of fixations (working space/perceptual space) performed using the simplified RCFT, from baseline to 12 weeks, as assessed using eye-tracking metrics. The secondary outcomes are changes in general cognition, clinical severity, activities of daily living, and visuospatial function assessed using standard rating scores and digital pen data. The analyses of the primary and secondary outcomes will be based on the difference in changes during follow-up between the donepezil and control groups using the t-test or MannWhitney U test, as well as adjusting for baseline values. Results: Our preliminary results showed a tendency for the ratio of the number of fixations (working space/perceptual space) to increase in the donepezil group compared to the control group (p = 0.036). Discussion: This study is designed to determine whether eye-tracking metrics can detect the effect of donepezil on visuospatial dysfunction more sensitively in patients with MCI. It is expected that multimodal data, such as eye-tracking and digital pen data, may provide helpful biomarkers for identifying subtle changes that are difficult to measure using conventional methods. This research was supported by Eisai Korea Inc.
P137- A PHASE 2B, RANDOMIZED, PLACEBO-CONTROLLED TRIAL TO EVALUATE THE EFFECTS OF SAGE-718 IN PATIENTS WITH ALZHEIMER’S DISEASE: STUDY DESIGN. A. Koenig 1, T. Lago 1, J. Johannesen 1, S. Li 1, E. Freitag 1, J. Wald 1, K. Paumier 1, M. Quirk 1, J. Doherty 1(1. Sage Therapeutics, Inc. — Cambridge, Massachusetts (United States))
Background: Alzheimer’s disease (AD) is a common neurodegenerative illness associated with cognitive impairment and loss of independence, accounting for 60–70% cases of dementia globally (1). Both executive functioning (eg, problem solving) and learning and memory deficits that are associated with AD occur early in the disease (2). Approved therapies for mild cognitive impairment (MCI) or mild dementia associated with AD have modest efficacy, and their use may be limited by side effects (3). There is unmet need for effective treatments that address early cognitive decline and impairment in daily functioning in patients with AD. N-methyl-D-aspartate receptors (NMDARs) are critical for neuronal network stabilization and are involved in many cognitive and behavioral processes (4, 5). NMDAR dysfunction has been implicated in multiple neuropsychiatric conditions (6). SAGE-718 is a novel NMDAR positive allosteric modulator that is being investigated by Sage Therapeutics for the treatment of cognitive impairment associated with AD and other neurodegenerative disorders. Treatment with SAGE-718 demonstrated improved performance on cognitive tests vs placebo following a ketamine challenge in a study of healthy volunteers (7). In the Phase 2, open-label, signal-finding LUMINARY Study (NCT04602624), SAGE-718 was generally well tolerated and associated with improved performance on cognitive tests in patients with MCI or mild dementia due to AD (n=26). Based on these preliminary results, a randomized, double-blind, placebo-controlled study to evaluate the effect of SAGE-718 on cognitive performance in patients with MCI or mild dementia due to AD was planned. Objectives: To describe the design of a randomized, double-blind, placebo-controlled study to evaluate the effect of SAGE-718 on cognitive performance in patients with MCI or mild dementia due to AD. Methods: Approximately 150 patients will be enrolled across 40 sites in the United States. Eligible patients are aged 50–80 years meeting diagnostic criteria for AD with a baseline Montreal Cognitive Assessment (MoCA) score of 15–25, a baseline Clinical Dementia Rating (CDR) score of 0.5 to 1.0 (inclusive), and a memory box score ≥0.5 will be randomized to receive either oral SAGE-718 or placebo. The primary endpoint is the change from baseline to Day 84 in the Wechsler Adult Intelligence Scale Fourth Edition-IV (WAIS-IV) Coding Test (total correct). The secondary endpoints are safety and tolerability and number of study withdrawals due to treatment-emergent adverse events (TEAEs). Other exploratory cognitive and functional endpoints will also be evaluated. The study design includes a 3-week screening period, a 1-week baseline period, a 12-week treatment period, and a 4-week follow-up period. During the initial 6 weeks of the treatment period, patients in the SAGE-718 arm will receive an initial dose of SAGE-718 (Days 1 to 42), then during the next 6 weeks of treatment, patients will receive a lower dose of SAGE-718 (different dose; Days 43 to 84). The dose regimen is selected to provide optimal pharmacokinetic exposures that are similar to those achieved in prior studies that demonstrate target engagement. Matching placebo will be given throughout the entire treatment period (12 weeks). At scheduled clinic visits during the treatment period, cognitive performance, safety, efficacy, and adherence will be assessed. Study initiation is planned for late 2022. Conclusion: This randomized, doubleblind, placebo-controlled study is intended to evaluate the safety and effects on cognitive performance of SAGE-718 in patients with MCI or mild dementia due to AD. The results of this study are expected to inform the potential of SAGE-718 for the treatment of cognitive impairment associated with AD. References: 1. Sharma K. Mol Med Rep. 2019;20(2):1479–1487. 2. Weintraub S, et al. Cold Spring Harb Perspect Med. 2012;2(4):a006171. 3. Han JY, et al. Alzheimer Dis Assoc Disord. 2019;33(2):87–94. 4. Ghanavati E, et al. Cereb Cortex. 2022. 5. Li F, et al. N Engl J Med. 2009;361(3):302–303. 6. Paoletti P, et al. Nat Rev Neurosci. 2013;14(6):383–400. 7. Koenig A, et al. ACNP 58(th) Annual Meeting: Poster Session I. Neuropsychopharmacology. 2019;44(Suppl 1):78–229. Funding Source: This study was sponsored by Sage Therapeutics, Inc. Acknowledgments: We would like to thank the patients and their families for helping us reimagine brain health. Medical writing and editorial support were provided by Symbiotix, LLC, funded by Sage Therapeutics, Inc. AK, TL, JJ, SP, SL, EF, JW, KP, MQ, and JD are employees of Sage Therapeutics, Inc., and hold stock or stock options. Note: SAGE-718 is an investigational drug and is not approved by the FDA or any other regulatory agency as safe and effective for any use.
P138- BRINGING MEANING TO PERSONALISED BRAIN HEALTH: A TOOL THAT EMPOWERS INDIVIDUALS TO DEFINE AND MONITOR PERSONALLY MEANINGFUL CHANGE. S. Saunders 1, D. Bates 2, A. Bharija 2,3, J. Gomes-Osman 2,4, S. Luz 1, G. Muniz-Terrera 1, Á. Pascual-Leone 2,5, C. Ritchie 1(1. Centre for Clinical Brain Sciences, University of Edinburgh, UK — Edinburgh (United Kingdom), 2. Linus Health Inc., Boston, MA, USA — Boston (United States), 3. Department of Medicine, Division of Primary Care and Population Health, Stanford Medicine, Stanford, USA — Stanford (United States), 4. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA — Miami (United States), 5. Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA — Boston (United States))
Background: In the early stages of Alzheimer’s disease (AD), the aim is to maintain brain health by preventing entirely, or delaying significantly, the development of symptoms. However, it is essential to demonstrate an intervention delivers a meaningful outcome for the patient. Therefore, it is critical to associate most commonly used outcome measures in clinical trials (i.e., biomarkers and symptoms) with outcomes that are relevant for the individual patient and account for the change in treatment priorities over time. To fill this knowledge gap, researchers at the University of Edinburgh have partnered with Linus Health to create a tool for capturing personally meaningful outcomes to monitor functional trajectory, and importantly, treatment effects over time. Objectives: Our aim is to create a tool to easily capture what aspects are most important for individuals to retain should their brain health deteriorate through conditions like AD. The presentation aims to (1) to update on the latest results of the electronic Person Specific Outcome Measure (ePSOM) programme, reporting findings from a large UK-wide survey on what outcomes matter to people when developing new treatments for AD and (2) outline a development plan to validate a new digital tool to capture and monitor personally meaningful outcomes in Brain Health. Method: The UK-wide survey (conducted Aug 2019 — Nov 2019) probed individuals to define most important individual priorities in five domains of Brain Health (Everyday functioning; Enjoying life; Thinking abilities; Relationships and Social interactions; Sense of identity). These data were collected using primarily free text responses, alongside relevant clinical and demographic data. We used natural language processing (NLP) techniques to analyse the data. We report findings from a subgroup analysis which includes individuals with a self-reported neurodegenerative disease diagnosis (primarily Mild Cognitive Impairment (MCI) or AD) whereby we conducted comparisons with an age and gender matched control group. We also describe the development and validation plan for a tool aimed at capturing personally meaningful outcomes for use in clinical trials as adjunct to biomarker, cognitive and functional endpoints. Importantly, this tool has the potential to create a critical anchor for personalised interventions by allowing individuals to define ‘what does treatment success look like for them? Results: The ePSOM survey was filled in by n=5808 respondents across the UK, with over 80,000 free text responses of what outcomes matter to individuals. The automated NLP analysis resulted in 184 unique themes of importance about Brain Health across the whole data set. A sub-set of n=167 respondents (2.9%) (women n = 91, men n = 69, other n = 7) had received one of our pre-defined neurodegenerative disease diagnoses: most commonly MCI n = 52, 1.1%; or Alzheimer’s disease n = 48, 1.0%. Several thematic clusters were significantly more important for the target diagnostic group, e.g.: Expressing opinions; and less important, e.g., Cognitive Games. Conclusion: The person specific digital tool developed by our team invites each person using the tool to first define their brain health priorities. While deriving a numeric score is less central in clinical practice than in regulatory trials where a change of score indicates improvement/decline/no change over time, this ‘personal outcomes tool’ allows patients to define the most important outcomes against which we should measure treatment success. It also informs the most appropriate interventions so that the person can ‘be the best version of themselves’, i.e., a truly personalised medicine approach. For instance, if a patient defines driving as the key outcome, then as well as personalised interventions to maintain brain health and risk factor modification, the person may also be directed to ‘coaching’ for driving to build resilience with driving, maintain confidence and develop new skills that helps keep them driving for as long as possible. By employing NLP of either speech or text, we ensure every outcome recorded is unique to that individual and immune to cultural/language biases inherent with tools using pre-defined items. In clinical trials, there is much value for such a tool in parallel with biological measures of AD and provide a secondary endpoint to offer further proof of drug effectiveness, from the study participant’s point of view. The ePSOM programme results to date suggest that outcomes that matter shift along the preclinical, prodromal and dementia continuum. This has important implications for the development of outcome measures that may be used in long-term clinical monitoring and interventional studies that may last several years. Our personalised medicine approach could have value more broadly in other diseases which affect brain health.
P139- DEMENTIA CONVERSION RATE DIFFERENCES BETWEEN PATIENTS WITH HIGH- AND LOW-RISK AMNESTIC MILD COGNITIVE IMPAIRMENT IN THE REAL-WORLD: A PROSPECTIVE, MULTICENTER, OBSERVATIONAL STUDY. H. Jang 1, D. Na 2, J. Kwon 3, M. Park 4, Y. Moon 5, J. Lee 6, K. Park 7, A. Lee 8, H. Cho 9, J. Lee 10, B. Kim 11, K. Park 12, B. Lee 13, H. Choi 14, K. Jieun 15, N. Jung 16(1. Samsung Alzheimer’s Convergence Research Center, Samsung Medical Center — Seoul (Korea, Republic of), 2. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine — Seoul (Korea, Republic of), 3. Department of Neurology, Changwon Fatima Hospital — Changwon (Korea, Republic of), 4. Department of Neurology, Yeungnam University College of Medicine — Daegu (Korea, Republic of), 5. Department of Neurology, Konkuk University Medical Center, Konkuk University School of Medicine — Seoul (Korea, Republic of), 6. Department of Neurology, Jeju National University College of Medicine — Jeju (Korea, Republic of), 7. Department of Neuroscience, Cognitive Disorders and Dementia Center, Dong-A University College of Medicine and Institute of Convergence Bio-Health — Busan (Korea, Republic of), 8. Department of Neurology, Chungnam National University School of Medicine — Daejeon (Korea, Republic of), 9. Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine — Seoul (Korea, Republic of), 10. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine — Seoul (Korea, Republic of), 11. Department of Neurology, Chonnam National University Medical School & Hospital — Gwangju (Korea, Republic of), 12. Department of Neurology, College of Medicine, Gachon University Gil Hospital — Incheon (Korea, Republic of), 13. Department of Neurology, Hallym University College of Medicine — Seoul (Korea, Republic of), 14. Department of Neurology, Hanyang University Guri Hospital — Guri (Korea, Republic of), 15. Department of Medical, Eisai Korea Inc. — Seoul (Korea, Republic of), 16. Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine — Yangsan (Korea, Republic of))
Background: Amnestic MCI (aMCI), a subtype of MCI associated with significant decline in memory with no impairment in activities of daily living, may represent the prodromal state of Alzheimer’s disease, with a greater risk of conversion to dementia. As aMCI is a heterogeneous clinical entity, prediction of conversion to dementia in aMCI is difficult but important in the real-world setting. Among clinical variables, neuropsychological profiles are significantly associated with dementia conversion; therefore, a nomogram to predict dementia conversion in aMCI was developed to incorporate various major neuropsychological indices. However, this nomogram has not yet been validated to predict dementia conversion in a real-world setting. Objective: The primary objective was to determine and compare the conversion rates of high- and low-risk MCI patients using a nomogram that incorporated Seoul Neuropsychological Screening Battery (SNSB) test results from multiple centers. The secondary objectives were (1) to evaluate neuropsychological test score changes, including those of the SNSB-dementia version (SNSB-D) total score, Clinical Dementia Rating Sum of Boxes (CDR-SB), and the Short Form of Geriatric Depression Scale (SGDS), and (2) to evaluate changes of structural magnetic resonance imaging (MRI) measures including cortical atrophy index, hippocampal volume, and cortical thickness between the high- and low-risk groups after 1 and 2 years. Methods: This prospective, multicenter, observational study was conducted at 14 study sites in South Korea. Patients were classified as having either high-risk or low-risk MCI according to their nomogram result. When applying the nomogram, the model without APOE genotype data (Model 1) was used to predict high-risk and low-risk groups considering age and SNSB features (modality of memory impairment [visual, verbal, or both], severity of memory impairment [early or late], and multiplicity of cognitive domains involved [single or multiple]). Based on these features, the predicted probability for dementia conversion was calculated using the nomogram, where the upper and lower 30% were categorized as high-risk and low-risk MCI groups, respectively. Data were collected at Visit 1 (Day 0, time of obtaining informed consent), Visit 2 (Month 12), and Visit 3 (Month 24) using case report forms. The primary endpoint was the differences of conversion rates to dementia between high- and low-risk MCI subgroups, according to the definition of dementia based on the CDR-SB (scores ≥3) and Korean version of the Instrumental Activities of Daily Living (K-IADL) scores ≥0.4. Changes in neuropsychological test scores and structural MRI measures at 1 and 2 years were also compared between high- and low-risk groups. Results: In total, 195 patients were included: 97 and 98 in the high-risk and low-risk groups, respectively. Of these, 160 patients, 77 and 83 in the high-risk and low-risk groups, respectively, completed the 2-year follow-up. CDR-SB, SNSB-D, and K-IADL scores; cortical atrophy index; temporal thickness; and hippocampal volume at baseline were significantly different between the high-risk and low-risk groups. The dementia conversion rate overall was 24.7% (39/158); in the high-risk group, 46.1% (35/76); and in the low-risk group, 4.9% (4/82) at the 2-year follow-up. The mean changes from baseline in CDR-SB, SNSB-D, and K-IADL scores and cortical atrophy index at 1 and 2 years were significantly different between the groups. The mean change from baseline at 1 year in temporal thickness and hippocampal volume was significantly larger in the high-risk group than in the low-risk group, while the mean change from baseline at 1 and 2 years in parietal thickness was larger in the high-risk group than in the low-risk group. Finally, significant differences between converters and non-converters in the high-risk group were noted for baseline CDR-SB and K-IADL, but no differences were noted in age, sex, or education. Linear mixed model analysis showed that CDR-SB and SNSB-D at 1 and 2 years were significantly different between converter and non-converter subgroups. Conclusions: The conversion rate to dementia after 2 years was greater in high-risk MCI patients than in low-risk MCI patients as determined by the nomogram. In addition, the high-risk MCI group showed worse cognition and neurodegeneration trajectory than the low-risk MCI group. This nomogram is a clinically useful predictor of conversion to dementia that categorizes patients into high-risk and low-risk groups.
P140- PREDICTING TAU PET SIGNAL IN PRODROMAL-TO MILD ALZHEIMER’S DISEASE FROM SPEECH BIOMARKERS AND MACHINE LEARNING. M.M.M. Mina 1, J.T. Troeger 1, L.S. Schwed 1, N.L. Linz 1, S.S. Bohórquez 2, S.H. Hashemifar 2, T.B. Boggiano 3, E.T. Teng 2(1. ki:elements — Saarbruecken (Germany), 2. Genentech Inc — San Francisco (United States), 3. F. Hoffmann-La Roche Ltd — Basel (Switzerland))
Background: In Alzheimer’s Disease (AD), the amount and extent of deposition of tau protein correlates with the severity of cognitive and functional impairment, and behavioral symptomatology. However, assessing cerebral tau levels currently requires PET imaging or lumbar punctures, which may be costly, inaccessible, and/or less acceptable for AD patients. Therefore, alternative approaches to estimating brain tau levels may have utility for facilitating decentralized trial designs, higher frequency intra-trial monitoring, or accelerated screening funnels at scale. In this context, speech-based digital measures have great potential as they offer remote assessment, pose lower participant burden, and can be collected frequently at low cost. Objectives: To examine whether cerebral tau pathology measured with tau PET can be modeled through speech biomarkers. Methods: We performed cross-sectional analyses of baseline assessments from the Phase 2 Tauriel study of semorinemab (an anti-tau antibody) in prodromal-to-mild AD (NCT03289143) in a subset of right-handed English-speaking participants recruited from sites in the United States (N=86, 59% female). Speech data were collected from recordings of the semi-structured Clinical Dementia Rating (CDR) interview with study participants, then processed by the ki:e speech pipeline, which extracts features that have construct validity with cognitive subdomains such as memory and language. Several machine learning models, including Support Vector Regressor, Random Forest Regressor, and Extra Trees Regressor, were trained on those features to predict [18F]GTP1 standardized uptake value ratio (SUVR) in left-hemisphere domain-specific brain regions of interest (ROIs) from the Hammers atlas for language (parahippocampal gyrus, inferior middle temporal gyrus, anteromedial temporal lobe, inferior frontal lobe, lateral inferior parietal lobe, posterior temporal), bilateral ROIs for memory (caudate nucleus, hippocampus, middle frontal gyrus, parahippocampal gyrus, inferior middle temporal gyrus, anteromedial temporal lobe), and whole cortical gray matter. For each model, we used feature selection based on mutual information to optimize performance with the most relevant features. Furthermore, we trained the same models using cognitive scores (including Repeatable Battery for the Assessment of Neuropsychological Status [RBANS] and Alzheimer’s Disease Assessment Scale-Cognitive subscale [ADAS-Cog13]) as input to predict [18F]GTP1 SUVR. We used a leave-one-out cross validation to maximize training data while still maintaining testing on the whole population. Speech features were also checked for correlation with cognitive scores, including ADAS-Cog13 and CDR-sum of boxes (SB). Results: Speech biomarkers consistently showed better performance relative to cognitive scores in predicting [18F]GTP1 SUVR in ROIs that correspond to language and memory function. Our model on speech features achieved a R2 equal to 0.22, 0.17, and 0.17 for the middle frontal gyrus, inferior frontal lobe, and whole cortical gray ROIs, respectively. Models derived from speech features yielded R2 values that are on average 41% larger than those achieved with the same models derived from cognitive scores. Importantly, incorporating speech features with cognitive scores improves model performance by increasing R2 up to 0.38. Speech biomarkers also moderately correlated with scores on the ADAS-Cog13 (r=−0.22) and CDR-SB (r=−0.39). Conclusion: The results show that speech biomarkers have the potential to predict cerebral [18F]GTP1 SUVR related to severity of cognitive impairment in prodromal-to-mild AD. Potential future applications include more rapid population-wide screening for trial inclusion, more frequent estimates of underlying cerebral tau burden during trials, and diagnostic screening to facilitate appropriate use of approved disease modifying therapeutics. Conflicts of interest: N.L. & J.T. are shareholders of ki:elements. N.L., J.T., M.M. & L.S. are employees of ki:elements. S.S., S.H. & E.T. are employees of Genentech Inc. T.B. is an employee of F. Hoffmann-La Roche Ltd.
LP85- A MULTICENTER, RANDOMISED, OPEN-LABEL, PROSPECTIVE STUDY TO ESTIMATE THE ADD-ON EFFECTS OF MEMANTINE AS EBIXA® ORAL PUMP (SOLUTION) ON LANGUAGE IN MODERATE TO SEVERE ALZHEIMER’S DISEASE PATIENTS ALREADY RECEIVING DONEPEZIL (ROMEO-AD). H.J. Kim 1, H.J. Han 2, Y. Shim 3, B.C. Kim 4, K.H. Park 4, S.Y. Moon 5, S.H. Choi 6, D.W. Yang 7, B. Yoon 8, E.J. Kim 9, J.H. Jeong 10, S.H. Han 11(1. Professor of Neurology Department of College of Medicine, Hanyang University — Seoul (Korea, Republic of), 2. Department of Neurology, Myongji Hospital, Hanyang University College of Medicine — Seoul (Korea, Republic of), 3. Department of Neurology, The Catholic university of Korea Eunpyeong St. Mary’s Hospital — Seoul (Korea, Republic of), 4. Department of Neurology, Chonnam National University Medical School — Seoul (Korea, Republic of), 5. Department of Neurology, Ajou University School of Medicine — Seoul (Korea, Republic of), 6. Department of Neurology, Inha University School of Medicine — Seoul (Korea, Republic of), 7. Department of Neurology, The Catholic University of Korea, Seoul St. Mary’s hospital — Seoul (Korea, Republic of), 8. Department of Neurology, Konyang University College of Medicine — Seoul (Korea, Republic of), 9. Department of Neurology, Pusan National University Hospital — Seoul (Korea, Republic of), 10. Department of Neurology, Ewha Womans University Seoul Hospital — Seoul (Korea, Republic of), 11. Department of Neurology, Konkuk University College of Medicineb — Seoul (Korea, Republic of))
Objectives: It is a multicentre, randomised, open, and prospective study to evaluate the effectiveness of speech function in additional treatment of memantine (memantine solution) in moderate to severe Alzheimer’s disease patients taking donepezil. Methods: There are two groups: Drug trial group is donepezil + memantine (memantine solution) and the Control group is the Donepezil only administered group. Patients in the test group should increase the dose of memantine by 5 mg/day per week for the first 4 weeks and maintain it at 20 mg/day until the end of administration. Results: Out of 188 participants, 24 participants dropped out, and the other 164 participants completed the final research process. As the primary outcome, K-WAB had an increase in scores in both groups compared to baseline, but was not statistically significant with a p-value of 0.678. After 12 weeks, donepezil treatment groups presented higher K-MMSE and lower CDR-SB score compared with combination donepezil with memantine, indicating better cognitive and functional status. However, this effect did not sustain until 24 weeks. Combination group presented slowly progressed in the clinical course (P < 0.0001). The secondary outcome, Relevant Outcome Scale for Alzheimer’s Disease (ROSA), was found in patients with donepezil. As compared with those who were assigned to receive combinations, patients had scores on the ROSA that were higher by an average of 4.6 points. NPI-Q index improved compared to baseline in both groups. The SIB scale did not change significantly compared to the study baseline. Conclusions and Relevance: Although several clinical studies have reported significant improvement in speech function after administration of memantine, clinical studies on speech function improvement in Alzheimer’s disease patients are still insignificant. There are no studies worldwide on the effect of donepezil and memantine on language function in combination treatment in moderate and severe stages of AD. Therefore, the effect on speech function in add-on therapy of memantine (memantine solution) was evaluated in moderate to severe AD patients who are taking Donepezil at a stable dose. Although it did not show superior effectiveness in the memantine add-on over the Donepezil monotherapy group, memantine is effective in improving behaviour symptoms in patients with moderate or severe stage of AD.
LP86- EFFECTIVENESS OF VORTIOXETINE IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER AND EARLY DEMENTIA: THE MEMORY STUDY. M.C. Christensen 1, S.N. Schmidt 1, I. Grande 2(1. H. Lundbeck A/S — Valby (Denmark), 2. Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM — Barcelona (Spain))
Background: Major depressive disorder (MDD) is a prevalent recurring psychiatric condition associated with cognitive and functional disabilities. Comorbid dementia worsens the prognosis in patients with MDD. Vortioxetine, a multimodal antidepressant, has demonstrated efficacy and safety in adults and the elderly population with MDD, including patients with comorbid Alzheimer’s disease (AD), showing improvement in cognitive performance and depressive symptoms. Objectives: To evaluate the effectiveness of vortioxetine flexible dose during 12 weeks of acute treatment of depressive symptoms in patients with MDD and early dementia. Methods: In this interventional, open-label, single-group, 12-week study, vortioxetine was administered orally starting at 5 mg/day from baseline to week 1 and increased to 10 mg/day at week 1. After week 1, the dose could be increased to 20 mg or decreased to 5 mg based on investigator judgment and patient response. Safety follow-up occurred up to 4 weeks after last treatment or withdrawal. Patients aged 55–85 years diagnosed with recurrent MDD (onset before age 55) and comorbid dementia diagnosed at least 6 months prior to screening were enrolled. Eligible patients required a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≥26 (moderate to severe depression) and a Mini-Mental State Examination (MMSE-2) score of 20–24 (mild dementia). The primary endpoint was change from baseline to week 12 in MADRS total score analyzed using a mixed model for repeated measurements. Secondary endpoints included change from baseline to week 12 in Digit Symbol Substitution Test (DSST) cognitive performance, Rey Auditory Verbal Learning Test (RAVLT) to assess memory, Instrumental Activities of Daily Living (IADL) for functioning, and Bath Assessment of Subjective Quality of Life in Dementia (BASQID). Change from baseline in IADL total score (dichotomized) was analyzed by sex. Subgroup analysis assessed severity of depression using MADRS total score in patients with AD, baseline DSST total score below average, and MMSE as a covariate. Safety and tolerability were assessed at week 12. Results: 83 patients were enrolled, and the full analysis set consisted of 82 (98.8%) patients. The majority were female (65.9% [n=54]) and White (95.1% [n=78]); mean age was 70.3 (n=82) years, and the most common type of dementia was AD (42.7% [n=35]). All 82 patients received vortioxetine 5 mg/day between baseline and week 1, 79 (100%) patients received vortioxetine 10 mg/day between weeks 1 and 4, 52.6% (n=40/76) received vortioxetine 20 mg/day between weeks 4 and 8, and 47.2% (n=34 / 72) of patients remained on vortioxetine 20 mg/day between weeks 8 and 12. Mean (SE) change from baseline to week 12 MADRS total score (n=70) was −12.4 (0.78; 95% CI, −14.0, −10.9; P<0.0001), indicating significant improvement in symptoms of depression. The standardized effect sizes for change from baseline to week 12 DSST total and RAVLT total scores (n=70) were 0.65 (least squares [LS] mean 4.9; SE, 0.90; P<0.0001) and 0.28 (LS mean 2.1; SE, 0.90; P=0.0199), respectively, exceeding clinically relevant effect sizes of 0.2, indicating cognitive improvement from baseline. Change from baseline to week 12 BASQID total score converted to percentages (n=72; LS mean 10.2; SE, 1.25; 95% CI, 7.8, 12.7; P<0.0001) showed a significant improvement in subjective quality of life. In the subgroup of patients with DSST total score <1 SD below DSST score at baseline, mean (SE) change from baseline to week 12 MADRS total score was −9.6 (2.56 [n=6; 95% CI, −15.94, −3.30]). Mean (SE) change from baseline to week 12 MADRS total score using MMSE-2 as a covariate was −12.4 (0.79 [n=70; 95% CI, −14.01, −10.86]). Mean (SE) change from baseline to week 12 IADL total scores in female and male patients was 0.26 (0.12 [n=48; 95% CI, 0.03, 0.50]) and 0.02 (0.24 [n=25; 95% CI, -0.47, 0.51]), respectively, indicating significantly better improvement in daily functioning among women (P=0.0308). At week 12, IADL (polytomous) scales for ability to handle finances, ability to use telephone, food preparation, housekeeping, laundry, mode of transportation, responsibility for own medications, and shopping were rated “1” by 18.8% (n=13), 49.3% (n=34), 43.5% (n=30), 27.5% (n=19), 42.0% (n=29), 42.0% (n=29), 50.7% (n=35), and 23.2% (n=16) of patients, respectively. Mean (SE) change from baseline to week 12 MADRS total score in patients with AD was −11.97 (1.22 [n=31; 95% CI, −14.42, −9.51]) and with other types of dementia was -13.15 (1.0 [n=39; 95% CI, −15.20, −11.09]). A total of 39 (47.6%) patients reported 60 occurrences of adverse events. Conclusion: Vortioxetine 10–20 mg at a starting dose of 5 mg for the first week demonstrated effectiveness in reducing symptoms of depression, improving cognitive performance in patients with MDD and comorbid early dementia, and was well tolerated. Approximately 50% of patients were treated with 20 mg by end of treatment. A consistent improvement in MDD symptom severity over time was demonstrated among patients with AD. Overall improvement in daily functioning was demonstrated through the IADL scores. Disclosures: MCC and SNS are employees of H. Lundbeck A/S. IG is an advisor, consultant, and/or speaker for Lundbeck, Otsuka, ADAMED, Angelini, CasenRecordati, Ferrer, and Janssen Cilag, and has received research funding from the Institut de Salud Carlos III, Ministry of Economy and Competitiveness, Spain.
LP87- ASSESSING CLINICALLY MEANINGFUL FUNCTIONAL OUTCOMES IN PRECLINICAL ALZHEIMER’S DISEASE. C. Romano 1, G. Novak 2, J. Choi 3, S. Qin 1, D. Henley 2, M. Donohue 3, G. Romano 4, R. Raman 3, R. Amariglio 5, P. Aisen 3, R. Sperling 5(1. RTI-HS — Research Triangle Park (United States), 2. Janssen — Titusville (United States), 3. USC — San Diego (United States), 4. Alector — San Francisco (United States), 5. Harvard — Boston (United States))
Background: Rigorously developed and highly sensitive composite neurocognitive measures have been created to assess very subtle changes in cognition related to preclinical Alzheimer’s Disease (AD). An example of these instruments includes the Preclinical Alzheimer Cognitive Composite (PACC) which is comprised of four scales that assess episodic memory, executive function and global cognition. Similar to cognition, subtle functional decline occurs in cognitively unimpaired individuals who later progress to MCI or AD dementia. Highly sensitive functional measures may capture these subtle changes and may help to define clinically meaningful clinical trial outcomes in preclinical AD. Janssen Research & Development LLC and Shionogi and Co Ltd were developing atabecestat, a nonselective oral BACE-1 and BACE-2 inhibitor. A phase 2b/3 confirmatory registration trial (the EARLY trial) was conducted to evaluate efficacy and safety of atabecestat for slowing cognitive decline in preclinical AD and was terminated prior to completion. This study included several functional measures: the Cognitive Function Index (CFI), the Cognitive Function Index Acute (CFIa), the Alzheimer’s Disease Cooperative Study Activities of Daily Living Prevention Instrument (ADCS-ADL-PI), the State-Trait Anxiety Inventory-6 item version (STAI-6) and the Geriatric Depression Scale (GDS), in addition to neurocognitive assessments; the PACC and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Objectives: Objectives of this research were to interrogate screening data collected in the EARLY trial to examine the relationship between functional measures and amyloid status, and to examine the relationship between functional and cognitive measures. These data will be useful to guide selection of clinically meaningful functional endpoints in future clinical trials. Methods: The analysis population included any participant screened for the EARLY study with amyloid status, based on either PET or CSF, and with any one of the following assessments: the self and study partner versions of the CFI (14 items to assess change over past 1 year across a 3 point scale), the CFIa (a modified version of the CFI with an expanded Likert scale and current recall period), the ADCS-ADL-PI (18 items across a 4 point scale, including 3 high-level function items), STAI-6 (6 items assessed with a 4 point scale) and the GDS-short form (15 items with a dichotomous response scale), in addition to the PACC and RBANS. Screening demographics were summarized by amyloid eligibility group, with frequencies and percentages for categorical variables, and mean and standard deviation for continuous data. Comparisons between groups (where sufficient data) were performed using t-tests for continuous variables, and Pearson’s chi-squared test for categorical data. Analysis of covariance (ANCOVA) models were used to examine the difference in functional measures between amyloid groups controlling for pre-specified covariates of age, gender and education. Pearson correlation coefficients were used to examine the cross-sectional relationship between the functional and cognitive measures. Results: The analysis sample included a total of 3,686 participants. Of these, 756 (21%) were Aβ+, 2182 (59%) were female, 2721 (74%) were married, and 3472 (94%) had a high school or greater education; 1154 (32%) were identified as APOE e4 carriers. Controlling for age, sex and education, scores were significantly higher (worse) for Aβ+ than Aβ- on the CFIa self [2.09 (CI 1.28 – 2.91), p<0.001] and study partner [1.91 (CI 1.09 – 2.73), p < 0.001], and on the CFI self [0.74 (CI 0.27 – 1.21), p=0.002] and study partner [0.56 (CI 0.13 – 0.99), p=0.011], but not for the ADCS-ADL-PI, GDS, or STAI. In Aβ+ participants, Pearson correlations to the PACC were moderate with the CFI (self and study partner, −0.31 and −0.34 respectively), moderate to small with the ADCS-ADL-PI (self and study partner, 0.33 and 0.25 respectively), and small with the CFIa (self and study partner, −0.20 and −0.28, respectively). Correlations of the RBANS were small with the CFI, CFIa, ADCS-ADL-PI and the STAI (range r= 0.10 — 0.23). The corresponding correlations were generally smaller among Aβ- individuals, except for a moderate correlation between the PACC and the ADCS-ADL-PI (0.34 for both self and study partner). Correlations between the CFI and CFIa were strong (ranging 0.59 to 0.67) and were similar between participant and study partner. Conclusions: In this cross-sectional assessment, self and study partner rated versions of the CFI and CFIa were sensitive to amyloid status, and the CFI and ADCS-ADL-PI-self demonstrated generally moderate relationships (Irl ≥ 0.30) to the PACC. While CFI and CFIa were well-correlated, the level of correlation did not indicate a redundancy between measures indicating these tools may measure different aspects of function. Results of this analysis provide important information on the sensitivity of these functional assessments to amyloid pathology and to neurocognitive assessment. Exploration of these relationships may provide valuable insight into clinically meaningful interpretation of clinical trial study endpoints. Longitudinal assessment of these measures will provide further discernment as to whether these functional measures may detect change over time.
LP88- CHARACTERIZING COGNITIVE CHANGES IN EARLY-STAGE ALZHEIMER’S DISEASE USING LATENT COGNITIVE MEASURES FROM THE ADNI DATASET. J. Bock 1,2, J. Hara 1,3, D. Fortier 1, B. Albala 4,5(1. Embic Corporation — Newport Beach (United States), 2. Dept. of Cognitive Sciences, University of California at Irvine — Irvine (United States), 3. Pickup Family Neuroscience Institute, Hoag Memorial Hospital — Newport Beach (United States), 4. UCI Center for Clinical Research — Irvine (United States), 5. UCI School of Medicine — Irvine (United States))
Background: Many Alzheimer’s disease (AD) drugs in development target early stages and could potentially enable AD patients to preserve cognitive abilities and quality of life. However, because cognitive deficits are more subtle in earlier stages, establishing meaningful cognitive treatment effects has become an increasingly difficult challenge for trial sponsors. Drug developers have shown an historical bias in favor of robust batteries (e.g., ADAS-Cog) that test many cognitive domains, including some that are often unaffected in the early stages of AD, and have used rudimentary analytic methods to score these batteries. The inclusion of tests on which all subjects are likely to perform well dilutes signals from wordlist memory (WLM) tests that are more sensitive to early signs of decline due to AD, and using weighted summary scores, even on the most well-designed tests, masks insightful information in response data. The dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) contains latent cognitive measures that quantify the underlying cognitive processes of encoding and retrieval. Constructed from these cognitive measures are behavioral measures that quantify probability of recall. One composite measure, M2, is comprised of encoding and retrieval processes involved in immediate recall and correlates closely with performance on immediate free recall (IFR) tasks. Another, M3, is comprised of encoding and retrieval processes involved in delayed recall and correlates with delayed free recall (DFR) tasks. Contrary to directly-observed behaviors (e.g., number of words recalled), these two measures of recall probability are more directly influenced by the processes that underlie behavior and are more sensitive to change. Objective: To compare sensitivity to progressive cognitive decline between generalized probability of recall (M measures) and the traditional summary score approach, using WLM test data obtained from the ADNI database. Methods: Item response data was obtained from ADAS-Cog WLM tests (n = 10,933) performed between the years of 2005 and 2021 on subjects (n = 2,348) enrolled in the ADNI, along with their demographics, AD biomarkers, Clinical Dementia Rating-Global Score (CDR-GS), and latent cognitive measures for each WLM test. The subjects were assigned to one of the three groups based on the number of available WLM tests (>=2), the CDR, and ATN status (amyloid, tau, neurodegeneration) via CSF. Since biomarkers were not assessed at each visit, ATN status was assumed to persist for ADAS-Cog assessments within 2 years if an update in status was not available. Stable CN (S-CN; n subjects=155, n assessments=581): CDR 0 and ATN- at baseline with subsequent CDR 0 following 2 years. Slow-progressing MCI (SP-MCI; n subjects=215, n assessment=942): CDR 0.5 and ATN+ at baseline with subsequent CDR 0.5 following 2 years. Fast-progressing MCI (FP-MCI; n subjects=133, n assessments=506): CDR 0.5 and ATN+ at baseline with subsequent CDR 1 or greater following 2 years. Four mixed fixed- and random-effects regression models were generated, each to examine one of the cognitive performance outcome measures: IFR summary scores, DFR summary scores, M2, and M3. Fixed predictors in all models were demographics, ADAS-Cog wordlist, group, and years of follow-up within each group. Random-effects predictors were per-subject intercept variance within each group. Data included in initial analyses was limited to the first 2 years of follow-up, while further analyses utilized the full dataset. Standardized coefficients of slopes were compared between SP-MCI and FP-MCI groups within each measure; they were also compared between measures (IFR vs. M2 and DFR vs. M3) within each group. Results: Initial models predicted the corresponding cognitive performance measures (all p’s < .001). Intercept coefficients for SP-MCI and FP-MCI groups showed significant difference from the S-CN (reference) group (all p’s < .001): IFR (−5.72 [SE=0.40] and −8.68 [SE=0.49] words, respectively), DFR (−3.57 [SE=0.21] and −5.13 [SE=0.21] words), M2 (−.113 [SE=.008] and −.183 [SE=.011] points), and M3 (−.140 [SE=.009] and −.210 [SE=.009] points). Per-year slope coefficients for SP-MCI and FP-MCI groups showed significant decline over time (all p’s < .001): IFR (−0.69 [SE=0.13] and −1.30 [SE=0.16] words, respectively), DFR (−0.37 [SE=0.06] and −0.56 [SE=0.07] words), M2 (−.022 [SE=.003] and −.048 [SE=.004] points), and M3 (−.018 [SE=.003] and −.029 [SE=.003] points). Tests of the Z statistic for comparison of standardized coefficients showed significant differences between slopes across years for SP-MCI and FP-MCI groups within each measure (all p’s < .01). Within the FP-MCI group, comparison between measures showed a significantly steeper slope for M2 than for IFR (Z = 2.07, p = .038). This trend was corroborated more prominently in analyses of the longer-followed, full data set. Conclusion: In early AD clinical trials, when disease progression and cognitive symptoms are mild, demonstrating cognitive benefits of treatment will require the most precise definition of change over time. This study demonstrates that latent cognitive measures, derived from ADAS-Cog WLM test data, are significantly more sensitive than summary scores both for differentiation of CN, slow-progressing MCI, and fast-progressing MCI subjects and for measurement of decline over time.
LP89- NEUROGENESIS HYPOTHESIS WITH A CASE STUDY- PHASE 2A CLINICAL TRIALS RESULTS OF NA-831 FOR THE TREATMENT OF ALZHEIMER’S DISEASE. M. Kurkinen 1, L. Tran 1(1. Biomed Industries, Inc. — San Jose (United States))
In the hippocampus, new neurons are generated throughout life via a process called adult hippocampal neurogenesis (AHN). In mild cognitive impairment (MCI) and mild to moderate AD (early AD), AHN is reduced suggesting that AHN impairment compromises hippocampal function. Accordingly, augmenting AHN could help prevent or slow cognitive decline in MCI and early AD. NA-831 is a small drug molecule, which activates synaptic AMPA receptors, and increases the expression of BDNF (brain derived neurotrophic factor). BDNF is crucial in synaptic plasticity, learning and memory formation in the hippocampus. NA-831 restores neurogenesis by increasing the number of DCX+PCNA+ neuroblast cells. A randomized clinical trial of NA-831 was conducted in 56 patients including 32 patients with MCI, who received 10 mg of NA-831 or placebo orally per day; and 24 patients with mild and moderate AD, who received 30 mg of NA-831 or placebo orally per day for 24 weeks. Results: NA-831 provided a significant delay in cognitive decline in MCI as measured by ADAS-Cog-13, an average score difference of 3.4 compared to placebo (p = 0.01; ITT) after 24 weeks of treatment. Similarly, NA-831 delayed cognitive decline in early AD, an average score difference of 4.1 com-pared to placebo (p = 0.001; ITT). CIBIC-Plus showed 78 % of the study participants receiving NA-831 improved (p = 0.01; ITT). NA-831 was well-tolerated at 30 mg/day for 24 weeks, and no serious adverse events were observed. The Neurogenesis Hypothesis, and details of these Phase 2A clinical trials will be presented and discussed.
LP89A- COGNITIVE COMPOSITE OUTCOME MEASURES FOR CLINICAL TRIALS: CAN YOU HAVE TOO MUCH OF A GOOD THING? X. Wang 1, D. Jacobs 1, D. Salmon 1, H. Feldman 1, S. Banks 1, S.D. Edland 1(1. University of California San Diego — La Jolla (United States))
Background: Cognitive composite outcomes measures are receiving increasing attention as endpoint for clinical trials. For example, the Preclinical Alzheimer Cognitive Composite (PACC) is an outcome measure designed for clinical trials targeting the preclinical to early stages of Alzheimer’s disease. The PACC is calculated as the weighted linear sum of four validated neuropsychometric instruments, the Mini-Mental State Examination, Logical Memory Paragraph Recall, Free and Cued Selective Reminding Test, and Digital Symbol Substitution Test. As of July of 2022, 20 clinical trials listed in clinicaltrials.gov report a PACC as the primary or secondary cognitive outcome measure. Moreover, there is an active literature describing variants of the PACC, including modified PACCs with less than or more than four components. Objectives: The performance of composite outcome measures such as the PACC is determined by the pattern of covariance of change of the component measures forming the composite. As we have previously shown by formal mathematical derivation and computer simulations, individual component measures used in a composite may actually reduce the efficiency and statistical power of clinical trials using the composite (Ard et al., Pharm Stat. 2015;14(5):418–26). It is important to understand the potential loss of power resulting from this phenomenon. Methods: We used standard power calculation formulas informed by longitudinal cohort studies to investigate the performance of cognitive composites as endpoints for clinical trials targeting prodromal Alzheimer’s disease. To investigate the performance within elderly persons with amnestic mild cognitive impairment we used longitudinal data from the National Alzheimer’s Coordinating Center (NACC) (n=1333 participants, age > 60, mean age 75.3 (standard deviation(SD) 7.3), 46.0% female, 41.6% with an APOE E4 allele). Only three instruments comparable to the components of the PACC are available in this dataset, the Mini-Mental State Examination, WAIS Digital Symbol Substitution Test, and Logical Memory IIA Test. We used these components to calculate a three-item NACC-PACC. Sample size estimates for powering clinical trials using the full NACC-PACC were compared to sample size estimates for the NACC-PACC with a component removed. Power calculations assumed a two-sample t-test with equal allocation to arms, power of 80%, type 1 error of 5%, and equal standard deviation of change in treatment and placebo. Results: The mean three year change in the three-item NACC-PACC was 1.20 with an SD of change of 2.38. Using these parameters, a three year clinical trial powered to detect a 50% reduction in mean change would require 246 subjects per arm. The two-item PACC formed by removing the Logical Memory component has a mean three year change of 1.14 (SD 1.95) and would require 186 subjects per arm to detect a 50% slowing of progression. Conclusions: Cognitive composites with fewer components and greater statistical power are preferred. The specific PACC variant investigated here is not proposed for an active clinical trial and therefore the findings presented here have no direct clinical relevance. However, this example definitively illustrate a potential problem of composite instruments. There is no guarantee that adding more components will improve the performance of a PACC. Careful examination of pilot data, including examination of reduced forms of the proposed composite, is warranted. To support this examination, we describe methods for identifying component measures that reduce the overall performance of proposed cognitive composite outcome measures.
COGNITIVE ASSESSMENT AND CLINICAL TRIALS
P141- SKT SHORT COGNITIVE PERFORMANCE TEST FOR THE DETECTION OF EARLY COGNITIVE DECLINE — DATA FROM INTERNATIONAL VALIDATION STUDIES. M. Stemmler 1(1. University Of Erlangen-Nuremberg — Erlangen (Germany))
Background: The SKT (= Syndrom-Kurztest; Erzigkeit, 2001) is a short cognitive performance test for the assessment of cognitive decline in older adults. The SKT, which is available in five parallel testing forms, takes about 10–15 minutes for its administration. The test consists of nine subtests assessing memory (three subtests) and attention/speed of information processing (six subtests). Factor analyses suggested that the SKT also taps executive functioning. The SKT was newly scaled using a regression-based norming (cf. Crawford & Garthwaite, 2006). The total score in accordance with the new German norms varies from 0 to 18 (Stemmler, Lehfeld & Horn, 2015). A traffic light system was developed based on optimal cutoffs for the discrimination between three diagnostic groups (cognitively healthy, mild cognitive impairment (MCI) or dementia). Summary scores between 0 and 4 suggest normal cognitive aging or cognitive health (green), scores between 5 and 10 suggest MCI (yellow), and scores above 11 are likely to represent pathological cognitive decline probably due to dementia (red). The regression-based norming was repeated in English speaking countries (Stemmler, Poon & Schneider, 2021) and in China (Lu, Hu, Stemmler & Guo). The testing material, which is almost culture free, was only slightly adapted for the Chinese culture. Objectives: To show the test and measurement equivalence of the SKT for the three different versions. Methods: In a multicenter study data from cognitively unimpaired volunteers aged 60 to 96 years were collected. Next to descriptive statistics, multiple regressions and of confirmatory factor analysis (CFA) were calculated. Results: Data from three culturally different cohorts were analyzed: n = 1054 from German-speaking centers, n = 285 from English-speaking centers, and n = 288 from China. Female adults were always in the majority, 60% (China) and 56% (German and English samples); the mean age varied between 68.1 years (China), 71.5 years (German sample) and 74.1 years (English sample); the mean IQ-value point ranged from 8.74 (China) via 10.7 (German sample) to 11.2 (English sample). Despite the found sample variations, the descriptive statistics suggested large similarities. In all cultures age, intelligence and gender were the most important predictors for assessing cognitive performance. In all samples the Subtest VII Reversal Naming revealed the largest explained variance based on R2. The CFAs compared the German factor solution to the English and Chinese dataset. Goodness of fit indices suggested high measurement equivalence. Conclusion: The SKT can be applied to German, English and Mandarin speaking older adults across the world. Conflicts of Interest: The international standardizations were supported by Dr. Willmar Schwabe Pharmaceutics, Karlsruhe, Germany. SKT copyright belongs to Andreas Erzigkeit, owner of Geromed Ltd. (Spardorf, Germany; [email protected]). Mark Stemmler received fees from Geromed Ltd. for scientific advice. References: Erzigkeit H. A short cognitive performance test for assessing deficits of memory and attention — User’s manual. Geromed; 2001. Crawford, J. R. & Garthwaite, P. H. Comparing patients’ predicted test scores from a regression equation with their obtained scores: A significance test and point estimate of abnormality with accompanying confidence limits. Neuropsychology 2006, 20, 259–271. Stemmler M, Lehfeld H, & Horn R. SKT Manual. 4th extended and revised edition. Spardorf: Geromed; 2015. Lu, Y., Hu, J., Stemmler, M. & Guo, Q. Validation of Chinese Version of SKT (Syndrom Kurztest): A Short Cognitive Performance Test for the Assessment of Memory and Attention. Diagnostics 2021, 11(12), 2253. Stemmler, M, Schneider, S. M. V. & Poon, L. W. The Application of the SKT Short Cognitive Performance Test to English-Speaking Populations. Psych 2021, 3(4), 717–727.
P142- IMPACT COGNITIVE ASSESSMENT: WHAT ARE WE MEASURING. J. Gyurke 1, P. Schatz 2(1. Riverside Insights — Lutz (United States), 2. Saint Joseph’s University — Philadelphia (United States))
Background: Evaluation of neurocognitive status has evolved significantly throughout the past several decades, including a transition from paper-based to computer-based assessment measures. This transition has created an increasing demand for a computerized neurocognitive battery that is practical, cost effective, and efficient for healthcare professionals to utilize, especially when assessing large numbers of individuals. The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT, Version 4) is designed to meet these demands while maintaining high standards for reliability, validity, sensitivity, and specificity. Within the elderly population, increased variability in measures of reaction time, working memory, and fluid intelligence has been consistently found in early research (Hale, Myerson, Smith, and Poon 1988; Morse 1993). In this regard, assessment of these domains using ImPACT Version 4 should show similarly increased variability in the Verbal Memory and Reaction Time composites. Complicating interpretation of test data in this age group, poor performance may be attributed to a number of factors such as health conditions (i.e., age related cognitive decline, Parkinson’s, etc.) or medication. In addition to increased variability, it also generally accepted that as individuals age, there is an age-appropriate level of cognitive decline in performance. The specific nature of cognitive decline is less well understood, as performance in different domains does not decline at the same rate within and across subjects. Such variability can complicate the assessment and classification of cognitive status, as tools that provide a single summary score often overlook cognitive issues that might occur in broader performance domains. This is particularly important when trying to qualify potential subjects for clinical trials. Objectives: The purpose of this study was to: 1) document normative, age-related neurocognitive performance changes across 10-year age bands (between 40 and 80) on measures of memory and response time, 2) establish construct validation of ImPACT as a valid measure of memory and response time in individuals ages 60–80, and 3) establish test-retest reliability of the measure in individuals ages 60–80. Methods: All measures in all samples were administered by neuropsychologists who were trained in test administration. All tests were administered according to standard procedures outlined in the associated Administration and Scoring Manuals. Normative sample: A normative sample of 1,680 individuals (964 males and 725 females), ages 40–80, completed the ImPACT Version 4. Dependent measures include 4 composite scores: Verbal Memory, Visual Memory, Visual Motor Speed, and Reaction Time. Construct Validation Sample: A sub-sample of 71 individuals (45 males and 26 females), ages 60–80 years old (mean= 67.27, SD=4.92) completed the construct validity study. The normative sample completed only the ImPACT Version 4, whereas the construct validation sample also completed widely utilized and previously validated instruments of Memory and Motor Speed, select subtests of the Hopkins Verbal Learning Test (HVLT), Brief Visuospatial Test-Revised (BVMT-R), and Symbol Digit Modalities Test (SDMT), and ImPACT Version 4 were administered within the same session. Test-Retest Sample: A sub-sample of 93 individuals (62 males, 31 females), ages 60–80 (mean age=68.18, SD=5.1 years), completed the ImPACT Version 4 across an average range of 30 days (mean=16.04, SD=8.65). Intraclass Correlations (ICCs) were calculated to examine test-retest reliability for the component tests across the time periods, along with Reliable Change Indices (RCI) to document the percentage of cases revealing change that exceeded a 95% confidence interval (CI). Results: Normative Data: ImPACT Version 4 performance reflected age-related changes across the 40–49, 50–59, 60–69, and 70–80 age bands, with decreased memory performance and slower speed of response time across all 4 ImPACT Version 4 Composite Scores. In addition, variability in response time increased along with age. Construct Validation: Results revealed that the ImPACT Verbal and Visual Memory Composite scores correlated with both the HVLT and BVMT-R, as well as the SDMT Memory Sub-scales (significant at p<.001) which represent measures of verbal and visual memory. ImPACT Motor Speed and Reaction Time Composite Score both correlated with the SDMT Total Correct Subscales, which represents a measure of psychomotor coding speed. Test-Retest: Intra-class correlation coefficients reflected stability across the test-retest period: Verbal Memory=.88, Visual Memory=.73, Visual Motor Speed=.91, Reaction Time=.65. Reliable Change Indices revealed only 1% of cases exceeded the 95% CI for Visual Memory and Visual Motor Speed (both 94% within the 95% CI), whereas 98% of cases fell within the 95% CI for Verbal Memory and 97% of cases for Reaction Time. Conclusions: These correlations provide validation for ImPACT as a measure of Verbal and Visual Memory and psychomotor speed, and support its use for assessment of speed and accuracy of neurocognitive performance in individuals 60–80 years of age. These findings support the use of ImPACT as a measure that should be considered when in-person or remote assessment of cognitive functioning is required.
P143- VALIDATION OF AN OBJECTIVE, SPEECH-BASED OBJECT CONTENT SCORE FOR MEASURING DISEASE PROGRESSION IN AD. J. Robin 1, M. Xu 2, M. Detke 3, W. Simpson 2(1. Winterlight Labs — Vancouver (Canada), 2. Winterlight Labs — Toronto (Canada), 3. Detke Biopharma Consulting — Indianapolis (United States))
Background: Speech and language changes are well-known to occur in AD, with patients frequently described as having “empty speech” lacking in information content. Novel tools to objectively measure speech and language content can help to quantify this clinical symptom and provide measures of disease severity and progression. By using a picture description task and natural language processing analyses, we developed an object content score to measure the information provided when describing a picture. In this study, we collected brief picture description speech assessments over the course of a 48 week AD clinical trial, which were administered via a tablet and took less than five minutes to complete. In this study, we validate the object content score by examining its progression within the placebo arm of the 48 week study period and correlations with other clinical scores. Objective: The objective of this study was to validate the use of an objective, speech-based object content score for tracking disease progression in Alzheimer’s Disease (AD). Methods: 148 English-speaking participants with mild-to-moderate AD who were randomized into the placebo arm of a clinical trial completed an app-based speech assessment at their baseline visit. Follow up assessment occurred at 12-weeks (n = 128), 24-weeks (n = 125) and 48-weeks (n = 98). Speech assessments were administered by a trained rater during a clinical visit. Each speech assessment included two picture description tasks: open-ended speech tasks in which participants are shown a line drawing of a scene and asked to describe it. Participants use their own words to describe the picture and have no time limit or feedback. Speech recordings were captured by the device’s microphone and processed using the Winterlight speech analysis platform. Text transcripts were generated for every recording and objective measures of information content were automatically computed based on custom natural language processing algorithms, reflecting how many items in the picture were correctly described. Object content scores were averaged across the two pictures at each assessment. Results: Object content scores were found to show significant decline over the course of the study at the group level, consistent with disease progression (estimated slope of change = −0.06, t = −5.02, p < 0.001). To test the validity of object content scores compared to standard trial endpoints, we computed correlations between object content scores and scores of cognition and function at baseline. Object content scores had significant correlations with baseline scores of cognition and function, including the ADAS-Cog (r = −.29, p < 0.001), the MMSE (r = .24, p = 0.003), ADCS-ADL (r = .23, p = 0.005), and a weak association with the CDR-SB (r = −.16, p = 0.06). Change in object content scores from baseline to endpoint (48-weeks) also had significant correlations with change in clinical scores, including the ADAS-Cog (r = −.35, p < 0.001), the MMSE (r = .36, p < 0.001), ADCS-ADL (r = .29, p = 0.004), but not the CDR-SB (r = −.17, p = 0.10). Conclusions: This study provides initial validation of a speech-based, objective measure of information content as a measure of disease severity in AD. We found that in a placebo group of individuals with mild-to-moderate AD, object content scores showed significant decline over 48 weeks, consistent with disease progression. Concurrent validation of object content scores showed moderate correlations with standard trial endpoints. Notably, the strongest correlations were with the cognitive scales, suggesting that object content scores were most related to other measures of cognition. In comparison, the object content score was derived from an app-based speech assessment, which took less than 5 minutes to complete and required minimal instruction or training. Digital speech-based measures have the potential to reduce patient burden and improve sensitivity in assessing AD in future trials.
P144- RELATIONSHIP BETWEEN TELOMERE SHORTENING AND EARLY SUBJECTIVE DEPRESSIVE SYMPTOMS AND COGNITIVE COMPLAINTS IN OLDER ADULTS. S.H. Koh 1, M.H. Han 1, E.H. Lee 1, H.H. Park 1, S.H. Choi 2(1. Hanyang University — Seoul (Korea, Republic of), 2. Inha University — Incheon (Korea, Republic of))
Background: Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. Methods: This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Results: Altogether, 137 relatively healthy elderly individuals (60–79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11–0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08–0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Conclusion: Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints.
P145- ACCURACY OF AUTOMATED SCORING OF WORD RECALL ASSESSMENTS. R. Kindellan 1, C. Fidalgo 1, W. Simpson 1, J. Robin 1(1. Winterlight Labs — Toronto (Canada))
Background: Natural language processing tools can be used to automate and standardize the scoring of clinical assessments. Many cognitive assessments used as endpoints in Alzheimer’s disease (AD) trials require manual scoring and review which can be costly and time consuming. Developments in natural language processing technology can be leveraged to develop automated and objective tools to generate text transcripts and produce scores for cognitive assessments. As a proof of concept, we tested an automated method to score the word recall portion of the ADAS-Cog, a standard endpoint in AD research. Objective: The objective of this study was to develop and test a method to automatically score the word recall portion of the ADAS-Cog assessment. Methods: Audio recordings of the ADAS-Cog from 23 older adult volunteers were collected. Audio recordings were manually split into the subsections of the ADAS-Cog assessment. The first trial of the word recall portion was transcribed using automatic speech recognition (ASR) software from Amazon Web Services (AWS) Transcribe. AWS ASR was preconfigured based on the expected ADAS-Cog word list to increase accuracy. Each recording was also manually transcribed and scored. Scores for the word recall portion were computed by counting how many words per trial were correctly recalled (out of a possible 10). Scores were compared to evaluate agreement using intraclass correlations and by comparing mean values. Results: There was 100% agreement between the manual transcription and scoring with the original clinical scoring of the assessment. In comparison, the automated scoring had an intraclass correlation of 0.87 (p < 0.01), indicating good agreement with the human-rated scores. Out of 23 samples, scores were identical on 9 assessments. Automated scoring tended to underestimate scores compared to the human raters, with an average score of 5.43 (SD = 2.25) compared to an average score of 6.31 (SD = 2.23) based on the human scoring. Underestimations tended to be due to incorrect transcriptions due to substitutions of similar sounding alternate words (e.g. “annual” instead of “animal”). Conclusions: This study demonstrates how scoring of word recall tasks can be automated using natural language processing tools. Tools such as these could be used to automate and increase the efficiency of quality assurance and review of clinical assessments conducted as part of trials. In this study, we found that preconfigured automated systems approached human accuracy, although still tended to underestimate scores due to transcription errors. Future work to refine the use of ASR to evaluate clinical endpoints includes optimizing ASR accuracy by filtering noise before processing samples and further customizing language models to suit the datasets at hand, as well as exploring the use of ASR in other elements of cognitive assessments, to provide more efficient and scalable scoring methods.
P147- PRE-SCREENING EARLY AD TRIAL POPULATIONS OVER THE TELEPHONE USING A SPEECH BIOMARKER FOR COGNITION — PRELIMINARY RESULTS FROM AUTONOMY PHASE 2 AD TRIAL RECRUITMENT. S. Ruhmel 1, J. Tröger 2, N. Linz 2, J. Herrmann 2, M. Quiceno 1, K. Langel 3(1. Janssen Research & Development, LLC (United States), 2. ki:elements — Saarbrücken (Germany), 3. Janssen-Cilag (Spain))
Background: Optimizing enrollment duration is one of the major challenges in Alzheimer’s Disease (AD) trials especially targeting early stages of the disease. Cost-efficient pre-screening could drastically enhance screen-in rate and accelerate early AD trials. We present results from the pre-screening in AUTONOMY Phase 2 early AD trial using a pre-screener based on the ki: elements (ki:e) speech biomarker for cognition (SBC) which is automatically collected over a phone bot system and integrated into a state-of-the-art electronic patient recruitment funnel. Objectives: The project set out to evaluate in the real environment an approach to scalable pre-selection of suitable participants for an early AD trial over the telephone using a speech biomarker for cognition. Methods: The AUTONOMY Phase 2 early AD trial (ClinicalTrials.gov: NCT04619420) expands traditional site-based enrollment with a global outreach strategy targeting a broad population. For selected sites in the US, the ki:e SB-C is integrated into an electronic patient recruitment funnel and automatically collected on the phone through robot calls to outreach responders. The ki:e SB-C leverages speech gathered during word list learning, semantic verbal fluency, and free speech tasks, then automatically extracts up to 100 explainable speech features composing three subdomain scores for episodic memory, executive function and processing speed. Subsequently, subdomain scores are merged into one overall cognition score. The SB-C is developed for automatic deployment over ordinary landline telephone using a 10 minute phone-bot assessment protocol. After completing the call which automatically collects the ki:e SB-C, responders are classified into referrals (possible MCI) and non-referrals (either healthy or dementia) based on a pre-screening engine that uses the SB-C and its subscores as input. To evaluate performance of this pre-screening approach, the pre-screening engine does not affect the actual invitation to the on-site screening in AUTONOMY. Results & Conclusion: The pre-screening system has been deployed since July 2022 and automated pre-screening calls will be conducted at a rate of 5 responders per week. Therefore, we will be able to present interim results from about 100 first responders evaluating the SB-C-based pre-screening performance in a real-world deployment to identify suitable MCI candidates for a clinical trial. .
P148- THE DIFFERENCE IN TRAJECTORIES ACCORDING TO EARLY AMYLOID ACCUMULATION IN NORMAL COGNITIVE ELDERLY. Y.J. Kim 1, M.Y. Chun 1, H. Jang 1, H.J. Kim 1, J.Y. Seo 1, S.W. Seo 1(1. Samsung Medical Center — Seoul (Korea, Republic of))
Background: Amyloid-β (Aβ) accumulation, a major biomarker in Alzheimer’s disease (AD), induces tau accumulation, eventually resulting in cognitive decline. However, Aβ trajectory in cognitively normal participants has not been extensively investigated. Modeling the Aβ trajectory remains an important goal, as future treatments targeting Aβ are expected to develop. Objectives: Through a longitudinal study on amyloid changes in normal elderly people, we investigated whether they might be divided into the normal aging group and the pathological group with increased amyloid. We also compared the differences between the groups according to the patterns of Aβ accumulation. Methods: We included 297 subjects from the Alzheimer’s Disease Neuroimaging Initiative database, which showed normal cognition. All subjects underwent neuropsychological test (mPACCdigit and mPACCtrt), apolipoprotein E (APOE) genotype test, brain MRI, and an average of 3.03 follow-ups 18F-florbetapir (AV45) PET scans. The original dataset was divided by 6:4 to create a training set (n=178) and a validation set. Latent Class Growth Analysis (LCGA) was used for statistical analysis. A linear mixed-effects model was used to analyze longitudinal changes in hippocampal volume and cognition analysis. Results: By applying LCGA to the training set and increasing the number of classes from 1 to 5, the slope shapes were tested from linear to cubic function. Considering the information criterion and interpretability, we determined that the 3-class model was the most suitable, and high entropy of 0.979 was shown: class 1 (non-accumulating group; n=117, 65.7%), class 2 (increasing group; n=46, 25.8%), and class 3 (high accumulating group; n=15, 8.4%). The increasing group, which converted from amyloid-negative to positive, had more APOE ε4 carriers and a higher tau burden than the non-accumulating group. In longitudinal analysis, the high accumulating group showed the steepest decline, and the increasing group showed a steeper decline than the non-accumulating group in cognition (mPACCdigit, p < 0.001; mPACCtrt, p < 0.001). Conclusion: Our study showed the heterogeneity of Aβ accumulation trajectories according to aging in the normal cognitive elderly. Heterogeneity of Aβ accumulation and early detection of the Aβ converter group may be helpful in the early diagnosis and treatment of AD. Key words: Alzheimer’s disease, Latent class growth analysis, Amyloid, Positron emission tomography, Longitudinal study
P149- RATER ERROR PATTERN ON THE CDR OUTCOME ASSESSMENT IN ALZHEIMER’S DISEASE CLINICAL TRIALS. J. Barbone 1, E. Barney 1, J. Crome 1, R. Leventhal 1, L. Kingery 1, S. Wacker 1(1. Cogstate — New Haven (United States))
Background: The Clinical Dementia Rating Scale (CDR) is a global staging measure used to characterize cognitive performance across six functional domains, often used as primary outcome in Alzheimer’s Disease clinical trials to provide meaningful information about effects of investigational therapies on patients’ cognitive decline. The CDR is administered in a semi-structured interview format with the patient and an informant, and scored in a semi-objective fashion, with data quality heavily dependent on rater’s clinical interviewing skill set and competency with scoring the instrument. Standardized training protocols and in-study data monitoring programs are routinely used to calibrate clinical raters to this nuanced scale with the goal to reduce rater error rates. Analysis of rater performance can enhance understanding of error pattern and inform rater training programs. Objectives: — Understand pattern of rater error; — Inform rater training programs to improve impact on rater performance. Methods: Completed CDR administrations were reviewed by calibrated, expert neuropsychologists and flagged for incidents of raters’ deviation from administration gold standards, proper recording of participants’ responses, and accuracy in applying scoring rules. Data source review process involved evaluation of test forms, documentation of participant responses and audio recordings of assessment sessions, and was highly standardized to ensure consistent approach across reviewers. Results: A total number of 3987 individual CDR administrations were reviewed across three multi-country programs. 44% of reviewed CDR administrations were flagged for at least one rater error. Administration (29%) and recording errors (24%) were more common than scoring (13%) or other (8%) errors. Most common errors flagged were related to raters’ general clinical interviewing skill sets, like following standardized questions with appropriate probing when needed, inquiring about concrete examples of reported behaviors, querying clinically inconsistent information to distinguish between current and premorbid functioning in order to score the most appropriate rating for a patient’s level of cognitive functioning. Individual review items with the highest rate of error (in 15% of administrations) showed inconsistent adherence to administration guidelines specifically in the personal care domain, where the rater must solicit enough information in questioning to distinguish between physical and cognitive limitations as barrier to effective functioning. Of note also was incomplete response recording in the judgment and problem-solving section, where raters often marked an answer choice without documenting the actual patient response (in 12% of administrations). Conclusions: Close monitoring of error patterns in rater performance illuminated areas of difficulties in raters’ clinical skill sets. Understanding the source of errors is paramount to inform rater selection and rater training programs. Administering the semi-structured CDR interview requires a seasoned tool kit of general clinical skills to obtain the rich, clinical information and concrete examples necessary to arrive at an accurate severity rating, and falling short of interviewing gold standards seemed to drive a majority of rater error. Results support the need to recruit highly qualified raters, equipped with excellent core clinical skills, and an increased emphasis on clinical interviewing tools as part of study calibration for raters in training to support clinical AD trials.
P150- PRELIMINARY PSYCHOMETRIC AND CLINICAL VALIDATION OF INFORMATION PROCESSING SPEED IN EARLY ALZHEIMER’S DISEASE USING A SMARTPHONE-BASED REMOTE ASSESSMENT. A.M. Wolfer 1, I.T. Kurniawan 1, K.I. Taylor 1, F. Lipsmeier 1, T.M. Perumal 1(1. Roche Pharma Research And Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 — Basel (Switzerland))
Background: Digital biomarkers potentially enable the remote assessment of cognitive and functional impairments in clinical trial participants’ daily lives at a higher frequency than standard in-clinic neuropsychological assessments. Early stages of Alzhiemers disease (AD) are marked by a disproportionate slowing of information processing speed (Nestor 1991) which may be measured using a simple smartphone-based cognitive task. Here, we present an assessment of psychomotor speed, called Information Processing Speed (IPS), designed to be regularly self-administered over the course of a trial. IPS has two components, a baseline digit-digit matching task measuring motor speed, and a digit-symbol substitution task measuring psychomotor processing speed. We report the preliminary validation and psychometric properties of the IPS assessment in a cohort of amyloid negative healthy individuals (HC), individuals with amyloid negative and positive subjective cognitive decline (SCDn and SCDp), and amyloid positive early AD (eAD) verified by a PET-scan. Objectives: The objectives were to investigate the feasibility of remote IPS self-administration in participants with eAD, SCD, and HC and to establish the reliability and validity of IPS metrics. Methods: 123 adults were enrolled as a part of a Proof-of-Concept (POC) study for Alzheimer’s Digital Assessment Suite (AD-DAS) (https://www.isrctn.com/ISRCTN17035495): 31 HC, 31 SCDn, 31 SCDp and 30 eAD. During this multicentre observational study, each participant was provided with a provisioned smartphone and instructed to execute 9 IPS assessments over the course of 30 days. IPS is a smartphone-based task designed to assess attention, visual scanning behavior and psychomotor speed, based on the Symbol Digit Modalities Test (SDMT). Participants were instructed to use a digit-symbol key to select the correct digit for every presented symbol. The task lasted 90s. Baseline speed was evaluated using a simple digit-digit matching task lasting 15s, during which participants were instructed to select the number from the keypad that matched the number shown on screen. Feasibility was evaluated as the proportion of completed IPS tasks relative to the 9 total scheduled IPS tasks. Two IPS performance metrics were estimated. Baseline motor speed was quantified with the number of correct answers provided in digit-digit matching (DD15). Psychomotor speed was quantified with the number of correct answers provided in digit-symbol matching (DS90). Intraclass Correlation Coefficients (ICC) tested the reliability of IPS metrics. Preliminary clinical validity (i.e., association with Digit-Symbol Coding Test (DSCT) and Trail Making Test (TMT)) and groups validity was evaluated using a linear modeling framework. Linear models predicting performance metrics of interest were fitted with age, sex, education level, ethnicity, study site and application version as covariates, and group to test known-groups validity and clinical comparator to test clinical validity. The specific contribution of either the group or the clinical comparator variables to the model was evaluated using the Bayesian Information Criteria (BIC) explaining the improvement in the decreased model error variance. As the POC study was not powered to identify cross-sectional differences between groups, all p-values reported are nominal and not corrected for multiple comparisons. Results: Out of 123 participants, 97.5% completed the POC study (n=120), and these participants completed 88.9% of assigned IPS (corresponding to 8/9 expected) tests with no difference in adherence between groups (F=0.88, p<0.45). DD15 and DS90 metrics showed excellent reliability (ICC=0.82, ICC=0.92 respectively). DS90 significantly distinguished between Non-eAD and eAD participants (p<0.001, partial r2=0.112). DD15 was associated with the total number of correct answers in DSCT (p<0.05, r2=0.91) and the time taken to complete the TMT-A (p<0.001, r2=0.186). DS90 was associated with the total number of correct answers in DSCT (p<0.001, r2=0.267), and time taken to complete TMT-A (p<0.001, r2=0.182) and TMT-B (p<0.001, r2=0.239). Conclusions: Remote self-assessments offer the possibility to characterize study participants in an ecologically valid environment and at a higher frequency, yet require validation against standard clinical outcomes in cognitively impaired populations. Our results demonstrate that a smartphone-based IPS task can be successfully self-administered by cognitively healthy participants and individuals in the eAD spectrum, with high adherence to the study protocol. IPS metrics differentiated between participants with objective dementia and other study groups. Finally, we demonstrated good reliability of IPS metrics and preliminary clinical validity of IPS measurements compared with DSCT and TMT-B/A. IPS aims to provide a remote clinically meaningful characterization of a participant’s cognitive impairment to support drug trials in preclinical and early AD. References: Paul G. Nestor, Raja Parasuraman & James V. Haxby (1991) Speed of information processing and attention in early Alzheimer’s dementia, Developmental Neuropsychology, 7:2, 243–256.
P151- RATER ERROR PATTERN ON THE MMSE AND ADAS-COG OUTCOME ASSESSMENTS IN ALZHEIMER’S DISEASE CLINICAL TRIALS. S. Wacker 1, J. Barbone 1, E. Barney 1, J. Cromer 1, L. Kingery 1, R. Leventhal 1(1. Cogstate — New Haven (United States))
Background: Cognitive assessments are critical in understanding the effects of investigational therapies in Alzheimer’s Disease (AD) clinical trials. Cognitive outcome measures, like the widely-used ADAS-Cog and MMSE tests, are complex and their use can be vulnerable to variability in test administration and scoring. Rigorous data quality programs in the form of thorough rater training and close monitoring of in-study administrations, with the goal to reduce rater error rates, are paramount to ensure optimal reliability and validity of clinical outcome data. Objectives: Understand pattern of comon rater error. Inform training programs to improve impact on rater performance. Methods: Completed administrations of Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) from multi-national clinical trials were reviewed by calibrated, expert neuropsychologists, and flagged for incidents of raters’ deviation from administration gold standards, proper recording of participants’ responses, and accuracy in applying scoring rules. Data source review process involved evaluation of test forms, rater notes, documentation of participant responses and audio recordings of assessment sessions and was highly standardized to ensure consistent approach across reviewers. Results: A total number of 8298 scale administrations were reviewed across three programs, including 3832 individual administrations of ADAS-Cog and 4466 individual administrations of MMSE. In 53% of ADAS-Cog reviews and 47% of MMSE reviews at least one item was flagged for rater error. Errors of administration were the most common errors across both scales (48% of ADAS-Cog reviews and 37% of MMSE reviews), over errors of response recording and scoring. Across both scales raters fell short of administration guidelines on delivery of introductory questions (21% error on ADAS-Cog open-ended conversation that precedes the first cognitive task and is intended to elicit an adequate sample of spontaneous speech; 12% error on MMSE introductory memory questions). Reviewers also identified raters’ deviations from standardized task directions, when instructing and especially when prompting the patient. Conclusion: Close monitoring of error patterns in rater performance revealed areas of difficulties in raters’ clinical skill sets. Understanding the source of errors is paramount to inform rater training programs and to prevent administration errors. Those aspects of scale administration requiring a solid tool kit of general clinical skills, such as guiding unstructured, open-ended conversations and delivering task instructions and prompts that are appropriate for a participant’s specific response or behavior, appear to be challenging for some raters. These monitoring results support the continued need for data quality monitoring programs to improve the conduct of cognitive assessments in-study, as well as the need for stringent rater qualification criteria, and increased focus on applied clinical interviewing skills as part of rater training.
P152- PRELIMINARY PSYCHOMETRIC AND CLINICAL VALIDATION OF EXECUTIVE FUNCTION IN EARLY ALZHEIMER’S DISEASES USING A SMARTPHONE-BASED ASSESSMENT. I.T. Kurniawan 1, A.M. Wolfer 1, C. Chatham 1, E. Aponte 1, S. Holiga 1, T.M. Perumal 1, K.I. Taylor 1(1. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124 — Basel (Switzerland))
Background: Early treatment initiation for Alzheimer’s Disease (AD) relies on timely detection at the preclinical and early stages. Validated in-clinic assessments demonstrate important neuropsychological signs of preclinical AD, including executive dysfunction 2 years prior to diagnosis. Digital remote monitoring may accelerate efforts to detect and track subtle cognitive changes via more frequent at-home assessments. However, these remote monitoring tasks require validation against standard clinical outcome measures and relevant biomarkers. Objectives: We present preliminary psychometric and clinical validity of Tilt Task (TT), a novel gamified smartphone-based assessment of executive function. This cognitive task was part of the AD digital assessments suite (AD-DAS) administered in a multicenter cross-sectional proof-of-concept study (POC) with healthy controls (HC), participants with subjective cognitive decline (SCD) and with early AD (eAD). The SCD group included individuals without and with beta amyloid (SCDn, SCDp, respectively) as assessed with amyloid Positron Emission Tomography (PET). Methods: 123 adults (aged 65 or above) were enrolled: 31 HC, 31 SCDn, 31 SCDp and 30 eAD. Groups were demographically comparable (https://www.isrctn.com/ISRCTN17035495; Perumal, et al., 2021). Each participant received a preconfigured smartphone for unsupervised at-home TT testing once a day for 9 consecutive days. TT was developed based on principles of the Trail-Making Test (TMT) and Stroop tests and named after the response modality: tilting the smartphone to move a ball towards a target location (north, east, south, or west). TT consists of five levels of increasing difficulty, whereby the next level is administered only if fewer than 3 errors are committed. Level 1 is a motor baseline task where participants see only one target. In level 2, participants hit numbers in squares in ascending order. Normalized by level 1, level 2 measures the ability to “stay-on-set”. Level 3 recapitulates level 2 except for trials when the ball changes to a star (50% chance), during which participants tilt in the opposite direction to hit the target. Normalized by level 2, level 3 measures “simple response inhibition”. In level 4, participants alternately hit a number in a square and a letter in a circle in ascending order. Normalized by level 2, level 4 measures “set shifting”. Level 5 recapitulates level 4, but with an opposite-tilt component. Normalized by level 4, level 5 measures “complex response inhibition”. Intraclass Correlation Coefficients (ICC) tested the reliability of TT metrics. Linear mixed models including age2, sex, years of education, study site, and session number as covariates and participant as a random intercept evaluated the group effect on total scores, reflecting maximum level reached (range from 0–5), and group effects at each level on normalized accuracy and response times (RT; log-transformed). Standardized regression coefficients (β) and the significance p-values for simple contrasts against eAD are reported. Spearman’s correlations (ϱ) tested for relationships between TT and TMT metrics. Results: 84.45% of scheduled TT sessions were completed (corresponding to 7.6/9 expected sessions). There was no difference in TT adherence between groups, F=1.52, p>0.22. Out of 120 participants that completed the study, 5 failed to complete at least 1 TT session and were therefore excluded from TT analyses (final n=115). 11% of participants did not reach level 2, 24% level 3, 69% level 4, and 87% level 5. Total score, and normalized accuracy and log-transformed RT at levels 1–3 showed moderate to good reliability (ICC 0.52–0.89). Group differences were observed in total scores, accuracy, and log-transformed RTs. Compared to HC and SCDn, eAD group had lower total scores than SCDn (β=0.52, p<0.007) but not HC (p>0.1), lower accuracy at levels 2-3-4 for both groups (smallest β=0.19, p<0.02), and slower response times at level 2 for SCDn (β=0.2, p<0.02) but not HC (p>0.07). Time taken to complete TMT-A correlated with level 2 log(RT) (ϱ=0.26, p<0.006), but time taken to complete TMT-B did not correlate with level 4 log(RT) (ϱ=0.11 p>0.39). We will report group contrasts compared to eAD and explore correlations between TT performance and Magnetic Resonance Imaging (MRI) measures of brain integrity. Conclusions: Clinical AD research requires reliable and valid measures of executive function. The TT was designed as a self-administered frequent and in-depth assessment of executive function at participants’ homes. The present findings demonstrate some group differences and preliminary clinical validity of digital performance metrics of executive function, namely poorer abilities to stay-on-set, inhibit responses, and shift mental sets in individuals on the early AD spectrum. Together with metrics from other cognitive tasks a composite score of cognitive functioning may support the identification of target subgroups of AD fast progressors and ultimately provide remote, clinically meaningful outcome measures for future clinical trials in preclinical and early AD.
P153- PRELIMINARY PSYCHOMETRIC AND CLINICAL VALIDATION OF VISUOSPATIAL WORKING MEMORY DEFICITS IN EARLY ALZHIMER’S DISEASE MEASURED WITH A SMARTPHONE BASED DIGITAL ASSESSMENT. E.A. Aponte 1, K.I. Taylor 1, A.M. Wolfer 1, C. Chatham 1, T.M. Perumal 1(1. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124 — Basel (Switzerland))
Background: The preclinical and early clinical stages of Alzheimer’s disease (AD) are chiefly characterized by deficits in episodic and semantic memory, yet other cognitive domains such as working memory may also be affected in the initial phases of the disorder. Scalable digital solutions offer the opportunity to quantify and track subtle changes in cognition remotely with a minimal burden to participants. Here, we present the preliminary clinical validation and psychometric properties of the gamified visuospatial working memory task Find the Egg (FtE) in healthy controls (HC), participants with subjective cognitive decline (SCD) and with early AD (eAD). The SCD group included individuals with and without beta amyloid (SCDp, SCDn, respectively) as assessed with amyloid Positron Emission Tomography (PET). Objectives: The objectives are to: (i) evaluate the feasibility of remote FtE self-assessments in healthy elderly, and in preclinical and early clinical stages of AD, (ii) identify the performance metrics that best differentiate between groups, and (iii) determine the reliability of these metrics. Methods: 123 adults of age 65 and older participated in a proof-of-concept (POC) study (https://www.isrctn.com/ISRCTN17035495) and were stratified in 4 groups: HC (31), SCDn (31), SCDp (31), and eAD (30). 120 participants successfully completed the study. 4 participants did not take part in FtE testing. During the course of an FtE session, a variable number of items (chickens) were displayed on the screen of the provisioned smartphone. Participants were instructed to search for targets (eggs) hidden behind the items by tapping on them and to avoid perseverative searching of locations where targets had already been found, or discovered not to be present. Depending on participants’ ability, they could reach any of 6 levels of difficulty, each corresponding to 4, 6, 8, 10, and 12 items on the screen. At the end of each session, the difficulty of the task was automatically calibrated by reducing the number of items presented during the next testing session according to participants’ performance. FtE was administered on nine days over the course of a month. Feasibility was examined with adherence metrics, and performance with five additional metrics: within- and between-search error rate, maximum difficulty level reached, and two computational metrics: total working memory (TWM) and attention level. TWM was estimated by extending Cowan’s K. This score represents the average number of items that an individual can simultaneously hold in working memory. Attention level is an index of how often participants make errors likely due to attention slips. The current report focuses only on the computational performance metrics to illustrate our most recent progress. All features were analyzed with a linear model with age, sex, education, site, and ethinicity as covariates. Differences between groups were computed using exploratory, unpaired t-tests. Reliabilities between the first and second half of the study were quantified with intra-class correlation coefficients (ICC). Because the study was not powered to detect cross sectional differences between groups, all p-values should be considered exploratory and nominal, and were not corrected for multiple comparisons. Results: On average, participants with FtE data (n=116) completed 85% of the assigned testing sessions. Adherence did not differ across groups (F=0.26, p>0.82). Each session lasted around 91s (± 59s). Ten participants were excluded from further analyses because they completed fewer than 5 sessions (n=5) or because their within-search error rate was above 2 standard deviations (SD) of the entire group mean (n=5). For the computational analysis, one eAD participant was excluded because their performance was 4 SD above the entire cohort. TWM significantly differentiated eAD from HC (t=3.1; p<0.003) and SCDn participants (t=2.5, p<0.013). SCDp had lower TWM compared to HC (t=−2.21, p<0.029). Overall, TWM followed the expected pattern across groups (mean and standard error): HC: 5.1 (0.2) > SCDn 4.9 (0.2) > SCDp 4.5 (0.2) > eAD 4.3 (0.5). There were no significant differences between groups related to attention level (F=2.0,p>0.11).Only TWM showed moderate to good reliability (ICC=0.72). Attention level displayed poor reliability (ICC=0.44). Conclusion: Find the Egg is a nove smartphone test of visuospatial working memory. Collecting high quality data with self-administered cognitive tests over the course of a clinical trial can be challenging, especially in elderly populations with memory impairments. Our results demonstrate the feasibility of self-administered FtE in this population. Importantly, FtE imposed minimal burden on participants, with sessions lasting on average less than 2 minutes. Although not part of the core deficits associated with eAD, we found impairments in visual working memory in early AD compared to amyloid negative individuals (HC and SCDn). In conclusion, FtE is a promising digital technology task that may enable the measurement of subtle changes in visual working memory in eAD.
P154- THE PHASE 2 LUMINARY TRIAL ASSESSING SAGE-718 IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT OR MILD DEMENTIA DUE TO ALZHEIMER’S DISEASE. A. Koenig 1, S. Malhotra 2, J. Wald 1, J. Petrillo 1, K. Paumier 1, J. Johannesen 1, S. Li 1, M. Quirk 1, E. Freitag 1, J. Doherty 1(1. Sage Therapeutics, Inc. — Cambridge, Massachusetts (United States), 2. Neuro-Behavioral Clinical Research, Inc. — North Canton, Ohio (United States))
Background: Cognitive impairment has a profound impact on the lives of patients with Alzheimer’s disease (AD) and their care partners. It is well-established that the early stages of AD are often characterized by memory impairment. However, a growing body of evidence indicates that executive dysfunction is also associated with early AD, which impacts the ability to perform complex activities, leaving a marked reduction in patients’ quality of life.1–5 There are no approved therapies to address cognitive impairment in nondemented patients with AD; approved therapies for dementia have limited efficacy in early cognitive impairment and are associated with substantial side effects.6 Novel strategies to treat cognitive impairment early in the course of AD are needed.6 N-methyl-D-aspartate receptors (NMDARs) play a critical role in neuronal network stabilization and are involved in many cognitive and behavioral processes. Additionally, NMDAR dysfunction has been implicated in multiple neurodegenerative disorders.7 SAGE-718 is a novel NMDAR positive allosteric modulator that is being investigated for the treatment of cognitive impairment in patients with neurodegenerative diseases such as AD. Objectives: The primary objective was to evaluate the safety and tolerability of orally administered SAGE-718 in patients with mild cognitive impairment (MCI) or mild dementia due to AD. Other objectives included the plasma pharmacokinetic (PK) profile of SAGE-718 following daily administration for 14 days and evaluating the effect of SAGE-718 on cognitive performance in patients with MCI or mild dementia due to AD. Methods: LUMINARY (NCT04602624) was an open-label, Phase 2 study evaluating SAGE-718 (3 mg QD for 14 days) in patients with AD. Patients (aged 50–80 years) were included if they had a memory complaint, a diagnosis of AD-related MCI or mild dementia confirmed by a Clinical Dementia Rating Scale (CDR) score of 0.5 or 1.0 with a memory box score of ≥0.5, essentially preserved activities of daily living, a score of 15–24 on the Montreal Cognitive Assessment (MoCA) at screening, normal premorbid intelligence quotient (IQ) at screening, and a reliable study partner willing to support the patient during the study. Patients were excluded from the study if they had any medical or neurological condition (other than AD) that might be contributing to the participant’s cognitive impairment or history of cognitive decline; any medical condition that could account for the observed cognitive impairment (excluding abnormalities consistent with underlying AD pathology); or current or recent suicidality. The study design included a 2-week screening period, a 1-week baseline period, a 2-week treatment period, and a 2-week off-drug follow-up period. The primary endpoint was safety and tolerability of SAGE-718 (treatment-emergent adverse event incidence through Day 28). Secondary endpoints included other safety outcomes. The effects of SAGE-718 on cognitive performance and functional outcomes were also analyzed. Results: Twenty-six patients with AD (69.2% female; mean age 67 years), and a mean±SD MoCA of 20.7±2.61 were enrolled. Most patients (23/26) had a global CDR score of 0.5. Eight TEAEs were reported in 7 (26.9%) patients; all were mild/moderate; 6 events were treatment related, but none resulted in study drug discontinuation or study withdrawal. No serious adverse events or deaths were reported. We have previously reported that after completion of dosing at Day 14, improvements from baseline were observed on tests of executive functioning (Digit Symbol Substitution and Multitasking), tasks of learning and memory (Pattern Recognition Memory and Verbal Recognition Memory tests), and that MoCA improvement (+2.3 points vs baseline) was observed at Day 28. No changes in attention/psychomotor speed were observed, consistent with the profile of SAGE-718 observed to date. Here we present results from additional executive functioning tests (One Touch Stockings, Spatial Working Memory, and 2-Back tests) showing improvement from baseline at Day 14, noting that an overall trend of improved performance from baseline at Day 14 was observed across all tests of executive functioning. Conclusions: In patients with MCI or mild dementia due to AD, SAGE-718 was generally well tolerated and associated with improvement across multiple measures of executive functioning and learning and memory. The improvement in cognitive performance was largely consistent with previous results from clinical studies assessing SAGE-718 in patients with cognitive impairment due to Parkinson’s disease or due to Huntington’s disease. These results support further investigation of SAGE-718 for the treatment of cognitive impairment associated with AD and other neurodegenerative diseases. A randomized placebo-controlled trial to further evaluate the effect of SAGE-718 on cognitive function in patients with AD is planned. References: 1. Collette F, et al. Neurobiol Aging. 2009;30(6):875–889. 2. Broks P, et al. Behav Neurol. 1996;9(3–4):135–148. 3. Bondi MW, et al. Neuropsychology. 2002;16(3):335. 4. Binetti G, et al. J Neurol Neurosurg Psychiatry. 1996;60(1):91–93. 5. Amieva H, et al. Arch Clin Neuropsychol. 2004;19(6):791–803. 6. Han JY, et al. Alzheimer Dis Assoc Disord. 2019;33(2):87–94. 7. Paoletti P, et al. Nat Rev Neurosci. 2013;14(6):383–400. Previous Presentations: Some of these data have been previously presented at the American Academy of Neurology Annual Meeting. April 2–7, 2022, Seattle, Washington. Funding Source: This study was sponsored by Sage Therapeutics, Inc. Acknowledgments: We would like to thank the patients and their families for helping us reimagine brain health. Medical writing and editorial support were provided by Symbiotix, LLC, funded by Sage Therapeutics, Inc. AK, JW, JP, KP, JJ, SL, MQ, EF, and JD are employees of Sage Therapeutics, Inc., and hold stock or stock options. SM is an employee of Neuro-Behavioral Clinical Research, Inc. Note: SAGE-718 is an investigational drug and is not approved by the FDA or any other regulatory agency as safe and effective for any use.
P155- LONGITUDINAL EVOLUTION OF FINANCIAL CAPACITY AND CEREBRAL TAU AND AMYLOID BURDEN IN COGNITIVELY NORMAL OLDER ADULTS, MILD COGNITIVE IMPAIRMENT, AND ALZHEIMER’S DISEASE DEMENTIA. K. Mimmack 1, E. Sprague 2,3, R. Amariglio 1,2,3, P. Vannini 1,2,3, G. Marshall 1,2,3(1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School — Boston (United States), 2. Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School — Boston (United States), 3. Center for Alzheimer Research and Treatment — Boston (United States))
Background: Financial capacity, which describes both an individual’s financial reasoning as well as their ability to perform certain financial tasks such as balancing a checkbook and making change, is an instrumental activity of daily living that can majorly impact independence and autonomy in older adults. Financial capacity can be measured with the Financial Capacity Instrument — Short Form (FCI-SF), a performance-based assessment which has been associated with the buildup of Alzheimer’s Disease (AD) pathology in the brain, specifically cortical tau and amyloid, but this relationship has only recently begun to be examined longitudinally. Objectives: This study aimed to investigate whether greater baseline cortical tau and amyloid burden was associated with worsening financial capacity over time across the AD spectrum. Methods: This study consisted of 490 older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 285 CN, 173 MCI, and 32 AD dementia who underwent flortaucipir tau positron emission tomography (PET) imaging and yearly FCI-SF exams, and a subset of 305 participants who additionally had florbetapir amyloid PET imaging. Separate linear mixed-effects models were run predicting longitudinal FCI-SF total score from baseline tau, baseline amyloid, and their interaction, all adjusted for age, gender, verbal intelligence (the American National Adult Reading Test), and cognition (Rey Auditory Verbal Learning Test total learning score and Trail Making Test Part B). Models were run on the whole sample, CN, and symptomatic (MCI and AD dementia combined) groups separately. A secondary analysis examined tau and amyloid in relation to only the composite checkbook subtask of the FCI-SF. A pivoted log+1 transformation was applied to FCI-SF scores for model fit, and confirmatory untransformed models were run additionally. P-values were adjusted for multiple comparisons using the False Discovery Rate (FDR) method. Results: The total sample was 51% female and 93% White, with a mean age of 74.0 (SD = 7.8), mean 16.6 (SD = 2.5) years of education, and total follow-up time ranging between 0.8 and 4.6 years (mean = 2.3, SD = 1.0). FCI-SF total scores for CN participants were clustered near the perfect score and were mostly stable, while the symptomatic group showed a wide range of scores which tended to worsen steeply over time. In the full sample, worsening financial capacity (FCI-SF total score) over time was significantly associated with greater baseline entorhinal (t = 3.39, p = 0.004), inferior temporal (t = 4.26, p < 0.001), and supramarginal tau burden (t = 2.81, p = 0.02) after correction for multiple comparisons. Within CN participants, significance was found in the inferior temporal (t = 3.55, p = 0.003), precuneus (t = 2.48, p = 0.049), supramarginal (t = 3.43, p = 0.004), and dorsolateral prefrontal cortex (DLPF) (t = 2.88, p = 0.02) regions, while in the symptomatic group, no regions were significant. No significant effect of amyloid over time or three-way interaction between amyloid, tau, and time was found. For the composite checkbook subtask of the FCI-SF, worsening financial capacity over time was significantly associated with greater inferior temporal (t = 2.67, p = 0.03) tau burden in the whole sample. No significance was found in the symptomatic or CN groups alone. Conclusion: Greater cerebral tau burden was associated with worsening financial capacity over time. This effect was most prominent in CN participants, which could be due to the smaller sample size of the symptomatic group, limiting its statistical power. With the strength of its relationship with AD biomarkers in CN participants, the FCI-SF may be a valuable tool in early detection of AD and a sensitive, clinically meaningful marker of early decline in clinical trials. Further research should continue the investigation of the longitudinal relationship between financial capacity and AD biomarkers, including in more diverse groups than our overwhelmingly White and highly educated sample to better represent the general population.
P156- POTENTIAL INFLUENCE OF COGNITIVE HETEROGENEITY IN A CLINICAL TRIAL FOR MILD-TO-MODERATE PROBABLE ALZHEIMER’S DEMENTIA. D. Jacobs 1, Y. Qiu 2, D. Salmon 1, K. Messer 1, L. Donahue 3, S. Kaplita3, I. Qureshi3, H. Feldman1(1. University of California San Diego — La Jolla (United States), 2. School of Statistics, East China Normal University — Shanghai (China), 3. Biohaven Pharmaceuticals, Inc — New Haven (United States))
Background: We previously identified and validated two distinct cognitive profiles among persons with mild-to-moderate probable Alzheimer’s dementia (AD) in two independent cohorts from the National Alzheimer’s Coordinating Center (NACC) who satisfied inclusion criteria for a typical AD clinical trial.1 Approximately 80% of participants exhibited a “typical” AD cognitive profile on the NACC Neuropsychological Test Battery (NACC-NTB), with greater impairment of episodic and semantic memory than other cognitive functions, while approximately 20% had an “atypical” profile characterized by comparable impairment across cognitive domains. Cognitive profiles were stable over time and had similar prevalence of AD pathology at autopsy. The atypical profile was associated with younger age, male sex, lower probability of APOE-e4, less severe global dementia, higher depression scores, slower cognitive decline, and lower Braak stage at autopsy but not with a higher prevalence of non-AD pathology. Here we apply this classification approach in a randomized clinical trial (RCT) for treatment of mild-to-moderate AD. Objectives: (1) To replicate and validate in a RCT cohort our previously published decision rule which identified two distinct cognitive subtypes within mild-to-moderate AD; (2) To determine whether cognitive subtypes differ in disease course or treatment response in a 48-week trial. Methods: 350 persons with mild-to-moderate probable AD were enrolled in T2 Protect AD, a phase 2, 48-week, multicenter, double-blind, placebo controlled RCT of the glutamate modulator, troriluzole (NCT03605667). Detailed trial methods and results are provided elsewhere.2 ADAS-Cog-11 and CDR sum of boxes (CDR-SB) were co-primary outcomes. The NACC-NTB was administered at baseline and end-of-study as an exploratory outcome. Sixteen participants missing follow-up or cognitive test data were excluded from these analyses, leaving n=334. Principal component analysis (PCA) was used to identify cognitive profiles in T2 Protect AD baseline NACC-NTB data, and concordance between these results and subtype classification using our previously published rule1 was examined. Statistical models were used to explore associations of cognitive subtype (determined by our published rule) with participant characteristics, AD biomarkers, and trial outcome measures; all models included an indicator for treatment arm. Results: Consistent with our previous findings, PCA identified two distinct cognitive profiles: a “typical” profile with greater impairment of episodic and semantic memory than other cognitive functions (N=282; 84%) and an “atypical” profile with comparable impairment across cognitive domains (N=52; 16%). Concordance between T2 PCA results and classification based on our previously described rule1 was high for the typical (98%) and atypical (82%) subgroups. As in our previous study, the atypical profile was associated with lower prevalence of APOE-e4 (50% vs. 69.5%; p<.01) and less severe global dementia (results reported as mean+SD) (ADAS-Cog 22.0+8.01 vs. 26.8+7.96; p<.001; CDR-SB 5.1+2.17 vs. 6.8+2.47; p<.001; MMSE 21.3+3.97 vs. 19.0+3.67; p<.001). Atypicality was also associated with greater baseline hippocampal (2.80+0.47 vs. 2.47+0.44; p<.001) and entorhinal cortex (2.26+0.46 vs. 1.96+0.41; p<.001) volumes, and with lower plasma GFAP (354.28+139.78 vs. 409.34+176.66; p<0.05) and total tau (1.98+0.75 vs. 2.44+1.31; p<0.05). Groups did not differ in plasma Aβ40/Aβ42 ratio (p=0.92); p-tau-181 (p=0.39); or NFL (p=0.87). After controlling for appropriate covariates in a mixed-effects repeated measures model, the three-way interaction between treatment arm, cognitive subtype, and time was not significant (p=0.152 for ADAS-Cog change and 0.367 for CDR-SB change). After dropping interaction terms with treatment arm from the model, the 2-way interaction between cognitive subtype and time remained nonsignificant (p=0.273 for ADAS-Cog change and p=0.098 for CDR-SB change). Conclusion: These results replicate our previous findings1 of two distinct cognitive profiles in mild-to-moderate probable AD and extend these findings to those enrolled in a RCT. The typical vs. atypical cognitive subgroups differed in some disease biomarkers at baseline (hippocampal and entorhinal atrophy, plasma GFAP, and total tau levels), but not others (plasma Aβ40/Aβ42 ratio, p-tau-181, or NFL). In contrast to our previous study, the typical and atypical subgroups did not differ in rate of decline on cognitive or functional outcome measures over the course of this 48-week trial, perhaps due to a shorter time period, smaller sample size, or slightly younger age and greater baseline global impairment in this trial cohort. Typical and atypical subgroups did not differ in response to treatment. These findings suggest that cognitive subtype had minimal consequences on the results of this RCT in mild-to-moderate probable AD. Impact of cognitive heterogeneity on RCTs may depend on the specifics of trial design (e.g., entry criteria, duration, and endpoints) as well as the treatment and its therapeutic target. References: Qiu Y, et al. Cognitive heterogeneity in probable Alzheimer disease: Clinical and neuropathologic features. Neurology.2019;93(8):e778–90. Feldman H, et al. T2 Protect AD: Results of a 48-Week Randomized Clinical Trial of Troriluzole in Mild-to-Moderate Alzheimer’s Disease. JPAD.2021;8(4):s46. Acknowledgements: The trial was funded and sponsored by Biohaven Pharmaceuticals, Inc. and undertaken through a cooperative agreement with the UC San Diego Alzheimer Disease Cooperative Study (ADCS).
P157- IMPACT OF DIFFERENT RATES OF DISEASE PROGRESSION IN INDIVIDUALS WITH AMYLOID POSITIVE ALZHEIMER’S DISEASE — FINDINGS FROM THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE. J.M. Chandler 1, M. Georgieva 2, U. Desai 2, N. Kirson 2, W. Ye 1, A. Gomez-Lievano 2, A. Hilts 3, D. Eid 2, A. Zhao 2, T. Schilling 1(1. Eli Lilly and Company — Indianapolis (United States), 2. Analysis Group — Boston (United States), 3. Groupe d’Analyse — Montréal (Canada))
Background: The heterogeneity in the rate of disease progression among individuals with Alzheimer’s disease (AD) has been well-documented. However, few studies have comprehensively assessed the implications of differential rates of disease progression in individuals with AD on longitudinal outcomes. A better understanding of the associations between initial rates of progression and cognitive and functional outcomes over time could help interpretation of clinical trial findings for treatments with potential to slow AD disease progression. Objectives: This study aimed to describe the underlying characteristics and long-term outcomes associated with different rates of disease progression as defined by the annualized change in Clinical Dementia Rating scale Sum of Boxes (CDR-SB) score, among amyloid-positive individuals with AD. An additional objective of the study was to estimate the effect of hypothetical reduction in change in CDR-SB on other outcomes over time. Methods: This retrospective observational study used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in the United States and Canada (09/2007-03/2022). Subjects with a clinical assessment of mild cognitive impairment (MCI), early MCI, late MCI, or AD/dementia were included; first observation with such diagnosis was defined as the index date. Eligible subjects were further required to have at least two visits after the index date with complete information on demographics, cognitive, and functional outcomes. Amyloid positive status was defined as cerebrospinal fluid amyloid-beta <192 pg/ml, florbetapir positron emission tomography (PET) global cortical uptake >1.11 standardized uptake value ratio (SUVR), or florbetaben PET global cortical uptake >1.08 SUVR. Eligible subjects were stratified into mutually exclusive cohorts based on the median positive annualized change (1.0 point) in CDR-SB score between the index visit and the first subsequent visit as follows: No progression (change≤0), Slower progression (0<change≤1.0 points), and Faster progression (change>1.0 points). For each cohort, the CDR-SB scores, Mini-Mental State Examination (MMSE) scores, Alzheimer’s Disease Assessment Scale Cognitive Subscale 13 (ADAS Cog-13) scores, and Functional Activities Questionnaire (FAQ) scores were described at index and each subsequent visit for up to four years. In addition, analysis of covariance (ANCOVA) on complete data will be conducted to assess the effect of change in CDR-SB score (as a continuous measure) on changes in MMSE, ADAS Cog-11, and ADAS Cog-13 scores over the follow-up period. All models will adjust for patient characteristics and scores at index. Results: Of the 495 eligible subjects, 233 (47.1%) were classified in the No progression, 131 (26.5%) in the Slower progression, and 131 (26.5%) in the Faster progression cohort over one year postindex. Demographic characteristics at index were similar across cohorts. Among all subjects, the mean±SD age at index was 73.5±7.3 years and 59.0% were males. At index, subjects in the Faster progression cohort were more likely to have a diagnosis of dementia than those in other cohorts: 27.5% vs. 14.6% for No progression and 19.1% for Slower progression. In addition, the Faster progression cohort had higher CDR-SB score (2.4±1.5 vs. 1.9±1.4 for No progression and 2.0±1.5 for Slower progression), lower MMSE scores (25.8±2.5 vs. 27.2±2.4 and 26.8±2.5 for the No and Slower progression cohorts, respectively), and higher ADAS Cog-13 scores (23.5±7.8 vs. 16.2±7.4 and 19.9±6.6 for the No and Slower progression cohorts, respectively) at index. The mean±SD FAQ scores were 7.8±6.8 (with 38.2% having FAQ≥9, an indication of impaired function and possible cognitive impairment) vs. 3.5±4.8 (15.5% had FAQ≥9) and 5.2±5.4 (25.2% had FAQ≥9) for the Faster, No and Slower progression cohorts, respectively. Over time, all cohorts progressively developed cognitive and functional impairment; however, the Faster progression one continued to experience worse outcomes compared with the other cohorts. By the fourth visit after the index, the CDR-SB score for the Faster progression cohort increased by 4.9 points on average, compared with 0.5 and 2.7 points for the No and Slower progression cohorts, respectively. The corresponding ADAS Cog-13 score increases were 10.0, 0.5, and 6.5 points, respectively. Nearly 60% of the Faster progression cohort had FAQ scores ≥9 compared with 20.5% and 47.7% among the No and Slower progression, respectively. Estimates from the ANCOVA models are under analysis and will be presented during the scientific congress. Conclusion: Despite similar demographic characteristics at baseline, amyloid-positive individuals with faster progression in CDR-SB early in the disease trajectory have higher disease severity at index and continue to experience worse outcomes over time than those with more gradual change in this metric. Conclusions from the ANCOVA models will be presented during the scientific congress. Full COI disclosure will be on the 2nd slide of the presentation or in the poster presentation.
P158- CAUSAL IN SILICO PATIENT MODELS CAN INFORM ALZHEIMER’S DISEASE PATIENT IDENTIFICATION AND ENDPOINT SELECTION FOR EARLY-STAGE CLINICAL TRIALS. S.Y. Shin 1, S. Deepanshi 1, A. Bharthur 1, T. Oakland 1, J. Latourelle 1(1. GNS Healthcare — Somerville, Ma (United States))
Background: The high cost of conducting clinical trials means that suboptimal trial design adds significant risk to developing a new drug. Clinical trial simulation shows promise as a tool to allow drug developers to test different trial designs in silico prior to enrollment. GNS Healthcare’s in silico Alzheimer’s disease (AD) patient model combines multi-omic, imaging and clinical profiles from patients diagnosed with AD and mild cognitive impairment (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The ability of these models to provide patient-level predictions of disease progression over time makes them a powerful tool for optimizing trials, especially in the critical earliest stages of disease progression. Objective: Here we describe the utility of our in silico AD patient models, AD Gemini, in design of trials, through understanding of the expected progression of individual patients at different disease stages for different cognitive measure. Use of the models will allow researchers to identify the fastest progressing patient subsets for outcomes of interest in their study. Methods: After data processing, the training data for the primary in silico patient model included 317 samples (with 29 AD, 191 MCI, 97 Controls) and 57,792 features from WGS, DNA methylation, Microarray Gene Expression, Metabolites, MRI and PET imaging, CSF biomarkers, demographics, medication and selected cognitive endpoints measured over time. All the -omics measures were obtained from whole-blood. Nine cognitive endpoints were evaluated (ADAS13, ADAS11, ADAS3, CDR-SB, CDR-SB-Cog, mPACCdigit, mPACCtrailsB, FAQ, MMSE) for both baseline and rate of change, estimated as the slope in the generalized linear mixed model on repeated measurements). A second in silico patient model was built in parallel from the independent multi-omic, longitudinal ANMerge data (with 71 AD, 63 MCI, 65 Controls) with complementary available omics features (e.g. metabolites in ADNI and proteins in ANMerge). Each in silico patient is comprised of an ensemble of Bayesian network models built from the training data. A Bayesian network model is a directed graphical representation of relationships between variables where each node is a variable and each arrow is a conditional dependency. Given this, our approach can simulate the causal effect of a given upstream variable on an outcome of interest by estimating the outcome changes conditional on fixed upstream values while appropriately adjusting for all the other covariates laying on the paths across all the networks. Results: The ADNI-based in silico patient models had strong predictive performance across a variety of cognitive outcomes, both at baseline and for progression-rate. Specifically, the proportion of variability explained by the model (measured by R2) in the full training set ranged from 0.57 (for CDR-SB) to 0.71 (for mPACCtrailsB) for the progression endpoints. Cross-validation test set R-squared values were similarly high with an average 0.1 decrease in R2 observed. This decrease is likely due to sample size reduction in the nested CV models, rather than overfitting bias, as evidenced by comparison of top predictors across the models. The predictive performance was further evaluated in the AD and MCI subsets, to specifically assess how well fast progressing patients could be identified at different disease stages. For MCI, the best predicted progression-rate endpoints included mPACCtrailsB (R2=0.63), mPACCdigit (R2= 0.60), and ADAS13 (R2= 0.61), while the least well predicted endpoints were CDR-SB (R2= 0.5) and FAQ (R2= 0.49). In comparison, for the smaller sub-cohort of AD patients, the most robustly predicted progression-rate endpoints were CDR-SB (R2= 0.39) and CDR-SB-Cog (R2= 0.38). While CDR-SB showed a higher R2 in MCI than AD, the reduced performance in AD group is likely from the reduced sample, and so the relative ranking of the measures within each subset is more appropriate to determine the optimum endpoints in each disease stage. Thus, we confirmed the relative effectiveness of the CDR measures in the AD cohort in the independent ANMerge-based model which included more comparable numbers of MCI and AD patients. In that model, the R2 for CDR-TOTAL progression was 0.72 for AD patients and 0.44 for MCI. Conclusion: These results highlight the relative utility of different measures in different disease stages, suggesting that PACC tests are more suitable for early detection of cognitive impairment whereas CDR tests are best to monitor progression rates once the dementia developed. This study is limited by the small samples sizes once looking at the stratified analyses and inability to directly validate the models with the independent data sets due to differences in data. It does however demonstrate the robustness of the causal in silico patient approach despite underlying data differences. Further work will also allow understanding the relative contributions to the predictive ability of each model dependent on different data modalities (including comparison of utility of metabolomics in ADNI and proteomics in ANMerge models). Use of these in silico patient models for identification of fast progressing patients can greatly enhance particularly in critical early stages of disease.
P159- CLINICAL PREDICTORS FOR CONVERSION TO ALZHEIMER’S DEMENTIA IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT USING AMYLOID PET IMAGING : INTERIM RESULTS. K.W. Park 1, S.J. Kim 1, D.Y. Kang 2, Y.J. Jeong 2(1. Department of Neurology, Dong-A University College of Medicine — Busan (Korea, Republic of), 2. Department of Nuclear Medicine, Dong-A University College of Medicine — Busan (Korea, Republic of))
Background and Objective: Alzheimer’s dementia (AD) has different pathogenesis and progression than dementia caused by other causes, and various studies have been conducted to target and treat it. In particularly, patients with mild cognitive impairment (MCI) are a clinically important group as they are at increased risk for the progression to AD, typically 10–15% per year. One of the predictive biomarkers of identifying AD, amyloid positron emission tomography (PET) is being used as an imaging test to overcome the accuracy of clinical diagnosis. Amyloid PET, which imaging beta-amyloid protein, is positive in the earlier stage of disease. Therefore? it is useful for clinically discriminating dementia before symptoms appearing. In this prospective study, we determined the rate of conversion to Alzheimer’s dementia between the two groups based on amyloid PET positivity. and investigated the clinical predictors for conversion to Alzheimer’s Dementia in Patients with Mild Cognitive Impairment Using Amyloid PET Imaging. Methods: Individuals aged 50 and above with consistent cognitive complaints without significant impairment of activities of daily living (ADL) were eligible of the study. Subjects with MCI according to Petersen’s criteria underwent neurologic examinations, laboratory test including ApoE genotyping, detailed neuropsychological tests, brain magnetic resonance imaging (MRI) and amyloid PET which was assessed by florbetaben (18F), flutemetamol (18F) and FC119S (18F). They have been clinically evaluated at baseline and followed up at least in one-year visit. Group comparisons and association analysis were performed using SPSS (version 26.0). Prognostic model was constructed with Cox proportional hazards regression analysis to predict progression to AD. Results: We consecutively recruited 50 patients who were clinically diagnosed with MCI and 42 subjects were included in the study (M:F 16:26, Age 71.36±6.92 years, Education 10.10±3.41 years). 19 of 42 (45.2%) subjects showed positive amyloid depositions, and we compared two groups according to amyloid PET positivity. The basic demographics were not significantly different between two groups except for Korea Instrumental Activities of Daily Living (KIADL) in baseline (p=0.006) and 1 year follow up study (p=0.003). 4 of 19 (21.1%) subjects with amyloid PET positive clinically converted to AD during follow up (mean duration 17.95±4.34 months) (p=0.158). Meanwhile, 5 of 42 patients (11.9%) were converted to Alzheimer’s disease, and the remaining group of MCI was compared with the group who converted to AD. There were not significantly different between two groups, but Clinical Dementia Rating-Sum of box (CDR-SOB) score was higher in AD group at baseline (p=0.015). Also, Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS) and CDR-SOB score were higher in AD group compared MCI group in 1 year follow up study. The effect of independent variables on progression to AD was analyzed using multivariate Cox proportional hazards regression. As a result, higher CDR-SOB score was considerably related to increased risk of AD conversion (hazard ratio 6.740, 95% confidence interval, 1.461–31.094, p=0.014). Conclusion: In this prospective study, patients with MCI who were amyloid PET-positive were more likely to progress to Alzheimer’s disease than patients who were amyloid PET-negative, but long-term follow-up was required. In addition, the group who converted to AD had higher CDR-SOB score than the stable MCI group at baseline and had higher MMSE, GDS, and CDR-SOB score in the 1-year follow-up period. We found that the CDR-SOB score was significantly considered as a clinically valuable prognostic predictor of disease progression from MCI status to AD.
P160- CLINICAL TRAJECTORY OF PRECLINICAL AD OVER 36 MONTHS IN THE CHARIOT STUDY. G. Novak 1, S. Baker 1, K. Karcher 1, D. Henley 1,2, C. Udeh-Momoh 3, O. Robinson 4, G. Price 3, T. Watermeyer 5, C. Ritchie 5, L. Middleton 3,4(1. Janssen R&D — Titusville, Nj (United States), 2. Indiana University School of Medicine — Indianapolis, In (United States), 3. Imperial College Healthcare NHS Trust — London (United Kingdom), 4. AGE Research, School of Public Health, Imperial College of London — London (United Kingdom), 5. Edinburgh Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh — Edinburgh (United Kingdom))
Background: Longitudinal studies in cognitively unimpaired individuals with biomarker evidence of Alzheimer’s pathology suggest that they show a greater rate of decline in performance on tests of memory and executive function, relative to individuals without such evidence. The recent shift towards preventative strategies in early-stage disease requires clinical trials with sensitive outcome measures suitable for detection of therapeutic effect. The ongoing CHARIOT-PRO Substudy aims to estimate the rate of cognitive change in the early Alzheimer’s pathological continuum, comparing individuals with and without baseline biomarker evidence of amyloid deposition (Aβ+ and Aβ−, respectively) over a 4.5 year follow up. The COVID-19 pandemic necessitated a shift to remote cognitive assessments over several months in 2020–2021. Here we present clinical outcome data through 36 months, comparing Aβ+ and Aβ− participants in both remote and in-person testing conditions. Objectives: To compare longitudinal cognitive performance in unimpaired Aβ+ and Aβ- individuals, using the Preclinical Alzheimer’s Cognitive Composite (PACC). To assess whether the PACC’s association with amyloid status remained evident under remote (rather than in-person) testing conditions. Methods: Healthy, cognitively unimpaired individuals (60–85 years), with Clinical Dementia Rating (CDR) scale = 0, underwent amyloid assessment via PET or lumbar puncture; approximately equal numbers of Aβ+ and Aβ-individuals were enrolled. Cognitive outcomes were assessed with the PACC, comprised of the Free and Cued Selective Reminding Task (FCSRT; total + free recall), Logical Memory II (LMII) from the Wechsler Memory Scale, Coding, and the Mini-Mental State Exam. The PACC was calculated as the sum of the z scores for each component calculated relative to the baseline mean and standard deviation for the entire sample. The PACC was obtained in screening and at baseline, and every 6 months thereafter. During the pandemic, remote assessments were conducted by videoteleconference. Verbal stimuli were presented by computer audio or phone. Visual stimuli were displayed via webcam or Power- Point and responses were recorded on forms unsealed at the time of the visit and were captured as screenshots by raters. Change from baseline was analyzed using a mixed effects model for repeated measures (MMRM) with amyloid status (negative, positive), visit, education level (9–12 years, college), APOE ε4 status (non-carrier, carrier) and visit-by-amyloid status interaction as factors, and age, hippocampal volume, and baseline value as covariates. Changes from baseline were calculated separately for remote and in-person testing in Aβ+ and Aβ− participants and were summarized with descriptive statistics. Results: A total of 258 Aβ+ and 261 Aβ− participants were enrolled in the study. At baseline, Aβ+ participants were older (mean (sd): Aβ+ =72.4y (5.7) vs Aβ− = 70.4y (5.3), p<0.00001), were more likely to be ApoE ε4 carriers (Aβ+ = 55.6% vs Aβ− =23.0%, p<0.001), and had lower scores on the PACC (Aβ+ = −0.40 (2.6) vs Aβ− =0.39 (2.7), p=0.001). Due to Covid-19, in-person visits were suspended from March 2020 to May, 2021. During these 14 months, 364 remote PACC assessments for Month 18, 24, 30, and 36 visits were carried out. As participants were at various timepoints in the study, the proportion of remote assessments within each visit window increased from 45 (9.6%) at Month 18 to 154 (44%) at Month 36. Performance on the PACC surpassed baseline at every visit in both groups with maximum mean change at Month 18 of +1.15 (Aβ−) and +0.64 (Aβ+). There was greater improvement for Aβ− than for Aβ+ participants at every visit, with statistically significant differences 18 months (LS mean difference [SE] = 0.39 [0.18], p=0.032), 30 months (0.54 [0.22], p=0.016), and 36 months (0.84 [0.20], p<0.001). Differences between Aβ+ and Aβ− in mean change from baseline were approximately the same magnitude for those that had in-person assessment (+1.03 Aβ− vs. +0.15 Aβ+ at Month 36) vs those that were tested remotely (+1.19 Aβ- vs. +0.37 Aβ+ at Month 36). Across both amyloid groups, mean PACC scores were lower at Month 18 for participants that had remote testing (0.04 Aβ-; −1.04 Aβ+) compared to those that had in-person testing (1.80 Aβ−; 0.51 Aβ+) but were comparable between the testing conditions at Months 24, 30, and 36. The difference at Month 18 appeared to arise from lower performance in coding and on the MMSE for remote testing, with minimal difference apparent for the FCSRT and the LMII. Discussion: In these cognitively unimpaired individuals, performance on the PACC improved over 36 months, though to a significantly greater extent in Aβ− than Aβ+ participants, consistent with differential practice effects previously reported on the first 2 administrations of the RBANS in this cohort. Though there were differences in performance between remote and in-person testing, the effects of amyloid status were similar in magnitude in both testing conditions. These findings highlight the value of the PACC as a sensitive measure for clinical trials and raises important consideration regarding remote versus in-person cognitive testing.
P161- IMPACT OF DIFFERENT RATES OF DISEASE PROGRESSION IN INDIVIDUALS WITH AMYLOID POSITIVE ALZHEIMER’S DISEASE — FINDINGS FROM THE NATIONAL ALZHEIMER’S COORDINATING CENTER. J.M. Chandler 1, M. Georgieva 2, U. Desai 2, N. Kirson 2, W. Ye 1, A. Zhao 2, D. Eid 2, A. Gomez-Lievano 2, A. Hilts 3, T. Schilling 1(1. Eli Lilly and Company — Indianapolis (United States), 2. Analysis Group — Boston (United States), 3. Groupe d’Analyse — Montréal (Canada))
Background: The heterogeneity in the rate of disease progression among individuals with Alzheimer’s disease (AD) has been well-documented. However, few studies have comprehensively assessed the implications of differential rates of disease progression in individuals with AD on longitudinal outcomes. A better understanding of the associations between initial progression rates and cognitive, functional, and neuropsychiatric outcomes over time could help interpretation of clinical trials findings for treatments with potential to slow AD disease progression. Objectives: This study aimed to describe the underlying characteristics and long-term outcomes associated with different rates of disease progression as defined by the annualized change in Clinical Dementia Rating scale Sum of Boxes (CDR-SB) score, among amyloid-positive individuals with AD. An additional objective of the study was to estimate the effect of hypothetical reduction in change in CDR-SB on other outcomes over time. Methods: This retrospective observational study used data from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) in the United States (06/2005-11/2021). Subjects with a clinical assessment of mild cognitive impairment or dementia and CDR-SB score 0.5–9.0 (inclusive; first visit defined as the index date) were included in the study. Eligible subjects were further required to have primary or contributing etiologic diagnosis of AD on at least half of the visits, including the most recent visit after the index date, and have at least two visits after the index date with complete information on demographics and outcomes of interest. Amyloid positive status was defined as either abnormally elevated amyloid on positive emission tomography scan or abnormally low amyloid in cerebrospinal fluid ante-mortem; or frequent density of neocortical neuritic plaques or Braak stage for neurofibrillary degeneration of Stage V or Stage VI post-mortem. Eligible subjects were stratified into mutually exclusive cohorts based on the median positive annualized change (2.0 points) in CDR-SB score between the index visit and the first subsequent visit as follows: No progression (change≤0), Slower progression (0<change<2.0 points), Median progression (2.0-point change), and Faster progression (change>2.0 points). For each cohort, the cognitive, functional, and neuropsychiatric outcomes were described at index and each subsequent visit for up to five years. In addition, analysis of covariance (ANCOVA) on complete data will be conducted to assess the effect of change in CDR-SB score (as a continuous measure) on changes in Mini-Mental State Examination (MMSE), Functional Activities Questionnaire (FAQ), and Neuropsychiatric Inventory-Questionnaire (NPI-Q) scores over the follow-up period. All models will adjust for patient characteristics and scores at index. Results: Of the 1,263 eligible subjects, 474 (37.5%) were classified in the No progression, 297 (23.5%) in the Slower progression, 213 (16.9%) in the Median progression, and 279 (22.1%) in the Faster progression cohort over one year post-index. Demographic characteristics and comorbidity profiles at index were similar across cohorts. Among all subjects, the mean±SD age at index was 72.7±9.7 years and 55.3% were males. The most common comorbidities at index were hypercholesterolemia (54.7%), psychiatric disorders (49.4%), and hypertension (48.5%), and 62.7% had at least one copy of APOE e4 gene. At index the Faster progression cohort had higher CDR-SB score (4.9±2.1 vs. 3.6±2.0 for No, 3.7±2.1 for Slower, and 3.5±2.2 for Median progression), higher FAQ score (15.7±7.1 vs. 9.4±7.1, 10.2±7.4, and 10.7±7.7 for the No, Slower, and Median progression respectively), and higher NPI-Q scores (4.5±4.0 vs. 3.5±3.5, 3.5±3.3, and 3.5±3.7 for the No, Slower, and Median progression cohorts). Additionally, fewer subjects in the Faster progression cohort were able to live independently (17.6% vs. 39.2%, 34.3%, and 36.6% among the No, Slower, and Median progression cohorts). Over time, all cohorts progressively developed cognitive and functional impairment; however, the Faster progression one continued to experience worse outcomes compared with the other cohorts. By the fifth visit after the index, the CDR-SB score for the Faster progression cohort increased by 11.4 points on average, compared with 6.6, 8.3, and 9.7 points for the No, Slower, and Median progression cohorts, respectively. Nearly 75% of the Faster progression cohort was completely dependent compared with 28.3%, 34.0%, and 49.3% among the No, Slower, and Median progression, respectively. The neuropsychiatric outcomes at five years post-index were similar for all cohorts. Estimates from the ANCOVA models are under analysis and will be presented during the scientific congress. Conclusion: Despite similar demographic and comorbidity profiles at baseline, amyloid-positive individuals with faster progression in CDR-SB early in the disease trajectory have higher disease severity at index and continue to experience worse outcomes over time than those with more gradual change in this metric. Conclusions from the ANCOVA models will be presented during the scientific congress. Full COI disclosure will be on the 2nd slide of the presentation or in the poster presentation.
P162- RESCREENING ON RBANS DELAYED MEMORY INDEX? FORGET ABOUT IT! M.N. Sabbagh 1, W. Michalak 2, C.T. Hansen 2, L.L. Raket 2, C.A. Wichmann 2, A. Clark 2(1. Barrow Neurological Institute — Phoenix, Arizona (United States), 2. Novo Nordisk A/S — Søborg (Denmark))
Background: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Memory Index (DMI) is frequently used to screen patients for early Alzheimer’s Disease trials. An RBANS DMI score ≤85 is typically used to select a patient population with cognitive impairment and increased likelihood of being amyloid positive, and thus avoid unnecessary amyloid PET scans and lumbar punctures. Trial investigators may consider some patients who do not meet the RBANS DMI ≤85 cut-off to otherwise have Alzheimer’s Disease, but it is unclear if they would meet eligibility criteria if rescreened at a later date. We sought to gain a better understanding of RBANS DMI trajectory over time and how, in combination with other Alzheimer’s Disease trial inclusion criteria, such as clinical scale scores, it relates to amyloid positivity. Objectives: To help inform trialists about the potential value of rescreening patients who initially fail RBANS DMI inclusion criteria, in order to aid trial recruitment. Methods: We conducted an analysis of data from the European Prevention of Alzheimer’s Dementia (EPAD) database. A study population was identified with the following criteria at baseline: 1) age 50–85 years; 2) no dementia diagnosis from the participant’s physician; 3) a Mini-Mental State Examination (MMSE) score ≥22; and 4) data on RBANS DMI. Data were stratified by RBANS DMI score at baseline (≤85, 86–95, and >95) and characterized in relation to distribution of age, ethnicity, amyloid positivity, ApoE genotype, MMSE and Clinical Dementia Rating (CDR) global score. RBANS DMI trajectories were visualized by spaghetti plots and modeled (mixed model with participants as random effects, and time, and time interaction with baseline RBANS DMI as fixed effects) using available longitudinal data to estimate average change from baseline to 6 and 12 months in the total population and by baseline RBANS DMI group. Logistic regressions were performed to determine the odds and probabilities for participants with baseline RBANS DMI 86–95 of meeting: A) the RBANS DMI cut-off of ≤85 at rescreening; B) criteria A + CDR global ≥0.5; and C) criteria B + being amyloid positive. These outcomes were assessed at 6 and 12 months, respectively. The proportion of participants with an RBANS DMI score ≤85 at 6 months was also assessed with different baseline RBANS DMI thresholds for rescreening. Results: Of the 2,096 participants in the database, 1,965 fulfilled the four inclusion criteria at baseline. Of these, 1,731 also had data on CDR global and amyloid status. For those who were assessed at both baseline and 6 months, 1,551 participants also had CDR and amyloid data. At baseline, amyloid positivity rates were 58.3% (147/252), 36.7% (76/207), and 28.5% (362/1,272) for RBANS DMI scores of ≤85, 86–95, and >95, respectively. Amyloid positivity increased to 73.4% (n=116/158) among participants with both RBANS DMI score ≤85 and CDR global score ≥0.5. There was large variability in the change in RBANS DMI scores over time, with a median change of 2.0 (interquartile range: −5.0; 9.0) at 6 months. For participants with baseline RBANS DMI scores of 86–95 (N=207), there was also no clear trend in RBANS DMI values at 6 and 12 months. It was estimated that 15% of participants would progress from RBANS DMI scores of 86–95 at baseline to ≤85 at 6 months, with 8% also achieving the CDR global criteria and 5% also being amyloid positive. This implies a need to rescreen approximately 7 participants with a baseline RBANS DMI of 86–95 to identify one participant fulfilling criteria A, 13 participants to meet criteria B, and 20 participants to meet criteria C. Modeling data for a 12-month follow-up resulted in similar findings. Regardless of the baseline RBANS DMI threshold used to rescreen, no more than 16% of participants would progress to a score of ≤85 at 6 months. The mixed model indicated that participants with baseline RBANS DMI scores <109 are likely to have a positive change in RBANS DMI and participants with scores >109 are likely to have a negative change. These findings could suggest an effect of regression to the mean. Conclusion: In this study, there was a large degree of variability in RBANS DMI scores, with no trend in the scores over time. Only a small proportion of participants not meeting the initial RBANS DMI criteria progressed to meet the RBANS DMI threshold of ≤85 at 6 and 12 months, and fewer still also met other common trial inclusion criteria. This indicates that there is limited value in rescreening patients based on their RBANS DMI score. Conflicts of Interest: MNS serves as a consultant to Novo Nordisk. However, MNS received no remuneration for participating in this project. WM, CTH, LLR, CAW, and AC are employees of Novo Nordisk A/S, and CTH also holds stocks in Novo Nordisk.
P163- PREDICTORS OF MEMORY IMPAIRMENT IN MILD COGNITIVE IMPAIRMENT WITH LOW MINI-MENTAL STATE EXAMINATION RECALL SCORES. S.Y. Ryu 1, S.B. Lee 1, T.J. Lee 1, Y.J. Jung 1(1. The Catholic University of Korea, Daejeon St. Mary’s Hospital — Daejeon (Korea, Republic of))
Background: Alzheimer’s disease (AD) is the main cauase of cognitive impairment in late-life, and the typical early presentation of AD in older aduts is amnestic cognitive impairment. Mini-Mental State Examination (MMSE) is widely used in screening cognitive impairment in elderly and includes recall item that measures memory. Objectives: The aim of this study was to examines if low MMSE recall scores would be associated with verbal memory impairment in individuals with mild cognitive impairment (MCI). Methods: 158 MCI subjects with low MMSE recall scores (MMSE recall subscore <= 1) (mean age: 74.28 ± 6.67 years) were included in this study. The participants underwent clinical assessments and completed detailed neuropsychological tests. The participants were divided into two groups according to Seoul Vebal Learning Test Delayed Recall (SVLT DR) scores: normal verbal memory performance (SVLT DR >= −1.0 SD) vs low verbal memory performance (SVLT DR < −1.0 SD) groups. Group comparisons between normal and low verbal memory performance were performed. Results: Low verbal memory performance group (n = 91) was older and had more males than normal verbal memory performance group (n = 67). For MMSE items, low verbal memory performance group had lower MMSE time orientation subscores and higher MMSE language subscores than normal verbal memory performance group. The results for MMSE time orientation remaind significant after adjusting age, sex, education. There were no differences in MMSE total scores, other MMSE items, instrumental activities of daily living, clock drawing tests or depressive symptoms between the two groups. Conclusion: In MCI individuals with low MMSE recall scores, low verbral memory performance was associated with lower MMSE time orintation scores, compared to the normal vermal memory performance group. These results suggest that more consideration for MMSE sub-items would be helpful for the clinical evaluation of individuals with MCI at first step.
P164- INCREASED NUMBERS OF MODIFIABLE DEMENTIA RISK FACTORS AMPLIFY ADVERSE EFFECTS ON COGNITION ACROSS THE ADULT LIFESPAN. A. Laplume 1, L. Mcketton 1, B. Levine 1,2?3, A. Troyer 4,5, N. Anderson 1,2,6(1. Rotman Research Institute, Baycrest Health Sciences — Toronto (Canada), 2. Department of Psychology, University of Toronto — Toronto (Canada), 3. Department of Medicine (Neurology), University of Toronto — Toronto (Canada), 4. Department Of Psychology, University Of Toronto — Toronto (Canada), 5. Neuropsychology and Cognitive Health Program, Baycrest Health Sciences — Toronto (Canada), 6. Department of Psychiatry, University of Toronto — Toronto (Canada))
Background: Prior studies showed that modifiable lifestyle behaviours can reduce dementia risk by 40%, however their prevalence and association with cognition extending to early adulthood is not well understood. Growing evidence suggests that age related cognitive decline begins in younger adults, which extends the critical period for targeting risk factors from older to early adulthood. Objectives: We sought to build on previous work to test whether prevalence of modifiable risk factors for dementia and their dose-response relationship with cognition is moderated by age. Methods: We used a large web-based dataset on participants who completed a free, self-administered online assessment (the Cogniciti Brain Health Assessment) that is psychometrically validated, and demonstrated adequate internal consistency, test-retest reliability, alternate version reliability, construct validity and adequate convergent validity when compared to clinician-administered neuropsychological tests of the same constructs. Moreover, the test was designed to be suitable for older adults and provides greater sensitivity at the high end of function than the Montreal Cognitive Assessment, offering sensitivity to assess a relatively healthy sample. Our sample included a dataset of N = 93,363 assessment attempts. After extensive data cleaning, associations between eight modifiable risk factors for dementia (low education, hypertension, hearing loss, traumatic brain injury, alcohol or substance abuse, diabetes, smoking, and depression) and cognition were examined using polynomial regression analyses in this online sample (N = 22,117, aged 18–89). Results: Our results extend previous findings to show that risk factors are more prevalent as age increases and show a larger dose-response association with cognition as age increases. Older adults (ages 66–89) had more risk factors than middle-aged (ages 45–65) and younger adults (ages 18–44). Polynomial regression revealed each additional risk factor was associated with a drop in cognitive performance (equivalent to three years of aging), with a larger association as age increased. Adults with no risk factors in their 40s–70s showed similar cognitive performance to people 10 or 20 years younger with many risk factors. Conclusion: Dementia has a long preclinical period which highlights the need to study risk factors and cognitive impacts long before a clinical diagnosis of dementia. We found that modifiable dementia risk factors may be more important than age in predicting cognitive performance.
P165- FEASIBILITY, RELIABILITY, AND VALIDITY OF REMOTE SMARTPHONE DATA COLLECTION IN FRONTOTEMPORAL DEMENTIA USING THE ALLFTD MOBILE APP. A. Staffaroni 1, J. Taylor 1, A. Clark 1, H. Heuer 1, A. Wise 1, M. Manoochehri 2, L. Forsberg 3, C. Mester 3, M. Rao 3, D. Brushaber 3, J. Rojas 1, J. Kramer 1, B. Boeve 3, H. Rosen 1, A. Boxer 1(1. UCSF — San Francisco (United States), 2. Columbia University — New York (United States), 3. Mayo Clinic — Rochester (United States))
Background: The successful identification of safe and effective therapies for frontotemporal dementia (FTD) is contingent on validated clinical trial endpoints that are capable of efficiently capturing the clinical heterogeneity of FTD. Moreover, FTD is relatively rare and affected individuals are geographically dispersed, making recruitment challenging. Clinical trials in the familial forms of FTD, for example, will likely require global recruitment. Remote assessment tools could address these challenges and potentially enable decentralized clinical trials. We developed the ALLFTD Mobile App, a smartphone application that includes assessments of cognition, speech/language, and motor functioning, to address some of these . There is a dearth of information about the feasibility, reliability, and validity of remote smartphone assessment in FTD. Objectives: The objectives were to determine the feasibility of implementing a remote smartphone data collection protocol in a multicenter FTD research study and evaluate the reliability and validity of the smartphone cognitive measures. Methods: A diagnostically mixed sample of 207 participants with FTD or from familial FTD kindreds (CDR®+NACC-FTLD=0 [n=91]; CDR®+NACC-FTLD=0.5 [n=39]; CDR®+NACC-FTLD≥1 [n=39]; unknown [n=38]) were asked to remotely complete a 25–35 minute smartphone assessment battery three times over two weeks. The battery included five executive functioning (EF) tests and an adaptive memory test. They also completed surveys about their experience interacting with the app. We analyzed adherence (percentage of available measures that were completed) and user experience. We evaluated split-half reliability using the first available assessment for each participant. We assessed test-retest reliability across all available assessments. To establish evidence for construct validity, linear models tested the association of the smartphone tests with gold-standard neuropsychological outcomes (UDS3-EF composite & CVLT-SF Immediate Recall), a measure of disease severity (CDR®+NACC-FTLD Box Score), and regional gray matter volumes. Results: Participants completed 70% of tasks. Those that completed at least one set of assessments reported that the instructions were understandable (93%), considered the time commitment acceptable (97%), and were willing to complete additional assessments (98%). Split-half reliability was excellent for the executive functioning tasks (r’s=0.93–0.99) and good for the memory test (r=0.78). Test-retest reliabilities ranged from acceptable to excellent (intraclass correlations: 0.70–0.96). Smartphone EF measures were strongly associated with the UDS3-EF composite (β’s=0.6–0.8, all p<.001), and the memory test was strongly correlated with total immediate recall on the CVLT-SF (ß=0.7, p<.001). Worse performance on all tests was associated with greater disease severity (ß’s=0.5–0.7, all p<.001). Poorer performance on the smartphone EF tasks was associated with lower frontoparietal/subcortical volume (ß’s=0.4–0.6, all p<.015) and worse memory scores with lower hippocampal volume (ß=0.5, p<.001), controlling for total intracranial volume. Conclusion: These results indicate that remote digital data collection in FTD research is feasible and acceptable. These findings also support the reliability and validity of the ALLFTD Mobile App cognitive tests. Future studies will aim to understand the validity of these measures for early detection of symptoms and longitudinal monitoring. Conflicts of Interest: The authors declare no conflicts of interest relevant to the current work.
P166- CALCULATING GENERALIZED RECALL PROBABILITY USING DIGITAL COGNITIVE BIOMARKERS DERIVED FROM WORDLIST MEMORY TEST ASSESSMENT. J. Hara 1,2, J. Bock 1,3, K. Shah 4, D. Fortier 1, M. Lee 3(1. Embic Corporation — Newport Beach (United States), 2. Pickup Family Neuroscience Institute and Hoag Center for Research and Education, Hoag Memorial Hospital — Newport Beach (United States), 3. Dept. of Cognitive Sciences, University of California at Irvine — Irvine (United States), 4. University of California at Berkeley — Berkeley (United States))
Background: Digital cognitive biomarkers (DCBs) quantify underlying, unobservable (latent) cognitive processes that are fundamental to cognitive function and that animate the cognitive domains of memory, orientation, and verbal fluency. DCBs of encoding and retrieval can be generated with a hierarchical Bayesian cognitive processing (HBCP) model, applied to item response data from commonly used wordlist memory (WLM) tests of learning and recall. Seven base DCBs have been well validated, each representing probability of information processed through different encoding (N1, N2, N3, or N4) or retrieval (R1, R2, or R3) paths and three distinct storage states (pre-task, transient, or durable storage states). While these base DCBs provide granular insight into cognitive function, additional measures that quantify the probability of recall from various storage states are valuable to bridge between underlying processes (encoding and retrieval) and observed behaviors (e.g., word recall). A generalized probability of recall, which includes the combination of encoding and retrieval processes that result in successful recall across WLM test tasks, can be constructed from base DCBs subsequent to modeling. Such additional measures can provide deeper insight into observed behavior and could aid in interpreting and communicating cognitive changes during clinical trials or in clinical settings. Objective: To calculate and validate additional measures that use digital cognitive biomarkers of encoding and retrieval to represent the probability of recall from transient and durable storage states for immediate and delayed recall. Methods: In calculating generalized probability of recall, the seven base DCBs were first generated on item response data from the ADAS-Cog WLM tests (n = 10,933) performed between the years of 2005 and 2021 on subjects (n = 2,348) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Their demographics and clinical diagnoses were also obtained. The HBCP model that generates these DCBs uses a multinomial processing tree to calculate the probability that each encoding or retrieval process is used during each learning and recall task of the WLM test. A post-modeling calculation was performed to summate the probabilities across the tree for the subsets of processes involved in recall from transient storage on immediate recall tasks, from durable storage on immediate recall tasks, and from durable storage on delayed recall tasks, generating M1, M2, and M3, respectively. These M parameters were calculated for each of the ADAS-Cog WLM test assessments and were visually compared to total word recall for each immediate and delayed recall task and all tasks combined. After randomly assigning 20% of the sample to a training subsample, we evaluated a pair of logistic regression models to compare subject assessments with diagnosis of mild cognitive impairment (MCI) to cognitively normal (CN) and compare dementia due to Alzheimer’s disease (AD) to MCI, respectively. Demographics and all three M parameters were included as predictors, and we used backward elimination of non-significant predictors. On the testing subsample (the remaining 80% of the sample), we plotted receiver operating characteristic (ROC) curves and obtained classification accuracy for both diagnosis pairs. Results: Visual comparison of M parameters and total word recall showed a clear curvilinear relationship. Both logistic regression models were significant (p’s < .001), with pseudo R2 = .23 for classification of MCI from CN and .38 for AD from MCI. The ROC AUCs = .79 and .88, respectively, and with a cutoff of .51 and .53, classification accuracies = 72.05% and 81.39%, respectively. Conclusion: The results demonstrate that the underlying cognitive processing parameters, when summated as a probability of recall from pre-task, transient, or durable storage states, highly resemble observed behavior of total word recall for each of the immediate and delayed recall tasks. This reinforces the accuracy of the base DCBs and validates the generalized measures of recall probability (M1, M2, M3) as predictors of observed behavior. Furthermore, these measures demonstrate predictive accuracy for classifying individuals according to AD impairment severity, based on a single assessment. Such measures are beneficial for characterizing subjects during the enrollment stage of clinical trials and for comparing treatment arms in clinical research.
P167- DIGITAL COGNITIVE BIOMARKERS FOR THE ADAS-COG WORD RECALL TEST: ACCURACY AND VALIDITY OF CLASSIFYING COGNITIVE IMPAIRMENT. J. Bock 1,2, J. Hara 1,3, D. Fortier 1, T. Mangrola 1, W. Shankle 1,2,3, M. Lee 2(1. Embic Corporation — Newport Beach (United States), 2. Dept. of Cognitive Sciences, University of California at Irvine — Irvine (United States), 3. Pickup Family Neuroscience Institute, Hoag Memorial Hospital — Newport Beach (United States))
Background: In Alzheimer’s disease (AD) clinical trials, episodic memory performance is frequently assessed with wordlist memory (WLM) tests during enrollment and/or as an outcome measure for individuals who are cognitive normal (CN) or who have mild cognitive impairment (MCI) or AD dementia. Most commonly, the total number of words recalled across tasks is used to score performance. However, this approach fails to use the majority of information available in a WLM test and is often insufficient for characterizing subtle cognitive changes. This is especially true in CN and MCI stages and when measuring changes in underlying cognitive processes that may be differentially affected by the course of AD. As the focus of AD clinical trials shifts toward prevention, pre-clinical, or MCI-stage AD, there is a vital need to quantify episodic memory more precisely, enabling more accurate classification of impairment. Digital cognitive biomarkers (DCBs) quantify underlying, unobservable (latent) cognitive processes, fundamental to cognitive function. We generate DCBs of encoding and retrieval with a hierarchical Bayesian cognitive processing (HBCP) model, applied to item response data from commonly used multi-task WLM tests of learning and recall. There are seven base DCBs, each representing probability of information processed through different encoding (N1, N2, N3, or N4) or retrieval (R1, R2, or R3) paths and three distinct storage states (pre-task, transient, or durable storage states). These DCBs provide new, granular, and insightful measures of cognitive function. There are several commonly used WLM tests, including the AVLT, CVLT, EVLT, CERAD, and ADAS-Cog. While these tests share a common test administration paradigm, consisting of multiple learning and recall tasks (immediate and delayed), the ADAS-Cog employs a shuffled wordlist presentation, whereby each of the 10 words in the wordlist are presented in a different order during each of the three learning tasks. Since shuffling the presentation order of words eliminates the serial position effects of primacy and recency on encoding (which is a loss of available information), generating DCBs for this test paradigm requires modeling the item-level responses with a distinct approach compared to that used for fixed-order tests. Objective: To validate generation of DCBs with ADAS-Cog WLM tests by comparing outcomes across individual assessments according to clinical diagnoses. Methods: Item response data was obtained from ADAS-Cog WLM tests (n = 10,933) performed between the years of 2005 and 2021 on subjects (n = 2,348) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), along with their demographics and clinical diagnoses (CN, MCI, and AD). An HBCP model was used to evaluate individual WLM assessments, independent of all other assessments being modeled. To enable characterization of latent processes with a single ADAS-Cog WLM test, three modifications were made that distinguish the model from that used for fixed order tests: 1) Bayesian prior distributions of DCBs were obtained through modeling of 77,000 subjects who were assessed with the EVLT, separated across female and male, low and high education, and ages 40 to 85, and individual ADAS-Cog assessments use the appropriate prior distribution for their demographic group; 2) position-specific parameters are used for each word, dependent on task; and 3) word-specific encoding and retrieval probability penalties were calculated and are applied to modeling recall. The resulting DCB posterior distribution means were examined to characterize patterns in cognitive performance and, after randomly assigning 20% of the sample to a training subsample, we evaluated a pair of logistic regressions to compare MCI to CN and AD to MCI subject assessments, respectively. Demographics and all seven DCBs were included as predictors, and we used backward elimination of nonsignificant predictors. On the testing subsample (the remaining 80% of the sample), we plotted receiver operating characteristic (ROC) curves and obtained classification accuracy for both diagnosis pairs. Results: DCB posterior distribution means, when grouped according to diagnosis, showed clear decline in cognitive processing ability with increasing severity and clear separation among groups. Both logistic regression models were significant (p’s < .001), with pseudo R2 = .24 for classification of MCI from CN and .38 for AD from MCI. The ROC AUCs = .79 and .88, respectively, and with a cutoff of .58 for both models, classification accuracies = 71.89% and 81.18%, respectively. Conclusion: This demonstration of accurate classification of cognitive impairment by diagnosis with DCBs, generated from item response data of individual assessments with established priors, obtained from a large population across demographic groups, validates our HBCP modeling approach on the ADAS-Cog WLM test. Because these DCBs characterize underlying cognitive processes, this enables more granular classification, pertaining to encoding and retrieval specifically, than total word recall can provide. Furthermore, it enables comparison of individual episodic memory performance across WLM tests, whether word presentation order is shuffled or fixed. This is valuable to clinical trial recruitment, enrollment, and outcome measurement by providing expanded information about subject cognition prior to and during study.
P168- A NOVEL 2-MINUTE HIGH-FREQUENCY ASSESSMENT OF EPISODIC MEMORY, SHOWS DIURNALITY, TIME VARYING PATTERNS IN FATIGUE AND MOOD WHICH BECOME MORE TIGHTLY COUPLED WITH AGE. A.L. Anwyl-Irvine 1, A. Kaula 1, N. Taptiklis 1, C. Nathan 1, F. Cormack 1(1. Cambridge Cognition — Cambridge (United Kingdom))
Background: A decline in episodic memory is a strong marker of neurodegenerative diseases such as Alzheimer’s. As such measuring, this faculty has potential for early detection of disease processes. This makes tasks which measure this an important target for cognitive assessment. Yet measures of memory can show variability across time, both in a linear way (e.g., neurodegeneration or recovery) and a stationary way (e.g., morning-afternoon patterns). Far from being noise, this information may offer more statistical power and insight into an individual’s life. High-frequency assessments, therefore, present a tempting opportunity to capture this rich information. Such a measure of episodic memory must involve recalling what, when and where some percept occurred. Additionally, to promote patient compliance with many sessions, it should ideally be easy to understand, brief, and compatible with mobile devices. Here we present such a tool, assessing memory for objects on a screen (what) in a specific order (when) and in a specific location (where). We show initial data in two healthy samples (n=133, 117) with a wide age range to evaluate appropriateness as a candidate tool in patient populations. Objectives: To present a novel, brief, high-frequency assessment of episodic memory. Assess the overlap of test-metrics with existing measures of memory. Test the compliance, learning curve and time-varying properties of the assessment metrics. Show if these co-vary with Age, time-of-day, fatigue and mood, as requirements before testing this task in a patient population. Methods: The task consists of a learning phase where participants see a sequence of four items (animal emoji) in a specific order and location, and then are asked to replicate the item order and location by dragging and dropping these items on-screen. A recall phase follows a minimum 12-hour delay, with replication of the earlier response. Each session takes less than 2 minutes. The first phase supplies visual short term memory metrics of spatial and order precision, with the second phase capturing these metrics as indications of long-term episodic memory. Participants were recruited online and tested remotely on their own devices. Experiment 1 (n=133, 18–68 y/o) is a cross-sectional study investigating age and comparing a single-use version of the task with established assessments (CANTAB Paired Associate Learning/PAL, Spatial Span/SSP). Adjusted Pearson’s r is used to assess the association between task metrics and age. Dominance analysis is used to compare variance unique and shared with existing measures. In Experiment 2 (n=117, 23–79 y/o) the novel task was repeated morning and afternoon for 7 days, alongside momentary mood, fatigue, and sleep ratings, and a more comprehensive battery of CANTAB tasks at the last timepoint. Diurnality was tested using one-sample t-tests. Group-level temporal patterns between metrics and momentary ratings are analysed using repeated-measures correlations (RMCOR), individual differences in these patterns and Age are modelled using individual partial-correlations to conduct a Monte-Carlo permuted multi-level General Linear Model (GLM). Results: Experiment 1 revealed that CANTAB measures and novel spatial and order metrics were correlated with age (r=.20 to r=.37, adjusted P= <.05). Multiple regression showed models with PAL total error score and delayed novel spatial metrics were significantly predictive of age (t= −4.08, 3.17, p <.005). The dominance analysis revealed novel immediate precision overlapped with existing measures in predicting age, while delayed precision had more unique variance (4.6% vs 0.62% unique sample variance explained in age, accounting for PAL). Experiment 2 showed compliance of 75% over 14 time points, with no evidence of learning curves. Morning scores were significantly higher for delayed spatial precision and order (order: t(88)=8.388, p<.001, d=0.89; spatial: t(88)=3.93, p<.001, d=0.42) suggesting sensitivity to memory consolidation. Delayed order was significantly coupled with fatigue ratings across time (rmcorr=−.098, adjusted p <.05). Individual differences GLM revealed that both coupling between mood and delayed order recall significantly (beta=.06, MontecarloP <.05), and fatigue and immediate order recall (beta=.059, MontecarloP <.05), increased with age. Conclusion: This short, high-frequency assessment of episodic memory displays promising characteristics, with no learning curve, allowing assessment from the first instance. Firstly, participants’ performance declines with age, in a similar pattern to more established measures. Secondly, it shows acceptable compliance over many sessions. Thirdly the temporal patterns are potentially sensitive to memory consolidation, fatigue and mood. Finally, we show that these temporal patterns also vary with Age. Future research will now involve gathering high-frequency data from different patient populations.
LP90- ACHIEVING 98% SCORING ACCURACY IN A NOVEL VOICE-BASED MULTI-DAY LEARNING PARADIGM. N. Taptiklis 1, A. Kaula 1, H. Tseng 1, F. Cormack 1(1. Cambridge Cognition — Cambridge (United Kingdom))
Background: Remote deployment of cognitive assessment makes high-frequency assessment feasible, enabling the use of novel paradigms to measure aspects of cognitive performance that cannot be addressed in a single timepoint assessment. Recently, remote testing approaches have been used in Alzheimer’s Disease (AD) studies to measure participants’ learning of stimuli over multiple timepoints, with the slope of their ‘learning curve’ being the prime outcome measure of interest. Verbal assessments of memory are frequently used in trials of AD. There is increasing interest in employing speech recognition technology to automate the delivery and scoring of these assessments. Automated speech recognition (ASR) technology reported word error rates in some cases approach 3% on test data sets but are significantly impacted by audio quality and background noise. By combining the output from multiple ASRs, it is possible to increase the accuracy of the automated scoring. An automated verbal stimuli learning paradigm could be a sensitive measure of memory function in clinical trials. However remote deployment of automated verbal assessments of learning depends on the ability to accurately score verbal responses in potentially noisy environments on a wide range of participant devices. Objectives: We were interested in exploring the feasibility of using remote automated verbal testing to measure a participant’s ability to learn verbal stimuli over multiple testing days using the Neurovocalix (NVx) verbal cognitive platform. The NVx platform can be configured to employ multiple ASR engines to improve scoring accuracy. We were interested in both the scoring accuracy of individual ASR engines, the overall accuracy of the aggregate system, and in understanding how the performance of individual ASR engines contributed to the overall system performance. We were also interested in understanding participant compliance. Methods: 20 older adults were recruited aged from 65 to 79 (M=10). Participants performed the assessments on their own devices at home. Participants were invited to perform a verbal learning task once a day for five days. The task consisted of a single attempt at Verbal Paired Associates with eight pairs of words. The task was modified so that from the second day, the recall phase was administered prior to the presentation phase of the same word pairs, in order to measure participants ability to learn the word pairs over the course of the study. The NVx platform was configured to use five ASR engines: Google Speech, IBM Speech US, IBM Speech GB, Amazon Transcribe and Amazon Lex. Amazon Lex and the IBM ASR engines were configured to bias recognition in a keyword list consisting of the 8 word pairs. All participant responses were manually reviewed, with the performance of each ASR being recorded, as well as whether the system correctly scored each utterance. Poor noise quality and other observations were recorded. Results: Participants performed in total 96 testing sessions (96% compliance), yielding 720 individual verbal responses (utterances). We found a 98% scoring accuracy, with 704 out of 720 utterances correctly scored by the system. Of the 16 incorrectly scored utterances, 11 were false positives (where the system scored an incorrect response as correct) and five were false negatives (where the system scored a correct response as incorrect). Seven of the 11 false positives were driven by Amazon Lex, which is the ASR configured with the highest degree of bias towards target words. We examined the contribution of individual ASRs to the overall accuracy of the system. In 12 cases only a single ASR correctly scored the utterance, including eight utterances which were only scored correctly due to the biased Amazon Lex engine. We explored system accuracy considering all possible combinations of the five ASR engines we deployed. The highest accuracy for a single ASR was .951 for Google Speech. In this study, the best performing combination of ASRs was Google Speech, IBM US, Amazon Transcribe and Amazon Lex which would have achieved an accuracy of .981, slightly higher than the deployed combination of five ASRs used in the trial, due to a single false positive from IBM GB. We found both word and participant effects on system accuracy, with the word ‘matter’ most likely to be mis-heard by participants. Six of the false positives appeared to be due to participants mis-hearing the target word, and responding with a phonetically similar word, which was interpreted as the target word by the biased ASR engines. Arguably, in the context of a memory test a human rate would score these as correct as well. Conclusion: This small study suggests that automated remote verbal assessment of learning over multiple timepoints is feasible. By aggregating the results of multiple ASR engines, the system achieves very high accuracy (98%) even when testing is conducted in noisy home environments on devices with poor quality audio. The novel verbal learning paradigm would appear acceptable to participants, achieving 96% compliance, and all participants completing at least four testing sessions.
LP91- SEX DIFFERENCES IN THE ASSOCIATION BETWEEN TAU PET AND COGNITION IN PRECLINICAL AD (A4 STUDY). X. Wang 1, E. Sundermann 1, S. Banks 1(1. University of California, San Diego — San Diego (United States))
Background: Sex differences in tau pathology and cognitive resilience have been reported in preclinical AD, with cognitively normal, amyloid-positive women showing higher regional tau PET levels and better verbal memory than men. Regional tau PET signal has been associated with subtle decrements in cognitive performance in preclinical AD. We are interested in how the associations between tau and cognitive measures differ by sex in preclinical AD. Objectives: The aim of this study was to detect the sex differences in the associations between tau PET and cognitive outcomes in preclinical AD. Methods: We included 343 cognitively unimpaired amyloid-positive individuals (205 women, 138 men) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study who self-identified as non-Hispanic white and had available 18F-flortaucipir PET data. Participants completed the neuropsychological tests of Computerized Cognitive Composite (C3) at the first screening visit (Visit 1) and an alternative C3 within 90 days (mean = 55 days) at the study eligibility visit (Visit 3) before study eligibility disclosure. Preclinical Alzheimer’s Cognitive Composite (PACC) were also completed at their first screening visit. Standardized uptake value ratio (SUVR) images were created using the inferior cerebellum grey matter as the reference region. A composite meta temporal region (entorhinal, amygdala, fusiform, inferior temporal and middle temporal region defined by Freesurfer) was the region of interest (ROI) in this study. We applied linear regression models to detect the sex differences in PACC and C3 components (Visit 1 and Visit 3), adjusting for age and education. Using linear regression models with an interaction term (tau SUVR in the meta temporal ROI by sex), we assessed the interaction effects between sex and tau SUVR in the meta temporal ROI on PACC and C3 components (at Visit 1 and Visit3), adjusting for age and education. Sex-stratified analyses were conducted to probe significant tau by sex interaction effects. Results: Women outperformed men on PACC (P < 0.001) and its components: Mini-Mental State Examination (MMSE) (P = 0.001), Digit-Symbol Coding Test (DSC) (P < 0.001), and Free and Cued Selective Reminding Test-Free + Total Recall (FCSRT96) (P < 0.001). For C3 components, women performed better than men on first letter name recall (FNLT) (Visit 1: P < 0.001, Visit 3: P = 0.008), face-name matching (FNMT) (Visit 1: P = 0.006) and face recognition (FSBT) (Visit 1: P < 0.001, Visit 3: P < 0.001). However, men outperformed women on Detection (DET)-reaction time (RT) (Visit 1: P = 0.007, Visit 3: P = 0.048). There were significant interactions effects between sex and tau in the meta temporal ROI on PACC component: DSC (interaction β = −1.974, SE = 0.895, P = 0.028) and C3 components: DET RT (Visit 1: interaction β = 0.202, SE = 0.101, P = 0.046), One-Card Learning (OCL) RT (Visit 1: interaction β = 0.207, SE = 0.097, P = 0.033; Visit 3 interaction β = 0.182, SE = 0.091, P = 0.045). After sex stratification, higher levels of tau in the meta temporal ROI were associated with poor cognitive performance specifically in women: DSC score (β = −1.669, SE = 0.542, P = 0.002), DET RT (Visit 1: β = 0.089, SE = 0.057, P = 0.117), OCL RT (Visit 1: β = 0.172, SE = 0.056, P = 0.002; Visit 3: β = 0.115, SE = 0.051, P = 0.026), not in men (Ps>.05). Conclusion: Our results suggest that sex differences in early AD might be due to higher amounts of tau in women’s brains with stronger relationships with certain tests in women. These findings have important implications for how cognition is assessed in sex-specific tau-targeted preventive AD clinical trials. Conflict of Interest and Disclosure Statement: Xin Wang, Dr. Sundermann and Dr. Banks have no relevant disclosures.
LP92- STEPPED-ASSESSMENT FOR COGNITIVE SCRENING AND EVALUATION: MEMTRAX-COGNIFIT. C. Ashford 1, J. Clifford 2, M. Bergeron 3, J. Andoni 4, J. Ashford 5, C. Rodriguez 6(1. MemTrax, LLC — Redwood City (United States), 2. College of San Mateo — San Mateo (United States), 3. University of Hartford — Hartford (United States), 4. Nebriia University — Madrid (Spain), 5. Stanford — Palo Alto (United States), 6. CogniFit, Inc. — Madrid (Spain))
Background: Cognitive and functional impairment are stigmata of dementia, traumatic brain injury, and many other conditions affecting mental processing. Neuropsychologists use paper and pencil tools and questionnaires for estimating cognitive function. However, this methodology is time-consuming, expensive, subject to rater variations and biases, and is not amenable to monitoring change over time. New directions are needed for neurocognitive assessment. With the advent of computerized cognitive testing, cognitive tests can be quickly implemented, providing robust information and rapid reporting of brain function, allowing frequent repetition within minutes. Brief computerized tests can provide rapid (< 2 minutes), accurate, reliable measures of memory and executive function, with processing speed in these domains precisely quantified. For example, MemTrax can be repeated frequently and indefinitely to screen for cognitive impairment and assess treatment and clinical trial outcomes. Other tests are computerized cognitive batteries that can assess performance of numerous cognitive domains, supplemented by questionnaires to assess daily function. CogniFit, can provide such information in a wide variety of domains, so that the underlying pathology can be precisely characterized. Objective: Describe one on-line computerized tool for screening and another for assessment of cognitive impairment. Methods: MemTrax is a rapid on-line test using a continuous recognition paradigm, assessing visual information processing, episodic memory, and recognition accuracy and speed: https://pubmed.ncbi.nlm.nih.gov/?term=memtrax&sort=date. CogniFit Cognitive Assessment Battery (CAB)® PRO (FDA Registration Number: 3017544020) is an extended computerized battery providing physical, psychological, and social function estimates. CogniFit PRO is a comprehensive online neuropsychological battery of 17 non-invasive tests that provide a broad, objective, and precise assessment of 22 well-documented cognitive skills. CogniFit is broadly used and implements state-of-the-art cognitive science, psychometrics and technology: https://pubmed.ncbi.nlm.nih.gov/?term=cognifit&sort=date. Results: MemTrax can be repeated frequently to provide indices of change over time. This 50 picture-based MemTrax has a variable N-back design developed to measure episodic memory and processing speed impairments associated with early AD; but it is useful for related conditions. MemTrax has been implemented and utilized online in different countries and on various platforms, available in 120 languages: http://www.memtrax.com and www.memtrax.com.cn. Administered to a senior cohort in an independent-living elderly population in the Netherlands and another group in China, MemTrax was more efficient than the Montreal Cognitive Assessment (MoCA) with similar clinical efficacy. MemTrax is used by the Brain Health Registry: https://www.brainhealthregistry. org and the Alzheimer’s Foundation of America: https://AFAmemorytest.com. MemTrax has been performed by over one million individuals on-line, and performance data in different settings has generated several reference norms. The performance measures, percent correct, percent hits, percent correct rejections, and response time, can be translated into the summary score and 4 of the component scores of the Montreal Cognitive Assessment (MoCA), with equal or better ROC measures for distinguishing normal cognitive function and mild cognitive impairment in less time, in any locale. CogniFit has 24/7 online availability, unlimited locations, and cost-efficiency, making it an ideal tool for clinical practice and research. Backed by highly accurate psychometrics, intelligent data science and advanced automation systems, CogniFit makes cognitive measurement and delivery of individual and group data effortless, instantaneous, and accessible. The reference normative dataset behind (CAB)® PRO matrix used 1,282,242 unique subjects (711,262 females, 570,980 males) ages 7–85 years. The Cognitive Assessment Battery (CAB)™ has been validated using construct and convergent validity. For details: https://www.cognifit.com/cab. The CogniFit assessment is designed for people ≥ 7 y/o and takes 30 to 40 minutes, on a computer, tablet, or smartphone. CogniFit’s automated platform facilitates individual and large-scale data collection and allows for simultaneous large-scale testing. Quantitative results report a global score for gauging overall cognitive function, individual scores on 22 cognitive skills, and a well-being score. The CogniFit Cognitive Assessment Battery (CAB)® assessment has a Validity Index of its measurements. The system detects absent-minded performance and asks the users to pay more attention. With corrected behavior, the variables measured during the task are considered valid. Otherwise, the variables measured are considered invalid, and reported. CAB accurately captures human cognitive development across lifespan, using normative data to depict cognitive growth during childhood, peak of cognitive abilities in young adulthood, and the progressive cognitive decline associated with ageing. For both tests, deeper analysis can be provided by artificial intelligence/machine learning, and with the capacity to assemble very large data sets of information, progressively more salient interpretations will become available. However, clinician oversight of the assessment continuum remains essential to confirm results and provide safety assurances. Moreover, stepped assessment combines an initial brief test (e.g., MemTrax) for initial broad cognitive screening, potentially providing an indication of the need for more comprehensive evaluation (e.g., CogniFit), including an in-depth series of measurements. Conclusion: This presentation outlines an initial screening test which can lead to a broad evaluation of brain function with biological, psychological, and social components. MemTrax and CogniFit are effective for screening and longitudinal assessment of cognitive function for clinical and research purposes.
BEHAVIORAL DISORDERS AND CLINICAL TRIALS
P169- A PROOF-OF-CONCEPT STUDY TO EVALUATE EFFICACY OF NANOLITHIUM ON THE PROGRESSION OF NEUROPSYCHIATRIC SYMPTOMS IN PATIENTS WITH MILD-TO-SEVERE ALZHEIMER’S DISEASE. M. Soto 1, S. Guilliot 2, P.J. Ousset 1, D. Angioni 1, N. Sastre Hengan 1, J.C. Maurel 2, J. Touchon 3(1. Department Of Geriatrics, Gerontopole, University Hôpital Toulouse, France — Toulouse (France), 2. Medesis Pharma — Baillargues (France), 3. Montpellier School Of Medecine; University Of Montpellier — Montpellier (France))
Background: In mild-to-severe forms of AD, neuropsychiatric symptoms (NPS) are frequent and highly disabling. There is currently no specific treatment for these symptoms. Lithium has been the mainstay of bipolar disorder (BP) treatment for many years. There is currently a renewed interest in lithium’s utility for the treatment of not only BP but also of neurodegenerative diseases, mainly due to in vitro and in vivo studies supporting the potential neuroprotective effect of lithium through multiple intersecting mechanisms. However, the narrow therapeutic window of lithium hampered its development in neurodegenerative diseases. Study drug: Medesis Pharma has applied the Aonys® technology to lithium. The Aonys® delivery system allows a significant decrease of the lithium dose (1.8 mg Li / 0.18 mEq per day; minimal dose used in clinical practice: 10 mEq / day) while allowing enhanced CNS uptake, optimizing lithium therapeutic window. Nanolithium is administered as a buccal mucosa deposit, structured in HDL lipoprotein in contact with apoproteins A1 in mucosa, protected plasma transport in HDL lipoprotein, intra-cellular delivery by HDL receptors and distributed in all cells of the whole body. An efficacy study for depression was conducted in behavioral test mimicking depression in wild type mice. Nanolithium induced a significant antidepressant-like effect after treatment at a dose 400 times lower than a lithium solution inducing the same effect. No drug-related mortality or clinical signs were observed in these experimental conditions. In rodent studies Nanolithium showed equivalent efficacy and lower toxicity than an oral solution of lithium. Pharmacology studies in AD transgenic rat model (McGill-R-Thy1 APP), after 8-week treatment at a low dose of lithium (0.04 mg Li/kg/ day), Nanolithium was shown to reverse many of the key AD pathologic hallmarks (cognitive deficit, BACE1 activity, neurogenesis, level of toxic Aβ42 peptides, etc) as well as cognitive symptoms at the early stages of the disease. In preclinical toxicology studies and phase 1 study in healthy volunteers, Nanolithium was well tolerated with no SAEs. Objectives: To evaluate the clinical safety and efficacy on NPS and on neuroprotection of NanoLithium in patients with mild-to-severe AD. Study Design: A prospective, multicenter Phase II study with a first randomized, placebo-controlled, parallel-group, double-blind 3 months period followed by an open-label trial period of 9 months. Primary outcome will be to evaluate the clinical efficacy of Nanolithium versus placebo, on the NPS progression between baseline and 12 weeks based on total NPI-12 score. Secondary outcomes includes assessment of the clinical safety of Nanolithium administered during 48 weeks; evaluation of the efficacy of Nanolithium over 48 weeks on progression of cognitive performances (CDR, MMSE, ADL), progression of NPS (score on each NPI-12 item and agitation based on NPI-C-IPA scale), progression of cortical hypometabolism in parieto-temporal regions (PET-FDG); evidence of potential disease-modifying effect of Nanolithium on the progression of AD pathophysiological biological peripheral biomarkers (Protein β-amyloid, Neurofilaments, BDNF, pTau protein) and nonspecific biomarkers (inflammatory cytokines); and to assess treatment compliance. Main inclusion criteria include patients between 50 and 90 years inclusive, patient with sufficient clinical and paraclinical information for the diagnosis of AD, patient presenting clinically significant BPSD requiring medication in the opinion of the study physician (NPI ≥ 4 in at least one item of NPI-12), patients with a MMSE score from 10 to 26). Statistical Method: Sixty-eight patients will be randomly assigned to two treatment arms, with a 1:1 randomization ratio: 34 patients will be assigned to the NanoLithium arm and 34 patients to the placebo arm. Analysis of the primary endpoint: NPI-12 total score change from inclusion to 12 weeks of treatment will be presented by randomization arm and overall. Comparison between randomization arms will be done using an ANCOVA analysis (LS-means, the CI and the adjusted differences between arms and p-value) adjusted on center, sex, age, severity of the disease based on MMSE, education level and other comorbidities. Analysis of secondary endpoints will be performed overall and by arm. Conclusion: Study has been initiated in 6 centers in France, primary outcomes at 12 weeks intermediate analysis are expected beginning of 2023, final outcomes are expected end of 2023 — Beguining of 2024.
P171- SAFETY AND TOLERABILITY OF BREXPIPRAZOLE FOR THE TREATMENT OF AGITATION IN ALZHEIMER’S DEMENTIA: POOLED RESULTS FROM THREE PHASE III TRIALS. D. Lee 1, M. Slomkowski 1, N. Hefting 2, D. Chen 1, K. Larsen 2, E. Kohegyi 1, M. Hobart 1, A. Shah 1, A. Estilo 1, M. Panni 1, A. Farovik 2, M. Miguelez 1, P. Such 2, G. Grossberg 3(1. Otsuka Pharmaceutical Development & Commercialization Inc. — Princeton, New Jersey (United States), 2. H. Lundbeck A/S — Valby, Copenhagen (Denmark), 3. Department of Psychiatry and Behavioral Neuroscience at Saint Louis University School of Medicine — St Louis, Missouri (United States))
Background: Despite the high burden of agitation in Alzheimer’s dementia (AAD) (1), there are no FDA-approved pharmacological treatments for the management of AAD. Certain medications, including antipsychotics, are commonly prescribed off-label to help control agitation symptoms. However, the use of off-label therapies is hindered by relatively poor adherence, and safety and tolerability concerns (2). Atypical antipsychotics carry an FDA boxed warning for mortality in elderly patients with dementia, due to analyses that show an increased risk of death versus placebo (3). Brexpiprazole, which has shown good tolerability in schizophrenia and major depressive disorder (4, 5), has been investigated as a potential therapy for AAD. Objectives: To assess the safety and tolerability of brexpiprazole in patients with AAD based on the combined results of three Phase III trials. Methods: Data were pooled from three 12-week, randomized, double-blind, placebo-controlled, parallel-arm trials of brexpiprazole versus placebo in patients with AAD (ClinicalTrials.gov identifiers: NCT01862640 [6], NCT01922258 [6], NCT03548584). Two of the trials evaluated fixed doses of brexpiprazole (0.5, 1 or 2 mg/day [0.5 mg/day arm discontinued], and 2 or 3 mg/day), whereas the other trial investigated a flexible dose (0.5–2 mg/day). The primary objective of these trials was to assess efficacy on agitation symptoms (reported elsewhere). Safety was assessed as a secondary objective using standard variables, including treatment-emergent adverse events (TEAEs). For this post hoc analysis, data for all brexpiprazole groups were pooled, as were data for placebo groups. Results: Overall, 658 patients were randomized to brexpiprazole, and 389 patients randomized to placebo. At baseline, mean age was 73.5–74.2 years, and mean time since diagnosis of Alzheimer’s disease was 28.2–35.6 months, depending on the trial and randomized treatment group. A total of 655 patients were exposed to ≥1 dose of brexpiprazole, and 388 patients to ≥1 dose of placebo. The majority of patients had ≥42 days’ exposure to study drug (95.1% for brexpiprazole, and 96.9% for placebo). Across all three trials, the incidence of TEAEs was 51.1% with brexpiprazole, with no notable differences between doses, and 45.9% with placebo. Serious TEAEs were experienced by 6.4% of patients receiving brexpiprazole and 4.1% of patients receiving placebo; TEAEs leading to discontinuation were experienced by 6.3% of patients receiving brexpiprazole compared with 3.4% receiving placebo. TEAEs that occurred in ≥2% of patients receiving brexpiprazole and more than in placebo-treated patients were insomnia (3.7% versus 2.8%), somnolence (3.4% versus 1.8%), nasopharyngitis (2.7% versus 2.6%), and urinary tract infection (2.6% versus 1.5%). Other TEAEs of interest in this patient population include falls (1.7% [brexpiprazole] versus 2.6% [placebo]), metabolism and nutrition disorders (3.5% versus 4.4%), sedation (0.3% versus 0%), and extrapyramidal disorder (0.8% versus 0%). No extrapyramidal symptom-related TEAEs occurred in ≥2% of patients receiving brexpiprazole and more than in placebo-treated patients. The mean change from baseline to last visit in body weight was 0.1 kg with brexpiprazole and −0.2 kg with placebo. The incidence of ≥7% increase in body weight from baseline was 1.7% with brexpiprazole and 0.8% with placebo. The mean change from baseline to last visit in Mini-Mental State Examination Total score was 0.21 with brexpiprazole (mean baseline 14.6) and 0.14 with placebo (mean baseline 14.9). Six patients receiving brexpiprazole (0.9%) and one patient receiving placebo (0.3%) died during the double-blind treatment period; none of these deaths were considered by the investigator to be related to brexpiprazole. Conclusion: Based on pooled results from three Phase III trials, brexpiprazole was well tolerated in patients with AAD, and had a clinical safety profile consistent with that of brexpiprazole in other indications. Brexpiprazole-treated patients had a similar incidence of sedation, extrapyramidal disorder, death, falls, and metabolic TEAEs compared with placebo, and no worsening of cognition. References: 1. Khoo et al. The impact of neuropsychiatric symptoms on caregiver distress and quality of life in persons with dementia in an Asian tertiary hospital memory clinic. Int Psychogeriatr 2013;25(12):1991–1999. 2. Antonsdottir et al. Advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother 2015;16(11):1649–1656. 3. Jeste et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5):957–970. 4. Kane et al. Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res 2016;174(1–3):93–98. 5. Thase et al. Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of four short-term studies. Expert Opin Pharmacother 2019;20(15):1907–1916. 6. Grossberg et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry 2020;28(4):383–400.
LP93- EFFECTS OF BREXPIPRAZOLE ON SEVERITY OF AGITATION IN ALZHEIMER’S DEMENTIA: AN ANALYSIS OF CLINICAL GLOBAL IMPRESSION DATA FROM TWO PHASE III FIXED-DOSE TRIALS. D. Lee1, M. Slomkowski 1, N. Hefting 2, D. Chen 1, K. Larsen 2, E. Kohegyi 1, M. Hobart 1, A. Shah 1, A. Estilo 1, M. Panni 1, A. Farovik 2, M. Miguelez 1, P. Such 2(1. Otsuka Pharmaceutical Development & Commercialization Inc. — Princeton, New Jersey (United States), 2. H. Lundbeck A/S — Valby, Copenhagen (Denmark))
Background: Neuropsychiatric symptoms of Alzheimer’s dementia, including agitation, are among the most difficult and stressful aspects of the disease for patients and caregivers (1). Agitation is a prevalent clinical manifestation of the illness (2, 3). Currently, there are no FDA-approved pharmacological treatments for the management of agitation in Alzheimer’s dementia (AAD). Brexpiprazole, which acts on noradrenergic, serotonergic, and dopaminergic neurotransmitter systems (4), has been investigated as a potential AAD therapy. The brexpiprazole AAD trials employed the 7-point Clinical Global Impression — Severity of illness (CGI-S) and Clinical Global Impression — Improvement (CGI-I) scales as secondary efficacy endpoints — simple, easy-to-use, and well-established clinician-rated measures of symptom severity and improvement, respectively (5). Objectives: To evaluate Clinical Global Impression data from two Phase III fixed-dose trials of brexpiprazole in patients with AAD. Methods: Three Phase III, 12-week, randomized, double-blind, placebo-controlled, parallel-arm trials of brexpiprazole versus placebo in patients with AAD have been conducted (ClinicalTrials.gov identifiers: NCT01862640 [6], NCT01922258 [6], NCT03548584). In those trials, the primary endpoint was the change in Cohen–Mansfield Agitation Inventory (CMAI) Total score from baseline to Week 12, and the key secondary endpoint was change in CGI-S score, as related to agitation, from baseline to Week 12. CGI-I response rate (defined as a CGI-I score of 1 [very much improved] or 2 [much improved]), was also assessed. One trial investigated flexible doses of brexpiprazole (0.5–2 mg/day), and the other two investigated fixed doses of brexpiprazole (0.5, 1 or 2 mg/day [0.5 mg/day arm discontinued], and 2 or 3 mg/day). The present post hoc analysis evaluates data from the two fixed-dose trials. Results: In the first fixed-dose trial, in the brexpiprazole 2 mg/day group, no patients had a CGI-S score of 1 (normal, not at all ill) or 2 (borderline mentally ill) at baseline compared with 17.5% at Week 12; in the placebo group, no patients had a CGI-S score of 1 or 2 at baseline compared with 10.2% at Week 12. In the same trial, in the brexpiprazole 2 mg/day group, 8.7% of patients had a CGI-S score of 6 (severely ill) or 7 (among the most extremely ill) at baseline compared with no patients at Week 12; in the placebo group, 7.6% had a CGI-S score of 6 or 7 at baseline compared with 0.8% at Week 12. On the change from baseline to Week 12 in CGI-S score, as related to agitation, numerical improvement was observed with brexpiprazole 2 mg/day versus placebo (nominal p=0.16). In the same trial, CGI-I response rate at Week 12 was 49.3% with brexpiprazole 2 mg/day and 45.8% with placebo. In the second fixed-dose trial, in the brexpiprazole 2 or 3 mg/day group, 0.4% of patients had a CGI-S score of 1 or 2 at baseline compared with 11.9% at Week 12; in the placebo group, no patients had a CGI-S score of 1 or 2 at baseline compared with 5.9% at Week 12. In the same trial, in the brexpiprazole 2 or 3 mg/day group, 9.8% of patients had a CGI-S score of 6 or 7 at baseline compared with 1.0% at Week 12; in the placebo group, 9.5% had a CGI-S score of 6 or 7 at baseline compared with 2.9% at Week 12. Brexpiprazole 2 or 3 mg/day was superior to placebo in change from baseline to Week 12 in CGI-S score, as related to agitation (p=0.0078). In the same trial, CGI-I response rate at Week 12 was 52.4% with brexpiprazole 2 or 3 mg/day and 40.5% with placebo. Conclusion: In patients with AAD, brexpiprazole 2 or 3 mg/day was associated with overall improvement in Clinical Global Impression, as related to agitation, compared with placebo. References: 1. Antonsdottir et al. Advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother 2015;16(11):1649–1656. 2. Halpern et al. Using electronic health records to estimate the prevalence of agitation in Alzheimer disease/dementia. Int J Geriatr Psychiatry 2019;34(3):420–431. 3. Fillit et al. Impact of agitation in long-term care residents with dementia in the United States. Int J Geriatr Psychiatry 2021;36(12):1959–1969. 4. Maeda et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther 2014;350(3):589–604. 5. Guy. ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, MD: National Institute of Mental Health, 1976. 6. Grossberg et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry 2020;28(4):383–400.
HEALTH ECONOMICS AND CLINICAL TRIALS
P172- HEALTH ECONOMIC CONSIDERATIONS IN THE DEVELOPMENT OF A PREVENTIVE ALZHEIMER’S TREATMENT. M.A.T.T.K. Mattke 1, K.K. Jun 1, S. Chu 2, M. Hanson 1, E. Reiman 3, J. Kordower 4(1. University Of Southern California — Los Angeles (United States), 2. Cornell University — Ithaca (United States), 3. Banner Alzheimer’s Institute — Phoenix (United States), 4. Arizona State University — Tempe (United States))
Background: Multiple amyloid-targeting drugs are currently in late-stage clinical trials of a preventive indication, i.e., identification and treatment of preclinical Alzheimer’s disease (AD). With the large patient pool, the potential cost to ascertain the AD pathology and the cost of treatment, careful consideration needs to be given which diagnostic pathway and which treatment cost would represent adequate value for money. Objectives: To project the cost per avoided case of progression to symptomatic AD under different assumptions for cost and performance of diagnostic tests and cost and effectiveness of treatment as well as the yield of the diagnostic process, i.e., the share of truly diseased persons, who were correctly identified. Methods: Using a Markov model and published estimates for prevalence of preclinical AD and annual progression to MCI, we project the disease trajectory of 2022 U.S. cohort age 50 to 79 without cognitive impairment (n=95 million) in the absence of treatment. For the counterfactual scenario of a disease-modifying treatment, we assume that all persons would receive a one-time blood test for the AD pathology at a cost of $75 and that a subset of persons with a positive test result would go to confirmatory testing before treatment while the others would go directly to treatment. Lifetime treatment cost would be $2,500 per person. Confirmatory testing would be done with PET scans (40%, cost of $4,000) and CSF analysis (60%, cost of $500). We calculate the cumulative number of avoided symptomatic AD cases over 20 years. Results: Without treatment, 13% of people (n=12.1 million) would become cognitively impaired over 20 years. Assuming a blood test with specificity and sensitivity of 80% and use of confirmatory testing in 25% of test-positive subjects, 18.0% of cognitively unimpaired persons (n=17.5 million) would be identified and treated with a false-positive rate of 16.5%. A treatment that reduced progression risk from cognitively unimpaired to impaired stages of AD by 30% would prevent 14.9% of cases (n=1.8 million) of incident developing symptomatic AD at a cost of $52,026 per case avoided and overall cost of $4,128 per person over 20 years. Conclusion: At the stated assumptions, prevention of symptomatic AD entails costs in line with established preventive interventions, such as prophylactic ICD implantation for patients at elevated risk of sudden cardiac death (∼$27,000 per life-year saved) and anticoagulation for stroke (16,675 per case avoided with abixaban and $36,777 with dabigatran). Ongoing work will look into overall net cost, i.e., considering cost offsets from reduced progression. and cost-effectiveness under a range of assumptions, such as treatment cost and effectiveness, and explore alternative detection approaches, such as periodic use of blood tests in those with initially negative results.
P173- LONG-TERM CARE INSURANCE SERVICE UTILIZATION PATTERN ACCORDING TO CLINICAL FACTORS OF DEMENTIA. J.H. Lee 1(1. National Health Insurance Service Ilsan Hospital — Goyang-Si (Korea, Republic of))
Background: After the opening of the Dementia Prevention Center at Ilsan Hospital in Korea, we plan to produce basic data for establishing a strategy for providing long-term care benefits for dementia patients by analyzing the use of medical and long-term care services according to various clinical factors including the severity of Dementia. Method: Information on patients who received cognitive function tests such as K-MMSE and neuropsychological test battery was collected at Ilsan Hospital. Based on this patient group, the National Health Insurance service’s customized DB and the elderly’s long-term care DB information were joined to verify the patient’s medical records and investigate the use of the elderly’s long-term care benefits. Result: A total of 1921 patients people were diagnosed with dementia at Ilsan Hospital in Korea, from 2011 to 2018, and 391 patients (20.35 %) were classified as long-term care rating judges, 76 patients (3.96%) were undecided, and 1454 patients (75.69 %) were not applied. Statistically significantly, the number of patients diagnosed with dementia in Ilsan Hospital also increased from 2011 to 2018, and the number of dementia rating groups increased continuously, especially after the introduction of the special dementia grade in 2014. 75.69 % of the patients diagnosed with dementia at Ilsan Hospital are not applied for long-term care insurance for the elderly, and they are showing a relatively young age and high level of education. Cognitive function tests in hospitals also reflect the severity and frequency of patients and the suffering of their guardians when assessing neurological behavioral abnormalities. However, currently, the evaluation score for long-term care service for the elderly are judged only by the presence or absence of symptoms, so it is considered necessary to take countermeasures as it shows differences in hospital examination results and the results of long-term care service evaluation. Conclusion: It is necessary to identify the long-term care benefits required for each characteristic of dementia patients, to indirectly verify the validity of the current benefit system by current status, and to develop policies to establish long-term care benefit types and service strategies for individual characteristics of dementia patients
P174- THE IMPACT ON R&D INVESTMENT OF THE CMS NATIONAL COVERAGE DETERMINATION FOR AMYLOID-DIRECTED MONOCLONAL ANTIBODIES IN ALZHEIMER’S DISEASE. D. Schulthess 1, H. Bowen 2(1. vital transformation — Wezembeek Oppem (Belgium), 2. Queens University — Charlotte (United States))
Background: This study investigates the potential impact of the recent National Coverage Determination (NCD) by The Centers for Medicare & Medicaid Services (CMS) on willingness of investors to continue to fund the development of new treatments in Alzheimer’s Disease. CMS will only cover FDA approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (AD) under Coverage with Evidence Development (CED) in “CMS approved randomized controlled trials.” Objectives: This analysis measures the potential impact of this NCD, using assumptions based on the current draft language and historical data about AD R&D trials and investments, based on current clinical development time, that the NCD will add 3 or more years to the time it takes for an AD asset to see any return on investment. Methods: Starting from 1993, a cohort of clinical trials for the treatment of Alzheimer’s Disease (AD) was extracted — 551 trials in total. All early stage investments, venture funding, grants, IPOs, and deals involving clinical research in AD were obtained by the date secured and then linked to the specific asset/company that entered into AD RCTs for FDA approval — 729 individual financing rounds and 287 deals in total. The length of time from launch to conclusion of an AD trial was calculated for the entire historical cohort, and the increase of time, increase of costs, and reductions of revenue caused by the CMS draft decision was incorporated into our assessment. The impacts of the CMS draft decision were applied to a revised estimate for ROI, taking into consideration several scenarios for reduced revenue relative to patent life. Results: Of the programs currently in development — if the proposed NCD was in place at the time of program initiation, 93% of investments would have had negative ROI and therefore would not have likely been made. A three year delay in market access also finds that existing clinical development programs would likely be halted based on a logistical regression model (p <0.0001) — 78% of the change in the probability of having a positive or negative ROI is determined solely by the decision made by CMS (i.e. the G2 Statistic). Given the current trends in declining AD developments before the CMS coverage decision, an >80% decline in the number of trials with a positive ROI if the CMS guidance is implemented, i.e. with a delay of 3 years, assuming those trials are stopped, brings active clinical developments from 30 to 3. Conclusions: Given their high failure rate, a delay of three or more years in the marketing authorization of new Alzheimer’s therapies renders the majority those under clinical investigation financially untenable, according to our model. The decision to potentially overturn an FDA decision further adds uncertainty to investors, as the evidence challenges to other neurological disorders is similar to that of Amyloid Beta based treatments. Even though the proposed CMS guidance applies specifically to amyloid-targeting antibodies, it introduces material risks to the ROI calculations for other assets in development, including other Alzheimer’s treatments as well as neurology more broadly, and all products approved under the accelerated approval pathway. The proposed guidance puts at risk the entire US Government’s strategy to create incentives via the prescription drug benefit to promote the adaption of targeted therapies, orphan drugs, and difficult areas of research such as neurological disorders. CMS’ guidance, if implemented, will have cooling effect on R&D, and funds will likely move to larger indications with lower risk profiles; it will push risk capital and biopharma away from areas of high unmet medical needs, into other ‘me too’ categories not seen since the 1990s. The use of accelerated approvals is vital to the financial viability of treatments with challenging economics such as orphan diseases and hard to treat neurological disorders; ultimately, these policies were put in place to promote the development of cures in clinical areas with the most challenging science with high probabilities of failure — the effect of this guidance, if implemented, will be less innovation where it is needed most. Disclosure: Vital Transformation, an international health economics and strategy consultancy, was asked to conduct an analysis of the impact of CMS’ draft decision on Amyloid Beta reimbursement under evidence on the biopharmaceutical innovation ecosystem, and specifically the impact on investment and new drug pipeline development in Alzheimer’s Disease. The opinions included in this work are those of Vital Transformation, LLC, and not necessarily those of the project’s sponsor, Biogen. The analysis was performed by Vital Transformation Consulting Economist Dr Harry P. Bowen and Vital Transformation Managing Director Duane Schulthess. The raw data behind this research can be found here. https://onedrive.live.com/?cid=fd1ceff1664dae51&id=FD1CEFF1664DAE51%2125067&authkey=!AAF8X-0iJeq 24Aw.
P175- BRIDGING CLINICAL TRIALS AND HEALTH ECONOMIC MODELS IN ALZHEIMER’S DISEASE. L. Jonsson 1, R. Handels 2, C. Green 1(1. Karolinska Institutet — Stockholm (Sweden), 2. Maastricht University — Maastricht (Netherlands))
Background: Evidence on cost-effectiveness of novel disease-modifying therapies (DMT) for Alzheimer’s disease (AD) is of increasing importance for patient access. Clinical trials do not fully capture the health economic (HE) consequences of DMT, such as potential effects on long-term disease progression, institutionalization rates or mortality. Decisions on reimbursement and introduction of these treatments in routine care are therefore to large extent informed by evidence from modelling studies, where trial data is combined with data on long-term disease progression, quality of life and costs of care in different disease stages. However, clinical trials are not primarily designed to provide input to HE models, and HE models are usually based on data sources with different characteristics from clinical trials in terms of patient populations, endpoints and other factors. In this study we identify challenges with incorporating efficacy data from clinical trials in HE models and provide best practice recommendations for reducing these issues. Methods: The International PharmacoEconomic Collaboration on Alzheimer’s Disease (IPECAD) conducted a series of workshops with research groups developing HE models in AD, to systematically characterize methodological approaches to HE modeling and benchmark results from these models in standardized scenarios. We reviewed published HE models in AD and contrasted the characteristics of these models with study design specifications of recent late-stage clinical trials of AD DMT to highlight potential issues with incorporating efficacy data from clinical trials into existing HE models. Results: We identified a number of areas of challenges as outlined below. Endpoints and scales: HE models are developed from observational studies that often include different endpoints and scales compared to clinical trials. Mapping between scales used in the trials and scales used in models can introduce considerable uncertainty. Multiple effect domains: Treatment effects can in HE models be represented either through a single domain (e.g. cognition), or on multiple domains (e.g. cognition / function / behaviour). Decision on which effect domains to include are often made post-hoc when trial outcomes are known. If effects are represented on multiple domains, the method for translating trial efficacy data into effects applied in the HE model becomes increasingly complex and sensitive to methodological choices. The use of composite endpoints carries the additional risk of spurious correlations between treatment effects and HE outcomes. It is plausible that the treatment may (mainly) have an effect on one subdomain of the composite endpoint, while the correlation with costs and quality of life outcomes may (mainly) be driven by other subdomains. Estimating treatment efficacy: There are important differences between standard biostatistical methods for clinical trial data analysis and the methods used in HE modeling. HE models often categorize patients into disease states rather than utilizing clinical scales as continuous variables. This facilitates the analysis of disease progression as well as calculation of costs and utilities. Estimating treatment effects for integration in HE models therefore involves post-hoc analysis of the trial data outside of the statistical analysis plan. This means that methodological decisions may not receive the same level of scrutiny and there may be higher risk of the methodological choices affecting the results. Patient population: Clinical trials are typically designed to optimize the probability of observing a treatment effect, rather than estimating the size of the potential treatment effect in a routine care population (which is typically the focus of HE modeling). Translating the effects of a trial into what might be effects in a broader, real-world unselected population might be accomplished by an adjustment process (e.g. weighting the trial sample based on the covariate profile in relation to a general patient population), though this has rarely been done in practice in past economic evaluations. Conclusions: Challenges involved in implementing efficacy data from clinical trials into HE models is an important source of uncertainty around the value of new AD therapies. The design of future clinical trials of DMT need to take into account the need to generate data to populate HE models. Pre-specifying analyses of trial data for HE modeling purposes can reduce uncertainty and improve confidence in results used for reimbursement decision making.
LP94- A MORE PRECISE DIAGNOSIS BY MEANS OF AMYLOID-PET CONTRIBUTES TO DELAYED INSTITUTIONALIZATION, LOWER MORTALITY AND REDUCED CARE COSTS IN A TERTIARY MEMORY CLINIC SETTING. W. Van Der Flier 1, I. Van Maurik 1, H. Broulikova 1, A. Mank 1, E. Bakker 1, A. De Wilde 2, F. Bouwman 1, A. Stephens 3, B. Van Berckel 1, P. Scheltens 1(1. Amsterdam UMC — Amsterdam (Netherlands), 2. EQT Life Sciences — Amsterdam (Netherlands), 3. Life-MI — Berlin (Netherlands))
Introduction: Previous studies demonstrated the diagnostic value of AD biomarkers in terms of clinicians’ confidence in the clinical diagnosis and impact on patient management. A more precise diagnosis could have long term health benefits as a result of arranging more proper care, but such clinical utility not yet been demonstrated. We aimed to study the effects of a more precise diagnosis — by means of amyloid-PET — on institutionalization, mortality, and health-care costs. Methods: Between October 27, 2014 and December 31, 2016, we offered amyloid-Positron Emission Tomography (PET) to all patients as part of their diagnostic work-up. Patients who accepted to undergo amyloid-PET (n=449) were propensity score matched with patients without amyloid-PET (n=571, i.e. no-PET). Matched groups (both n=444; 64±8yrs, 40%F, MMSE 25±4, 38% SCD, 19%MCI, 43%dementia) were compared on rate of institutionalization, mortality and health-care costs in the years after diagnosis. Results: Amyloid-PET patients had a lower risk of institutionalization 10% (n=45) vs. 21% (n=92); HR=0.48 [0.33–0.70]) and mortality rate (11% (n=49) vs. 18% (n=81)); HR=0.51 [0.36–0.73]) over a four year period, and less healthcare costs in the years after diagnosis compared to matched no-PET patients (β=−4573.49[−6524.76: −2523.74], p-value<0.001). Conclusion: We show that memory clinic patients who had a more precise diagnosis and were better informed based on amyloid PET, had more beneficial long term outcomes in terms of institutionalization, death and health-care costs, which may translate into considerable cost savings on a macro-economic level. Randomized trials are required to validate these findings.
LP95- ECONOMIC BURDEN OF DAILY TRANSITIONS TO LATER STAGES OF AD DEMENTIA IN THE US. M. Razavi 1, W. Herring 2, C. Gillis 3, N. Maserejian 3, P. Pemberton-Ross 4, M. Nejati 3(1. Schneider Institutes for Health Policy and Research, Brandeis University — Waltham (United States), 2.RTI Health Solutions — Research Triangle Park (United States), 3. Biogen — Boston (United States), 4. Biogen — Baar (Switzerland))
Background: The economic burden associated with inefficiencies and waste in the US healthcare system ranges from $760 to $935 billion annually (1). Certain categories of healthcare inefficiencies, such as missed prevention opportunities, leave a significant impact on society from both health and economic perspectives (2). In the context of health economics, prevention of a chronic condition includes opportunities to slow disease progression. In patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or AD dementia, the costs of potential missed prevention opportunities correspond to the economic burden associated with progression to later stages of AD. Objectives: To estimate the economic burden of daily transitions to later stages of AD in the US. Methods: A comprehensive literature review was conducted to estimate the number of patients transitioning to the next stage of AD severity and the associated costs. Using a funnel-based approach, we first estimated the number of biomarker-positive MCI due to AD and AD dementia cases in the US among those ≥50 years old. Starting with the Centers for Disease Control and Prevention WONDER data in the population ≥50 years old, we applied age- and race/ethnicity-stratified estimates of the prevalence of all-cause MCI or AD dementia clinical syndrome from a recent study in individuals ≥65 years old (3). In those <65 years old, literature on MCI prevalence was limited and estimates were derived from 2 additional sources (4, 5). Likewise in AD, estimates in individuals <65 years old were sourced from the Alzheimer’s Association (6). We then estimated the number of all-cause MCI cases that would be clinically attributable to AD (7) and the proportion of AD cases by dementia severity (mild, moderate, severe) (8). Finally, we estimated the number of these cases likely to be amyloid-positive using results from the Amyloid Biomarker Study (9). Annual transition probabilities from the National Alzheimer’s Coordinating Center (10) were applied to the amyloid-positive case estimates, and these counts were used to approximate the number of daily transitions from each stage to the next advanced stage of AD severity. Next, we identified direct medical, nonmedical, and unpaid caregiving costs in the US by disease stage. The GERAS-US study (11) was selected as the most appropriate source of costs in patients with MCI due to AD and mild AD dementia. Costs for moderate and severe AD dementia were estimated using between-stage ratios from an observational study (12). Both studies relied on the Resource Utilization in Dementia questionnaire (13) and US-specific unit costs to estimate care costs. For the proportion of patients in institutional settings (14), direct medical costs were assumed to equal costs in the community, direct nonmedical costs were obtained from the Genworth Cost of Care Survey (15, 16) and unpaid caregiving costs were set to 44% of those in the community based on results from the What Matters Most study (17). Costs were inflated to 2021 US dollars where required (18, 19). Results: The economic burden associated with progression of AD was estimated using the number of patients who transition from one stage to the next each day. Progression of 5792 patients from MCI due to AD to mild AD dementia per day accounted for the highest burden with an incremental daily cost of $323,891 (approximately $118 million per year). Likewise, the burden associated with daily transitions from mild to moderate AD dementia (n=2308) and from moderate to severe AD dementia (n=1438) were $88,747 and $143,923, respectively. Cost of progression to more advanced stages of AD dementia might be even higher when including transitions of >1 stage annually or when accounting for the potential impact of AD caregiving on a caregiver’s direct medical costs (11). Results should be considered in the context of limitations of the available data. Conclusion: The estimated daily impact of disease progression to later stages of AD on a populationlevel in the US is associated with significant economic burden that represents potential missed prevention opportunities. Any timely intervention that slows the progression could substantially mitigate the economic and health burden of AD in the US. References: 1. Shrank WH, et al. JAMA. 2019. 2. Berwick DM, et al. JAMA. 2012. 3. Rajan KB, et al. Alzheimers Dement. 2021. 4. Petersen RC, et al. Neurology. 2018. 5. Lopez-Anton R, et al. Acta Psychiatr Scand. 2015. 6. Alzheimer’s Association. Alzheimers Dement. 2019. 7. Knopman DS, et al. Alzheimers Dement. 2016. 8. Hebert LE, et al. Arch Neurol. 2003. 9. Jansen WJ, et al. JAMA Neurol. 2022. 10. Potashman M, et al. Neurol Ther. 2021. 11. Robinson RL, et al. J Alzheimer’s Dis. 2020. 12. Gustavsson A, et al. Alzheimers Dement. 2011. 13. Wimo A, et al. The Health Economics of Dementia. London: Wiley’s; 1998. 14. Davis M, et al. Curr Alzheimer Res. 2018. 15. Genworth. 2022. 16. Tahami Monfared AA, et al. Neurol Ther. 2022. 17. DiBenedetti DB, et al. Alzheimers Res Ther. 2020. 18. Dunn A, et al. Health Serv Res. 2018. 19. US Bureau of Economic Analysis. 2021.
EPIDEMIOLOGY AND CLINICAL TRIALS
P176- IDENTIFICATION OF MEDICAL CONDITIONS AS RISK FACTORS FOR MILD COGNITIVE IMPAIRMENT — A US CLAIMS DATABASE STUDY. G. Li 1, T. Nicola 2, B. Richard 3, G. James 4, H. David 5, D.S. Susan 6, H. Harald 6(1. Eisai Inc — Hillsborough (United States), 2. Rome University — Rome (Italy), 3. Eisai Inc — Basel (Swaziland), 4. Miami University —Miami (United States), 5. Janssen — Indianapolis (United States), 6. Eisai Inc — Nutley (United States))
Introduction: Early identification of Alzheimer’s disease (AD) is crucial for increasing the likelihood of effective treatment outcomes. As novel therapeutic strategies for AD emerge, targeting accurate and timely detection and diagnosis of early AD becomes increasingly relevant, particularly at the prodromal, symptomatic, mild cognitive impairment (MCI) stage. The MCI detection rate using clinical assessment by primary care physicians has proven woefully insufficient and can be as low as 6%. We aimed to determine: a) whether medical conditions commonly known to be AD risk factors are also risk factors for MCI, b) how well do these risk factors discriminate MCI individuals from non-MCI controls, and c) what specific medical conditions are the risk factors for MCI incidence. Methods: Using data from MarketScan, a US claims database, we performed a retrospective analysis that included a cohort of 5185 MCI individuals without an established dementia diagnosis aged 50 years or older. An additional 15555 subjects were included as controls (no MCI nor dementia diagnosis) and were matched on age, sex, and geographic region. A literature review was conducted to identify a list of medical conditions including cardiovascular, thyroid, and metabolic disease, and central nervous system/psychiatric disorders previously associated with risk for AD. A medical condition was considered a risk factor if it appeared in the MCI cohort with a statistically significantly higher frequency compared to the control cohort. Both logistic regression model and extreme gradient boosting (XGBoost), a machine learning method, were applied to discriminate MCI from control subjects. To apply the XGboost approach the dataset was split into a training (20%) and test (80%) set. This approach addressed the potential collinearity issue among medical conditions. Results: Twenty-five medical conditions were found to have a statistically significantly higher frequency in the MCI cohort compared to controls and therefore, were considered MCI risk factors. Five of them with a frequency >10% in MCI and an odds ratio > 2 were: depression, stroke / transient ischemic attack (TIA), obstructive sleep apnea, insomnia, and hearing loss, with odds ratio of (MCI vs Control) 3.8 (95%CI = 3.5–4.1), 3.3 (95%CI = 3.0–3.6), 2.9(95%CI = 2.7–3.1), 2.7 (95%CI = 2.4–2.9), and 2.1 (95%CI = 1.9–2.3), respectively (p’s <0.0001). Across three age groups (55–64 years, 65–79 years, and ≥80 years), for every medical condition, the odds ratios (MCI vs Control) decreased as age increased, e.g., the 3 age groups had odds ratios of 6.4 (95%CI = 5.4–7.5), 3.0 (95% CI = 2.6–3.5), 2.1 (95%CI = 1.8–2.5) in stroke/TIA; and 4.4 (95%CI = 4.0–4.9), 3.1 (95% CI=2.7–3.6), 2.9 (95% CI =2.4–3.6) in depression. Further, the logistic regression model reached an AUC of 0.71 in discriminating MCI individuals from controls. In comparison, the XGBoost approach reached an AUC = 0.94 on the training set and AUC = 0.75 on the test set. Based on performance as measured by AUC in both approaches, the importance of age in the MCI prediction was found to be higher for the younger age group. The two leading MCI risk factors for all age groups were depression and stroke/ TIA. Conclusion: The results from both traditional logistic regression and XGBoost approaches are consistent. MCI individuals show a different medical condition profile compared to controls. The risk factors for AD were also found to be risk factors for MCI. Evaluation of medical condition profiles has the potential to formulate accurate MCI discrimination and hence to identify individuals at high risk of developing MCI.
P177- SAFETY OF FLUORINE 18-LABELED AMYLOID TRACERS: PHARMACOVIGILANCE VALIDATION USING A LARGE REAL-WORLD DATABASE. K. Sato 1, Y. Niimi 2, R. Ihara 3, K. Suzuki 4, A. Iwata 3, T. Iwatsubo 1(1. University Of Tokyo — Tokyo (Japan), 2. University Of Tokyo Hospital — Tokyo (Japan), 3. Tokyo Metropolitan Geriatric Medical Center Hospital — Tokyo (Japan), 4. National Defense Medical College — Saitama (Japan))
Background: Amyloid PET has been widely used as one of the gold standards to screen positive amyloid accumulation in brain to identify individuals who are eligible for Alzheimer’s disease (AD) prevention trials (1, 2). Its PET tracers are fluorine 18-labeled tracers including florbetapir (AmyvidTM), flutemetamol (VizamylTM), or florbetaben (NeuraCeqTM). Because these amyloid tracers are drugs not for treatment of AD but rather for diagnosis/screening of AD pathology, they should require higher level of safety when compared to disease-modifying therapies for AD itself. Indeed, these amyloid tracers are reported as generally safe: their known potential adverse events (AEs) are limited to a few numbers of mild and acceptable ones such as injection site reaction, hypertension, flushing, or headache (2). Objectives: Along with the expanding increase in the number of individuals screened by amyloid PET for AD clinical trials, we need to validate whether there may be any rare but serious AEs that could not be identified at the pre-marketing clinical trials. For this purpose, in this study we analyzed potential AEs of amyloid tracers using the FDA Adverse Event Reporting System (FAERS) database that contains a very large number of case reports with potential drug AEs. Methods: This study was approved by the University of Tokyo Graduate School of Medicine institutional ethics committee [ID: 11754-(1)]. Informed consent was not required for this type of study. On March 2022, from the FDA’s website (https://www.fda.gov) we downloaded patient data that were reported between 2012 and 2021. In our analysis, we included only reports that were classified as ‘primary suspected’ and ‘secondary suspected’ as to the suspected causality between the AE and the drug. In addition, we included only reports that were reported from medical doctor, pharmacist, or other medical staffs, but not from lawyers or consumers. We classified each case report based on the following binomial factors: ‘with’ or ‘without’ exposure to the use of sold amyloid tracers (i.e., florbetaben, florbetapir, or flutemetamol), and ‘with’ or ‘without’ the development of each of the AEs which are determined by the Medical Dictionary for Regulatory Activities (MedDRA). Since there were no cases reporting AEs following the use of florbetaben, so we only included florbetapir or flutemetamol as amyloid tracers to consider here. To evaluate the degree of self-reporting, for each of the included tracers (florbetapir or flutemetamol) we calculated the reporting odds ratio (ROR) using a logistic regression model targeting the development of AE of interest and including age, sex, and the exposure to the tracer of interest (in binary) as explanatory varaibles. The ROR was calculated only for AEs which were reported twice or more (i.e., n ≥ 2) following the use of each amyloid tracer. When the p-value of the AE term in the derived logistic regression model was less than 0.05, the AE was considered to be significantly highly reported following the use of the amyloid tracer, compared with the report of the same AE following the use of any other drugs. Results: As a result, our analysis included 3,792,541 unique AE case reports following the use of any drugs. Among them, there were 50 AE cases with the exposure to florbetapir (n = 11) or flutemetamol (n = 39), and these cases were generally in their 70’s. The frequency of reported AEs in cases with exposure to amyloid tracers was low (i.e., 4 at best), and ‘Hypertension’ (adjusted ROR = 53.4, p < 0.001) was the only significantly highly reported AE in cases with florbetapir, and those with flutemetamol had the significant reporting of ‘Blood pressure increased’ (adjusted ROR = 18.0, p = 0.008), ‘Flushing’ (adjusted ROR = 44.7, p < 0.001), and ‘Headache’ (adjusted ROR = 14.8, p = 0.001). Conclusion: These results showed a statistically significant association (albeit marginal) between the use of amyloid tracers and a few of AEs, all of which are well-known as mild and acceptable AEs with the use of amyloid tracers (2). In addition, no any other AEs were suggested as potential unrecognized AEs of amyloid tracers. Despite the limitations that our approach has due to some bias that derived from the nature of self-reporting database, the major strength of our study is that it was based on a database that includes global real-world data from a very large number of patients. These results might provide some supportive evidence as to the safety of amyloid tracers, and would be of help for researchers to further facilitate current AD prevention trials. References: 1. Barthel H, Sabri O. Clinical Use and Utility of Amyloid Imaging. J Nucl Med. 2017 Nov;58(11):1711–1717. 2. Filippi L, Chiaravalloti A, Bagni O, Schillaci O. 18F-labeled radiopharmaceuticals for the molecular neuroimaging of amyloid plaques in Alzheimer’s disease. Am J Nucl Med Mol Imaging. 2018 Aug 20;8(4):268–281.
P178- DIAGNOSIS AND CLINICAL TRIAL RECRUITMENT OF PATIENTS WITH EARLY ONSET ALZHEIMER’S DISEASE IN CLINICAL PRACTICE: SINGLE CENTER EXPERIENCE IN JAPAN. M. Kurihara 1, R. Ihara 1, K. Ishibashi 2, K. Ishii 2, K. Kanemaru 1, A. Iwata 1(1. Department Of Neurology, Tokyo Metropolitan Geriatric Hospital And Institute Of Gerontology — Tokyo (Japan), 2. Research Team For Neuroimaging, Tokyo Metropolitan Geriatric Hospital And Institute Of Gerontology — Tokyo (Japan))
Background: Early onset Alzheimer’s disease (EOAD) is a devastating condition that presents with cognitive decline before the age of 65 years. Sporadic EOAD is more common than autosomal dominant AD (ADAD) due to PSEN1, PSEN2, and APP mutations. Most of the current clinical trial recruitment focuses on patients with ADAD or sporadic patients above a certain age, such as 50 or 55 years, and young patients are often excluded due to different clinical characteristics and course of disease. Recruitment of patients with sporadic EOAD for clinical trials can be difficult because there is no framework focusing on the recruitment of this patient group, at least in Japan. Objectives: This study aimed to summarize the characteristics of patients with EOAD diagnosed in clinical practice and to consider problems in clinical trial recruitment. Research setting: The Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology is a community-based hospital located in urban Tokyo that provides clinical care and conducts research focusing on age-related medical conditions, including AD and other cognitive disorders. Although the Japanese national insurance covers only cerebrospinal fluid (CSF) p-tau181 as an AD biomarker to date, we conduct amyloid PET and CSF biomarker analyses, including Aβ42 in patients with suspected EOAD after obtaining informed consent. Since the last author A.I., a neurologist specializing in general neurology and cognitive disorders, moved to this institution in April 2020, the institution started to participate in three international randomized controlled trials for AD and also started to introduce clinical trials conducted at other institutions if deemed appropriate. Methods: We retrospectively reviewed all patients who underwent amyloid PET from April 2020 to April 2022, and included patients with EOAD based on the results of [11C] Pittsburgh compound B, [18F] THK5351, and [18F] FDG PET imaging. CSF biomarker analyses were also conducted in patients who consented. Clinical information, test results, and information on clinical trial enrollment were extracted through a chart review. Variables are summarized as mean ± standard deviation or median (full range). Results: From April 2020 to April 2022, out of approximately 1300 new patients who presented to the last author’s clinic, 175 had cognitive disorders, and 82 had AD. There were 13 patients with EOAD (15.9%), all of whom had biomarkers confirmed by PET imaging. The mean age at symptom onset was 54.9 ± 5.7 years old, and 38.5% of patients were female. While 61.5% had a family history of dementia, none had an obvious family history of EOAD. Three of the 11 patients tested were APOE ε4 homozygotes (27.3%) and one patient was APOE ε4 heterozygote (9.1%). The median duration from symptom onset to the first hospital visit was 6 (3–60) months, and the median duration from the first visit to referral to our hospital was 3 (0–38) months. Twelve patients (92.3%) were referred from another hospital or clinic, including tertiary care hospital and private specialty clinic. At the time of presentation to our hospital, the disease stage was mild cognitive impairment in 4 patients (30.8%), mild dementia in 9 patients (53.8%), and moderate dementia in 2 patients (15.4%). The median MMSE score was 24 (11–29). The median number of comorbidities was 1 (0–2). Available clinical trial information was provided to eight patients (61.5%), and seven patients of interest were introduced to nearby study sites. Two were introduced to a phase 1 trial, four were introduced to a phase 2 trial, and two were introduced to a phase 3 trial. The only patient who declined the proposal was due to relocation to a rural area. The reasons for unavailability of a suitable clinical trial were advanced stage (n = 2), young age (n = 1, 46 years old), multiple cortical superficial siderosis (n = 1), and the absence of an appropriate study partner (n = 1). Conclusion: We summarized the characteristics of patients with biomarker-confirmed EOAD diagnosed during clinical practice at our institution. Although the timing of referral to our hospital varied widely, most patients were in the early symptomatic stage and had few comorbidities. Most patients were willing to participate in a clinical trial after being given information on clinical trials in 2020. Patients with sporadic EOAD also have a great interest in clinical trials and should have the opportunity to obtain information on available clinical trials.
P179- TREATMENT STATUS OF ALZHEIMER’S DEMENTIA USING COMMON DATA MODEL IN SOUTH KOREA. S. Jeong Yun 1, J. Jae-Won 1,2(1. Kangwon National University Hospital — Chuncheon (Korea, Republic of), 2. Kangwon National University College of Medicine — Chuncheon (Korea, Republic of))
Background: Medications for dementia are prescribed to patients with Alzheimer’s dementia (AD) widely in South Korea. Objectives: The aim of this study was to assess the treatment pattern of anti-dementia medication in AD using standardized manner at multiple hospitals. Methods: The status of medical management in patients with AD was analyzed using a standardized data format that the Observational Medical Outcome Partnership Common Data Model from five hospitals were used in this study. The anti-dementia treatment data from datasets during 2009–2020 and the medication usage status was analyzed with regarde to persistence and treatment trends for 12 years. Results: Among the 8653 patients withnewly diagnosed AD, donepezil was the most commonly prescribed anti-dementia medication (4218; 48.75%), followed by memantine (1565; 18.09%), rivastigmine (887; 9.33%), and galantamine (494;5.19%). The rising prescription trend during observation period was found only with donepezil. Thetreatment pathways for the three cholinesterase inhibitors combined with N-methyl-d-aspartatereceptor antagonist were different according to the drugs (18.5%; donepezil; 26.1%; rivastigmine, and 16.1%; galantamine). A 12-month persistence analysis showed values of about 50%for donepezil and memantine and approximately 40% for rivastigmine and galantamine. Conclusion: There were differences in persistence and the prescribing pattern among anti-dementia medications from database using the Observational Medical Outcome Partnership Common Data Model in South Korea.
P180- GLOBALIZATION OF ALZHEIMER DISEASE CLINICAL TRIALS: RECOMMENDATIONS FOR TRIAL IMPLEMENTATION IN LOW- AND MIDDLE-INCOME COUNTRIES. J. Llibre-Guerra 1(1. Washington University School Of Medicine In St.louis — St. Louis (United States))
Background: Alzheimer’s disease and related dementias (ADRD) have emerged as a global priority, and the need for therapies that could delay or stop AD progression is urgent. Despite the increase in the number of clinical trials in AD over the last decade, ethnoracially diverse individuals and populations from low- and middle-income countries (LMIC) remain underrepresented in ADRD trials. Globalization of ADRD trials is key to addressing context-specific questions related to biological and non-biological variations that may exist across populations. Objectives: We aimed to determine the global distribution of dementia clinical trials and provide recommendations for implementing ADRD clinical trials in LMICs. Methods: A two-step strategy was utilized. The first step aimed to determine the global distribution of dementia clinical trials. Our primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform. Data analysis included the number of clinical trials per country, regional distribution, funding source, and regional annual growth rate relative to dementia estimates. The second step aimed to identify existing barriers and provide recommendations for conducting dementia clinical trials in LMICs via expert consensus. Results: Over the last two decades, 1237 ADRD modifying therapies (ADRD-DMT) have been tested in 74 countries for a total of 3467 clinical trials. Among those, 3065 (88.4%) clinical trials were conducted in high-income countries and 405 (11.6%) in developing countries. 78.8% of all clinical trials were conducted in Europe and North America. LMICs had the lowest annual trial density (2000–2021) despite the relatively large population living with dementia. Experts’ consensus (including pharma representatives, clinical researchers, and government representatives) provided guidance on barriers and recommendations for trial implementation. Conclusion: Although LMICs countries bear the most significant burden of ADRD, less than 15% of ADRD clinical trials are conducted in developing countries; failing to include the true diversity of the population facing ADRD. We identified several barriers to successfully implementing the ADRD trial globally, including lack of investment due to limited commercial opportunities, resource limitations, poor efficiency of regulatory systems, and unresolved operational complexities.
P181- THE MINORITY REPORT: AN UPDATE ON MINORITY RECRUITMENT FROM A LARGE SITE IN CENTRAL FLORIDA. S. Torres 1, S. Baez-Torres 1, S. Cassidy 1, B. Lenox 1, S. Stanton 1, J. West 1(1. K2 Medical Research, LLC, Orlando (United States))
Participation in Clinical Trials for Alzheimer’s Disease have led a very small numer of minority and underserved population over the past 30 years. In many registration trials the number of participants that randomize have been lower than 2% of the total number of people in the the study. K2 Medical Research is large clinical trial netowrk in Central Florida with 4 sites between Orlando, FL and The Villages. In 2022, the site has been able to enroll 1326 patients worried about or diagnosed with MCI and/or Alzheimer’s Disease. The site has 50% minority staff and is able to speak spanish, creole, french, and arabic. There have been 726 partcipants enrolled in Clinical Trials for Alzheimer’s Disease, which represents 53%. The epdeiolgy in Central Florida is 60% Caucasian, 22% Balck, 35% Hispanic, and 12% other. This presentation will outline the path to success to enroll particpants of minority representation.
P182- GENERALIZABILITY OF COGNITIVE RESULTS FROM CLINICAL TRIAL PARTICIPANTS TO OLDER ADULT POPULATION: ADDRESSING EXTERNAL VALIDITY. V. Aslanyan 1, H.N. Hodis 1,2,3, J. St. John 1,2, N. Kono 1,2, V. Henderson 4, W.J. Mack 1(1. Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California — Los Angeles, CA (United States), 2. Atherosclerosis Research Unit, Keck School of Medicine, University of Southern California — Los Angeles, CA (United States), 3. Department of Medicine, Keck School of Medicine, University of Southern California — Los Angeles, CA (United States), 4. Department of Epidemiology and Department of Neurology and Neurological Sciences, School of Medicine, Stanford University — Stanford, CA (United States))
Background: Generalizability of findings from a randomized clinical trial (RCT) refers to the ability of extending these findings from the trial sample to a target population, the population from which the sample is drawn. Singlesite RCTs may recruit a nonrepresentative sample from the target population, often due to sociodemographic differences attributed to location-specific recruitment practices. RCTs often exclude participants with comorbidities that may be of interest. Trial criteria and recruitment practices introduce external bias and limit the generalizability of RCT findings. Statistical approaches using the probability of sampling individuals provide a basis for generalizability of outcomes from trial populations. These approaches assign greater weights to the randomized participants with lower probability of trial participation. The assessment of generalizability is crucial for post-hoc analyses from RCTs, thus differences between randomized and non-randomized participants from the target population should be properly adjusted before performing such analyses. Objectives: To generalize cross-sectional findings from clinical trials conducted at the Atherosclerosis Research Unit (ARU), University of Southern California. As an illustration, the relationship between cognition and depression, a modifiable risk factor for Alzheimer’s disease, will be assessed using the cohort with and without adjustment for differences from the target population. Methods: Female clinical trial participants were recruited for four RCTs (B-Vitamin Atherosclerosis Intervention Trial (BVAIT), Women’s Isoflavone Soy Health (WISH) trial, Early versus Late Intervention Trial with Estradiol (ELITE), and the Nattokinase Atherothrombotic Prevention Study (NAPS)). All participants had similar cardiovascular profiles and were screened against diabetes and clinical symptoms of cardiovascular disease. Global, verbal memory, executive function, and visual memory composite cognitive scores were derived from the battery of fourteen neuropsychological tests. Participants’ demographic and health data were collected during screening. Non-randomized participants were selected from the Health and Retirement Study (HRS), a representative sample of older adults. This HRS sample was surveyed in 2016 and consisted of female participants with complete demographic and health profiles. A logistic regression prediction model was used to estimate the probability of being randomized into the trials. Participants’ weight of generalizability was determined from these probabilities using inverse probability weighting. Linear regression was used to estimate the magnitude of the association between depression (measured using Center for Epidemiological Studies-Depression (CESD) scale) and cognitive performance. The depression—cognitive function associations were adjusted for age, race/ethnicity, APOE4 carrier status, and education. Results: 3180 female survey participants from HRS and 1309 trial participants from ARU (196 from BVAIT, 343 from WISH, 607 from ELITE, and 163 from NAPS) were selected for the current study. Randomized participants had statistically significant differences from non-randomized participants in all sociodemographic and basic health variables used in the prediction model (age, sex, education, marital status, race/ethnicity, body mass index, blood pressure and blood cholesterol). The prediction model had a sensitivity of 0.87 and specificity of 0.84 at the empirical optimal cutpoint of 0.30, and the area under the curve was 0.93. Weights were calculated from the inverse probability of belonging to the randomized cohort estimated in the prediction model. Weights for the randomized cohort followed a skewed distribution (median weight=1.35, IQR=1.07, range: 1.00–488.26). There was no significant depression—global cognition relationship in the randomized sample (β=−0.004 per 1-unit CESD scale increase, 95% Confidence Interval (CI) (−0.01, 0.003), p=0.25). After applying weights from the prediction model, a unit increase in CESD scale corresponded a mean decrease of global cognition score of 0.017 (95% CI: (−0.025, −0.01), p<0.001). Similarly, while the relationship between depression and verbal memory score was not significant (β=−0.003 per 1 unit increase, 95% CI: (−0.009, 0.002), p=0.24), the relationship was statistically significant after applying the weights (β=−0.019 per 1 unit increase, 95% CI: (−0.025, −0.012), p<0.001). The relationship between depression and executive function was statistically significant using both approaches (β=−0.006 per 1 unit increase in cohort, 95% CI: (−0.01, −0.001), p=0.017; β=−0.006 per 1 unit increase using weights, 95% CI: (−0.012, −0.001), p=0.023). The relationship was not significant for visual memory using both approaches (β=−0.001 per 1 unit increase in cohort, 95% CI: (−0.003, 0.006), p=0.58; β<−0.001 per 1 unit increase using weights, 95% CI: (−0.005, 0.004), p=0.9). Overall, findings from the cohort without any adjustments tended to misalign with accumulated evidence and confirmed previous findings only after adjustments for representation. Conclusions: Combining modeling the probability of trial participation with modeling the expectation of the outcome results in less biased estimates from specialized trial cohorts. This approach helps generalize findings from the cohort to a target population in a less biased manner, weighting participants according to the probability of being selected into the trial if they were coming from the target population, which is calculated using a representative reference cohort. The current study presents an example where previously confirmed findings were not present in a non-representative trial cohort but were evident after weighting the participants to make the cohort generalizable. Authors report no conflict of interests.
P184- PREVALENCE ESTIMATIONS FOR THE ALZHEIMER’S DISEASE CONTINUUM IN THE US HEALTH AND RETIREMENT STUDY. A.A. Tahami Monfared 1,2, Q. Zhang 1, A. Chandak 3, A. Khachatryan 4, L. De Benedetti 5, N. Hummel 6(1. Eisai Inc. — Nutley (United States), 2. Biostatistics and Occupational Health, McGill University — Montreal (Canada), 3. Certara Inc. — New York (United States), 4. Certara Ltd. — Sheffield (United Kingdom), 5. Certara Canada Corporation — Montreal (United States), 6. Certara GmbH — Lörrach (Germany)))
Background: Alzheimer’s disease (AD) prevalence data by severity across the AD continuum, including mild cognitive impairment (MCI), is limited. These prevalence estimates are important for health services planning and the development of new disease-modifying therapies targeting different stages of the disease. Objective: To estimate prevalence of MCI, mild, moderate and severe AD in a representative sample of the US population. Methods: Data from the Health and Retirement Study (HRS) was used. The HRS provides a representative sample of the US population containing data for Americans over 50 years old, with more than 43,000 individuals interviewed to date. Interviews are conducted bi-annually. The three most recent time points were assessed: surveys collected in 2014, 2016 and 2018. AD patients were identified in two ways: they were included (1) if they reported an AD diagnosis (diagnosis-based approach), or (2) if they were considered as having AD based on their cognitive performance, at or before the considered time points (cognitive performance-based approach). MCI patients were identified by their cognitive performance only. MCI and AD severity staging was assessed using a crosswalk from results of the modified telephone interview of cognitive status (TICS-m) to the mini-mental state examination (MMSE). For the diagnosis-based approach, the prevalence was estimated by dividing the number of patients with self-reported diagnosis by the total number of survey respondents. For the cognitive performance-based approach, the prevalence for MCI or AD was estimated by dividing the number of patients with TICS-m score ≤ 22 (i.e., a TICS-m score satisfying at least MCI) by the total number of survey respondents that had TICS-m scores available. Prevalence estimates were also pooled across 2014–2018. Severity distribution among the patients identified through the two methods were assessed by year and pooled. Results: With the diagnosis-based method, 2%, 1%, 1% patients were identified as having AD in 2014, 2016 and 2018, respectively (3% pooled). Overall, these AD patients were 80.0 years old (SD=9.8) at their first survey between 2014–2018, 63% female, and 17% passed college or above. Severity distributions among patients with available TICS-m scores were as follows: 27%, 27% and 46% for mild AD in 2014, 2016 and 2018, respectively (32% pooled); 43%, 38% and 36% for moderate AD in 2014, 2016 and 2018, respectively (39% pooled); and 31%, 35% and 18% for severe AD in 2014, 2016 and 2018, respectively (29% pooled). With the cognitive performance-based method, 55%, 51%, 44% were identified as having AD or MCI in 2014, 2016 and 2018, respectively (61% pooled). Overall, these MCI or AD patients were 70.9 years old (SD=11.8) at their first survey between 2014–2018, 57% female, and 27% passed college or above. Severity distributions among patients with available TICS-m scores were as follows: 44%, 47% and 53% for MCI in 2014, 2016 and 2018, respectively (41% pooled); 29%, 29% and 31% for mild AD in 2014, 2016 and 2018, respectively (30% pooled); 23%, 22% and 15% for moderate AD in 2014, 2016 and 2018, respectively (25% pooled); and 4%, 3% and <1% for severe AD in 2014, 2016 and 2018, respectively (4% pooled). Conclusions: There is a discrepancy in AD prevalence estimations using self-reported diagnoses of AD vs. using cut-offs of TICS-m, with the latter identifying higher proportion of MCI or mild AD cases. Both methods bear potential limitations: while AD diagnoses may be under-reported, especially in early stages of the disease, identification based on TICS-m relies on the score cut-offs that were benchmarked using MMSE and are not validated. Due to missing data, the final sample for prevalence estimation is quite small especially for severity specific prevalence. As a result, the prevalence rates based on HRS are likely subject to sizable error variability. Depending on the method of identification used in this study, approximately one-third of the patients had mild AD and almost half of the patients had MCI. This suggests the need for effective clinical interventions to prevent or slow the progression of this disease.
P185- ASSOCIATION BETWEEN A/T/N PROFILES AND MORTALITY IN PATIENTS WITH COGNITIVE DISORDERS. M. Régy 1,2, A. Dugravot 1, B. Hanseeuw 3, J. Dumurgier 1(1. CRESS U1153 Epidemiology of Ageing and neurodegenerative diseases (Inserm) — Paris (France), 2. Brain Ageing Lab (Catholic University of Louvain — Brussels (Belgium), 3. Brain Aging Lab (St-Luc Hospital) — Bruxelles (Belgium))
Background: Alzheimer’s disease (AD) is the 5th leading cause of death for people aged 65 years and older. The A/T/N classification has been proposed as an unbiased definition of AD with markers of Aβ deposition (A), pathologic tau (T), and neurodegeneration (N), based on CSF or PET biomarkers assessment. Objectives: Few is known about the relationship between A/T/N status and the risk of mortality, therefore we here report the association between A/T/N profiles and mortality, in a large population of patients with cognitive disorders consulting in a memory clinic. Method: Our study used data from the BioCogBank Study, including patients explored for cognitive disorders in Lariboisiere hospital (Paris, France), followed up to 15 years. All participants underwent a lumbar puncture in clinical setting, with the assessment of the levels of CSF total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta 42 (aβ42). Vital status on July 1st, 2020 was recorded for each participant using French open data on mortality. Individuals were categorized according to their A/T/N profiles based on their level of CSF aβ42 or aβ42/40 ratio, p-tau and t-tau. Short term (5 years) and long term (15 years) Kaplan Meier and multivariate Cox analyses were performed with A−/T−/N− subjects as reference. Result: Among the 1353 patients included (mean age: 68 years old, 53% of women, mean MMSE score: 22.6), 262 died during the follow-up. At 5 years of follow-up, A−/T−/N+ individuals showed the highest risk of mortality in Kaplan Meier and adjusted Cox analyses (HR (IC) = 2.83 (1.25–6.42)). At 15 years of follow-up, patients in the AD spectrum had an higher mortality risk with a gradient effect between A−/T+ (HR: 1.63 (1.04–2.58)), A+/T− (HR: 1.96 (1.29–2.99)), and A+/T+ individuals (HR: 2.25 (1.55–3.27)), compared to A−/T−/N− patients. Adjustments on potential confounders had little impact on these associations. Conclusion: This study shows the association between A/T/N profiles and mortality in a large population of patients explored for cognitive disorders. At short term, patients with isolated evidence of neurodegeneration showed the higher mortality rate. At long term, patients with the AD profile (A+/T+) had the highest mortality rate.
P186- ULTRA HIGH RISK AND HIGH PREDICTABILITY OF ALZHEIMER’S DISEASE ONSET IN PEOPLE WITH DOWN SYNDROME: IMPLICATIONS FOR CLINICAL TRIALS. J. Fortea 1,2,3, A. Lleo 1,2, A. Bejanin 1,2, M.F. Iulita 1,2(1. Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau — Barcelona (Spain), 2. Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED) — Madrid (Spain), 3. Barcelona Down Medical Center, Fundació Catalana Síndrome de Down — Barcelona (Spain))
Background: Down syndrome is the most frequent cause of intellectual disability and a genetically determined form of Alzheimer’s disease. Alzheimer’s disease has near full penetrance in this population, and the natural history of clinical and biomarker changes is very similar to that of autosomal Alzheimer’s disease. However, age at onset is considered variable and the longitudinal age-associated risk of progression to symptomatic Alzheimer’s disease has not been established. Objectives: To assess the variability in symptom onset of Alzheimer’s disease dementia in Down syndrome in comparison with autosomal dominant Alzheimer’s disease, and to provide the 5-year progression rate to symptomatic Alzheimer’s disease at different ages. Methods: We extracted data from two systematic reviews and meta-analyses to investigate the age at onset of Alzheimer’s disease dementia in Down syndrome and in autosomal dominant Alzheimer’s disease. We compared the 95% prediction intervals, the coefficients of variation and the span of age at onset in the two forms of the disease. We analysed the clinical change to symptomatic Alzheimer’s disease in adults with Down syndrome in a large population cohort of 607 adults with Down syndrome with at least 6 months of follow-up from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI). Results: The estimate of age at onset in adults with Down syndrome was 53.8 (95%CI, 53.1 to 54.5) years (n=2595). Coefficients of variation and 95% prediction intervals of age at onset were comparable to those reported in autosomal dominant Alzheimer’s disease. In our cohort study of cognitive stable adults with Down syndrome, we found a high age-dependent risk to develop symptomatic Alzheimer’s disease at 5 years: 0.1% [0–1.8%] for <40 years; 21.1% [8.0–32.5%] for 40–44 years; 41.4% [23.1–55.3%] for 45–49 years and 57.5% [38.2–70.8%] for >50 years. Conclusion: Down syndrome is probably the best population in which to perform Alzheimer’s disease prevention trials due to its high prevalence and the ultra-high risk to develop symptomatic Alzheimer’s disease at a predictable age.
LP96- ASYMPTOMATIC EXTRACRANIAL CAROTID ATHEROSCLEROSIS AND ITS ASSOCIATION WITH INCIDENT ALZHEIMER’S DEMENTIA. F. Vitali 1, I. Bolakale-Rufai 1, G. Branigan 1, J. Arias 1, E. Reinman 1, R. Brinton 1, C. Weinkauf 1(1. University of Arizona — Tucson (United States))
Background: Dementia is a major cause of disability and dependency among older people worldwide. Growing evidence suggests that vascular diseases contribute to the development and progression of cognitive dysfunction. Symptomatic extracranial carotid atherosclerosis resulting in stroke or transient ischemic attack has been well defined as a risk for dementia. However, the relationship between asymptomatic extracranial carotid arterial disease(aECAD) and dementia is not well established. Objective: Our study aims to determine the association of aECAD with incident Alzheimer’s dementia (AD) in a cohort of patients. Methods: Longitudinal data were obtained from the Mariner insurance claims data set which contains over 122 million patients from private and Medicare insurance in the United States. The data set was queried retrospectively for patients with a first diagnosis of aECAD from 2010 to Q2 of 2018. Only patients that were continuously enrolled for at least 3 years prior to the index date were included. Population with no diagnosis of aECAD 6 months after 1st claim was selected as the control group. Patients who were 45 years or older with no previous diagnosis of dementia at the index date were included in our study and followed up for an outcome of AD. Propensity score matching was performed to adjust for vascular comorbidities that were confounding factors. Demographic and incidence statistics were analyzed using unpaired 2-tailed t-tests or χ2 tests, as appropriate, to test the significance with P < .05 considered statistically significant. Results: 784,062 patients were included in our study. The age of patients ranged from 65–80years with a mean [SD] age of 59.5[4.05] years. 52.9% of the patients were female. The mean duration of follow-up before the AD diagnosis was 4.8years. 8736 out of 247,119(1.55%) patients with aECAD and 8015 of 536,943(0.92%)without aECAD developed AD respectively. After a propensity score match of the aECAD group versus the control group (without aECAD), 247,119 patients with aECAD and without aECAD were included in the final analysis. Over the period of follow-up, 5041(2.04%) patients with aECAD and 4187(1.69%) without aECAD developed AD. Unadjusted, aECAD was associated with a risk of incident dementia. (RR: 2.29, 95% C.I: 2.20–2.38, p<.001). After matching the population for covariates, the group with a diagnosis of aECAD had a significantly higher risk of Alzheimer’s disease compared to the group without aECAD (RR: 1.2, 95% CI, 1.15–1.25 P < .001). Conclusions: This study suggests that aECAD increases the risk of incident Alzheimer’s dementia by 20%. Well-designed prospective studies will further aid our understanding of the interaction between the two conditions. Defining the contribution of aECAD to Alzheimer’s disease is compelling because effective treatments exist for aECAD yet are not currently offered for AD risk reduction. Declaration of Conflicts: Authors have no conflict of interest to declare at this time.
ANIMAL MODEL AND CLINICAL TRIAL
P187- THE PROBUCOL IN ALZHEIMER’S TRIAL: A DOUBLE-BLIND RCT INVESTIGATING COGNITIVE OUTCOMES, CEREBRAL AMYLOID AND BRAIN MORPHOMETRY BASED ON POSITIVE PROOF-OF-CONCEPT PRECLINICAL FINDINGS. J. Mamo 1, R. Clarnette 2, V. Lam 1, M. Bynevelt 3, G. Watts 4, C. Orr 4, P. Loh 4, C. Reid 1, S. Dhaliwal 1, S. Robinson 1, R. Takechi 1, R. Adam 5, M. Vaccarezza 1(1. Curtin University — Perth (Australia), 2.Australian Alzheimer’s Research Foundation — Perth (Australia), 3.Sir Charles Gardiner Hospital — Perth (Australia), 4. University of Western Australia — Perth (Australia), 5. University of Queensland — Perth (Australia))
Background: Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-Aß mediated axis for AD risk. To test the indicated hypothesis, we engineered C57BL/6J mice to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain). HSHA mice with synthesis of lipoprotein-human Aß restricted to liver had marked neurodegeneration concomitant with capillary dysfunction, brain parenchymal extravasation of lipoprotein-Aß and neurovascular inflammation. HSHA mice also showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy showed marked neurovascular disruption in HSHA mice. Probucol, a historic cholesterol lowering agent was found to profoundly suppress the synthesis and secretion of lipoprotein-Aß. In HSHA mice, provision of probucol completely prevented cognitive dysfunction. Collectively, the preclinical studies provided the primary foundation to establish a clinical trial exploring the putative efficacy of Probucol to stabilize cognitive decline in Alzheimer’s. Objectives: The Probucol in Alzheimer’s (PIA)-Study (ACTRN12621000726853) will evaluate the efficacy of 2x daily 250 mg probucol provided as Lorelco™ on cognitive performance in Alzheimer’s patients over a 102 week treatment period. Evaluate cerebral amyloid abundance in the brain of Alzheimer’s Disease patients treated with probucol. Evaluate the Mesial temporal lobe (hippocampus and entorhinal cortex via Scheltens grading) in Alzheimer’s Disease patients treated with Lorelco™. Activities of daily living will be assessed using the Alzheimer’s Disease Co-operative Study Mild Cognitive Impairment Activities of Daily Living scale (ADCS-MCI-ADL24). Depression, anxiety, and stress will be assessed using Depression Anxiety Stress Scale (DASS-21). Conclusion: Exaggerated peripheral metabolism of lipoprotein-Aβ may be a risk factor for Alzheimer’s that can be positively regulated with provision of probucol.
P188- A NOVEL SMALL MOLECULE INHIBITOR REDUCES TOXIC AMYLOID OLIGOMERS TO RESCUE DISEASE IN AD MICE. V. Mathur 1, K. Burk 1, X. Liu 2, S. Gaikwad 3, R. Kayed 3, M.T. Bowers 2, K. Planey 1, A. Singh 1(1. Acelot Inc. — Santa Barbara (United States), 2. Department of Chemistry and Biochemistry, University of California — Lubbock (United States), 3. Departments of Neurology & Neuroscience & Cell Biology & Anatomy, University of Texas Medical Branch — Galveston (United States), 4. Acelot Inc — Santa Barbara (United States))
Background: Alzheimer’s disease (AD) is associated with the deposition of insoluble aggregates of amyloid beta 1–42 (Abeta42) fragment of amyloid precursor protein (APP) and hyperphosphorylated Tau protein which further causes neuronal loss and inflammation in the central nervous system. What causes damage in AD is still debated, however small oligomers, but not higher order aggregates, are shown to be associated with toxicity leading to neuronal death. While Abeta42 and Tau are being tested as individual targets, a combination therapy is not tested and might prove beneficial. Objectives: To show in vitro potency and mechanism of action of Acelot’s novel small molecule AC0203, determine pharmacokinetic properties and target engagement in vivo and to show efficacy in 3xTg mouse model of AD. Methods: Using our joint pharmacophore space (JPS) machine learning platform, we have identified novel small molecules that bind to multiple amyloid oligomers. We now show in vitro mechanism of action using ion mobility -mass spectrometry (IM-MS) for Abeta42 and cellular target engagement for Tau using oligomer toxicity assay. Lastly, we show drug efficacy in vivo using 3xTg mouse model of AD which has both Abeta and tau pathologies. Results: We show that AC0203 targets both Abeta42 and tau oligomers. IM-MS shows that Abeta42 peptide forms dimers to dodecamers in vitro. Either coincubation with AC0203 or incubation post oligomerization, reduces oligomers and increases Abeta42 monomers in solution. Additionally, AC0203 rescues Tau oligomer dependent rat primary neuronal toxicity suggesting that the drug is cell permeable and potent in neuronal cells. Furthermore, AC0203 rescues Tau oligomer dependent electrophysiological defects in mouse hippocampal brain slices. Orally administered AC0203 is well tolerated in mice and is detected in the brain for up to 24 hours. Lastly, AC0203 rescues certain behavioral deficits in 3xTg mouse model of AD. Conclusion: AC0203 is a clinical candidate drug with good pharmacokinetic properties and brain penetration that targets toxic forms of both Abeta42 and Tau. We show that AC0203 inhibits toxic amyloid oligomers in vitro, reduces oligomer dependent neuronal toxicity, partially rescues oligomer associated nerve conduction and rescues behavioral defects in 3xTg AD mice. Conflict of Interest: AS, KP, KB, VM are founder/board member/employed by and hold stock options for Acelot Inc.
P189- T-TYPE CALCIUM CHANNEL MODULATOR AD101 IMPROVES COGNITIVE FUNCTION IN ANIMAL MODELS OF MEMORY AND LEARNING IMPAIRMENT AND PROVIDES A RATIONALE FOR THE POTENTIAL CLINICAL USE OF AD101 IN THE SYMPTOMATIC TREATMENT OF ALZHEIMER’S DISEASE. J. Burmeister 1, S. Gauthier 2, S. Rogers 1(1. AmyriAD Pharma, Inc. — Los Angeles (United States), 2. McGill University — Montréal (Canada)
Background: AD101 is a novel synthetic compound in development as an orally administered treatment for probable AD. After AD101 showed potential effects in animal models of learning and memory function in phenotypic screening, a series of investigations in animal models for normal aging, memory and learning impairment, and Alzheimer’s Disease were performed. While AD101 stimulates the presynaptic release of acetylcholine in hippocampal neurons, some these studies suggested other additional mechanisms of action which potentially contribute to its beneficial effects on learning and memory function. Objectives: Summarize the effects of AD101 on learning and memory function in animal models for normal aging, induced memory and learning impairments and Aβ and tau dependent models. Describe combined effects of AD101 administration with available therapies such as cholinesterase inhibitors and memantine. Methods: Review of previously published and unpublished nonclinical studies. Results: Initial dose finding studies in rodents investigated doses of AD101 ranging from 0.001 to 1.0 mg/kg. The behavioral outcome measures used were the Novel Object Recognition (NOR), the Passive Avoidance (PA), the Radial Arm Maze (RM) and the Morris Water Maze Task (WWM). In normally aged rats (22 months) treatment with AD101 for 23 days elicited increased exploratory preference over untreated rats in the NOR task. Monotherapy with memantine 10 mg/kg as a positive control produced a significant effect over the untreated group as well, whereas the combination of AD101 and memantine produced the highest effect size. The effects of AD101 were explored further using learning and memory impairments induced either chemically or via neuronal lesioning: After muscarinic blockade via scopolamine administration AD101 (doses > 0.001 mg/kg) significantly attenuated step-through latencies in the passive avoidance task. While in the positive control group a significant effect was seen after administration of 0.1 mg/kg donepezil, combination treatment of donepezil and AD101 produced higher effect sizes. Glutamatergic blockage via oral administration of 0.2 mg/kg MK-801 significantly reduced step-through latency in the passive avoidance task. A single dose administration of 0.1 mg/kg but not of 1 mg/kg AD101 significantly ameliorated step-through latency. 7 days of exposure to methamphetamine-induced significant impairments of recognition memory in the NOR. Those effects were attenuated by administration of 1f/g/kg AD101. While AD101 administration was increased hippocampal phosphorylated ERK1/2 levels treatment effects, were negated by pretreatment with a ERK kinase inhibitor SL327. Administration of the dopamine D1 receptor antagonist, SCH23390 and the NMDA receptor antagonist MK-801 blocked the ameliorating effect of AD101 effect as well. These results suggest that indirect activation of ERK1/2, as well as modulation of dopaminergic (D1) and glutamatergic (NMDA) pathways may contribute to the effects of AD101 on learning and memory function. Neuronal lesioning: Lesioning of the Nucleus Basalis Magnocellularis (NBM) with ibotenic acid or lesioning via intracerebroventricular Aβ25–35 Injections both led to reduced step-through latencies in the PA task in the rat. These impairments were partially mitigated by AD101 administration (0.01 and 0.1 mg/kg in the NBM model and 0.1 and 1 mg/kg in the Aβ25–35 model which led to prolonged step-through latencies in the PA task 14 days after NBM lesioning and 4 days after the Aβ25–35 injection. Models dependent on Aβ and tau were used to investigate the potential effects of AD101 on AD hallmark features and associated neurobehavioral problems: Intracerebroventricular Infusion of Aβ1–40 in rats produced deficits in the step-through latency in the PA task which were fully reversible by administration of 0.01 and 0.1 mg/kg AD101. This improvement was later shown to be associated with a reduction in Aβ accumulation. Senescence Accelerated Mouse-Prone 8 (SAMP8) mice are a mouse strain that, via a spontaneous gene mutation, develops age-related deficits in learning and memory along with an accelerated accumulation of Aβ-like deposits in brain tissue. SAMP8 mice were investigated at 12 months age. In the NOR untreated SAMP8 mice demonstrated an expected decrease in exploratory preference while treatment withAD101 (0.0015 to 0.14 mg/ kg/day) attenuated this effect and significantly increased exploratory preference. LaFerla triple transgenic Mice (3xTG) are an animal model for AD in which AD neuropathological features such as Aβ-plaques, neurofibrillary tangles and neurobehavioral problems are expressed in an age dependent manner. After two months of treatment with AD101 3xTG mice were assessed using the Morris Water Maze. During retention testing at 24- and 72-hours animals treated with AD101 required significantly less time to reach the former platform. Conclusion: AD101 demonstrated beneficial effects on learning and memory function in animal models of normal aging, impaired learning and memory function and Alzheimer’s Disease.
P190- EFFECTS OF T-TYPE CALCIUM CHANNEL MODULATOR AD101 ON THE ACCUMULATION OF BETA AMYLOID, TAU AND POLYUBIQUITINATED PROTEINS IN ANIMAL MODELS OF ALZHEIMER’S DISEASE. J. Burmeister 1, S. Gauthier 2, S. Rogers 1(1. AmyriAD Pharma, Inc. — Los Angeles (United States), 2. McGill University — Montréal (Canada))
Background: AD101 is a first-in-class small molecule with demonstrated positive effects on learning and memory function in animal models for both normal aging and Alzheimer’s Disease (AD). While AD101 modulates T-type voltage gated calcium channels and thus stimulates the presynaptic release of acetylcholine in hippocampal neurons, further studies investigated the potential role of AD101 in protein processing and accumulation as potential contributors to its clinical effects. Objectives: Summarize the effects of AD101 on Beta Amyloid and Tau aggregation, Amyloid Precursor Protein processing and modulation of proteasomal and lysosomal protein degradation. Methods: Review of sponsored and previously unpublished in-vitro and in vivo animal studies of AD models conducted as part of a collaboration with UC Irvine led by Kim Green, Ph.D. Results: In vitro studies using protein quantification via ELISA showed that AD101 reduces Amyloid-beta (Aβ) 1–42 in Neuro2a neuroblastoma cells and both Aβ 1–40 and 1–42 in primary neuronal cultures derived from transgenic mice overexpressing APP. These results were reproduced in several studies using brain tissue of LaFerla triple transgenic mice (3xTgAD) of varying age (12–24 months). A similar effect was eventually reported from brain tissue analyses derived from Cynologus monkeys. Western-blots derived from the same 3xTgAD mice demonstrated a decrease in C99 and C83 c-terminal APP fragments as signs of altered APP processing via α- and β-secretase. Further Western-blot analyses demonstrated a reduction of beta-secretase (BACE) and alpha-secretase pro-enzyme (pro-ADAM) as well. Immunohistochemical staining with H7 anti-human tau monoclonal antibody of hippocampal brain section from 3xTgAD mice treated with AD101 showed a clear reduction of pathological tau staining in comparison to controls. Further experiments were conducted to assess whether changes in protein degradation may contribute to the reductions in Aβ and Tau protein concentrations. Changes in the ubiquitin-proteasome pathway were assessed with Western-blot analyses using an anti-ubiquitin antibody: 12-month-old 3xTgAD mice that had been treated with 5/mg/kg/day ST101 over 2 months have shown a consistent and profound reduction of polyubiquitinated protein concentrations. While long term treatment with AD101 in younger 3xTgAD mice of 3 months demonstrated similar effects in the 1mg/kg/day dose group after 10 months of AD101 administration, shorter treatments durations (3 months) and higher doses (5 mg/kg/day) showed negative results. Functional studies of proteins involved in autophagy and lysosomal degradation (LC3, Cathepsin D, Becllin 1 and LAMP2A) have not been conducted, however Western Blot analysis did not suggest significant changes in the concentrations of these proteins. Follow-up experiments showed that AD101 reduces ubiquitinated proteins in other models (C57 and SAMP8 mice) as well. Conclusion: These series of studies demonstrate that there are potential mechanisms of action of AD101 targeting protein processing and degradation in neuronal cells. The reduction of polyubiquitinated proteins could be a result from increased rates of proteasomal degradation. Alongside the known effect of AD101in increasing cholinergic neurotransmission, enhanced removal of nonfunctional proteins known to be associated with AD and other neurodegenerative diseases may contribute to the beneficial treatment effects of AD101 in AD.
LP97- MODULATION OF PERIPHERAL MONOCYTES BY A PROTEOSOME-BASED ADJUVANT (PROTOLLIN) FOR THE TREATMENT OF ALZHEIMER’S DISEASE. P. Kolypetri 1, L. Liu 1, E. Solana 1, C. Gauthier 1, T. Singhal 1, S. Gale 1, T. Chitnis 1, D. Selkoe 1, H. Weiner 1(1. BWH — Boston (United States))
Background: Amyloid beta (Aβ) accumulation is considered the primary initiating event in Alzheimer’s disease (AD) pathogenesis. Our previous work has shown that nasal administration of Protollin — a proteosome-based adjuvant acting as a TLR2/TLR4 agonist — leads to reduction of insoluble, fibrillar and soluble Aβ accumulation in the brains of young and old AD mice (1–4). Objectives: We investigated the effects of nasal Protollin on activation and recruitment of peripheral monocytes in the brains of APP/PS1 mice as well as their ability to clear Aβ and improve cognitive behavior. We also investigated transcriptional and functional changes in blood CD14+ monocytes from early AD patients receiving nasal Protollin as part of a phase 1 single ascending dose trial at Brigham and Women’s Hospital. Methods: APP/PS1, APP/PS1-CCR2RFP+/− and APP/PS1-CCR2RFP/RFP transgenic mice received nasal Protollin. Transcriptional profiling of FACS-sorted monocytes from cervical lymph nodes (CLN), spleen and bone marrow (BM) was performed by bulk RNA sequencing and differentially expressed (DE) genes were analyzed by Ingenuity Pathway Analysis (IPA). Quantification and visualization of brain infiltrating immune cells was performed by multi-color flow cytometry and confocal imaging. Quantification of brain Aβ was performed using ELISA and immunofluorescence staining. Assessment of the cognitive abilities of mice was examined using the Y-maze, Morris water maze and Barnes maze tests. Single-cell (sc)-RNAseq analysis of mouse brain cells from Protollin and PBS-treated mice was examined using the 10x Genomics Chromium technology. The phagocytic ability of blood CD14+ monocytes from AD patients was assessed by an in vitro phagocytosis assay and gene expression was analyzed by qPCR. Results: We examined the in vivo effect of nasal Protollin on peripheral monocytes from APP/PS1 mice and we found that certain monocytes from CLN, spleen and BM of Protollin treated-mice acquired tissue-specific signatures with DE genes involved in cell migration, complement activation, Aβ clearance and M2 polarization pathways. In the brains of treated mice, analysis of infiltrating immune cells showed a selective, increased recruitment of certain monocytes, located adjacent to Aβ aggregates. We also investigated which brain cortical cells undergo transcriptional changes after monocyte infiltration and identified unique subsets of glial and choroid plexus epithelial cells expressing high levels of genes affecting neuronal growth and function, in brains of Protollin-treated mice. We also addressed whether monocytes from treated mice are sufficient to promote Aβ clearance and improve the cognitive behavior of APP/PS1 mice following an adoptive transfer approach. APP/PS1 mice receiving Protollin-treated monocytes had improved performance in the Y-maze, Morris water maze and Barnes maze tests as well as lower levels of brain Aβ compared to control mice. In parallel, blood CD14+ monocytes from an AD patient receiving Protollin (days 1 and 14) had increased phagocytic ability against Aβ1–42 in a dose-dependent manner as well as differential expression of phagocytosis-related genes compared to monocytes from placebo treated subjects. Currently, we are investigating transcriptional profiles of blood CD14+ monocytes from these patients using bulk RNA and (sc)-RNAseq. Conclusion: Our data demonstrate that nasal Protollin induces: 1) tissue-specific transcriptional changes in peripheral monocytes which infiltrate in the brains of APP/PS1 mice promoting Aβ clearance and improving cognitive deficits; 2) generation of unique glial and choroid plexus epithelial cell subsets promoting neuronal growth and function in the cortex of Protollin-treated APP/PS1 mice and 3) an increase in the phagocytic ability of blood CD14+ monocytes against Aβ1–42 from nasal Protollin-treated AD patients plus alterations in the transcriptional profile of blood monocytes. A phase 1 single ascending dose trial of nasal Protollin in early AD is in progress. Given its safety profile and immune effects in both animal models and human AD subjects, Protollin represents a novel immunologic approach for the treatment of AD. 1. D. Frenkel, R. Maron, D. S. Burt, H. L. Weiner, Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. Journal of Clinical Investigation 115, 2423–2433 (2005). 2. D. Frenkel et al., A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann. Neurol. 63, 591–601 (2008). 3. D. Frenkel et al., Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4, 2030 (2013). 4. V. Lifshitz et al., Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model. Neurobiol. Aging 33, 432 e431–432 e413 (2012). The authors declare there is no conflict of interest. Jiangsu Nhwa Pharmaceutical (NHWA) and I-Mab Biopharma (I-Mab) are responsible for the development, manufacturing and marketing of the immune modulator Protollin.
LP98- AN EFFICACIOUS THERAPY FOR ALZHEIMER DISEASE ALREADY EXISTS, AND IT IS COMMERCIALLY EXPLOITABLE. D. Dolcetta1, S. Giovagnoli2, D. Roberto3(1. Istituto di Neuroscienze di Rosà - Vicenza (Italy), 2. Department of Pharmaceutical Sciences, University of Perugia, Italy - Perugia (Italy), 3. Dep of Biochemistry, Desio Hospital - Brianza (Italy))
Background: Since 2010 (Caccamo et al, JCB 2010) oral administration of rapamycin has been shown to allow the prevention of cognitive impairment of many mouse models of dementia (Spilman P, et al, PLoS One. 2010; Lin AL, et al, J Cereb Blood Flow Metab. 2017; Tramutola A, et al, BMC. 2018). This seems to be mainly due to the pro-autophagic effect obtained with the inhibition of m-TOR: cognitive maintenance or recovery is accompanied by a significant reduction in Aβ intracellular storages. However, Caccamo, unlike many others, has shown not to prevent decay, but, by administering rapamycin at the onset of memory disturbances, to recover an already evident and measurable cognitive deficit. In other words, she demonstrated that it is possible to recover an already established initial dementia. Subsequent studies have shown that initial memory deficits could be due to an initial toxic effect of Aβ on synapses: adminisdtrating rapamycin in this phase, the stimulation of autophagy progressively enables neurons to degrade Aβ. It reduces its intraneuronal accumulations and recovers neuronal and synaptic health. Only later in the clinical progression, the Aβ accumulation would cause neuronal death with irreversible loss of the ability to store new memories. Rapamycin therapy is effective only if performed prior to the formation of Ab plaques. After this stage, the effect of functional recovery disappears (Majumder et al, PLoS One 2011). Two clinical trials are finally underway (NCT04200911 & NCT04629495) with oral rapamycin in AD: their aim is to replicate Caccamo’s results on patients. In our opinion, these trials carry two main limitations: 1) the administered doses cannot be maximal, due to the serious metabolic and immunosuppressive side effects that rapamycin causes: this involves very long expected administration protocols (many months, years), while patients’ decay is often rapid. 2) Rapamycin and many other mTOR inhibitors are no longer patent protected, so they have no commercial interest at all. We instead chose to give a high-dose mTOR inhibitor via intra-cerebroventricular (ICV) route of administration. It is good to remember that AD is a local, organ-specific disease: why to bear heavy systemic side effects (immunosuppressive and metabolic) if they can be avoided with a local and short administration? In some fortunately rare clinical conditions affecting sometimes children (e.g. cerebral lymphomas resistant to maximal doses of oral or parenteral administration of anticancer drugs) ICV administration has now become a routine and safe clinical practice, even if used for long periods (Peyrl et al, J Neurooncol 2014). In our strategy its invasiveness had the advantage of allowing both the administration of high local doses with limited systemic immunosuppression, and for a short period. We then administered ICV the most thermostable mTOR-Inhibitor we had (everolimus) for 12 days, in the Caccamo’s model (3xTg-AD mouse), at the same age (6 months), when the animals had an already serious decay, although initial (in short, mice with MCI). Unfortunately everolimus (although more stable than rapamycin) was still very unstable at body temperature (BT). This means that over the 12 days the drug gradually declined and eventually disappeared. Despite the short administration, which in the first days was at high doses, we obtained a surprising recovery (cognitive and pathological), and even more lasting than expected (Cassano et al, Exp Neurol 2019). This last unexpected observation will be deepened in the future. However, the lack of a thermostable formulation made our strategy clinically inapplicable. It was absolutely necessary to develop a new formulation of mTOR-inhibitors resistant at BT, which would allow ICV administration of known and reproducible doses of mTOR-Inhibitors, lasting several days in the ICV administration devices. We then made and patented it (WO2021205297 (A1) - 2021-10-14). This patent, applicable to mTOR-Inhibitors, has been filed in the EU, US, China, Canada and India. Now, after a short in vivo preclinical validation, this new formulation will be ready to reach the bedside. Objectives: We aim to exploit the pro-autophagic activity of mTOR inhibitors and replicate, in 10 patients with initial AD, what we observed in 3xTg-AD mice (Cassano et al, Exp Neurol 2019). Methods: Everolimus was loaded in distear oylphosphatidylethanolamine-polyethyleneglycole 2000 (DSPE-PEG2000) micelles by the thin layer method. The compounds were dissolved in chloroform. The solvent was evaporated at r.t. under nitrogen stream and vacuum dried for 1 hour. Micelle formation was obtained by hydration of the thin layer with an Everolimus physiologic solution. Results: We have developed a micellar formulation stable at BT for over 15 days, and then decaying quite slowly (PCT: WO2021205297 (A1) — 2021-10-14). Moreover, the already known biocompatibility, its ease of production, storage, and preparation for use are also interesting features. Conclusion: Despite the need of a further in vivo preclinical validation of the formulation, it has been bridged the missing step towards the clinical translation of the local administration of mTOR inhibitors strategy in AD and other neurodegenerative proteinopathies.
PROOF OF CONCEPT/TRANSLATIONAL RESEARCH FOR ALZHEIMER DRUG DEVELOPMENT INTERVENTIONS
P191- A COMBINATION OF PET TRACERS SERVES AS A POTENTIAL TRIAL BIOMARKER FOR EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1 (ENT1) INHIBITION TREATMENT OF ALZHEIMER’S DISEASE. C.P. Chang1,2, C.W. Wu1,2, C.Y. Lin1,2, K.C. Wu1,3, H.H. Yeh4, C.Y. Wu5, C.C. Weng6, L.W. Hsin3, C.J. Lin3, Y. Chern1,2(1. Biomedical Translation Research Center, Academia Sinica - Taipei (Taiwan, Republic of China), 2. Institute of Biomedical Sciences, Academia Sinica - Taipei (Taiwan, Republic of China), 3. School of Pharmacy, National Taiwan University - Taipei (Taiwan, Republic of China), 4. Brain research center, National Yang Ming Chiao Tung University - Taipei (Taiwan, Republic of China), 5. Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University - Taipei (Taiwan, Republic of China), 6. Department of Medical Imaging and Radiological Sciences, Chang Gung University - Taoyuan (Taiwan, Republic of China))
Background: Alzheimer’s disease (AD), the major cause of dementia, is a substantial healthcare burden for aging societies. To date, the treatment of AD remains to be an unmet medical need. The major pathogenic hallmarks of AD include extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. However, additional variables (e.g., stress, diet, concurrent disease, and other drugs) may also contribute to the disease progression and/or affect the efficacy of the treatments. In recent years, imaging- and blood-based biomarkers have also been actively investigated to facilitate the developments of sensitive assessment for the early detection and progression of AD. Another major pathological feature of AD is energy dysfunction associated with mitochondrial impairment and reduced ATP production. We have previously demonstrated that a novel inhibitor of equilibrative nucleoside transporter 1 (ENT1), (J4) can prevent and reverse AD pathology via modulating the adenosine homeostasis, which is tightly linked to the energy metabolism in the brain. Targeting the adenosine metabolism thus becomes a new strategy for the development of AD treatments. To this end, we aimed to develop suitable biomarker(s) for J4 and/or energy-related treatments for AD. Objectives: We set out to identify the proper biomarker(s) for J4, an orally active ENT1 inhibitor by non-invasive positron emission tomography (PET) scans in AD mouse models. Methods: Two distinct AD mouse models (APP/PS1 for amyloidosis and THY-Tau22 for tauopathy) with the onset of memory deficiency at the age of 6 months were employed. To examine the therapeutic effects, mice were treated with J4 (3 mg/kg/day) in drinking water containing 1% HPβCD at the late disease stage (10–12 months old) for one month. We monitored the therapeutic efficacy of J4 in vivo using PET images including mitochondria-, FDG-, amyloid-, and Tau-PET in this preclinical study. Results: Our results showed that one-month treatment with J4 rescued cognitive decline and impaired spatial memory in symptomatic APP/ PS1 and THY-Tau22 mice. In addition, J4 treatment elevated the mitochondria- and FDG-PET signal in the brain of AD mice, indicating that J4 ameliorated the impairments of mitochondria and glucose metabolism. Moreover, reduction of Aβ and tau deposition by J4 administration could be observed not only by immunofluorescence staining but also by the amyloid- and Tau-PET imaging in APP/PS1 and THY-Tau22 mice, respectively. Conclusion: Data from the present study showed that oral administration of J4 after the onset of cognitive decline provided therapeutic effects against AD pathology. In addition, a combination of PET images (e.g., mitochondria-, FDG-, amyloid-, and Tau-PET) may serve as biomarkers for the assessment of for AD progression. Conflict of interest statement: Yijuang Chern holds patents on J4 for the treatment of neurodegenerative diseases.
P192- XANAMIA PHASE 1B TRIAL WITH XANAMEM® ACHIEVES PRIMARY ENDPOINTS: RESULTS AND STRATEGIC UPDATE. M. Woodward1, P. Rolan2, M. Roesner2, J. Taylor2, T. Miller2, P. Maruff3(1. Aged Care Research And Memory Clinic, Austin Health - Melbourne (Australia), 2. Actinogen Medical - Sydney (Australia), 3. Cogstate Ltd - Melbourne (Australia))
Background: Xanamem® is a potent and selective inhibitor of 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyzes the conversion of cortisone to cortisol. In the brain, 11β-HSD1 is highly expressed in regions such as the hippocampus, frontal cortex, and cerebellum. There is evidence from studies in animals and in humans linking elevated cortisol with cognitive dysfunction and neurotoxicity. Thus, reducing cortisol levels in the brain is considered an important therapeutic goal in the treatment of Alzheimer’s Disease (AD) and other conditions where cognitive impairment and cortisol excess is a major component of the disease. Nonclinical and clinical studies to date indicate that Xanamem offers potential to be rapidly cognitive enhancing and disease modifying. Objectives: The results of the recently completed XanaMIA Part A Phase 1b trial, which aimed to understand the minimally effective dose of Xanamem for effects on cognition, will be presented. A strategic update on the development of Xanamem will also be presented. Methods: XanaMIA Part A was a double-blind, placebo-controlled, dose-ranging Phase 1b study to assess the efficacy, pharmacodynamics, and safety of Xanamem in healthy older volunteers. Participants were randomized to receive either 5 mg Xanamem (n=36), 10 mg Xanamem (n=34), or matching placebo (n=37) orally for 6 weeks. Primary objectives were safety of the 2 dose levels, pharmacodynamics of the adrenocorticotropic hormone response, and effects on cognition, using the Cogstate Cognitive Test Battery (CTB) with International Digit Symbol Substitution Test - Symbols (IDSST-S). The study was designed to measure effect sizes in cognition, rather than statistical significance. Effect sizes vs. placebo were estimated from modeled data as Z scores and raw data as Cohen’s d statistics. The a priori criterion for effect detection was Cohen’s d ≥ 0.3 in one or more tests. Results: Xanamem was safe and well-tolerated over the 6-week treatment period in this cognitively normal population aged 50–80 years (mean age 64 years, mixed female and male population). There were no treatment-related serious adverse events, and other predominantly mild adverse events were generally equally distributed across the 3 groups (including placebo). Both 5 mg and 10 mg dose levels showed pharmacodynamic activity by raising mean ACTH by 2.03 to 2.35 times, respectively, principally within the normal laboratory range and to a similar extent as higher doses in prior studies. Clinically significant improvements were seen in the Cogstate CTB with both doses for the three domains making up an attention composite, including working memory. This included improvement in the visual attention domain with 5 mg at the end of treatment, achieving the a priori primary endpoint criterion of Cohen’s d > 0.3 (Cohen’s d = 0.32, Z = 1.97, p < 0.05). Improvements were not seen in those domains making up a memory composite or the IDSST-S. The cognitive findings were consistent with those seen with a 20 mg dose in a prior randomized trial and with the high brain activity seen at 5 mg and 10 mg doses in a Positron Emission Tomography (PET) study. Conclusion: The XanaMIA Part A trial met its primary objectives, demonstrating rapid improvements in cognition for attention tests, pharmacodynamic activity on ACTH and good tolerability. While the cognition data were somewhat variable, the pattern of response was consistent with results from the prior randomized trial. These results strongly support continuation of the Xanamem Phase 2 trial program using a dose range ≤ 10 mg. The XanaMIA Part B Phase 2 trial will assess the effect of Xanamem on cognition in participants with early AD.
P193- LEVERAGING UNTAPPED NATIONAL SYNERGIES TO ACCELERATE REPRESENTATION OF HISPANIC/LATINOS IN CLINICAL TRIALS ON DEMENTIA: THE PROGRESS OF THE NEW CONSORCIO BETWEEN THE NATIONAL ASSOCIATION OF HISPANIC NURSES AND THE ALZHEIMER’S ASSOCIATION. E. Portacolone1, A. Perez2, C.V. Hill3, J.C. Rojas1(1. University California San Francisco - San Francisco (United States), 2. Penn University - Philadelphia (United States), 3. Alzheimer’s Association - Chicago (United States))
Background: Most efforts to recruit Hispanic/Latinos into clinical trials on dementia have typically leveraged community engagement strategies via partnerships with local community-based organizations (CBOs). Local organizations - churches, community clinics, advocacy organizations - have helped increase recruitment of Hispanic/Latinos. However current approaches to community engagement are labor- and time-intensive and limited to specific geographic areas such as particular cities. Nevertheless, many trusted CBOs have an infrastructure at both national and local levels, thus, a key missed opportunity is the inadequate leveraging of this infrastructure to facilitate recruitment. For example, the National Association of Hispanic Nurses (NAHN) has a national office, including 49 chapters and 1,834 members. The Alzheimer’s Association (ALZ) has 77 chapters nationwide. As a result, our research will test the hypothesis that partnering with organizations with national reach and trusted by local Latino/Hispanic communities can provide the infrastructure needed to rapidly implement scalable recruitment strategies nationwide. Specifically, in the summer of 2021 we established a research recruitment Consorcio driven by Latino/Hispanic stakeholders involving NAHN and the ALZ; both organizations found to be trusted in focus groups that included 178 Latinos. First activities included establishing a Consorcio Advisory Group including leaders of NAHN and ALZ (n=8) advised by a Community Experts Group of Latinos/Hispanic community members (n=16). The first 9 months of the Consorcio were devoted to identifying synergies, establishing decision-making procedures, and developing a common message with the support of a senior Latina messaging designer. The next phase will include testing the efforts of the Consorcio in the Ahead A3–45 clinical trial, a large clinical trial partially funded by the NIA testing an anti-amyloid therapy for Alzheimer’s disease prevention. Specifically, we will implement the Consorcio intervention in 4 sites of the clinical trial and we will compare recruitment metrics with 4 other comparable sites with usual activities. The intervention will include the presence of an outreach specialist supporting NAHN and ALZ to increase awareness among Latino/Hispanic communities of the importance of participating in clinical trials and the risks and benefits involved in participating in the Ahead clinical trial. The intervention involves: local presentations, radio shows, Facebook posts, flyers, and ads in the news, and a website. To assess the effectiveness of the intervention we will draw from mixed methods. Specifically, we will analyze: 1) recruitment metrics of sites receiving the intervention vs. those using usual recruitment activity in the Ahead A3–45 clinical trial, and; 2) experiences and perceptions of the recruitment process from semi-structured interviews with research team of the trial and Latino community members who choose to enroll, or not, in this trial. The results will help accelerate critical participation of Latinos in dementia research. Our approach can be replicated in other sites nationwide and adapted to accelerate recruitment of other racial/ethnic minorities and other underrepresented groups into clinical trials on dementia.
P195- ASTROCYTIC REGULATORY MECHANISM ON PM2.5-INDUCED NEURONAL CELL DEATH AND NEUROINFLAMMATION. S.H. Han1, R.E. Kim2, K.J. Kwon2,3(1. Department Of Neurology, Konkuk Hospital Medical Center, 120–1 Neungdong-Ro, Gwangjin-Gu - Seoul (Korea, Republic of), 2. Department Of Neuroscience, School Of Medicine, Konkuk University - Seoul (Korea, Republic of), 3. Department of Neurology, Konkuk Hospital Medical center, 120–1 Neungdong-ro, Gwangjin-Gu - Seoul (Korea, Republic of))
Background: Several evidences demonstrated that PM2.5 exposure is associated with increased risk of neurological disorders. including Alzheimer’s disease (AD), Parkinson’s disease (PD), and other forms of neurodegenerative diseases, but the underlying pathological mechanisms are not clear. Chlorophyll is a green pigment found in plants, which is packed with a range of powerful nutrients. This pigment is reported to prevent cancer, aging and neurological disorder such as AD based on the potent antioxidant properties. Objective: The aim of this study is to investigate whether chlorophyll can prevent PM2.5-induced neuronal cell death through the alteration of neurotoxic reactive astrocytes. Methods: In this regard, we examined 1) the mRNA expression of inflammatory mediators including iNOS, IL-1b, TNFa, TGFb and PAI-1, 2) nitric oxide (NO) and reactive oxygen species (ROS) production, and 3) phagocytotic function using pHrodo dyes in rat cultured astrocytes cells. We used a well-characterized Diesel particulate matter, PM2.5, from SIGMA-Aldrich. Results: PM2.5 increased NO and ROS production in C6 glioma cells and iNOS, IL-1b and TNFa mRNA expression. However, chlorophyll attenuated PM2.5-induced iNOS and reactive astrocytes markers expressions and prevented neuronal cell death in rat primary cortical neurons. Our results show that PM2.5 can induce neurotoxic reactive astrocytes leading to neurotoxicity, and that chlorophyll can prevent the neurotoxicity with reduction in astrocyte activation. Conclusion: These results demonstrate the potential beneficial effects of chlorophyll against air pollutant exposure (PM2.5)-associated neurodegenerative disease, such as AD. Funding Source: This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2019M3C7A1031455 and 2022R1A2C1005917) and by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9G2077568).
P196- IMPACT OF SEMAGLUTIDE IN AMYLOID POSITIVITY (ISAP): PROTOCOL FOR A RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL IN AMYLOID POSITIVE INDIVIDUALS. I. Koychev1, A. Adler1, P. Edison2, B. Tom3, J. Milton1, J. Butchart4, A. Hampshire2, C. Marshall5, E. Coulthard6, H. Zetterberg7, F. Cormack8, C. Mummery9, R. Holman1(1. University of Oxford - Oxford (United Kingdom), 2. Imperial College London - London (United Kingdom), 3. University of Cambridge - Cambridge (United Kingdom), 4. Royal Devon University Healthcare NHS Foundation Trust - Exeter (United Kingdom), 5. Queen Mary University of London - London (United Kingdom), 6. University of Bristol - Bristol (United Kingdom), 7. University of Gothenburg - Gothenburg (United Kingdom), 8. Cambridge Cognition - Cambridge (United Kingdom), 9. University College London - London (United Kingdom))
Background: Alzheimer’s Disease (AD), characterised by synaptic dysfunction and neurodegeneration, is thought to be mediated by the accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. The latter drives neurodegeneration modulated by neuroinflammation. Treatment approaches aimed directly at amyloid and tau have been largely disappointing. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may offer novel mechanisms to delay or even prevent neurotoxicity in individuals at-risk for developing AD. GLP-1 is an incretin hormone produced by intestinal enteroendocrine L-cells which enhances insulin release and reduces glucagon release-responses. Preclinical studies have shown that GLP-1 RA administration is associated with decreased AD protein and neuroinflammatory burden, improved blood-brain-barrier integrity, and improved memory function. Pooled data from three double-blind, randomised, GLP-1 RA placebo-controlled Cardiovascular Outcome studies in patients with type 2 diabetes mellitus (T2DM) of liraglutide and semaglutide have shown in post-hoc analyses that GLP-1 RA treatment reduced the risk of developing all-cause-dementia, an exploratory endpoint, compared with placebo, over a 3.6-year follow-up period (hazard ratio 0.47, 95% CI 0.25–0.86). Additionally, the REWIND trial showed that another GLP-1 RA, dulaglutide, reduced cognitive impairment compared with placebo, in patients with T2DM. These data suggesting GLP-1 RAs may be beneficial in AD led us to investigate whether semaglutide could reduce the accumulation of cortical tau protein and neuroinflammation in individuals at risk of developing AD (defined as being amyloid positive in the brain by imaging). This mechanistic study will complement data from two semaglutide compared with placebo phase 3 trials (EVOKE and EVEOKE+) which investigate modification of Alzheimer’s disease effects in patients diagnosed with dementia or mild cognitive Impairment. Objectives: Primary: To investigate the difference in effect of oral semaglutide versus placebo on tau accumulation in preclinical AD. Secondary: To assess the safety and effect of oral semaglutide versus placebo on measures of neurodegeneration, neuroinflammation and AD pathology in blood, cognition, quality of life, physical activity and circadian rhythm. Methods: The Impact of Semaglutide in Amyloid Positivity (ISAP) trial is an investigator-led randomised, double-blind, placebo-controlled, superiority study of oral semaglutide. It will randomise 88 individuals aged 55 years or above with no or mild cognitive impairment and amyloid positivity in the brain assessed through positron emission tomography (PET). T2DM Individuals will comprise up to 30% of the randomised sample. Participants with low affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene will be excluded, as this could affect interpretation of their TSPO PET scans. Following a screening visit and assessment for amyloid positivity, eligible participants attending their baseline visit will be randomised in an overall 1:1 ratio to semaglutide or placebo and booked for tau and TSPO PET scans prior to initiating study treatment. MRI data will be collected at the TSPO PET scan using a combined PET-MRI machine. Baseline physical activity and cognitive data will be collected using a wrist-worn actigraph and from CANTAB (in-clinic) and Cognitron cognitive battery (remotely) respectively. Oral semaglutide or placebo will be started at 3mg once-daily and be escalated at four-weekly increments, to 7mg and then 14mg. Participants will attend safety visits at weeks 4, 8, 26 and 39 to assess tolerability of medication and obtain blood samples to measure AD biomarkers. All cognitive assessments will be repeated at week 26. Last study visit will be at Week 52, when all baseline measurements will be repeated. Results: Recruitment is projected to take 15 months, commencing in Q2 2022. The primary analysis will be an intention-to-treat analysis of the mean annualized change in PET tau standardized uptake value ratio, comparing the semaglutide and placebo groups. Results are expected in 2024. Discussion: Mechanisms for the potential disease modifying action of GLP-1 RAs with regard to AD remain unclear. As therapies targeting AD core pathology have yet to achieve clinical efficacy, efforts to develop alternative treatment approaches have intensified. GLP-1 RAs appear to be a promising option with semaglutide being trialled in two phase 3 studies (EVOKE and EVOKE+) of people with early AD. This investigator-initiated trial will complement on-going research by offering insights into the potential pathophysiological mechanisms through which GLP-1 RA may offer a treatment option for Alzheimer’s disease across the disease spectrum.
P197- THE NOVEL FKBP51-HSP90 INTERACTION INHIBITOR ATTENUATES HIGH-FAT-INDUCED COGNITIVE IMPAIRMENT. B. Winblad1, L. Wang1, J. Wojcieszak1, R. Kumar1, P. Pavlov1(1. Karolinska Institutet - Stockholm (Sweden))
Background: Obesity increases the risk of type 2 diabetes mellitus and Alzheimer disease. Heat shock protein 90 (Hsp90) co-chaperone FK506-binding protein 51 (FKBP51) is and important regulator of metabolic and cognitive dysfunction. FKBP51 knockout mice are resistant to diet-induced obesity, exhibit elevated glucose and insulin tolerance, and have less endogenous tau. FKBP51 overexpression preserves tau and impairs spatial reversal learning and memory. Our group has identified a new family of FKBP51 inhibitors that can disrupt FKBP51-Hsp90 interactions. A previous study has shown that our inhibitors can dose-dependently reduce lipid accumulation in adipocytes differentiated from primary human mesenchymal stem cells and stimulate neurite outgrowth in differentiated neuroblastoma SH-SY5Y cells. Objective: This study aims to investigate the potential roles of FKBP51-Hsp90 interaction inhibitors on metabolic and cognitive dysfunction in vivo. Methods: Pharmacokinetic study: Plasma and brain samples were ocollected and analyzed by liquid chromatography-mass spectrometry. High-fat diet (HFD) study: Male C57BL/6J mice were fed either chou diet or HFD for 4 weeks and then treated with vehicle or inhibitor E8 (20 mg/kg, Sc) and their respective diets for another 4 weeks. Behaviors, body composition measurements by EchoMRI, fasting glucose/insulin detections and glucose/insulin tolerance tests were performed during the last week. Hippocampus was collected for western blot, RNA sequencing and quantitative real-time PCR analysis. Results: After subcutaneous injection, E8 can be quickly absorbed into the blood and penetrate the blood-brain barrier. In HFD model, E8 can attenuate the impairment of locomotor activity and short-term memory. But it could neither reduce body weight gain, nor improve insulin sensitivity and glucose/insulin tolerance. In the hippocampus, E8 reduces the elevated p-tau (Ser214)/tau levels induced by HFD but does not show any effects on insulin signaling. It suggests that E8 reverses the behavioral impairments independently of metabolic regulation in vivo. The underlying mechanisms were further investigated by RNA sequencing and quantitative real-time PCR analysis. Conclusion: We showed that inhibiting FKBP51-Hsp90 interactions with small molecules provides novel therapeutic targets on cognitive dysfunction in obesity. Disclosures: The authors declare no conflict of interest. Key words: cognition; FK506-binding protein 51; inhibitor; high-fat diet; obesity.
P198- INTRACELLULAR AB ACCUMULATION IN HIPPOCAMPAL NEURONS LEADS TO ENDOSOMAL/LYSOSOMAL LEAKAGE. S. Schedin Weiss1, Y. Gao1, L.O. Tjernberg1(1. Karolinska Institutet - Solna (Sweden))
Background: Alzheimer disease (AD) is characterized by plaques loaded with accumulated amyloid β-peptide (Aβ) and neurofibrillary tangles composed of tau. Still, the molecular details behind AD are largely unknown. However, intracellular levels of Aβ containing 42 amino acids (Aβ42) has been shown to correlate with AD neuropathology (1). Using super-resolution microscopy, we have identified different pools of Aβ42 in hippocampal neurons (2, 3). We hypothesize that some intracellular pools of Aβ42 are physiologically relevant whereas other pools are toxic. As an important source of intracellular Aβ, extracellular Aβ can be internalized and accumulated in endocytic vesicles. Previously, we treated hippocampal neurons with Aβ42 monomers and detected Aβ42 oligomerization in the late endosomes/lysosomes by using Förster resonance energy transfer (FRET) live cell imaging (4). However, it is still unknown how intracellular aggregated Aβ causes toxicity to the cells. In this study, we investigate whether low extracellular Aβ42 levels can be endocytosed and accumulated in late endosomes/lysosomes to a high concentration and cause endosomal/lysosomal membrane permeabilization in primary neurons. Objectives: Our aim is to - at a cellular level - further understand the uptake and subcellular polymerization of Aβ and explore the mechanisms of cytotoxicity of intracellular Aβ in neurons. Our overarching goal is to specifically use intracellular Aβ as a target for pharmaceutical intervention of AD. Methods: Hippocampal neurons were isolated from E16–17 C57BL/6 mice embryo brains and cultured for 21 days in vitro. Neurons were treated with monomeric Aβ42 with or without fluorescent labels at different concentrations for different time periods in an acute or chronic model. Intracellular accumulation of Aβ42, taken up from the medium, was monitored over time by lattice light sheet microscopy. Aβ42 concentrations in neuronal vesicles were determined by live cell imaging by using confocal microscopy. Immunocytochemistry and Airyscan microscopy were used to detect the loss of endosomal/lysosomal integrity in neurons. Results: Monitoring uptake of Aβ42 during 24 h showed that the majority of Aβ42 was transported to the soma region where it accumulated in late endosomes/lysosomes. Treatment with 1 nM Aβ42 for 20 days caused three orders of magnitude higher concentrations in late endosomes/lysosomes as compared to the cell culture medium. Accumulated Aβ42 induced endosomal/lysosomal leakage when Aβ42 concentration reached micromolar levels in those vehicles. Conclusion: These data suggest that extracellular Aβ42 is endocytosed, gradually accumulates in late endosomes/lysosomes where it polymerizes and damages vesicle integrity. The damaged vesicle may release Aβ42 and other lysosomal components into the cytosol and thus generate toxicity. We therefore consider the late endosomal/lysosomal pool of aggregated Aβ42 as a target for AD treatment. References: 1. Hashimoto, M., et al., Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer’s disease neuropathology. Acta Neuropathol, 2010. 119(5): p. 543–54. 2. Yu, Y., et al., Neuronal Abeta42 is enriched in small vesicles at the presynaptic side of synapses. Life Sci Alliance, 2018. 1(3): p. e201800028. 3. Yu, Y., et al., A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons. J Alzheimers Dis, 2021. 83(2): p. 833–852. 4. Gao, Y., et al., Live Cell FRET Imaging Reveals Amyloid beta-Peptide Oligomerization in Hippocampal Neurons. Int J Mol Sci, 2021. 22(9).
P199- ALZ-201, A MONOCLONAL ANTIBODY THERAPY FOR SPECIFIC NEUTRALISATION OF TOXIC AMYLOID-B IN ALZHEIMER’S DISEASE. A. Sandberg1(1. Alzinova AB - Gothenburg (Sweden))
Background: The conspicuous plaques in Alzheimer’ disease (AD) brains are mainly deposits of insoluble fibrillar assemblies of the peptide amyloid-β (Aβ). These assemblies are effectively targeted by monoclonal antibodies (mAb) exhibiting selectivity for aggregated forms of Aβ (aducanumab, lecanemab, and gantenerumab) or specificity for pyroglutamated forms (donanemab). Plaques are, however, not nearly as toxic as some soluble oligomeric forms of Aβ and clinical benefits of plaque reduction are very modest. The oligomer-targeting vaccine candidate ALZ-101 (NCT05328115) was therefore used to develop a murine mAb, ALZ-201, as a potential therapy capable of specifically targeting toxic oligomeric Aβ thereby avoiding binding to plaques and non-aggregated Aβ altogether. We here show data on how this antibody was developed, characterised, validated, and humanised in preparation for clinical trials on AD patients. Objective: Develop mAb ALZ-201 as a potential AD therapy. Methods: Monoclonal murine ALZ-201 was purified from a mouse hybridoma isolated after vaccination with ALZ-101. Conformational specificity for oligomeric Aβ was confirmed with ELISA against various non-aggregated and aggregated forms of the peptide and therapeutic potential investigated using human AD brain extracts and automated high content microscopy analysis of primary mouse neuron cultures in vitro, as previously reported. A chimeric antibody, chALZ-201, with backbones for human IgG1 HC constant region and human kappa LC constant region was then designed and transiently expressed in CHO cells. Binding specificity of chALZ-201 was verified and benchmarked with biosimilars of aducanumab, lecanemab, and gantenerumab using ELISA against different aggregated forms of Aβ. Further humanisation of ALZ-201 resulted in several promising candidates. Biacore analysis was used to determine the binding affinity towards the stabilised oligomer antigen in vaccine ALZ-101. Results: ALZ-201 was isolated as a murine IgG3 and found to be truly specific, not just selective, for structured oligomers as opposed to control antibody 6E10 which was reactive towards all forms of the peptide. Murine ALZ-201 and chALZ-201 did exhibit a small yet statistically significant difference in EC50 for the oligomeric form by 29 ng/mL (95% CI, 22.3267 to 35.9192, p<0.0001), but did not bind any other conformations of the peptide, indicating that the antigen-binding properties are retained in the chimeric human IgG1 variant of murine ALZ-201. In contrast, aducanumab, lecanemab, and gantenerumab had similar affinities for all different conformations of the peptide. Biacore measurements demonstrated that chALZ-201 had high affinity for ALZ-101 oligomers, with a binding off-rate (koff) of 4.67x10-4 s-1 and a binding constant of 1.56 nM (humanised variants had similar values). Furthermore, our studies indicate that very few species of Aβ are ALZ-201 reactive. In actively aggregating Aβ42, for instance, these “ALZ-201 reactive oligomers” reach a maximum of 39.4 ± 5.6 ng/mL after 20 min after which they slowly disappear over the course of 40 min as the rate of fibrillisation increases. This corresponds to only 0.047% of all Aβ42. As previously shown, similar results were found when immunodepleting AD brain extracts with ALZ-201, which did not significantly impact the measured amounts of Aβ. Remarkably, immuno-depletion of AD brain extracts with ALZ-201 efficiently neutralised the Aβ-mediated neurotoxicity in these extracts to a similar extent as 4G8 (removes all Aβ) despite the low abundance of ”ALZ-201 reactive oligomers”. Conclusion: Our studies confirm the binding specificity of the unique mAb ALZ-201, which recognises a conformational epitope on the stabilised oligomer antigen in vaccine ALZ-101 and a subset of synthetic Aβ42 oligomers. We previously demonstrated that ALZ-201 specifically binds to a toxic species in post-mortem AD brain extracts to cause a positive physiological and protective impact on the integrity and morphology of mouse neurons. Biosimilars of aducanumab, lecanemab, and gantenerumab, on the other hand, were here shown to exhibit no conformational preference for Aβ, indicating that their weak binding to non-aggregated forms stem almost exclusively from fast binding off-rates. Consequently, these antibodies will target plaques with high functional affinity because plaques are likely to be the largest multivalent Aβ structures in the brain. Given the modest clinical effect plaque reduction has on pathology, next generation anti-Aβ therapies ought to instead focus on antibodies that are truly specific for toxic forms of soluble oligomeric Aβ. To this end, a lead humanised candidate of ALZ-201 is now in preparation for clinical trials on AD patients.
P200- REDUCING TOXIC AMYLOID-B OLIGOMERS IN AD THROUGH PRECISE TARGETING OF THE MOLECULAR MECHANISMS OF OLIGOMER FORMATION WITH SMALL MOLECULE INHIBITORS. J. Habchi1, K. Jenkins1, S. Pandey1, R. Staats1, S. Sarwat1, B. Mannini1, X. Yang1, L. Rajah1, S. Cohen1, S. Brewerton1, A. Plowright1(1. Wren Therapeutics Limited - Cambridge (United Kingdom))
Background: Oligomeric forms of Aβ, as opposed to monomers or large fibrils and plaques, have been shown to have wide-ranging neurotoxicity and underlie the onset and progression of Alzheimer’s Disease. These Aβ oligomers bind directly to membranes and receptors, disrupt key cellular and neuronal functional pathways, and cause neuronal death, but have so far proved challenging to target with conventional drug discovery approaches. Using the framework of “chemical kinetics”, we have mapped the key molecular mechanisms that generate oligomers: primary nucleation (where several monomers come together to form an oligomer) and secondary nucleation (where oligomer formation is catalysed and accelerated by the presence of Aβ fibrils / plaque). Here, we present initial data with small molecule oligomer inhibitors, discovered using our proprietary drug discovery platform, that precisely target these molecular mechanisms of oligomer generation. This unique approach is designed to inhibit both intracellular and extracellular sources of toxic Aβ oligomer species, to address neurodegeneration across progressive stages of AD, and is distinct from conventional antibody approaches that focus on clearing fibrils and plaques in the extracellular space. Objectives: To develop potent and precise inhibitors of oligomer generation from both primary and secondary nucleation of Aβ, examine their effect on Aβ aggregation, and investigate their therapeutic efficacy in a range of pre-clinical models. Methods: In vitro screening and validation assays were used to screen and characterise compounds that inhibit Aβ aggregation, starting from recombinant human Aβ(1–42) in monomeric form. These assays were carried out in a range of conditions (different buffers, protein mutants and isoforms, with and without the presence of pre-formed fibrils, as well as using human patient brain tissue to seed in vitro aggregation). Following compound optimisation including potency, oral pharmacokinetics and brain penetration, the effect of these compounds was explored in several translational models: transgenic, human-Aβ-expressing C. elegans; iPSC-derived glutamatergic neurons and a transgenic mouse model (APPSL). In the transgenic C. elegans model, animals expressing human Aβ in their muscular cells were grown on media dosed with WTX in the nM to mM range. Measurements of aggregated Aβ in the head region of the C. elegans and phenotypic motility (the “bends per minute” seen in the animals) were taken and compared to those for untreated and wild type animals. In the iPSC-derived glutamatergic neuron model, differentiated cells were incubated with Aβ monomer, pre-formed fibrils, or a combination of monomer and pre-formed fibrils (where oligomer generation is expected to be high), in the absence or presence of WTX. The cells were then stained and their levels of synapsin and aggregated Aβ (pFTAA) quantified. In the APPSL mouse model, 6-month old male transgenic mice were treated orally for 8 weeks with a daily dose of 100mg/kg WTX. Whole brain hemispheres from treated and control mice were homogenised and the oligomer levels in each mouse were quantified using a proprietary ELISA-based assay. Results: Wren has discovered and developed extremely potent small-molecule inhibitors of Aβ oligomer generation from primary and secondary nucleation, with up to 96% inhibition of each mechanism in vitro. This inhibition is conserved across different conditions and forms of Aβ, and is highly specific to Aβ vs other aggregating proteins. In C. elegans, aggregate levels in treated animals were reduced to those seen in wild-type animals, with a 75% recovery in motility phenotype vs untreated animals. In iPS cells, WTX treatment significantly reduced Aβ aggregate levels in cells insulted with a combination of monomer and fibrils, along with a significant recovery in synapsin levels, indicative of a recovery in synaptic function. In the APPSL mouse model, daily treatment with 100mg/kg WTX was well tolerated and provided consistent and robust pharmacokinetics throughout the study duration. In this model WTX reduced oligomer levels by 69% vs vehicle mice. Conclusion: We have demonstrated a robust platform for the discovery and development of precise and potent small molecule inhibitors of Aβ oligomer generation. We have shown that these small molecules are potent inhibitors of oligomer generation across a range of different in vitro conditions and assays, and that they can be optimised to enable the reduction of both oligomer and aggregate levels, with a clear link to functional benefit, across multiple translational models.
P201- THE BROMODOMAIN AND EXTRATERMINAL DOMAIN PROTEIN INHIBITOR APABETALONE INHIBITS THE NEUROTOXIC KYNURENINE PATHWAY IN MONOCYTES AND BRAIN ENDOTHELIAL CELLS. S. Wasiak1, L. Fu1, S.D. Stotz1, D. Gilham1, L.M. Tsujikawa1, C.D. Sarsons1, J. Kroon2, E.S.G. Stroes2, N.C.W. Wong1, M. Sweeney3, J. Johansson3, E. Kulikowski1(1. Resverlogix - Calgary (Canada), 2. University of Amsterdam - Amsterdam (Netherlands), 3. Resverlogix - San Francisco (United States))
Background: The kynurenine pathway (KP) is activated in several neurodegenerative and neuropsychiatric disorders including Alzheimer’s disease. During chronic inflammation, multiple cell types express KP enzymes, with monocytes being the most active producers of KP metabolites. Proinflammatory cytokines induce the expression of two KP rate-limiting enzymes: indoleamine 2,3-dioxygenase 1 (IDO1) responsible for the conversion of tryptophan to kynurenine, and kynurenine 3-monooxygenase (KMO) that facilitates conversion of kynurenine into 3-hydroxykynurenine. These three metabolites can cross the blood brain barrier where they are processed by brain cells into neuroactive molecules, the ratio of which can either be neuroprotective or neurotoxic. The kynurenine-to-tryptophane ratio, an indicator of IDO1 peripheral activity, is elevated in patients with neurodegenerative disease. Reducing the activity of the KP pathway in the circulation favorably alters the ratio of KP metabolites in blood and the brain and has been shown to improve disease outcomes in mouse models of Huntington’s disease and Alzheimer’s disease. Objectives: Epigenetic regulators bromodomain and extraterminal domain (BET) proteins control responses to cytokines in monocytes, endothelial cells and hepatocytes. Here, we tested the ability of a clinical-stage BET inhibitor (BETi) apabetalone (also called RVX-208) to counter the cytokine-dependent production of KP enzymes and kynurenine in cultured cells. Methods: The monocyte-like THP-1 cell line, the hCMEC/D3 human brain endothelial cell line, primary human monocytes, hepatocytes and whole blood were treated with apabetalone and/or TNFa+IFNy or IFNy alone (10 ng/mL, 4 to 48h). mRNA levels measured by real time PCR or gene expression microarrays. Intracellular proteins were measured by flow cytometry. KP metabolite levels in cell culture media were measured using ELISAs (ImmuSmol) or UHPLC-MS/MS (biocrates). Results: In primary human monocytes, IDO1 mRNA was undetectable in basal conditions. Stimulation with IFNy strongly induced its transcription (>300-fold), which was largely countered by cotreatment with apabetalone (-62% at 5 µM, −95% at 25µM, 4h). In TNFα+IFNγ stimulated THP-1 cells, apabetalone reduced IDO1 mRNA (−62% at 5 µM, −90% at 25 µM, 4h) and protein (−36% at 5 µM, −80% at 25µM, 24h) levels and countered the accumulation of kynurenine in the cell supernatant (−30% at 5µM and −70% at 25µM, 24h). In IFNγ-treated primary monocytes, apabetalone (25µM, 24h) completely reversed tryptophan consumption and reduced kynurenine accumulation in the cell culture supernatant (−85%), resulting in lower kynurenine-to-tryptophane ratio (−87%). These results show that BETi reduced IDO1 activity in monocytes. In human brain microvascular endothelial cells, which form the blood brain barrier, apabetalone downregulated the cytokine induced IDO1 mRNA (−44% at 5µM, −85% at 25µM, 24h) and protein (−58% at 5µM, −85% at 25µM, 24h) levels, as well as kynurenine production (−50% at 25µM, 24h). Finally, apabetalone reduced non-stimulated KMO levels in ex vivo treated human whole blood (−60% at 5 µM, −74% at 20µM, 24h, n=3 donors), primary monocytes (−80% at 25µM, 4h, n=10 donors) and hepatocytes (−70% at 30µM, 48h, n=2 donors). Cytokine-mediated KMO induction in THP-1 cells was also countered by apabetalone at both gene (−41% at 5µM, −90% at 25µM, 24h) and protein (−60% at 25µM, 24h) level. Conclusions: Apabetalone decreases proinflammatory activation of the KP in vitro in multiple cell types. These findings provide mechanistic insights to the beneficial effects of apabetalone on cognition that were recently demonstrated in a phase 3 clinical trial (BETonMACE): diabetic coronary artery disease patients with baseline MoCA scores ≤21 experienced a significant 1.8-unit improvement in MoCA scores following apabetalone treatment versus placebo (p=0.02) over 24 months. Conflicts of Interest: SW, LF, SCS, DG, LMT, CDS, NCWW, MS, JOJ, EK are employed by Resverlogix and hold Resverlogix stock. JK and ESGS have no competing interests.
P202- A NOVEL THERAPEUTIC APPROACH TO TREAT ALZHEIMER’S DISEASE: THE BRAIN-SPECIFIC SIGNAL PEPTIDE PEPTIDASE-LIKE 2B (SPPL2B). S. Tambaro1, R. Maccioni2, C. Travisan3, S. Zerial3, A. Wagener4, Y. Andrade-Talavera1, F. Picciau2, C. Grassi5, G. Chen6, A. Fisahn1, B. Schröder7, P. Nilsson1(1. Department of Neurobiology, Care Sciences and Society (NVS) Division of Neurogeriatrics, Karolinska Institutet - Solna (Sweden), 2. Department of Biomedical Sciences, Neuroscience and Clinical Pharmacology, University of Cagliari - Cagliari (Italy), 3. Department of life science, University of Trieste - Trieste (Italy), 4. Interdisciplinary center for Neuroscience, Heidelberg University - Heidelberg (Germany), 5. Department of Pharmacy and Biotechnology, University of Bologna - Bologna (Italy), 6. Department of Biosciences and Nutrition, Karolinska Institutet - Huddinge (Sweden), 7. Institute of Physiological Chemistry, Technische Universität Dresden - Dresden (Germany))
Background: Alzheimer’s disease (AD) is a multifactorial disorder in which the abnormal brain production of amyloid β-peptide (Aβ) plays a crucial role in the disease onset. Identifying new proteins and pathways involved in the Aβ cascade is essential to providing novel, effective therapeutic targets. The intramembrane enzyme signal peptide peptidase-like 2 b (SPPL2b), which belongs to the same protein family as Presenilin, is a new potential target since it is involved in the proteolysis of the AD-related proteins: TNF-alpha and BRI2, implicated in the inflammatory response and Aβ production, respectively. The SPPL2b substrate BRI2 is considered an anti-Alzheimer gene that negatively regulates Aβ production by binding to APP and inhibiting its secretase processing by secretases. SPPL2b modulates the APP-BRI2 interaction by cleaving BRI2 in its transmembrane region. Most importantly, it has been reported that SPPL2b levels drastically increase in the early stage of AD. SPPL2b localizes in the cell membrane and is expressed predominantly in the hippocampus and cortex, suggesting a role of SPPL2b in learning and memory. Objectives: Based on these findings, we believe that the SPPL2b enzymatic activity may play an essential role during AD pathogenesis. In the present study, we investigated the expression levels and the pathogenic role of SPPL2b in AD. Methods: For this purpose, the pathophysiological role of SPPL2b in Aβ metabolism was evaluated in vitro by using human cell lines stably expressing APP (SH-SY5Y and HEK293), mouse primary neuronal cell cultures, and acute mouse brain slices. Furthermore, we evaluated the SPPL2b expression in the new state-of-the-art App knock-in AppNL-G-F AD mouse and human postmortem AD brain tissues. Results: The overexpression of human APP in SH-SY5Y cells leads to an increase in the levels of SPPL2b. A biphasic expression of SPPL2b was observed in SH-SY5Y cells upon treatment with Aβ42. In brain slices-maintained ex vivo, Aβ42 exposure induced a strong up-regulation of SPPL2b. SPPL2b expression was also evaluated in the AD mouse model AppNL-G-F. Interestingly, an increased level of SPPL2b was observed in the cortex in the early stage of the AD-associated Aβ pathology of 3 months old AppNL-G-F mice. However, at 22 months of age, when Aβ pathology is severe and accompanied by neuroinflammation in this mouse model, SPPL2b protein expression was significantly lowered compared to control mice. Similarly, a significantly decrease in SPPL2b was also observed in human AD samples at Braak stages V and VI. Furthermore, immunofluorescence staining showed that SPPL2b is expressed in neurons and glia deposited in the Aβ plaques in AppNL-G-F but not in astrocytes. Further, the overexpression of SPPL2b in human cells led to an increase in APP cleavage by cleaving Bri2, whereas neurons derived from SPPL2b knock-out mice exhibited lower APP cleavage, reinforcing the involvement of SPPL2b in the APP processing. Conclusions: These results strongly support the involvement of SPPL2b in AD pathology. Most importantly, Aβ42 directly effects SPPL2b expression, inducing a vicious cycle where Aβ42, SPPL2b, BRI2, and APP are involved. Our findings show that SPPL2b is increased in the early stages of AD, indicating its involvement in the pathogenesis of the disease by promoting both the inflammatory (TNF-alpha cleavage) and amyloidogenic pathway (BRI2 cleavage). In a global scenario characterized by the urgent need to identify novel strategies to prevent and counteract AD progression, this study points out the importance of SPPL2b. This data provides an incentive to explore more the SPPL2b role in AD and eventually develop selective inhibitor compounds targeting SPPL2b. In this context, the systemic administration of SPPL2b inhibitors/modulators in mouse AD models will be necessary to evaluate the potential of targetting SPPL2b for treating AD. Furthermore, the brain-specific expression and the few substrates related to SPPL2b may lower the risk of side effects in pharmacological treatment.
P203- INCREASED CSF-DECORIN PREDICTS BRAIN PATHOLOGICAL CHANGES DRIVEN BY ALZHEIMER’S AB AMYLOIDOSIS. R. Jiang1, U. Smailovic1, H. Haytural1, B. Tijms2, H. Li1, G. Shevchenko3, J. Gobom4, S. Nyström5, P. Hammarström5, S. Syvänen3, H. Zetterberg4, B. Winblad1, J. Bergquist3, P. Jelle Visser2, P. Nilsson1(1. Karolinska Institutet - Stockholm (Sweden), 2. Amsterdam UMC - Amsterdam (Netherlands), 3. Uppsala University - Uppsala (Sweden), 4. Sahlgrenska Academy at the University of Gothenburg - Gothenburg (Sweden), 5. Linköping University - Linköping (Sweden))
Background: Alzheimer’s disease (AD) is caused by amyloid-beta (Aβ) amyloidosis which starts 20 years before onset of clinical symptoms. Biomarkers reflecting early events in the development of the pathology are needed for early diagnosis, prevention, and treatments. Objectives: AD brains are characterized by extracellular Aβ deposition and autophagy dysregulation. Here we aimed at deepening the understanding of how these brain pathologies translate to the CSF to identify potential biomarkers by combining preclinical and clinical data. Methods: We used two state-of-the-art App knock-in AD mouse models, AppNL-F and AppNL-G-F, exhibiting AD-like Aβ pathology to analyze how the brain pathologies translate to CSF proteomes by label-free mass spectrometry (MS). The mouse CSF proteomes were further stratified to a previous CSF proteome dataset obtained from patients across the AD spectrum in the large human European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) cohort (n = 310). Correlations of newly identified CSF proteins were performed with CSF-Aβ, CSF-tau and CSF-t-tau, followed by receiver operating characteristic (ROC) analysis. Results: The label-free MS identified several extracellular matrix (ECM) proteins as significantly altered in App knock-in mice. The mouse CSF proteomes were compared with previously reported human CSF MS results acquired from patients across the AD spectrum. Intriguingly, the ECM protein decorin was similarly and significantly increased in both AppNL-F and AppNL-G-F mice, strikingly already at three months of age in the AppNL-F mice and preclinical AD subjects having abnormal CSF-Aβ42 but normal cognition. Notably, in this group of subjects, CSF-decorin levels positively correlated with CSF-Aβ42 levels indicating that the change in CSF-decorin is associated with early Aβ amyloidosis. In addition, CSF-decorin highly correlated with both CSF-t-Tau and CSF-p-Tau. Importantly, ROC analysis revealed that CSF-decorin can predict a specific AD subtype having innate immune activation and potential choroid plexus dysfunction in the brain. Consistently, in AppNL-F mice, increased CSF-decorin correlated with both Aβ plaque load and with decorin levels in choroid plexus. In addition, a low concentration of human Aβ42 induces decorin secretion from mouse primary neurons. Interestingly, we finally identify decorin to activate neuronal autophagy through enhancing lysosomal function. Altogether, the increased CSF-decorin levels occurring at an early stage of Aβ amyloidosis in the brain may reflect pathological changes in choroid plexus, present in a subtype of AD subjects. Conclusions: Decorin has the potential to be a CSF biomarker for early Aβ amyloidosis and may reflect changes in choroid plexus.
P204- ANTIBODIES GENERATED AGAINST AN AB-DERIVED OLIGOMER: EFFORTS TOWARD A NOVEL ALZHEIMER’S DISEASE IMMUNOTHERAPY. C.M. Parrocha1, A. Kreutzer2, J. Pascual3, C. Stringer3, J. Nguyen1, A. Ith1, E. Head3, J. Nowick1,2(1. Department of Pharmaceutical Sciences, University of California Irvine - Irvine (United States), 2. Department of Chemistry, University of California Irvine - Irvine (United States), 3. Department of Pathology and Laboratory Medicine, University of California Irvine - Irvine (United States))
Background: β-Amyloid (Aβ) peptide vaccines are promising therapeutics against Alzheimer’s disease (AD) which rely on the generation of antibodies after an endogenously administered Aβ antigen. These newly generated anti-Aβ antibodies neutralize endogenous targets of interest that are similar to the antigen. Thus far, there are no Aβ peptide vaccine candidates that have received FDA approval. Current Aβ peptide vaccine clinical candidates rely on non-conformationally defined fragments of full-length Aβ as the antigen. However, these fragments could self-aggregate into heterogeneous higher orders of assembly which may lead to inconsistent treatments and potentially harmful side effects. Due to their cytotoxic properties, Aβ oligomers are strong contributors to the progression and pathogenesis of AD, as they induce cognitive impairment, and inhibit long-term potentiation. For this reason, Aβ oligomers have become an attractive target for novel peptide vaccines and immunotherapies. However, Aβ oligomers are an elusive species; there is no structural definition for Aβ oligomers due to their diversity in size, heterogeneity, and propensity to self-assemble into fibrils. To study the properties of Aβ oligomers, we generated synthetic peptides derived from fragments of full-length Aβ that share properties similar to Aβ oligomers. These Aβ-derived oligomers are well characterized by X-ray crystallography, SDS-PAGE, size exclusion chromatography, cytotoxicity assays on SHSY-5Y human neuroblastoma, and incorporate native residues that stabilize their higher order assemblies. In our extensive collection of Aβ-derived oligomer peptide models, the 4AT-L Aβ-derived oligomer contains the most native residues of full-length. Our aim was to generate a novel peptide vaccine with 4AT-L that ameliorates AD pathology in the 5xFAD transgenic mouse model and could serve as a potential new therapeutic against AD. Objectives: We hypothesized that 4AT-L would stimulate the production of antibodies that target endogenous Aβ and may lead to amelioration of cognitive impairment and pathology in the 5xFAD AD transgenic mouse model. As a proof of concept, rabbit polyclonal antibodies were generated against 4AT-L creating the 4AT-L polyclonal antibody (pAbs) to determine if these can recognize Aβ ex vivo by immunofluorescent microscopy. Using the same immunization strategy we generated rabbit polyclonal antibodies to immunize C57BL/ mice and obtained antibody titers similar to those reported in literature for other preclinical AD vaccine studies. Once the immunizations strategy was confirmed via antibody titers in C57BL/6, 5xFAD mice were immunized with previously reported immunization regime. After the mice had grown into their pathology (ca. 8 months) memory, cognition, and reduction in Aβ loads, will be accessed by a battery of behavior assays as well as histology and biochemical assays. Methods: 4AT-L is the product of three macrocyclic peptide monomers that are covalently stabilized into a trimer with disulfide bonds. To assess if 4AT-L can stimulate the production of 4AT-L pAbs rabbits were immunized with 4AT-L by Pacific Immunology (Ramona, CA). 4AT-L pAbs were then sent to the Nowick Group for affinity purification. Immunofluorescence microscopy on brain samples from 5xFAD mice and people with AD was used to determine if antibodies generated from 4AT-L recognize Aβ ex vivo. Optimal vaccine regime and formulation was determined in C57BL/6. 5xFAD received interperitoneally injections of 100 mg of 4AT-L conjugated to Keyhole limpet Hemocyanin and formulated with AddaVax™ once every 28 days for a total of five immunizations. Results: Preliminary studies indicate that rabbits immunized with 4AT-L sustained a strong immune response (reported antibody titer >1:5000). Through immunofluorescent staining, the 4AT-L pAb, recognizes Aβ pathology brain samples of 5xFAD mice as well as people with AD and people with Down Syndrome and AD. We have additionally observed that 4AT-L recognizes cerebral amyloid angiopathy, which is the accumulation of Aβ within blood vessel walls, a pathology highly prevalent in people with Down Syndrome and AD. C57BL/6 immunized with 4AT-L demonstrated a sustained immune response with antibody titers as high as ca. 1:1000. 5xFAD mice immunized using the same vaccine approach with antibody titers as high as approaching 1:2000. Behavior assays assessing for improvement in memory and cognition will begin in June 2022. Conclusion: Based on preliminary data, the 4AT-L pAb recognizes pathology in brain samples of 5xFAD mice, as well as people with AD and people with Down Syndrome and AD. Further characterization of the polyclonal antibody will be performed to determine the potential of the polyclonal antibody as a tool to better understand the molecular basis of AD, and isolate monoclonal antibodies for potential passive immunotherapy studies. Both C57BL/6 and 5xFAD mice generated literature precedent antibody titers against 4AT-L which may infer an amelioration of AD pathology in 5xFAD mice. This body of work is not yet published, and final results will be presented at CTAD.
LP99- REDUCTION OF PLASMA P-TAU181 FROM A PHASE1A RANDOMIZED TRIAL OF NNI-362 IN A HEALTHY AGED POPULATION CONSISTENT WITH AMELIORATION OF TAU HYPERPHOSPHORYLATION IN HUMAN DIFFERENTIATED NEURON CULTURES. R. Turner1, M. Mielke2, J. Kelleher-Andersson3(1. Georgetown Univ. - Washington, Dc (United States), 2. Mayo Clinic - Rochester, Mn (United States), 3. Neuronascent, Inc. - Clarksville, Md (United States))
Background: NNI-362 is a novel small molecule discovered by phenotypic screening of compounds that have neuroprotective capacity and promote new neurons from endogenous human neural progenitor cells. A placebo-controlled, double-blind Phase 1a trial* examined the safety and tolerability of NNI-362, as well as a pharmacodynamic outcome - the level of plasma p-tau181 - a blood-based biomarker of Alzheimer’s disease (AD) pathology. Objectives: The aim of this study was to determine the safety, tolerability, and biomarker effects of NNI-362 in a first-in-human study of healthy aged subjects, and to relate biomarker outcomes to preclinical efficacy models. Methods: Oral NNI-362 and matching placebo were formulated by Parexel (Glendale, CA). Healthy, cognitively-unimpaired individuals (age 50–72) were randomized at a 1:3 ratio to placebo:drug, with the sponsor, PI, and subjects all blinded. Duplicate frozen plasma samples were analyzed (blinded to treatment) at Mayo Clinical Laboratories (MN) from the placebo group and the two highest SAD/ MAD dose arms of 120 and 240 mg NNI-362. Levels of plasma p-tau181 were determined using a SimoaTM HD Analyzer (Lot Number 503008) with an Advantage V2 Kit. Calibration curves of p-tau181 ranged between 0.00–74.6 pg/mL. Plasma biomarkers were examined at pre-treatment (baseline), day 15 (12 h post final dose), and day 16 (24 h post final dose). Statistical analyses examined a change from the pre-treatment level of p-tau181. Results: NNI-362 treatment was safe and well-tolerated in cognitively unimpaired older individuals. NNI-362, at the two highest multi-doses, 120 mg and 240 mg, significantly reduced plasma p-tau181 in participants compared to pre-treatment levels (p<0.0012 and p<0.0009, respectively), while on average no change occurred in subjects receiving placebo (Chengxie Xiong, Ph.D. - Lily Consultants). These results are consistent with a reduction of tau phosphorylation by NNI-362 in vitro using differentiated human neural progenitor cells (Lonza, MD) stimulated by Ab25–35 exposure. Conclusion: These findings suggest that even in a small number of healthy older subjects, oral NNI-362 appeared safe and well-tolerated, and reduced plasma p-tau181 levels - a blood-based biomarker of AD pathology. Further study, including a Phase 2 trial of NNI-362, are warranted in individuals with neurodegenerative tauopathies including AD. *NIA grant-R01AG056561 (PI-JKA). COI statement: RST is a consultant for Neuronascent, Inc. and Re:Cognition Health; Georgetown University receives research funding from Lilly, Biogen, Eisai, Novartis, Roche, Genentech, Janssen, and Alector.
LP100- INHIBITION OF EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1 (ENT1) INHIBITOR AS A NOVEL THERAPEUTIC TREATMENT TO RESCUE ALZHEIMER’S DISEASE PATHOLOGY AND COGNITIVE IMPAIRMENT. C.W. Wu1,2, C.P. Chang1,2, C.Y. Lin1,2, K.C. Wu2,3, H.H. Yeh4, C.J. Lin2,3, Y. Chern1,5(1. Institute of Biomedical Sciences, Academia Sinica - Taipei (Taiwan, Republic of China), 2. Biomedical Translation Research Center, Academia Sinica - Taipei (Taiwan, Republic of China), 3. School of Pharmacy, National Taiwan University - Taipei (Taiwan, Republic of China), 4. Brain research center, National Yang Ming Chiao Tung University - Taipei (Taiwan, Republic of China), 5. Biomedical Translation Research Center - Taipei (Taiwan, Republic of China))
Background: Alzheimer’s disease (AD) is the most prominent neurodegenerative disease in aging societies and generates a significant burden on the healthcare system. Abnormal protein aggregations (e.g., extracellular amyloid plaque and intracellular neurofibrillary tangles) are commonly observed in the brain of AD patients, and cause AD pathogenesis including neuritic dystrophy, synapse loss, microgliosis, astrogliosis, and cognitive impairment. To date, most of the potential AD treatments in clinical trials were designed based on the amyloid hypothesis and tauopathy. Effective drugs that ameliorate the symptoms or progression of AD remain to be found. Therefore, new drug targets for AD are urgently needed. The adenosinergic system is dysregulated in AD. Adenosine is an important homeostatic building block of many important metabolic pathways, which modulates physiological functions in the central nervous system. Equilibrative nucleoside transporter 1 (ENT1) is a bidirectional transporter that transports adenosine in a concentration-dependent manner. Our previous study demonstrated that inhibition of ENT1 before the disease onset prevents cognitive dysfunction of two AD mouse models, which further support that targeting the adenosine homeostasis may become a new strategy for the development of AD treatment. Objectives: We set out to characterize an orally active small compound (designed J4) that inhibits ENT1 in the blockage of the amyloid- and tau-related pathologies of AD. Methods: Two distinct AD mouse models (APP/PS1 for amyloidosis and THY-Tau22 for tauopathy) with the onset of memory deficiency at the age of 6 months were employed. To examine the therapeutic effects, mice were treated with J4 (3 mg/kg/day) in drinking water containing 1% HPβCD at the late disease stage (10–12 months old) for one month. The cognitive functions of AD mice and their littermate controls were examined using the Morris water maze task. The mitochondrial mass, neuroinflammation, and abnormal protein aggregations (e.g., Aβ and tau deposition) were evaluated by biochemical and pathological analyses (including positron emission tomography, immunofluorescence staining, and western blot analysis). Results: Our results showed J4 exhibited superior profiles in pharmacokinetics (including decent oral bioavailability, good exposure to the brain, and low potential for drug-drug interaction) and safety (no obvious toxicity during high-dose repeated treatments and a low binding affinity to hERG). One-month treatments with J4 in symptomatic APP/PS1 and THY-Tau22 mice rescued cognitive decline and impaired spatial memory. In addition, J4 treatment ameliorated the mitochondria loss and energy deprivation accompanied by the reduction of Aβ and tau deposition, oxidative stress, and neuroinflammation of APP/PS1 and THY-Tau22 mice at the symptomatic phase. Conclusion: Data from the present study showed that modulation of adenosine homeostasis by J4 provided beneficial effects in two AD models at the symptomatic stage, supporting that targeting adenosine metabolism is a novel and effective therapeutic strategy for AD.
LP101- CHARACTERIZING THE MOLECULAR DETERMINANTS OF THE LECANEMAB PARATOPE BINDING SITE BY COMBINING IN SILICO PREDICTION AND IN VITRO FAB ANALYSIS ON AD BRAIN EXTRACTS. J.P. Bellier1, L. Liu1, D.J. Selkoe1(1. Brigham and Women’s - Boston (United States))
Background: In Alzheimer’s disease (AD), soluble amyloid beta-protein (Aβ) aggregates have been reported to be more neurotoxic than insoluble aggregates. Some Aβ antibodies have been developed to include these diffusible forms of Aβ. Lecanemab (BAN2401) is a humanized IgG1 version of the mouse monoclonal antibody mAb158 directed against early, more soluble Aβ aggregates. Lecanemab is said to bind preferentially to Aβ assemblies referred to as protofibrils or soluble oligomers and to a lesser extent to insoluble amyloid fibrils. Phase II clinical trials showed that lecanemab was well tolerated and, at the highest doses, lowered brain amyloid levels and appeared to slow cognitive decline. In the absence of structural details regarding lecanemab binding to its antigens, the basis of the molecular interaction that defines its binding site (paratope) remains to be determined. Objectives: Here, we investigated the molecular determinants of the binding site between lecanemab and Aβ using complementary in silico prediction and in vitro biochemical analysis. Methods: MOE software (Molecular Operating Environment, Chemical Computing Group) was used to predict the 3-dimensional structure from the publicly available amino acid sequence of lecanemab. The resultant in silico structural model was then analyzed to identify amino acid residues potentially involved in binding (i.e., hydrophobic and electrostatic patches in CDR regions of lecanemab). Next, E.coli were used to express and purify Fab fragments of both lecanemab and certain engineered variants in which predicted key amino acid residues potentially involved in binding Aβ were mutated to alanines. Brain extracts from AD patients were then used in indirect ELISAs to examine the criticality of the mutated lecanemab residues for degree of binding to Aβ. We further used Fabs of lecanemab or its engineered mutants coupled with well-established Aβ antibodies in sandwich ELISAs to assay both Aβ-rich AD brain extracts and recombinant Aβ peptide fragments of varying lengths. Results: Lecanemab antibody structure was predicted from its primary sequence. Analysis of this structural model identified amino acid residues that may be involved in the binding site (paratope). Lecanemab Fab as well as Fab mutants of the predicted paratope residues were produced and analyzed for their binding abilities to native AD brain extracts, thereby confirming the role of the predicted residues in the binding site. Further, indirect ELISAs using lecanemab Fab as capture antibody and established Aβ antibodies as detectors indicated that lecanemab competed with the binding sites of several known antibodies that recognize the middle region of Aβ. Immunoassays using corresponding synthetic Aβ fragments confirmed these observations. Conclusion: In silico prediction of the structural details of Lecanemab provided a useful starting point that could be tested and confirmed in vitro via the expression of WT and mutant Fabs of lecanemab. The molecular determinants of the Aβ binding site as well as the antigen regions where they bind were characterized. Disclosures: D.J.S. is a director and consultant of Prothena Biosciences. All other authors declare no competing interests.
LP102- EFFECTS OF THE P38A KINASE INHIBITOR NEFLAMAPIMOD ON THE BASAL FOREBRAIN, ASSESSED BY STRUCTURAL MRI, IN ALZHEIMER’S DISEASE (AD). J. Alam1, C.P. Lin2, S. Noteboom2, N. Prins3, F. Barkhof4, L. Jonkman2, M. Schoonheim2(1. EIP Pharma - Boston (United States), 2. Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam Neuroscience - Amsterdam (Netherlands), 3. Brain Research Center - Amsterdam (Netherlands), 4. Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience - Amsterdam (Netherlands))
Background: The rationale for developing acetylcholinesterase inhibitors (AChEIs) in the 1990s was the “cholinergic hypothesis”, a pathogenic model based on Alzheimer’s disease (AD) being associated with loss of neurons producing acetylcholine in the basal forebrain (i.e., “basal forebrain cholinergic neurons”, BFCNs). However, with not treating the underlying degenerative process, merely compensating for it, the efficacy of AChEIs was found to be transient and cholinergic-directed therapeutics research fell into the background. With the development of MRI techniques to evaluate the degenerative process in the basal forebrain, there is an increasing recognition that basal forebrain degeneration is an early event in AD and is a driver of neurodegeneration in the cortex, including in the temporal lobe, (Nat Commun. 2016, 7:132492016;; Brain. 2020, 43:993–1009; Brain, 2022;145:2869–2881). Further, with this understanding there has been a resurgence of interest in therapeutics research directed at BFCN degeneration (JPAD, 2019, 6:2–15; Neuropsychopharmacol, 2022;47,405–406). The p38α kinase inhibitor neflamapimod acts on molecular mechanisms underlying cholinergic degeneration, including reducing the expression of BACE1, and restores the number & morphology of BFCNs in Ts2 (Down Syndrome) transgenic mice (Nature Commun, 2022;13:5308). In addition, in a phase 2a clinical-study in dementia with Lewy bodies (DLB), neflamapimod improved BFCN-associated clinical outcomes (Nature Commun, 2022;13:5308). Recently, MRI-based volumetry (as a measure of atrophy) of the Nucleus basalis of Meynert (NbM) within the basal forebrain has been correlated to clinical outcomes in AD, PD and DLB (Neurology, 2022 98:e947–e957; Brain 2021 36:611–621;Brain Comm, 2022, 4:fcac013; Brain, 2022;145:2869–2881). Herein, we retrospectively assessed MRI scans obtained in a previously reported phase 2a pilot clinical study of neflamapimod in AD (ACTN, 2018;5:464–473), utilizing analytic techniques to assess NbM volume that were not available at the time of the study was originally conducted. Objectives: To evaluate the effect of neflamapimod on basal forebrain cholinergic degeneration in AD, as assessed by structural MRI. Methods: Blinded longitudinal study of neflamapimod (40mg BID or 125 mg BID) in patients with amyloid-PET documented early AD (MMSE 20–28). Structural (3D T1 Isotropic) MRI was obtained before, and after 12 weeks treatment (n=13 participants). NbM volume was assessed using a probabilistic atlas and followed over time. Results: At baseline, mean NbM volume was 353(SD=33) mm3. At the end-of-treatment, NbM volume increased significantly from baseline (p=0.025), with a mean 3.2%(SEM=0.7) increase for the study overall, and 8 of 13 participants showing >3% increase in NbM volume. As previously reported, global brain volume was decreased by a mean 0.6%(SEM=0.2). Analyses by dose group will be conducted after ongoing additional analyses are complete. Conclusion: Neflamapimod treatment is associated with increasing NbM volume, suggesting p38α kinase inhibition positively impacts the cholinergic degenerative process in AD. The results are in line with the recently reported preclinical mechanistic results in Ts2 mice, in which neflamapimod increased the number and size of cholinergic neurons in the basal forebrain (Nature Commun, 2022;13:5308). In addition, an effect of neflamapimod on NbM volume is consistent with results of a separate clinical trial of neflamapimod in AD (Alz Res Ther, 2021;27:106) in which compared to placebo, neflamapimod significantly lowered CSF levels of total tau, a reported CSF biomarker of NbM atrophy Neurology 2020 Jan 7;94:e30–e41). Further evaluation of this potential effect of neflamapimod on the basal forebrain in placebo-controlled clinical trials in AD and other diseases in which the basal forebrain is impacted (e.g., dementia with Lewy bodies) is warranted. Correlation between clinical outcomes with effects on NbM volume in such studies would inform on the relative contribution of cholinergic deficits (vs. atrophy in other brain regions) to the clinical expression of disease in such disorders.
LP103- CONNECTIVITY-BASED AMYLOID-TAU INTERACTION MODEL: STAGES, STRATIFICATION, AND PREDICTION OF CLINICAL BENEFIT. W.J. Lee1, J. Brown2, H.R. Kim3, R. La Joie2, H. Cho4, C.H. Lyoo4, G. Rabinovici2, W. Seeley2, J.K. Seong1,5(1. Neuroxt, Inc. - Seoul (Korea, Republic of), 2. University of California, San Francisco - San Francisco (United States), 3. Seoul Women’s University - Seoul (Korea, Republic of), 4. Gangnam Severance Hospital - Seoul (Korea, Republic of), 5. Korea University - Seoul (Korea, Republic of))
Background: With the emergence of disease-modifying treatments for Alzheimer’s disease (AD), there is a critical need to understand the molecular anatomical progression of AD. This information will inform disease pathogenesis and may enhance patient selection for specific therapies. Researchers have proposed that brain amyloid-beta (Ab) deposition triggers tau neurofibrillary tangles to spread beyond the medial temporal lobe and into the heteromodal neocortex, but to date it has remained unclear how this might occur when Ab and tau deposition begin within spatially disparate brain regions. Objectives: We aimed to discover: (1) How brain connectivity enables Ab to interact with tau before tau spreads beyond the medial temporal lobe, (2) When and why AD tauopathy propagates throughout the neocortex, (3) Why Ab-lowering drugs have shown only modest clinical benefit, even when Ab-lowering is achieved, and (4) An image-based algorithm to identify who is most likely to benefit from Ab-lowering drugs across the full AD clinical spectrum from cognitively normal (CN) to mild cognitive impairment (MCI) to dementia. Methods: We included participants from two non-overlapping datasets. The discovery dataset was derived from the ADNI cohort and included patients with AD-type dementia (n=11), MCI (n=94), and CN (n=187). The validation dataset included participants clinically diagnosed at Gangnam Severance Hospital, South Korea: 96 CN, 84 MCI, and 71 AD-type dementia patients. All participants underwent structural MRI, amyloid-PET, and tau-PET. Our stratification algorithm proposes two important transitions during the natural history of AD, based on: (1) remote connectivity-based Ab-tau interaction in the lateral entorhinal cortex (EC) and (2) local Ab-tau interaction within the inferior temporal gyrus (ITG). To examine each subject’s status with respect to these transitions, we computed two quantitative scores. The first was computed using the EC remote Ab influence metric, derived as a weighted sum of regions’ connectivity to the EC multiplied by the Ab SUVR in those regions, and the EC tau W-score. Similarly, for the second score, the ITG local amyloid SUVR was multiplied by the ITG tau W-score. We then applied a threshold to each score to classify each subject into one of four groups: (1) least affected by the tau pathology (“tau-negative”) in EC, (2) subthreshold EC remote Ab-tau interaction despite the presence of EC tau (“latent tau”), (3) suprathreshold EC remote Ab-tau interaction but subthreshold ITG local Ab-tau interaction (“spreading tau”), and (4) suprathreshold ITG local Ab-tau interaction (“propagating tau”). Results: Plotting EC remote and ITG local Ab-tau interaction metrics using cross-sectional and longitudinal data demonstrated a fundamental arc of disease progression reflecting sequential occurrence of two interactions across and within individuals. The EC remote Ab influence metric was determined through the EC-connected regions including fusiform gyrus, parahippocampal gyrus, precuneus, posterior cingulate gyrus, parietooccipital sulcus, and hippocampus. Quadratic regression models based on the mean (left/right) cross-sectional values fit both datasets well (ADNI: R2 = 0.664, Korean: R2 = 0.652). Using this stratification method, subjects assigned to the “spreading tau” group fall just before or shortly after the tau deposition exhibits a nonlinear acceleration[SB1], whereas those designated “propagating tau” are nearly all found within and beyond the acceleration phase. As expected, longitudinal subjects within the “spreading” and, in particular, “propagating tau” groups showed dramatically greater whole-brain annualized tau accumulation. For both datasets, most CN subjects were assigned to the “tau-negative” or “latent tau” group, but 17.1% of Ab+ subjects were stratified to one of the more advanced groups. In symptomatic subjects, patients with MCI were more often classified as having “spreading tau” (14.4%; 9.2% in AD) whereas the AD group showed the most “propagating tau” group (78.5%; 46.7% in MCI). Interestingly, 11% of Ab+ pre-symptomatic subjects were classified as having “spreading tau”, which implies that amyloid-lowering drug could be suitable for participants without cognitive deficits. Conclusion: Expert recommendations for the use of the amyloid-lowering drug, aducanumab, emphasize the importance of positive AD biomarkers and a clinical label of MCI or mild dementia. The model-driven subject stratification method presented here overlays inconsistently on the biomarker-anchored clinical groupings conventionally used in AD clinical trials. These findings raise the possibility that molecular-anatomical disease staging may outperform clinical labels in predicting clinical responsiveness to amyloid-lowering drugs and other AD therapies. References: 1. Wha Jin Lee, Jesse A. Brown, Hye Ryun Kim, Renaud La Joie, Hanna Cho, Chul Hyoung Lyoo, Gil D. Rabinovici, Joon-Kyung Seong, and William W. Seeley. “Regional Aβ-tau interactions promote onset and acceleration of Alzheimer’s disease tau spreading”, Neuron, 2022.
LP104- MRI-BASED REAL-WORLD IMPLEMENTATION FOR PREDICTING REGIONAL TAU PATHOLOGY AND ITS APPLICATION TO AMYLOID-LOWERING TREATMENT INDICATION. W.J. Lee1, H. Cho2, C.H. Lyoo2, J.K. Seong1,3(1. Neuroxt, Inc. - Seoul (Korea, Republic of), 2. Gangnam Severance Hospital - Seoul (Korea, Republic of), 3. Korea University - Seoul (Korea, Republic of))
Background: Most of the recent clinical trials of Ab-lowering therapies have shown only modest clinical benefit even when Ab-lowering is achieved. The Phase 3 studies of Aducanumab in early Alzheimer’s Disease (AD) (EMERGE and ENGAGE) and the Phase 2b study of Lecanemab in early AD (BAN2401-G000-201) show inconsistent clinical benefits of Ab-lowering treatments, while the Phase 2 proof-of-concept trial of Donanemab (TRAILBLAZER-ALZ (NCT03367403)) proves to slow progression of early symptomatic AD. The major change in TRAILBLAZER-ALZ study is the tau-based inclusion criteria in the patient selection scheme. Moreover, the exploratory sub-group analysis shows that the lower third sub-group among selected patients shows the best clinical benefits, which strongly implies that early tau may represent an important treatment window for Ab-lowering drugs. Objectives: Although tau burden provides an important indication for Ab-lowering treatments, like all PET techniques, its clinical utility in medical practices has been limited due to cost, availability, and safety regarding radiation exposure. We therefore aim to develop (1) an MRI-based algorithm to predict regional tau accumulation level, (2) a brain connectivity-based prediction method for future cortical atrophy, and (3) a fully automated system for calculating global tau eligibility scores to identify patients who are most likely to benefit from Ab-lowering drugs in AD clinical trials. Methods: We included participants from Gangnam Severance Hospital, South Korea: 74 cognitively normal (CN), 61 amnestic mild cognitive impairments (MCI) due to AD, and 38 AD-type dementia patients. All participants underwent two structural MRI scans separated by a 2-year interval, as well as18F-florbetaben PET for Ab and 18F-flortaucipir PET for tau. Standardized uptake value ratio (SUVR) values were obtained from PET images using Desikan-Killiany cortical atlas with the cerebellar crus as the reference region. These values were then converted to W-scores based on amyloid-negative controls as reference. Cortical atrophy patterns were extracted for each participant using FreeSurfer. Correlation-based brain connectivity was then constructed between follow-up structural MRI and baseline tau PET. Specifically, a connectivity weight between brain regions i and j was defined as a partial correlation between baseline tau burden at brain region i and follow-up cortical atrophy at brain region j. This connectivity encodes a region-wise association of baseline tau burden and future cortical atrophy, which well represents an ATN downstream hypothesis. We then employed this connectivity for predicting baseline tau pathology using follow-up structural MRI. Finally, follow-up tau pathology was again predicted using the baseline tau information by employing a simple linear regression model. The efficacy of the proposed model was validated using a 5-fold cross validation scheme. The predicted tau burden was further applied to Ab-lowering treatment indication: A global tau eligibility score was calculated similarly to the previous PERSI-based methods, and the performance was compared with the results from the TRAILBLAZER-ALZ study. Using the same stratification method with the previous study, subjects were assigned to either “low tau” group, “intermediate tau (inclusion window)” group, and “high tau” group. Results: The predicted follow-up tau burden exhibited significant regional correlations (r=0.69 [0.61–0.74], median [IQR]) with the original tau burden, which appears to be particularly higher in AD-related regions like the entorhinal cortex (r=0.78, left/right mean), inferior parietal lobe (r=0.77), precuneus (r=0.76), and inferior temporal gyrus (r=0.76). Within each amyloid-positive subject, the predicted and original values were also highly correlated (r=0.71 [0.56, 0.81], median [IQR]). Global tau scores, computed from the predicted tau burden, fitted scores from original burden well (R2=0.51), showing high performance in treatment window determination as compared to the TRAILBLAZER-ALZ study. The “low tau” group was classified from the other two groups with an area under the receiver operating characteristic curve (AUC) of 0.83, and the “high tau” group was classified from the other two groups with an AUC of 0.92. Conclusion: We believe AD is indeed an Ab-triggered tauopathy and that Ab-lowering trials have shown modest and inconsistent benefits due to problems concerning patient selection. Considering the identification of optimal patients who are most likely to benefit from Ab-lowering drugs, neurofibrillary tangles (NFTs) formed by tau are highly predictive indicators for treatment window. In this study, we proposed a brain connectivity-based algorithm for predicting tau pathology using only structural MRI and validated its performance. The predicted tau pathology was further utilized to find an optimal treatment window based on clinical trial results of the previous TRAILBLAZER-ALZ study. These findings raise the possibility that MRI-based real-world implementation may outperform clinical labels in predicting clinical responsiveness to Ab-lowering therapies.
LP105- HYDROXYLATED DOCOSAHEXAENOIC ACID AS AN ALTERNATIVE THERAPEUTIC APPROACH FOR ALZHEIMER DISEASE IN TERMS OF EFFICACY AND SAFETY. V. Llado1,2, S. Parets2,3, J. Cabot2,3, M. Miralles2,3, M.A. Fiol-Deroque2, L. Trujillo-Estrada4, P. Fernández-García3,5 X. Busquets2, A. Gutiérrez4, P.V. Escribá3,6, M. Torres6(1. Laminar Pharma Inc - Acton, Ma (United States), 2. Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Palma (Spain), 3. R&D Department, Laminar Pharmaceuticals - Palma (Spain), 4. Department of Cell Biology, University of Malaga, CIBERNED, IBIMA - Málaga (Spain), 5. Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Palma (Spain) - Palma (Spain) - Palma (Spain), 6. Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands - Palma (Spain) - Palma (Spain))
During the last 20 years, a multitude of molecules has been designed to halt or delay AD-related neurodegeneration. So far, only aducanumab (passive immunotherapy against β-amyloid peptide -Aβ-) has recently obtained accelerated approval by the FDA (Food & Drug Administration) amidst great controversy due to poor clinical evidence regarding efficacy in preventing AD-related cognitive decline. Most of these molecules were designed based on the «amyloid cascade hypothesis» that assumes Aβ aggregation as a primary cause of this pathology. Unfortunately, AD is a complex disorder whose pathophysiological basis is not well understood yet. In the present work, we introduce 2-hydroxy-docosahexaenoic acid (DHA-H) as a promising alternative therapeutic approach for AD. Oral administration of DHA-H to a transgenic model of AD (5xFAD mice) prevents cognitive, synaptic, and neuronal degeneration in both, animals treated early (from 2 to 6 months of age) or late (from 8 to 12 months). These effects are accompanied by increased neuronal cell proliferation in the hippocampus, suggesting that part of its neuroprotective effect might be mediated by restoration of neurogenesis up to healthy levels. On the other hand, tau protein phosphorylation and Aβ accumulation revealed a significant brain reduction in animals under treatment with DHA-H, as compared to untreated control. All these results together indicate that DHA-H administration must preserve neuronal density. The latter has also been demonstrated in cell models, where DHA-H prevents neuronal death induced by oligomeric Aβ or NMDA (N-Methyl-D-Aspartate)/Ca-mediated excitotoxicity. In terms of safety, 90-day repeated-dose regulatory toxicology in rats revealed that NOAEL for DHA-H must be established at ca. 280 mg/kg/day which is equivalent to ca. 45 mg/kg/day in humans (conversion based on Body Surface Area). At this dose, minimum acanthosis/hyperkeratosis (without erosions or edema) were observed, and these alterations were considered non-adverse events. No increased incidence or severity of these gastric lesions were observed during the recovery period. On the other hand, the minimal effective dose in mice was defined at 20 mg/kg/day which is equivalent to 1.6 mg/kg/day in humans. This data points towards a large therapeutic window and a good safety profile for DHA-H for clinical trials in humans. COI: Victoria Llado holds an employment agreement and is a directors board member of Laminar Pharma Inc, subsidiary of Laminar Pharmaceuticals which is the company responsible for DHA-H development.
LP105A- RIGOR AND REPLICATION IN ALZHEIMER’S THERAPEUTIC DEVELOPMENT: A CASE STUDY. A. Heilbut1, J. Brodkin2, P. Markey3, E. Milioris4(1. Logphase Research - New York (United States), 2. Behavioral Instruments - New Jersey (United States), 3. Berlin (Germany), 4. London (United Kingdom))
Background: Alzheimer’s disease (AD) presents an enormous unmet medical need which incentivizes research and development of novel therapeutic candidates. Early identification of drug candidates and clinical trials destined to fail would allow more effective public and private research investment, and ensure that patients volunteer to participate in clinical trials that are likely to offer benefit, are scientifically informative, and are ethical. Objectives: We sought to develop a framework to predict likelihood of success for clinical trials of novel therapeutics based on comprehensive, rigorous, independent evaluation of preclinical and clinical data, together with targeted experimental replication of key biological claims. As a case study, we assessed Simufilam, a novel drug candidate currently in Phase 3 trials for AD (NCT04994483, NCT05026177). Methods: We systematically reviewed the Simufilam literature, including post-publication reviews, to assess the quality of biological (1,2,3) and clinical (4,5) evidence for this drug candidate. We then employed isothermal titration calorimetry (ITC) to experimentally measure for the first time the binding enthalpy of both Simufilam and Naloxone to their reported molecular target, the VAKGL peptide, in an attempt to recapitulate their discovery and validate the biochemical basis for Simufilam as a drug targeting Filamin-A (1,2). While there are no other known interactions between any small molecules and VAKGL or other pentapeptides available as positive controls, we also measured binding between Carbonic Anhydrase II (CAII) and its well-characterized inhibitor Acetazolamide to validate our technical capability to measure high-affinity interactions by ITC. Results: A thorough evaluation of both pre-clinical and early-stage clinical data identified concerns with statistical analysis and presentation, biochemistry methods, biophysics, thermodynamics, pharmacokinetics, and inconsistencies with expected human physiology across many of the experiments and trials critical to motivating Simufilam development. Using ITC, we failed to observe any evidence for binding of either Naloxone or Simufilam to their previously reported high affinity target, the VAKGL pentapeptide, and no difference between ITC thermograms when Simufilam was mixed with VAKGL versus a negative control VAAGL peptide. In contrast, the enthalpy of Acetazolamide binding with CAII was easily and reproducibly detected. Conclusion: Careful independent re-evaluation of preclinical and early clinical literature about a novel therapeutic identified potential scientific problems of relevance to later clinical programs. Focused biophysical experiments provided further validation of these concerns. The apparent absence of binding of Simufilam to its purported molecular target has important implications for the interpretation of published preclinical studies, potential efficacy, and future clinical development of this molecule. This case study demonstrates the value of independent, rigorous scientific evaluation and replication to maximize success rate and integrity for all trials of experimental Alzheimer’s therapeutics. References: (1) Wang HY, Frankfurt M, and Burns LH. “High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence” PLoS One. 2008 Feb 6;3(2):e1554. doi: 10.1371/journal.pone.0001554 (Retracted). (2) US Patent 8653068B2 “Filamin A binding anti-inflammatory and analgesic” (3) Wang HY et al. “PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer’s disease pathogenesis”. Neurobiol Aging. 2017 Jul;55:99–114. doi: 10.1016/j.neurobiolaging.2017.03.016 (4) Wang HY et al. “PTI-125 Reduces Biomarkers of Alzheimer’s Disease in Patients.” J Prev Alzheimers Dis. 2020;7(4):256–264. doi: 10.14283/jpad.2020.6 (5) Wang HY et al. “Effects of simufilam on cerebrospinal fluid biomarkers in Alzheimer’s disease: A randomized clinical trial.” Research Square 2021. 10.21203/rs.3.rs-249858/v1. Disclosures: The authors have or previously had short positions and/or related hedges in Cassava Sciences stock.
DIGITAL HEALTH / E-TRIALS
P205- ASSESSMENT OF DEEP LEARNING ALGORITHM OF DIAGNOSING ALZHEIMER’S DISEASE WITH KOREAN ELDERLY. J.B. Bae1, J.W. Han1, K.W. Kim1,2,3,4, J.S. Kim2,5(1. Department Of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggido, Korea - Seongnam (Korea, Republic of), 2. Institute of Human Behavioral Medicine, Seoul National University Medical Research Center, Seoul, Korea - Seoul (Korea, Republic of), 3. Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea - Seoul (Korea, Republic of), 4. Department of Brain and Cognitive Science, Seoul National University College of Natural Sciences, Seoul, South Korea - Seoul (Korea, Republic of), 5. Department of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggido, Korea - Seongnam (Korea, Republic of))
Background & Objectives: Although the number of the people with Alzheimer’s disease (AD) is increased year by year, most hospitals, specialized in diagnosis and management of AD, are centralized in urban areas despite that AD is more prevalent in rural areas. Despite the fact that the MRI unit is constantly increasing worldwide, lack of specialists on AD may miss the timing of diagnosis of AD that must be quick and accurate. Our previously developed deep learning algorithm is capable of diagnosing AD using brain MRI. In this study, we investigated whether the VUNO Med-DeepBrain AD (DBAD) using brain MRI can be employed as a decision support service on the diagnosis of AD in the hospital. Methods: The study included 98 elderly subjects with 60 or older from the visitors to the Seoul Asan Medical Center and the Korea Veteran Health Service. We administered a standard diagnostic assessment for AD including standardized diagnostic interview, neuropsychological test, laboratory test, acquisition of T1-weighted MRI and amyloid PET at Seoul National University Bundang Hospital and considered as golden diagnosis. DBAD and three panels of medical experts (ME) diagnosed subjects whether normal cognition (NC) or AD using only T1-weighted MRI. We estimated sensitivity, specificity and accuracy of the diagnoses made by the DBAD and ME using receiver operating characteristic curve analysis. Results: DBAD classified 37 subjects as AD (DBAD-AD) and the rest as NC (DBAD-NC). Among 37 DBAD-AD subjects, 17 were finally diagnosed as AD in the standard diagnostic assessment. Among 61 DBAD-NC subjects, 47 were diagnosed as NC with Aβ-. On the other hand, ME classified 36 subjects as AD (MEAD) and the rest as NC (ME-NC). Among 36 ME-AD subjects, 15 were finally diagnosed as AD in the standard diagnostic assessment. Among 62 ME-NC subjects, 47 were diagnosed as NC with Aβ- negative in the standard diagnostic assessment. The sensitivity (93.3% for DBAD and 80.0% for ME), specificity (85.5% for DBAD and 85.5% for ME) and accuracy (87.1% for DBAD and 84.3% for ME) of both DBAD and ME on diagnosing AD were comparable, however, DBAD showed trend of being higher than ME in every analysis. Conclusion: We assessed that DBAD has identical diagnostic capability to AD specialists. It approved DBAD is able to assist doctors in diagnosing AD.
P206- A CASE-CONTROL CLINICAL TRIAL ON THE DIAGNOSTIC PERFORMANCE FOR ALZHEIMER’S DISEASE OF A DEEP LEARNING-BASED CLASSIFICATION SYSTEM USING BRAIN MAGNETIC RESONANCE IMAGING OF KOREAN ELDERLY. J.S. Kim1,2, J.B. Bae1, S. Lee3, J.W. Han4, K.W. Kim2,4,5(1. Department Of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Korea - Seongnam (Korea, Republic of), 2. Institute of Human Behavioral Medicine, Seoul National University Medical Research Center, Seoul, Korea - Seoul (Korea, Republic of), 3.Department Of Electrical And Computer Engineering, Seoul National University, Seoul, Korea - Seoul (Korea, Republic of), 4.Department Of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Korea - Seoul (Korea, Republic of), 5.Department of Psychiatry, Seoul National University, College of Medicine, Seoul, South Korea - Seoul (Korea, Republic of))
Background: A deep learning-based classification system (DLCS) which uses structural brain magnetic resonance imaging (MRI) to diagnose Alzheimer’s disease (AD), was developed in a previous recent study. Here, we evaluate its performance by conducting a single-center, case-control clinical trial. We retrospectively collected T1-weighted brain MRI scans of subjects who had an accompanying measure of amyloid-beta(Aβ) positivity based on a 18F-florbetaben positron emission tomography scan. The dataset included 188 Aβ-positive patients with mild cognitive impairment or dementia due to AD, and 162 Aβ-negative controls with normal cognition. We calculated the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC) of the DLCS in the classification of Aβ-positive AD patients from Aβ-negative controls. The DLCS showed excellent performance, with sensitivity, specificity, positive predictive value, negative predictive value, and AUC were 85.6% (95%CI, 79.8–90), 90.1% (95%CI, 84.5–94.2), 91.0% (95%CI, 86.3–94.1), 84.4% (95%CI, 79.2–88.5), and 0.937 (95%CI, 0.911–0.963), respectively. The DLCS shows promise in clinical settings, where it could be routinely applied to MRI scans regardless of original scan purpose, to improve the early detection of AD.
P207- THE EFFECT OF HOME-BASED COGNITIVE TRAINING USING WORKBOOK AND TABLET PC IN PRESENILE DEMENTIA PATIENTS. J. Kwon1, K. Lee2, T.Y. Kim3, T.K. Eom1(1. Department Of Neurology, Changwon Fatima Hospital - Changwon (Korea, Republic of), 2. Department Of Neurology, Samsung Medical Center - Changwon (Korea, Republic of), 3. Department Of Neurology, Busan Wilis Hospital - Busan (Korea, Republic of))
Background: Although, the effectiveness of cognitive training has previously been established, adherence or maintenance to these program is difficult to achieve due to the lack of validated and convenient tools and programs. Furthermore, presenile dementia patients are usually physically normal but their welfare programs are overlooked compared to senile patients. The aims of this study are to evaluate the effects of home-based cognitive training and usefulness of workbook and tablet personal computer focusing on presenile dementia patients. Materials and Methods: We enrolled 48 dementia patients who met the predefined inclusion criteria from two dementia outpatient clinics. Finally, 34 presenile dementia patients (age; 63.03±4.58, 16 men and 18 women, educational attainment; 10.03±4.30 years, CDR sum of box; 3.21±1.97, MMSE; 21.74±5.24, ADAS-Cog_total; 20.12±8.13, K-IADL; 0.43±0.36) were randomly assigned to a 12-week scheduled cognitive training program using either an workbook (W group age; 62.53±4.03, 9 men and 10 women, educational attainment: 10.05±3.05, CDR_SOB; 3.68±2.07, MMSE; 21.42±5.46, ADAS-Cog_total 20.95±8.49, K-IADL; 0.50±0.40) or tablet personal computer (T-group age; 63.67±5.26, men 7 and women 8, Education; 10.00±5.63, CDR_SOB; 2.60±1.71, MMSE; 22.13±5.11, ADAS-Cog_tatal; 19.07±7.81, K-IADL; 0.33±0.29). All patients underwent 1 hour/day for 5 days/ week of training with support from their caregiver. During the program, levels of difficulties were adjusted according to rater’s regular measurement. Before and after the training program, all patients were tested for MMSE, CDR-SB, IADL and ADA-Cog. Results: On ADAS-cog tests, patients showed improvement post training (p=0.021). T group showed more improvement in CDR-SB than W group (P=0.01). In subgroup analyses including subdomain, there were no significant differences between pre and post tests. All patients and caregivers were well-tolerated for 12 weeks. Conclusion: We suggest that cognitive training using workbook and tablet personal computer is a well-tolerated and comparable tool for presenile dementia patients and their caregivers.
P208- EFFICACY OF THE ‘FINGER-TO-BRAIN’ GAME ON COGNITIVE FUNCTION OF OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT: A RANDOMIZED CONTROLLED CROSSOVER TRIAL. J.W. Han1,2, D.G. Moon1, J.U. Shin1, Y. Park3, M.J. Kwon3, H.I. Kim3, W. Moon1, D.J. Oh2,4, J.B. Bae1,2, K.W. Kim2,3,5(1. Department Of Neuropsychiatry, Seoul National University Bundang Hospital - Seongnam-Si (Korea, Republic of), 2. Department of Psychiatry, Seoul National University College of Medicine - Seoul (Korea, Republic of), 3. Department Of Brain And Cognitive Science, Seoul National University College Of Natural Sciences - Seoul (Korea, Republic of), 4. Department Of Psychiatry, Smg-Snu Boramae Medical Center - Seoul (Korea, Republic of), 5. Department Of Neuropsychiatry, Seoul National University Bundang Hospital - Seongnam-si (Korea, Republic of))
Background: We developed the Finger to Brain (F2B) which is a functional game app for training memory and executive function. The F2B consists of eight games that are organized in usual daily life of community-dwelling older adults so that the training effect is more likely to be generalized in real life. Objectives: We investigated the efficacy of the F2B on cognitive function and functional activity of brain in older adults with mild cognitive impairment (MCI). Methods: This study was a single-center, double-blind, randomized, placebo-controlled, two-period, crossover trial. Sixty-four participants with MCI aged 60 years or older were randomized into the F2B group or the Mock intervention (MI) group. The MI consists of reading articles on health and web surfing that are incorporated as a sub-menu in the F2B app so that the participants were blinded to intervention type. Each participant was asked to play the F2B or the MI for 15 minutes or longer per session, five sessions per week for eight weeks. After a four-week washout period, each participant began an alternative treatment for the next eight weeks. The primary outcome measure was the Cognitive Subscale of Alzheimer’s Disease Assessment Scale (ADAS-COG) and the secondary outcome measures were Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS) and functional near-infrared spectroscopy (FNIRS). All measures were administered at the beginning of the trial (week 0), and after the first treatment period (week 9) and the second treatment period (week 21). We performed an intention-to-treat analysis using linear mixed modeling. This study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital. Results: Of 64 randomized participants, 60 completed the study. There were no significant differences in the changes of ADAS-COG, MMSE, and GDS scores between the F2B and MI groups (p=0.215 for ADAS-COG, p=0.168 for MMSE, p=0.974 for GDS). However, the F2B group showed significantly lower oxyHb while the MI group showed increased oxyHb during the verbal fluency task and encoding/immediate recall task after intervention in frontal cortex (p=0.025 in right middle frontal, p=0.047 in right superior frontal, p<0.001 in right medial superior frontal, during verbal fluency task; p=0.027 in right superior frontal, during encoding task; p=0.003 in right superior frontal, p=0.009 in left medial superior frontal, during immediate recall task). There were no F2B-related adverse events. Conclusion: The F2B for eight weeks showed comparable efficacy on cognition to active control (reading and web-surfing). However, the F2B may increase the neural efficiency of the frontal cortex in performing semantic and episodic memory. (Trial registration: Clinical Research information Service No.: KCT0005061)
P209- FEASIBILITY, ACCEPTABILITY, AND ADHERENCE OF A REMOTE SMARTPHONE-BASED SELF-ASSESSMENT OF COGNITION, FUNCTION, AND BEHAVIOR IN EARLY ALZHEIMER’S DISEASE. T.M. Perumal1, A. Wolfer1, M. Veloso2, I.T. Kurniawan1, G. Keita3, N. Hagenbuch4, B. Shi5, F. Orfaniotou6, D. Watson7, M. Boada Rovira8, K.I. Taylor2(1. Roche Pharma Research And Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland - Basel (Switzerland), 2. Roche Pharma Research And Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 - Basel (Switzerland), 3. Cytel Inc., Wilmington Del Usa, Succursale De Meyrin, Route De Pre-Bois 20, C.p. 1839, Ch-1215 - Geneve (Switzerland), 4. Global Product Development Data And Statistical Sciences, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 - Basel (Switzerland), 5. Global Product Development Medical Affairs, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 - Basel (Switzerland), 6. Global Product Development, Personalized Healthcare, Digital Health, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 - Basel (Switzerland), 7. Alzheimer’s Research And Treatment Center - Wellington (United States), 8. Networking Research Center On Neurodegenerative Diseases (ciberned), Instituto De Salud Carlos Iii - Madrid (Spain))
Background: Trials in early Alzheimer’s disease (eAD) require the quantification of cognitive and functional progression. This is traditionally accomplished with in-clinic standard neuropsychological assessments administered via trained clinical professionals. Digital health technologies (DHT) tools now offer the possibility to collect complementary cognitive and functional information remotely and frequently. Online cognitive testing in lieu of in-person testing at site visits during the COVID-19 pandemic demonstrated the importance and feasibility of remote monitoring of cognition in clinical trials. Compared with traditional in-clinic assessments, remote assessments via DHTs enable the collection of a broader palette of cognitive and functional measures at higher frequency and in patients’ home environments. However, these must demonstrate acceptability and participant adherence, as well as validation against standard clinical outcome measures and relevant biomarkers, before their broader use in clinical trials. Objectives: The objectives were to determine the feasibility, acceptability, and adherence to remote monitoring via the AD Digital Assessment Suite (AD-DAS) in the AD continuum. Methods: AD-DAS comprises 9 active tasks of cognitive and motor functioning and four survey questionnaires installed on a preconfigured study smartphone, along with a passive monitoring of behavior in daily life measured using sensors in participants’ own smartphones. The 9 active tasks measure episodic memory, conceptual fluency and logical memory, executive functioning based on principles of the Trail-Making Test (TMT) and Stroop interference test, visuospatial working memory, attention and visual scanning behavior based on the Symbol Digit Modalities Test (SDMT), dual-task gait, semantic memory, psychomotor speed and language, and simple motor dexterity and reaction time. 4 survey questionnaires queried sleep quality, sociability, mood and orientation in time. Aspects of social cognition and functioning in daily life were measured with an optional smartphone application on participants’ own smartphones. This application quantified participants’ gait, life space, and sociability as measured by app usage from application logs. Participants included 32 amyloid PET negative healthy controls (HC Aβ-), 61 participants with subjective cognitive decline (SCD) (i.e., 31 SCDn who are Aβ- and 30 SCDp who are Aβ+) and 30 individuals with early Alzheimer’s disease (eAD Aβ+). They were recruited in two countries (USA and Spain) across 5 sites in 2 languages (English and Spanish) as part of the multicenter cross-sectional Proof-of-Concept (POC) study (https://www.isrctn.com/ISRCTN17035495). Participants aged 65 and above underwent amyloid PET Aβ +/-classification and MRI for measurement of brain atrophy. All completed a battery of standard in-clinic neuropsychological, motor, activities of daily living, and health-related assessments. All 123 participants were instructed to perform a subset of 9 different active smartphone tasks and 4 survey questionnaires daily on the AD-DAS for a period of 28 days remotely without supervision. Participants acceptability and perceived difficulty of the AD-DAS tasks were assessed using an end-of-study visit questionnaire. Results: The primary results showed ∼98% feasibility (i.e., 120 out of 123 participants successfully completed the study). Among the 120 who completed the study, the median adherence, defined as at least one task completed on a given day, was ∼96% (i.e., corresponding to ∼27 days) in the 28-day remote monitoring period. More than 85% of respondents rated their experience of using the study smartphone and the AD-DAS as ‘good’ or ‘very good’ on a 5-point Likert scale. Over 89% of participants agreed that the task instructions were clear and easy to follow. Participants took part in remote assessments for an average of 10.9 minutes per day, and the majority (∼91%) rated their perceived burden as acceptable. No differences were observed in feasibility (percent completed: HC: 97%, SCDn: 100%, SCDp: 100%, eAD: 93%), adherence (median (standard deviation) HC: 89% (±30%), SCDn: 96% (±24%), SCDp: 96% (±12%), eAD: 96% (±15%)), and acceptability (all groups’ median Likert rating 4/5, i.e. ‘good’) between groups. Little impact from the COVID19 pandemic was observed. Preliminary validity analyses indicate that age, sex, education, and site impact the cognitive and functional measures collected in the study. Conclusions: Primary outcomes of the AD-DAS POC study show excellent feasibility, good acceptability, and good adherence to performing remote cognitive and functional assessments in individuals on the early AD spectrum. This study shows the promise of using remote DHT to measure cognition and function in the real-world, without relying on participant or caregiver recall, and with relatively low burden to the trial participants. The AD-DAS aims to support future clinical trials by identifying target populations, stratifying subgroups of fast progressors, and providing sensitive cognitive measures of disease progression, to ultimately provide clinically meaningful outcomes for observational and interventional trials in preclinical and early AD.
P210- EFFECT OF INTERNET-BASED MINDFULNESS TRAINING ON COGNITIVE AND PSYCHOLOGICAL WELL-BEING AND EEG BRAIN ACTIVITY IN THE ELDERLY: PRELIMINARY RESULTS. S. Galluzzi1, M. Lanfredi1, A. Chiesa2, C. Festari1, S. Meloni1, R. Rossi1, E. Tomasoni1, D. Moretti1, M. Pievani1(1. IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli - Brescia (Italy), 2. Istituto Mente e Corpo and Associazione di Psicología Cognitiva - Scuola di Psicoterapia Cognitiva - Bologna, Rome (Italy))
Background: As the worldwide population of older adults will rapidly increases in the coming years, effective strategies are needed to maintain cognitive and psychological well-being. Mindfulness training (MT) has been proposed as an efficacious way to enhance cognition and regulate emotion. Objectives: Aim of the study is to evaluate cognitive, psychological, and electrophysiological effects of a standard 8-week MT delivered via a live internet-based videoconference in healthy older adults. Methods: Fifty older adults aged 60 to 75 years took part in a standardized MT program consisting of 2-hour group sessions that were delivered at weekly intervals for 8 weeks. A comprehensive cognitive (verbal memory, attention and executive functions) and psychological (anxious and depressive symptoms, dispositional mindfulness, worries, emotion regulation strategies, wellbeing, interoceptive awareness, sleep) evaluation and EEG recording were collected at pre- and post-MT and at 6-month follow-up. Data were analyzed using an intention-to-treat approach by a linear mixed model. Estimated mean and standard error were reported, with age, gender and education as covariates. Results: The participants had 14+5.2 years of education and were predominantly women (74%). Eight out of 50 participants (16%) withdrew due to personal or medical problems. Only one subject was lost at 6-month follow-up. We found significant improvement between pre- and post-MT on California Verbal Learning Test, immediate recall (50.3+1.2 vs 54.4+1.3, p=.04), short and long delayed cued recall (11.4+.3 vs 12.7+.3, p=.004, and 11.5+.3 vs 12.6+.3, p=.046, respectively) and on Multidimensional Assessment of Interoceptive Awareness, self-regulation (2.4+.1 vs 3.1+.1, p<.0005). These improvements remained significant at 6-month follow-up (p<.01 for all scales). In a subgroup of 20 consecutive participants, EEG alpha1 and alpha3 frequencies increased from pre- to post-MT (p<.05). Conclusion: Our preliminary results suggest that MT has positive effects on cognitive and psychological features in healthy older adults, even when delivered in an internet-based format. Moreover, the electrophysiological results suggest that the mechanism of action of MT might involve a modulation of alpha power. No conflict of interests to declare.
P211- INCREASING STUDY POWER VIA FREQUENT SPEECH-BASED ASSESSMENTS OF COGNITION. G. Stegmann1, S. Hahn1, J. Liss1, V. Berisha1, K. Mueller2(1. Arizona State University and Aural Analytics - Scottsdale, Az (United States), 2. University of Wisconsin - Madison - Madison, Wi (United States))
Background: With an increase in clinical trials targeting patients early in their disease course comes challenges in trial design. Powering a trial focused on traditional biomarkers in early-stage patients requires large sample sizes and lengthy trials, with significant consequences for recruitment and retention. To address these problems, there is interest in novel biomarkers that are more sensitive than traditional biomarkers and can be measured frequently, at low cost to patient and trial sponsor. One way to increase the power, and therefore decrease the sample size requirement for a clinical trial, is by collecting data at more frequent time intervals. Rutkove et al (2020) demonstrated how frequent sampling of both traditional and digital biomarkers improved the ability to detect small changes in disease progression. Frequent data collection is made feasible if the participants are measured remotely. Stegmann et al. (2022) demonstrated that speech samples could be collected outside of the clinic, without clinical supervision, and that it was possible to use it to measure cognitive function. The authors used transcripts from healthy and cognitively impaired participants performing the Cookie Theft picture description to automatically extract a speech-based measure of communicative efficiency, Semantic Relevance, and showed that it correlated with the Mini Mental State Exam. Speech is therefore a promising candidate biomarker for measuring clinically-relevant changes to cognition in a low-burden manner. Objective: In our study, we used Semantic Relevance as the cognitive outcome of interest, and the model described in Stegmann et al. (2022), to show the relationship between power and speech sampling frequency in participants with mild cognitive impairment. Methods: A power analysis was conducted using the longitudinal parameter estimates from Stegmann et al. (2022). In the published article, a growth curve model (longitudinal mixed-effects model) was estimated such that the longitudinal change in a Semantic Relevance was modeled for participants from different levels of cognitive impairment. The parameter estimates from the mild cognitive impairment participants’ longitudinal model were used as the basis for the power analysis. The power analysis was performed through a simulation study. In the simulation study, a treatment and a control group were generated. The control group followed the longitudinal decline according to the parameter estimates obtained from the article, and the treatment group declined 10%, 30%, 50%, and 75% slower than the control group. Sample sizes of N = 100, 125, and 150 participants per group were generated for a hypothetical 2-year study. Finally, sampling frequencies of 15 (every 15 days), 30, 60, 90, 180, and 365 were generated. For each combination of simulation conditions, the slopes were estimated for each participant, and a two-sample t-test was used to estimate the mean difference in slopes between the two groups. 200 replicates were performed for each simulation condition, and the proportion of replicates where the t-test was significant was used to compute the power to detect the treatment effect. Results: The power (proportion of replicates with significant differences between the two groups) was calculated for each simulation condition. The power increased as the differences between the hypothesized treatment and control group increased, but more importantly, the power increased substantially as the sampling frequency increased. For example, for an effect size of 50% difference in mean slope between a treatment and control group of 100 participants per group, the power to detect a significant effect was 14% when sampling every 365 days, and it increased to 71% when sampling every 15 days. Conclusion: This study highlights the value of frequent sampling in clinical trials as a way to increase the power to detect significant treatment effects. An added benefit of this approach is that participants do not need a clinic visit for data to be obtained, and this also reduces participant burden and attrition. References: Rutkove, S. B., Narayanaswami, P., Berisha, V., Liss, J., Hahn, S., Shelton, K., Qi, K., Pandeya, S., & Shefner, J. M. (2020). Improved ALS clinical trials through frequent at-home self-assessment: A proof of concept study. Annals of Clinical and Translational Neurology, acn3.51096. Stegmann, G., Hahn, S., Bhandari, S., Kawabata, K., Shefner, J., Duncan, C.J., Liss, J., Berisha, V., Mueller, K. (2022). Automated semantic relevance as an indicator of cognitive decline: Out-of-sample validation on a large scale dataset. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, 14. Conflicts of Interest: Visar Berisha and Julie Liss are co-founders of Aural Analytics. Gabriela Stegmann and Shira Hahn are employed by Aural Analytics. Acknowledgements: This work was supported by NIH SBIR (1R43DC017625-01), NSF SBIR (1853247), NIH R01 (5R01DC006859-13), NIA/NIH R01 (AG027161, AG054059, AG070940), Prime award SPA00001764/ASUB00000177.
P212- A MULTIMODAL DEEP LEARNING APPROACH TO PREDICTION OF COGNITIVE DECLINE AND ITS POTENTIAL APPLICATION IN CLINICAL TRIALS FOR ALZHEIMER’S DISEASE. C.H. Wang1, Y.Z. Li1, H. Yamaguchi2, H. Tachimori3, A. Sekiguchi4, Y. Yamashita2(1. Imaging Technology Center, FUJIFILM Corporation - Kanagawa (Japan), 2. Department of Information Medicine, National Institute of Neuroscience, National Center of Neurology and Psychiatry - Tokyo (Japan), 3. Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry - Tokyo (Japan), 4. Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry - Tokyo (Japan))
Background: For decades, numerous efforts were made for Alzheimer’s disease therapeutics, but almost all the clinical trials failed to show their effects on slowing or halting cognitive decline. Among several challenges in such trials, one came into notice recently but have not been investigated thoroughly yet is that the large variation of cognitive decline speeds in individuals may result in uneven distributions of fast and slow cognitive decliners in treatment and placebo groups allocated in randomization. This may strongly influence the outcome of a trial aimed at preventing cognitive decline. Objectives: The objective of this study is to propose a novel approach to reduce allocation bias in randomization by introducing a prediction artificial intelligence (AI) technology based on deep learning, and then demonstrate the effectiveness of the proposed approach by simulation. Methods: A hybrid multimodal deep learning model consisting of deep neural networks (DNNs) and a linear support vector regression (SVR), was developed to predict CDR-SB changes during the trial period. The prediction was based on T1-weighted MRI images and non-image information including APoE4, MMSE, FAQ and ADAS-cog available at baseline. The DNNs were trained to automatically extract features from sub-regions related to cognitive decline, such as hippocampus and anterior temporal lobes and the SVR was trained to predict CDR-SB changes using image features extracted by DNNs together with nonimage information. The model was trained, validated and test using samples from longitudinal data in NA-ADNI dataset selected with following criteria’s: (1) a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer’s dementia (AD) with MMSE score ≥24; (2) amyloid-beta positive in CSF or PET imaging; (3) a global CDR scale of 0.5; (4) with information needed for model training and a 1.5 to 2 years follow up CDR-SB available. A total of 1194 samples of 506 participants were used for training, validation and test of the model, and 506 samples at the baseline visit of each participant were used for randomization simulation. Predictions of CDR-SB changes were obtained from the test sets in a participant-based 10-fold cross-validation test setting. Simulations of randomization were carried out to mimic a typical phase II trial with a sample size of 300. A simple randomization and stratified ones using APoE4, CSF Amyloid beta-42, MMSE, ADAS-cog and AI predictions of CDR-SB changes as stratification indices were considered. While the former directly allocated participants into treatment and placebo, the later separated participants into subgroups according to stratification indices and then did allocation in each subgroup. With each randomization method, 300 participants were randomly selected and allocated to treatment and placebo groups. The mean of actual CDR-SB changes in each group were calculated, and their difference was regarded as allocation bias caused by randomization methods. For each method, the simulation was repeated 10000 times to get a distribution of allocation biases. Results: The mean and standard deviation of CDR-SB changes of the 506 samples used for simulation are 0.978 and 1.899 respectively. The mean absolute error (MAE) of AI predictions is 1.074 (0.892 for 95% of inners of distribution of actual CDR-SB changes and 4.567 for %5 outers). The correlation coefficient of AI predictions and actual values is 0.580 (0.620 for inners and −0.036 for outers). Deviations of the distributions of allocation biases brought by simple and stratified randomizations were 0.221 and 0.213, 0.203, 0.202, 0.199, 0.175 for APoE4, Amyloid beta-42, MMSE, ADAS-cog, AI predictions respectively. Compared with simple randomization, stratified randomization using AI predictions could reduce the allocation bias by 20.8%. As allocation biases can also be reduced by increasing sample size, reduction in allocation bias by a specific randomization method means it can reduce sample size needed to assure that there was actually an effect in the treatment when a same outcome was obtained. For example, provided that a moderate outcome of 0.3 on CDR-SB decline slowing was obtained, the minimum sample size needed to assure the effect of the treatment was not null, that is, the outcome was not purely due to the allocation bias, with a confidence over 95% for above randomization methods are 618, 572, 539, 525, 503 and 390, respectively. Using AI predictions can reduce the sample size by 37% compared to simple randomization. Randomization using ground truth of CDR-SB changes resulted in 71.5% and 85.3% reduction in bias deviation and sample size respectively, that implies a large potential of using AI predictions in randomization. Conclusion: We proposed a hybrid multimodal deep learning model to predict CDR-SB changes and a novel stratified randomization method using its prediction outputs. Simulation results showed effectiveness and big potential of using AI predictions in randomization. In the future, salvages of some failed trials may be possible if we re-evaluate them using a much less biased allocation obtained by randomization method based on AI prediction. All authors have no conflict of interest to disclose.
P213- PRELIMINARY RESULTS OF A DIGITAL PILOT TO IMPROVE AD TRIAL RETENTION BY MANAGING CAREGIVER STRESS. R. Laird1,2, J. Branning1(1. ClinCloud Clinical Trials - Viera (United States), 2. Navigating Aging Needs LLC - Orlando (United States))
Background: Clinical research activity directed toward an increased understanding of and cure for Alzheimer’s disease (AD) represents a critical advance in providing relief for the 6 million patients and families impacted. The FDA has approved four drugs with 411 active clinical trials in 2022. The study design for most AD trials requires a subject/study-partner dyad for the trial duration, which averages 18 months. Retention of subjects and study partners in these long trials is challenging given the realities of disease progression; the likelihood of the subject’s cognitive, physical, and emotional decline; and the potential for health or other stressors affecting study partner participation. In many trial dyads, study partners are also engaged as Family Caregivers (FCs) for the subject. This dynamic adds a unique set of responsibilities and stressors that increase the risk of trial withdrawal. The average retention rate for mild cognitive impairment (MCI) AD trials is 71.6%, mild-to-moderate AD trials 77.7%, and moderate-to-severe and severe AD trials 75.4%. Each early termination reduces overall study scientific potential and is costly to trial sponsors. The replacement costs for a patient who drops out average $19,533. Failure to retain patients and caregivers is costly and delays 80% of clinical trials by at least a month, causing potential losses of $600,000 to $8M daily. To address this problem, ClinCloud Clinical Trials partnered with Navigating Aging Needs LLC (NAN) to pilot a virtual FC support service focused on improving retention rates for AD trials and stabilizing or reducing the perceived burden of stress on FCs. Objectives: To explore the potential to increase the rate of study completion and reduce early termination due to caregiver stress in AD clinical trials by stabilizing or reducing the burden of stress for “study partners,” typically FC of patients with AD. Methods: -Family caregivers volunteering as study partners in phase 3 trials from two key sponsors were offered a 12-month subscription to the Navigating Aging Needs (NAN) Program. - Sponsors funded subscription costs through invoiceable retention fees per each randomized subject. Subscriptions included weekly Zoom sessions with a personal NAN Navigator (licensed social worker). - The initial meeting between each FC and social worker consisted of an assessment that included 80 questions on the AD patient’s medical, emotional, social, and legal/financial well-being and the validated battery of 12 questions comprising the Zarit Burden Scale. - Following the initial meeting, the social worker provided the FC with a plan that identified areas of risk that “need attention” or “may need attention,” along with resources to address identified needs. - For the following six months, the social worker met with the FC weekly to guide how to resolve areas identified as high-risk and discuss other relevant issues as they arose. - At each session, FCs were queried about their current satisfaction of clinical trial participation. As needed the social worker engaged site personnel to mitigate areas identified as “stress of participation.” - The social worker re-assessed the family caregiver’s Zarit Burden Score twice, after three months and six months of guidance and support. - FCs had access to and round-the-clock availability of resources on the nanforcaregivers.com website. Results: Data are available for the first six FC to enter the pilot. (We continue to enroll additional family caregivers in this ongoing program.) Initial results demonstrate a positive impact of the NAN program with no instances of drop-out due to FC stress and two instances of reducing FC “stress of participation.” Five of the six family caregivers showed stable Zarit Burden Scale scores. Caregiver engagement was high for virtual sessions, website use, and open rate for NAN support materials. Conclusion: Providing support to FC shows signs of reducing study drop-out due to related to FC stress, supporting retention in clinical trials by monitoring “stress of participation” and intervening as needed, and stabilizing perceived burden of stress. Based on these early results, NAN and ClinCloud are working together to expand the number of FC enrolled and the duration of support. They will continue to monitor the impact of this intervention and plan to expand the program to address both recruitment and retention needs.
P214- BRAIN NETWORK DIFFERENCE BETWEEN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE DEMENTIA USING EEG. H. Yuseong1, B. Kyoungwon2, P. Ukeob1, Y. Byoung Seok2, K. Seung Wan1(1. iMediSync Inc. - Seoul (Korea, Republic of), 2. Yonsei University College of Medicine - Seoul (Korea, Republic of))
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive memory impairment along with neuropsychiatric symptoms. Early detection of the disease in mild cognitive impairment (MCI) or prodromal AD stage is important for effective treatment and the proper use of expected disease modifying therapies. Proven biomarkers for AD including CSF amyloid β and amyloid positron emission tomography imaging, which are invasive or expensive, have restrictions on access in clinical environment. Electroencephalography (EEG) is one of the general methods to explore brain activities. It can inspect the change in brain activity in the real time with inexpensive equipment, so it is commonly used in the clinical environment and several studies proposed various EEG features as a biomarker for brain disorder. Objectives: In this paper, we investigated the difference between AD dementia and MCI by using brain functional network from EEG. Global efficiency and clustering coefficient calculated from brain functional network were adopted to compare AD and MCI. By using two features representing integration and segregation of the network, we propose a new biomarker that could find out the difference between MCI and AD dementia compared to cognitive normal case. Materials and Methods: The EEG data of 66 AD dementia (72.3 ± 7.0 years) and 55 MCI (70.8 ± 5.0 years) subjects were used in this paper. The same number of age and sex controlled normal subjects were selected among the dataset of iMediSync to compare AD dementia and MCI. EEG recorded more than 2 minutes with eye closed resting state was used to construct the brain functional network. Each EEG signal was pre-processed using 1–45 Hz band pass filter and time-series rejection. Also, to remove the remaining artifact signal, we adopted independent component analysis (ICA). The filtered EEG signal was decomposed and the artifacts were excluded. EEG recorded from 19 channels (international 10–20 system) was converted to 68 cortical regions of interest (ROIs) using standardized low resolution brain electromagnetic tomography (sLORETA). The functional connectivity was calculated from these 68 ROIs, which was imaginary part of coherence (iCoh). Finally, the brain functional network was constructed from the iCoh values between 68 ROIs. Before investigating the brain functional network, we firstly divide the brain regions to the subregions. The whole brain regions were divided into the three functional subregions: default mode network, central executive network, salience network and six regional subregions: left frontal, right frontal, left temporal, right temporal, left parietal-occipital, right parietal-occipital lobes. Then, except the top 25% iCoh values, the remainder was removed to construct partially connected network. To compare AD dementia and MCI group with normal control group, we used two network features, which were global efficiency and clustering coefficient. Two features were selected to compare integration and segregation of the network, respectively. Results: Global efficiency of AD dementia group was lower than that of normal control group in all subregions. On the other hand, clustering coefficient of two groups showed the opposite result, which is higher in AD dementia. Especially, the network features of DMN and both lateral temporal lobes were significantly distinguished. Global efficiency of DMN (0.077 ± 0.015 / 0.097 ± 0.017, AD dementia and normal control respectively), left temporal lobe (0.075 ± 0.026 / 0.109 ± 0.022) and right temporal lobe (0.073 ± 0.025 / 0.105 ± 0.025) showed statistically significant (< 0.01). Clustering coefficient of DMN (0.507 ± 0.046 / 0.442 ± 0.045), left temporal lobe (0.479 ± 0.044 / 0.457 ± 0.042) and right temporal lobe (0.457 ± 0.043 / 0.427 ± 0.059) also showed the same results (< 0.01). Both features of MCI group were greater compared to the normal control group. Overall results of clustering coefficient were similar to that of AD dementia. In case of global efficiency, MCI group showed rather higher values than normal control group. The most significant difference was both lateral frontal lobes that is nearly the same with normal in AD dementia results. Global efficiency of left frontal lobe (0.096 ± 0.026 / 0.079 ± 0.018, MCI and normal control respectively) and right frontal lobe (0.095 ± 0.027 / 0.079 ± 0.018) showed statistically significant (< 0.01). Conclusion: In this study, we found different brain network change between normal control, patients with MCI and AD dementia. Noninvasive EEG biomarker would be used as a possible source for AD biomarkers for early detection of AD.
P215- USING ECOLOGICAL MOMENTARY ASSESSMENT TO MEASURE REAL-WORLD EFFECTS OF A COMBINED COMPUTERIZED COGNITIVE AND FUNCTIONAL SKILLS TRAINING PROGRAM IN MILD COGNITIVE IMPAIRMENT. P. Harvey1, P. Kallestrup1, S. Czaja3(1. University of Miami Miller School of Medicine - Miami (United States), 2. i-Function - Miami (United States), 3. Weill Cornell Medical Center - New York (United States))
Background: Pharmacological treatments for Mild Cognitive impairment (MCI) have not been particularly successful, leading to attempts to use computerized cognitive training (CCT) to improve cognition and functioning. Studies of CCT have had some success in healthy older people with normal cognition (NC) and MCI, but one of the major concerns in CCT is generalization to real-world functioning. As a result, computerized technology-based skills training systems have been developed. Recent studies have reported that combining commercially available CCT (Brain HQ) and computerized functional skills assessment and training (FUNSAT) software leads to gains in both the ability to perform everyday functional skills and in cognitive performance, across both NC and MCI populations (Czaja et al, 2020). The combination of CCT and FUNSAT led to synergistic gains in both cognition and functional skills compared to training with just one strategy (Harvey et al., 2022). However, in those studies, despite considerable improvements in MCI in both cognition and functional skills performance, training was conducted in person and real-world transfer was not assessed. The current study uses a fully remotely delivered CCT and FUNSAT platform for monitored at-home training, combined by daily ecological momentary assessment (EMA) paging. EMA pages query the performance of both training and untrained technology related skills. Objectives: The objectives are: 1: to examine the efficacy of remotely delivered cognitive and functional skills training for performance on computerized measures of cognition and functional skills in rigorously diagnosed participants with MCI across two different training conditions; 2: to examine real-world transfer of these training gains using EMA. Methods: 120 participants with MCI (Defined with the Jak-Bondi criteria) and 60 NC constitute the sample. 50% of the participants in both groups are being fully assessed and trained in Spanish. 50% of the MCI participants were randomized to FUNSAT alone while 50% receive combined training. All NC receive FUNSAT alone for development of training norms. Outcomes are measured with training gains on the training software (time to completion of the tasks and errors), performance on measures of untrained cognitive abilities (Brief Assessment of Cognition) untrained functional skills (Virtual Reality Functional Capacity Assessment Tool), and real-world functioning assessment with daily EMA. EMA surveys query performance of trained tasks and untrained but related technology-focused tasks. FUNSAT training tasks include ATM, Ticket Kiosk, Telephone Voice Menu, Medication Management, and Internet Banking and Shopping. Training in FUNSAT alone includes two 1-hour training sessions per week for 12 weeks. Combined treatment includes a training burst of 4 weeks with twice-weekly BrainHQ followed by 8 weeks of FUNSAT training. Participants who master individual tasks graduate and no longer train. End of training, 3 month, and 6 months outcomes are measured. Participants were all provided with a Chromebook device, along with accounts and passwords for accessining training software. Data plans were also provided if needed. EMA surveys were also launched on the same device. Results: As of the present time, 120/180 cases have been assessed at baseline and randomized. This includes 55 NC participants and 65 MCI participants, of whom 32 are randomized to combined training and 33 to FUNSAT alone. 27 NC and 23 MCI participants have completed training. All participants have been recruited in the past 5 months, so the study will be done by November. Percentage improvement in time to completion from baseline to end of training across the 6 tasks in MCI participants ranges from 41% to 56% across the tasks, with tasks that were more difficult at baseline improving more. For example, it took MCI participants 1303 seconds on average to complete the 6 online-banking subtasks at baseline; endpoint performance averaged 620 seconds. There are no differences in training gains associated with combined vs. FUNSAT only training. NC participants had equivalent improvements, although they performed about 1.0 SD better at baseline, typically mastered the tasks somewhat more rapidly, and more commonly graduated before completion of the full complement of 24 training sessions. Number of errors improved even more, with all tasks showing a minimum improvement in error rates of 80% across participant groups and training conditions. Thus, training results were similar to the previous study. For EMA data, participants were paged every day (Monday through Saturday) and asked to respond to three surveys per week. Adherence to EMA surveys averaged three surveys per week, suggesting that participants were adhering as instructed. A total of 1142 EMA surveys were answered to date. Changes in EMA-assessed activities were detected. The proportion of surveys where the respondents reported using the internet since the last survey (outside of third training) increased by 35% over the 12 weeks of the study. Increases were greatest in the first 3 weeks. Specific internet related activities increased by more, including accessing social media, which doubled in frequency. Nontrained, but technology focused, activities also increased. There was a 54% increase in the proportion of surveys where respondents reported that they had sent a text message since the last survey and a 20% increase in the proportion of surveys reporting mobile phone use. Conclusions: A fully remotely deliverable functional skills and CCT training program is feasible and shows evidence of efficacy consistent with our previous study. Training related gains across technology-related task domains were consistent with prior results. Again, CCT plus FUNSAT led to synergistic gains, in that equivalent functional skills gains over the training period were achieved with only 8 weeks of FUNSAT training following a 4-week burst of CCT. EMA assessment of everyday activities manifested excellent adherence and generated a large survey database. Importantly, participants were found to engage in activities that were related to their training and also to engage in other technology-related activities that were untrained.
P216- THE EFFECTS OF HOME-BASED COGNITIVE INTERVENTION WITH CHAT-BOT ON BRAIN FUNCTION IN PATIENTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT. G.H. Kim1, B. Kim1, J.H. Jeong1(1. EwhaW. University - Seoul (Korea, Republic of))
Background and Purpose: Cognitive intervention (CI) has been known to improve cognition and to delay cognitive decline in patients with mild cognitive impairment. The purpose of this study was whether our newly developed, home-based CI with a chat bot for 12 weeks changed brain function and cognitive performance in patients with amnestic mild cognitive impairment(MCI). Methods: A single-blind randomized controlled trial was conducted in 72 patients with amnestic MCI. Participants were randomized into the two groups: the CI with chat bot (CI) (n=36) group and waitlist control group without CI (Control) (n=36) groups. A total of 13 chat-bot based CI programs were developed targeting for attention, memory, visuospatial, calculation, language and frontal executive functions. The CI comprised 30-min-session per day for 12 weeks. The primary outcome was the changes in brain function measured by resting state electroencephalogram (EEG), which was measured in eyes open and eyes closed conditions for 3 minutes each, with a 19-channel wireless EEG device. The secondary outcome was the changes of cognitive function measured using the Cambridge Neuropsychological Test Automated Battery. Results: There were no baseline demographic and clinical differences between the CI and the control groups. EEG analysis after 12-week showed increased beta wave on the frontal areas in the CI group, while decreased beta wave on the frontal areas in the control group. In addition, CI group also demonstrated improvement in attention domain compared to the control group. Conclusions: Considering that increased beta wave is associated with attention performance, our results suggest that the 12 week home- based CI with chat bot could help improve brain function in patient with MCI.
P217- REMOTE COMPUTER-BASED COGNITIVE TRAINING: SHORT- AND LONG-TERM BENEFITS ON COGNITION AND DAILY LIVING IN PATIENTS WITH ALZHEIMER’S DISEASE. S. Dimachki1, F. Tarpin-Bernard2, S. De Chalvron2, B. Croisile3, H. Chainay1(1. Laboratoire d’Étude des Mécanismes Cognitifs, Université Lyon 2 - Lyon (France), 2. Scientific Brain Training SA - Lyon (France), 3. Service de Neuropsychologie, Centre Mémoire de Ressource et de Recherche de Lyon, Hôpital Neurologique - Lyon (France))
Introduction: Considering increasing occurrence of neurodegenerative disorders in older adults, such as Alzheimer’s disease (AD), and in the absence of effective drug treatment, cognitive training appears to be a promising alternative for improving cognitive functioning and daily living. The efficacy of cognitive training in patients with AD is still under the debate regarding the best methodological approaches to optimize the training outcomes, commitment, and motivation. The computer-based cognitive training (CBCT) provides wide variety of well-calibrated exercises easily adaptative to each patient. The short- and long-term benefits of CBCT first shown in healthy older adults have also been proven in patients with AD and MCI. Overall, studies recommend early intervention with 30 minutes to 1 hour sessionseveral times a week. Such recommendations are hard to apply as most people will only consult when symptoms become more pronounced and high-frequency cognitive training protocols require frequent travels between home and speech-language pathologists’ (SLP) offices. The patients’ compromised autonomy . and many health problems are additional difficulties leading to training interruptions. One way of circumventing these problems is to design remote CBCT sessions. Our main hypothesis is that remote CBCT is an effective way to increase the cognitive and psychological benefitsthrough increased frequency of training. Objectives: The aim of this study was to examine short- and long-term benefits of CBCT at home in patients with mild to moderate AD, as a complement to the training in SLP’s offices. The secondary purpose was to study training frequency required to obtain noticeable effects. Material and Method: The study followed a conventional protocol used to evaluate cognitive and psychological benefits of CBCT. A multicenter study was conducted in SLP’s offices. Because of COVID pandemic, only a limited number of patients have been included. Twelve women and 12 men (n=24) diagnosed with AD according to DSM-V criteria (MMSE mean = 26.25; SD = 3.06) were included for 8-month duration protocol. They gave their informed consent to participation to this study, which obtained the authorization of the national ethical committee CPP Sud Méditerranée III (Nr. 2019-A00458-49) and was registered on clinicaltrials.gov (NCT04010175). Patients received CBCT for 4 months under one of three conditions: (1) in SLP’s office once a week (REG - regular group), (2) in SLP’s office once a week plus once at home (MFG - moderate frequency group), and (3) in SLP’s office once a week plus three times at home (HFG - high frequency group). The trainings’ content in SLP office and at home were identical. Eight SLP’s offices (inclusion centres) were pseudo-randomly assigned into training frequency groups. During the CBCT patients performed a series of short exercises targeting memory, executive functions, processing speed, visuospatial abilities for 45 minutes using the Happyneuron Professional software (https://www.happyneuronpro.com). To test the training’s effect, three types of instruments were used: experimental tasks, neuropsychological tests, and questionnaires. The primary measures were patients’ scores in executive and working memory experimental tasks. The secondary were patients’ scores in neuropsychological tests and questionnaires. These measures were performed at 3-point: T1 (pre-training), T2 (post-training) and T3 (3-month posttraining). Because the inclusion of expected number of patients per group was not possible due to the pandemic COVID-19 the innovative statistical approach was used to analyse the data. Sequence analyzes (Abbott & Tsay, 2000) was performed based on an event: the number of exercises carried out and of a state (scores obtained each time) to identify typical trajectories, these trajectories were then compared to the three groups and with well-being scores. We used R software with TramMineR. Depending on the exercises type (executive or working memory) between two and three typical trajectories came out. In a case of two trajectories, one has shown an absence of progress and the second a progression. In the case of three trajectories, one has shown an absence of progress, one a slight progress and another one a real progress. For well-being, three trajectories were observed: one without progression, another with a small progression and comprising undulations (progression, regression, progression) and a third where the progression was more important and more linear. The pre-post-training comparisons have shown significantly more important improvement in working memory and executive functions (inhibition) in HFG group than two other groups. This study shows the progression with training and some of the benefits of training on cognition and well-being in patients with Alzheimer’s disease.The main limitation of the study is a small number of patients included to the study due to the health crisis. However, this work opens a new way to identify parameters for optimizing the CBCT (selection of exercises, adaptation of difficulty levels and frequency of training). Key words: Alzheimer’s disease, MCI, computer-based cognitive training, at home cognitive training, cognitive benefits, daily living. Competing interests’ statement: Franck Tarpin-Bernard and Bernard Croisile are cofounders and shareholders of SBT Humans Matter.
P218- TAKING CARE OF FAMILY DEMENTIA CAREGIVERS: A QUALITATIVE EXAMINATION OF PATIENT PERSPECTIVES AND PERCEIVED HEALTH OUTCOMES AFTER RECEIVING USUAL CARE AND AFTER A DIGITALLY SUPPORTED CARE MANAGEMENT PROGRAM. O.A. Klein1, A. Karras2, W. Hoffmann3,4, S. Teipel1,2, I. Kilimann1,2(1. Deutsches Zentrum fuer Neurodegenerative Erkrankungen - Rostock (Germany) - Rostock (Germany), 2. Clinic for Psychosomatics and Psychotherapy, University Medical Center Rostock - Rostock (Germany), 3. Deutsches Zentrum fuer Neurodegenerative Erkrankungen - Greifswald (Germany), 4. Institute for Community Medicine, Section Epidemiology and Community Health, University Medicine Greifswald - Greifswald (Germany))
Background: Almost two-thirds of people with dementia (PwD) living at home receive care from a family or other informal caregiver. For caregivers this often results in a workload comparable or above a full-time position. Evidence shows that family caregivers experience increased physical, psychological, emotional, and social stress which, in the long term, results in adverse health outcomes. The development of effective healthcare and support management for family caregivers is vital. Objectives: Therefore, our aim was to examine and compare the perceptions of participants who received a digitally supported care management program with those who received usual care. Methods: This study was embedded within a large, multi-center cluster randomized controlled trial (GAIN study) examining the effectiveness of a care management program for family caregivers of people with dementia. Ethical approval has been obtained from the Ethical Committee of the University Medicine Greifswald (Registry number BB 120/2019). The trial is still ongoing and registered at ClinicalTrials.gov (NCT04037501). Data collected through 30 semi-structured telephone interviews with participants of the GAIN trial will be recorded, transcribed and analyzed using framework analysis. Based on previous research, we developed two semi-structured interview schedules, each tailored to the content of the group (control or intervention). Both interview schedules (control and intervention) covered participants’ health, care situation and responsibilities, use of medical and non-medical services (before and during the trial), changes regarding their health and wellbeing in the past six months, and any feedback based on their experience of being involved in the trial. Participants in the control group were also asked about their experience and thoughts on being part of the control group. Participants in the intervention group were asked about their perspectives on the most and least useful aspects of the GAIN care management program, the impact the intervention had on their health and daily life activities after the trial, the participants’ experience and thoughts on being part of the intervention group, as well as participants’ overall experience of the care management program. Results: To date we have interviewed 27 participants, out of which 11 belonged to the control group and 16 to the intervention group with the majority being female. We have started the analysis of the transcripts. Complete results will be available and presented at the conference. Conclusion: The results of this interview study will be useful in informing and better understanding the results of the GAIN trial. In addition, the results will further improve the care management program developed as part of the trial and will be useful for future trials.
P219- INTUITION: A BRAIN HEALTH STUDY USING MULTIMODAL DIGITAL BIOMARKERS TO DECIPHER COGNITIVE PROFILES OF INDIVIDUALS AT-RISK FOR ALZHEIMER’S AND RELATED DEMENTIAS. M. Butler1, A. Porsteinsson2, S. Kenny1, H. Lenyoun3, M. Hobbs1, R. Brown1, M. Bianchi3, J. Williams1, A. Gabelle1, S. Belachew1, I. Intuition Study Scientific Committee1(1. Biogen - Cambridge (United States), 2.University of Rochester Medical Center - Rochester (United States), 3.Apple - Cupertino (United States))
Background: Identifying individuals at-risk for Alzheimer’s disease (AD) and related dementias is critical for early diagnosis, monitoring, and treatment. Emerging digital health technologies offer unique opportunities to describe and decipher cognitive trajectories in at-risk populations. Consumer-grade digital devices can unobtrusively trace real-world behaviors and generate digital signatures of everyday cognition. Passive and active data collection with digital tools may open new avenues for early detection in non-clinical settings and expand the scope and scale of screening for cognitive decline. Remote and frequent cognitive sampling allows for increased spatiotemporal resolution at an individual level and has the potential to optimize prediction of clinical progression in a robust, dynamic fashion. Development and validation of personalized digital tools may equip and empower patients to track cognitive wellness and promote societal awareness of brain health. Objectives: The co-primary objectives of the INTUITION study are to (1) develop real-world high-accuracy classifier models that distinguish cognitive impairments from healthy aging to promote screening and monitoring of people at-risk to develop AD and related dementias, and (2) to construct a trackable cognitive health score. The secondary aims are to predict cognitive decline and risk of conversion to mild cognitive impairment (MCI) in healthy and subjective cognitive complaint (SCC) populations. In a subset of participants, AD-biomarkers define the at-risk populations and will be used to assess classifier selectivity for suspected underlying pathology. Methods: The INTUITION study (NCT 05058950) is a two-year observational digital study enrolling 23,000 U.S.-based participants aged 21 to 86 years of age inclusive, including healthy controls, SCC, and MCI. The study launched in September of 2021 and continues recruitment in 2022. This virtual app-based study uses multimodal sensor devices, including an iPhone and Apple Watch, for longitudinal data collection from consenting participants. The study has been designed with privacy, control, and transparency in mind as well as data security. Device use is coupled with passive sensor-based monitoring in conjunction with validated cognitive tests and behavioral surveys. The sources of passive data collected from the study specific app using Apple Watch and iPhone cover multiple domains, including motor and autonomic function, diurnal rhythms, speech and language, social function, and everyday cognition. We aim to demonstrate the utility of using data from features derived from sensor streams to distinguish cognitive status between cognitively intact participants and those with MCI. Those features which drive model outputs will be mapped to cognitive outcome measures with the purpose of deriving a trackable cognitive health score. There are two study arms with a design to support the development of a classifier model which is both accurate and generalizable. In one study arm, model accuracy will be appraised in subjects with recently established cognitive status based on expert clinical evaluation, phenotyping, and AD-biomarkers. In the second study arm, a larger population-based cohort will provide data to understand classifier model generalizability. In this arm cognitive status is established by self-report and the confidence in cognitive status labeling is adjudicated by tele-research evaluation. Cognitive assessments are deployed at monthly and quarterly intervals using neuropsychological methods adapted for virtual research and with a high-frequency, repeated measurement approach. Cognitive test selection was designed to probe the integrity of learning and memory, processing speed, attention, executive and visuospatial function. App-based administration of validated surveys occurs at regular intervals and covers multiple domains, including mood, sleep, diet, substance use, exercise, quality-of-life, stress and discrimination, self-efficacy, medical history, medications, risk-factors for dementia, global cognitive health, and instrumental activities of daily living. Results: The INTUITION study is currently enrolling and is proceeding along expected timelines with full enrollment expected before the end of 2022. Baseline characteristics and cognitive profiles of the whole population and subgroups of interest (e.g., SCC, MCI) will be presented at the conference. We will provide preliminary results of the normative cognitive data of the population both with and without cognitive complaints across the aging spectrum from the third to ninth decades of life. Conclusions: The INTUITION study is the first digital health and medicine study of this scope and will provide a large and comprehensive dataset of passive and active digital biomarker assessments on participants with and without vulnerability to cognitive decline due to AD or other underlying disease processes.
P220- COGNITIVE HEALTH IN UNDERREPRESENTED POPULATIONS: EARLY LEARNINGS FROM THE INTUITION BRAIN HEALTH STUDY. R. Au1, M. Butler2, H. Lenyoun3, S. Kenny2, R. Brown2, P. Saha-Chaudhuri2, M. Bianchi3, J. Williams2, A. Gabelle2, S. Belachew2, I. Intuition Study Scientific Committee2(1. Boston University School of Medicine - Boston (United States), 2. Biogen - Cambridge (United States), 3. Apple - Cupertino (United States))
Background: An evolving challenge for clinical research is how to recruit and retain demographically diverse populations. Barriers and facilitators to participate in research are complex and influenced by a host of factors, such as the burden of travel to study sites or schedule flexibility. It remains to be seen how digital, de-centralized studies might transform the engagement landscape for research that aims to enroll cohorts reflective of large, heterogeneous populations, such as those in the United States. Given the rapid growth and ubiquity of digital devices in everyday life, research that utilizes real-world consumer technology offers the possibility to overcome traditional obstacles to join research. Strategies to lower barriers to participation aim to enroll representative study populations, deliver increasingly generalizable results, and promote a culture of equitability. Cognitive health in underrepresented populations is less studied and this area of unmet need is due at least in part to challenges related to accessibility of research. Given that socioeconomic factors are associated with vulnerability to cognitive decline and potential determinants of health, then research to characterize risks to brain health ought to utilize tactics to enroll representative populations. Objectives: The INTUITION study (NCT 05058950) is an observational two-year virtual study in adult residents of the United States aged 21 to 86 years, and with the goal to enroll 23,000 individuals that are stratified into cohorts based on age and risk of cognitive decline. The aim is to develop real-world high-accuracy classifiers that distinguish cognitive impairment from healthy aging, and to construct a trackable cognitive health score. Recruitment and engagement strategies have been deployed to enroll a diverse study population, including 20% or greater participants who self-report ethnicity as Hispanic/ Latino or self-report race as Asian, Black/African American, American Indian/Alaska Native, Native Hawaiian/Pacific Islander, or other/multi-racial. Additional recruitment goals are to enroll individuals with a range of educational attainment, regional geographical diversity, and to maintain a relative balance in the male-to-female ratio. Methods: The study recruitment strategy includes multiple channels, such as email/ direct mail campaigns, paid search and social media, word-of-mouth, and event-based outreaches in collaboration with patient advocacy groups. This virtual study uses an iPhone and Apple Watch to collect digital multimodal longitudinal data from consenting participants. The study has been designed with privacy, control, and transparency in mind as well as data security. Device use is collected via passive sensor-based monitoring through the study specific app, and this is coupled with validated cognitive tests and behavioral surveys. Cognitive assessments are served at monthly and quarterly intervals and measure different neuropsychological domains, such as episodic learning and memory, working memory, psychomotor and processing speed, sustained attention, executive and visuospatial function. App-based administration of validated surveys occurs at regular intervals and covers multiple areas, including psychosocial function, nutrition, substance-use, sleep, physical activity, stress, discrimination, medical and cognitive history, prescription and supplemental medications, and global function. We will compare the recruitment strategies and evaluate the adherence to digital tool use with a focus on data from underrepresented populations by age group and cognitive status. Descriptive and summary statistics are used to evaluate the demographic data. Results: The study launched in September 2021 and as of June 2022, the INTUITION study has successfully enrolled more than 80% of its total target population. The population contains individuals with varying degrees of risk for cognitive decline and 75% of the participants are over the age of 50 years. The study is on track to meet and possibly exceed enrollment goals with respect to racial/ethnic diversity and spread in educational attainment. The study is also achieving geographic diversity in terms of regional representation from across the United States. The most successful recruitment strategies include word-of-mouth and direct email campaigns that draw from focused databases of individuals with interest to participate in research. At the conference, up-to-date study population characteristics will be shared in addition to an assessment of the recruitment strategies used to enroll a diverse population. Cognitive, clinical, and behavioral profiles will be presented, as well as early learnings from passive and active data collection. Conclusions: The INTUITION study has the potential to demonstrate that virtual studies can readily enroll individuals from generally underrepresented populations. A diverse U.S.-based population continues to enroll in this large-scale observational study. De-centralized studies leveraging digital health technology tools such as the INTUITION study so far appear to lower barriers for individuals to participate and may offer the potential to enroll populations that accurately reflect the diverse constitution of the larger society.
P221- ANALYZING FACIAL EXPRESSIONS AND POSES CAPTURED DURING VIDEO CHATS FOR EARLY IDENTIFICATION OF MCI - PROOF OF CONCEPT STUDY: I-CONECT PROJECT. M. Alsuhaibani1, A. Pourramezan Fard1, H. Dodge2,3, M. Mahoor1(1. School of Electrical and Computer Engineering, University of Denver - Denver (United States), 2. Layton Aging and Alzheimer’s Disease Center, Oregon Health & Science University - Portland (United States), 3. Oregon Center for Aging and Technology (ORCATECH), Oregon Health & Science University - Portland (United States))
Background: Artificial Intelligence algorithms such as Computer Vision (CV) might be able to detect early cognitive declines by analyzing facial expressions and movements captured during casual video chats. Objectives: In this study, we have utilized deep-learning-based CV techniques to extract facial features in facial videos of older adults with two cognitive statuses (those with normal cognition (NCO) and mild cognitive impairments (MCI) and then used extracted features to distinguish subjects with MCI from NCO. Methods: Data: Data came from the facial videos collected in the Internet-Based Conversational Engagement Clinical Trial (I-CONECT) (NCT02871921), the behavioral intervention randomized controlled trial aimed to examine the effect of increased social interactions through video chats on cognitive functions. The socially isolated older subjects aged 75 were recruited and the experimental group conversed with trained conversational staff 4 times per week for 6 months and 2 times per week for additional 6 months using internet webcam. Over 6000 files of 30 minutes long video chat sessions were recorded with each session discussing a different topic. In this proof of concept study, we extracted 18 videos where the elderly discussed their summertime memories with the conversational staff. These videos were selected based on the video quality (brightness of the screen, no eyeglasses, acceptable distance between face and camera, and visibility of the subject’s face during the video). Two third of the 18 subjects were clinically diagnosed as MCI with the rest being NCO. The detail of the study protocol for this intervention was published elsewhere (Yu et al., 2021). Analyses: We first analyzed the videos using our deep neural models on a frame level to detect the subjects’ faces in the videos, and then recognize facial attributes/features. The videos have variable frame rates, but we extracted the faces using a fixed frame rate among all videos. Currently, two types of features are extracted: Head Pose (HP) and Facial Emotion Recognition (FER). HP has three values representing the Yaw, Pitch, and Roll of the subject’s head movement. FER contains seven values that represent probabilities of six basic emotions (Happy, Sad, Surprise, Fear, Disgust, Anger) and neutral. We investigated several machine learning approaches to analyze the features but two models gave the best classification accuracies: Support Vector Machine (SVM) with Radial Basis Functions (RBF) and Random Forest (RF). We trained SVM and RF models using the cross-validation technique, where one subject data is left for testing and the remaining for training. We trained the models at the frame level and then use them to classify each frame whether belong to the MCI group or the NCO group. The model determined the subject’s cognition status based on pose, FER, fusing of HP, and FER. We also explored the average of FER for all frames of the same subjects. Results: The evaluation metrics are accuracies, F1 score, and the Area Under the Curve (AUC). The HP data shows a promising classification result of the subjects’ cognitive status. The best model had 83.3%, 0.889, and 0.75 for accuracy, F1 score, and AUC, respectively, using Head Pose (HP). On the other hand, the accuracies are 66.7% for the 18 subjects if we use FER data. Thus, the HP features have carried more information about the subjects’ cognitive status. Conclusion: The Head Pose features extracted using Computer Vision provided reasonable discriminatory ability in distinguishing those with MCI from NCO. In this proof of concept study, we limited the conversational session to one theme where all discussed the same topic. In the next study, we plan to apply our method to more diverse sessions utilizing all the recorded video chats could improve the generalizability of our results.
P222- USING AI AND NATURAL LANGUAGE PROCESSING ALGORITHMS TO SCREEN OLDER ADULTS WITH MILD COGNITIVE OR EARLY ALZHEIMER’S DISEASE. S. Melgar-Donis1,2, J. Siewierski3, R. Zandie1,3, D. Pittman1, L. Chileshe1, H. Abdollahi3, M. Habibi3, B. Soicher3, E. Emamian3, M. Mahoor3,4(1. University of Denver - Denver (United States), 2. DreamFace Technologies, LLC, 3.DreamFace Technologies, LLC - Centennial, Co (United States), 4.Univesrity of Denver - Denver (United States))
Background: Cognitive impairment, a known precursor to Alzheimer’s disease/related dementias (AD/ADRD), is many times not recognized in early stages. This might be due to many barriers to early detection of ADRD that can delay diagnosis and treatment. One of the main barriers is a lack of trained staff at care facilities, coupled with an increasing number of residents to care for. This situation adds strain to an already diminishing caregiver population. Along with an ongoing senior caregiver shortage, the pandemic has revealed an unmet need for caring for those with MCI and dementia. A suggested method of doing this is by care communities and independent living communities implementing memory screening programs and employing a systematic use of a screening tool, which has been shown to be one of the best ways for people to get referrals for neuropsychological evaluation and testing. In this study, we evaluate the feasibility of the MyRyan App to monitor the language and cognitive function in older adults with Mild Cognitive Impairment (MCI) and early AD/ADRD. MyRyan is an interactive mobile software application developed at DreamFace Technologies, LLC. It is designed in the form of a photo-realistic and engaging virtual agent that is used for meaningful daily conversation. It is designed to improve the psychological well-being and loneliness in individuals with MCI and AD/ADRD by giving seniors the opportunity to engage in dynamic conversation about topics consistent with the aging population demographic. It is a tool that is not only engaging for daily use but also uses state-of-the-art Artificial Intelligence (AI), including speech recognition, natural language processing (NLP) and deep machine learning algorithms, to assess mild cognitive impairment in participants according to Saint Louis University Mental Status Exam (SLUMS) screening tool. Objective: With this pilot study we demonstrate the need for a low-barrier screening tool for mild cognitive impairment and how an AI based application can serve this purpose. We used the MyRyan App to evaluate the effectiveness of such a screening tool in our study. This abstract presents the results of our clinical trial on a group of participants with MCI and early AD/ADRD on evaluating how automated AI/NLP algorithms can score cognitive impairment. Methods: We designed and conducted a pilot/feasibility study for the MyRyan App and recruited 12 older adults (average age: 76.92 years, std: 4.93 years; 8 Females) who participated in the study, six with MCI and six with early-stage AD/ADRD (12 participants total) living in three different independent living facilities located in Denver Metro areas. Participants interacted with MyRyan in two sessions over a period of three weeks. Each participant spent between 25–30 minutes interacting with MyRyan in every session. Participants conversed with MyRyan about different topics of interest and at the end completed the Cookie Theft Picture description. For the picture description test, we transcribed the speech automatically and ran it through our Deep Neural Network Model (A Transformer model call RoBERTa) where the model assigned a score between 0 to 1 indicating whether the participant has dementia and cognitive impairment. In training the RoBERTa model, we used the University of Pittsburgh (Pitt) dataset, the largest publicly available language dataset on dementia and AD/ADRD, containing transcripts and audio files of 3,228 conversations from a normal control group and 19,305 conversations from a population with probable dementia, administered by the Alzheimer and Related Dementias Study at the Pitt School of Medicine. The participants were able to interact with the application on two different visits to ensure variation in the picture descriptions. At the beginning of the first visit, the participants were administered the SLUMS as a benchmark to compare against our predicted results. Results and Analyses: Our prediction rate on the training set showed just under 90% accuracy, with a similar 80% prediction accuracy rate from the field results with a sample size of N = 12. These results are much higher than prediction rates found in other studies that use LASSO and tree-based classification methods. Furthermore, we fitted a linear regression model with the predicted dementia scores plotted against the participants’ SLUMS (the lower the SLUMS score, the higher the cognitive impairment). The regression model shows that the SLUMS is inversely correlated with the model prediction (R2 = 0.6001). To measure user engagement in conversation, we used words per minute (WPM). We automatically counted the number of words per minute for each utterance (or interaction). Results show that on average, participants spoke 101 (STD = 37) WPM. According to the National Center for Voice and Speech, the average conversation rate for English speakers in the U.S. is about 150 WPM. Studies show that the WPM is slightly lower when people speak with a virtual agent (MyRyan is a virtual agent). In addition, 50% of the participants in our study have MCI or early-stage AD/ADRD, which is another factor that slows down speech rate. Results show that participants in our study are engaged in conversation with MyRyan. Conclusion: Based on these preliminary results, we believe that an AI-based mobile app such as the MyRyan App can provide a low-barrier testing tool to care providers and facilities that can be used as an objective and independent diagnostic tool for ADRD in aging populations. Use of such tools would aid in labor shortages of care givers and allow facilities to be able to provide better care for their residents. In addition to being a screening tool, the application can be engaging for users and can improve their quality of life.
LP106- DEVELOPMENT OF A MACHINE LEARNING MODEL TO DIAGNOSE DEMENTIA USING QUESTIONNAIRES ASSESSING SUBJECTIVE MEMORY COMPLAINTS AND DEPRESSIVE SYMPTOMS. M. Kim1, J. Hong1, J. Park1 J. Han1, K.W. Kim1(1. Seoul National University Bundang Hospital - Seongnam-Si (Korea, Republic of))
Background: Rapid diagnosis of dementia in the early stages is a key factor in successful dementia management. Existing diagnostic methods such as cognitive tests, biomarkers, and brain imaging are expensive and time-consuming, limited in use in the clinical field. Dementia screening based on patient characteristics and self-report questionnaires is highly accessible and easily applied to the majority of the population in a very short time. However, the method of determining the risk of dementia based on the total score of the questionnaire or a specific risk factor showed low accuracy and sensitivity. In this study, we attempt to implement a dementia prediction model that learns dementia risk factors and clinical characteristics using a machine learning algorithm. Methods: Data were collected from a nationwide dementia cohort, which is the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), and a retrospective cohort consisting of outpatient data from Seoul National University Bundang Hospital. A total of 28,001 people who completed the Subjective Memory Complaint Questionnaire (SMCQ) and the Geriatric Depression Scale (GDS) from the two cohort studies were included in this study. Several demographic variables and individual items of SMCQ and GDS were selected as input features to train the prediction model. Labeling the diagnosis of dementia was conducted through interviews with clinicians. Samples with even one missing value were excluded, and 5,730 participants were included for final model development. Five algorithms including logistic regression, support vector machine, random forest, XGBoost, and light gradient boosting machine were tried and hyperparameter tuning was conducted using GridSearchCV. The model with the highest area under receiver operating curve was selected as the best model. For model interpretation, the Shapley additive explanations (SHAP) analysis was performed on the model with the best predictive performance. By plotting a calibration curve, we identified the best-calibrated model. Ensemble model combining the most predictive model and calibrated model was created using the soft voting method. Results: Of the five individual algorithms, the model with the highest AUC was the XGBoost algorithm (AUC=0.928) and the best-calibrated model is logistic regression when checking calibration curves visually. The ensemble model combining with the XGBoost logistic regression model showed both higher predictive performance (AUC=0.929) and an improved level of calibration, compared with individual models. Age was the most predictive feature in the results of the XGBoost model interpretation analyses. Among the top 10 features, there were five items of SMCQ and two items of GDS. The education year was ranked third among the demographic variables. Conclusion: Our prediction model can successfully identify individuals with dementia with good calibration. This prediction tool can be used in clinical trials to enroll individuals who are more likely to diagnose dementia. Using our model, clinicians can identify individual dementia risk factors and establish treatment strategies accordingly. Future clinical trials are needed to prove the efficacy of our algorithm in the early prediction of dementia and the establishment of treatment strategies.
LP107- THE COMMUNITY ENGAGED DIGITAL ALZHEIMER’S RESEARCH (CEDAR) STUDY: DIGITAL ENGAGEMENT STRATEGIES TO INCREASE ADRD RESEARCH PARTICIPATION OF BLACK AMERICANS. A. Aaronson1,2,3, M. Ashford1,2,3, D. Zhu4, H. Cham4, C. Conti1,2,3, X. Deng4, R. Alaniz5, R.S. Mackin2,3, M. Weiner1,2,3, D. Byrd6, R.W. Turner7, C. Hill8, R. Nosheny2,3, M. Rivera Mindt4,9(1. Northern California Institute for Research and Education (NCIRE), Department of Veterans Affairs Medical Center - San Francisco (United States), 2. Veterans Affairs Advanced Research Center - San Francisco (United States), 3. University of California, San Francisco - San Francisco (United States), 4. Department of Psychology, Latin American Latino Studies, African and African American Studies, Fordham University - New York (United States), 5. Alaniz Marketing - Novato (United States), 6. CUNY, Queens College - Queens (United States), 7. George Washington University - Washington (United States), 8. Alzheimer’s Association - Chicago (United States), 9. Department of Neurology, Icahn School of Medicine at Mount Sinai - New York (United States))
Background: Underrepresented populations (URPs), including Black older adults, experience significant inequities in Alzheimer’s disease and related dementias (ADRD) prevalence, incidence, and outcomes. However, ADRD research studies and clinical trials fail to adequately include Black American older adults. Community Engaged Research (CER) is an evidence-based approach for improving URP engagement in ADRD research, but CER strategies often lack scalability to the national level. As internet usage among URP older adults increases, internet-based research demonstrates promise as a feasible, valid approach for engaging and longitudinally assessing Black older adults. Objectives: The CEDAR study aims to develop, deploy, and evaluate a culturally informed, digital platform utilizing a CER approach, to increase the engagement (i.e., longitudinal task completion) of Black American adults included in the Brain Health Registry (BHR) and in additional ADRD clinical research. Methods: BHR is a public, online registry consisting of over 100,000 members. BHR aims to recruit, screen, and longitudinally monitor participants for aging and cognitive-related research. BHR participants are also referred to other research studies. BHR participants complete a sequence of well-validated, unsupervised, online self-report questionnaires and cognitive tests. A subpopulation of BHR participants who self-identify as Black/African American and who agreed to be contacted about future research opportunities were recruited to join CEDAR via automated email invitations describing the study. After signing an electronic informed consent, all enrolled participants were directed to a 5–15-minute online survey about motivators (i.e., reasons to participate in research) and barriers (i.e., obstacles that make participation challenging) to BHR participation, as well as preferences for communication channels and engagement methods. All participants were invited to volunteer for a Community Science Partnership Board (CSPB). All participants were encouraged to complete BHR questionnaires, including the Everyday Cognition Scale (ECog), and cognitive tests, including the Cogstate Brief Battery, MemTrax Memory Test, and Cambridge Cognition Paired Associates Learning. In collaboration with a marketing team and the CSPB, we developed and deployed a series of engagement strategies and materials to address barriers to research participation, including (1) compensation for task completion, (2) culturally informed websites, email campaigns, and social media posts, and (3) written and video testimonials from CEDAR participants and investigators. We compared the demographics, cognitive profile, and baseline BHR task completion rates between enrolled CEDAR participants and those invited to join CEDAR who did not enroll. We used independent sample t-tests to compare group means for continuous variables and reported Cohen’s d as effect size. For categorical variables, we used Chi-square tests if ≤ 20% of expected cell counts were less than 5 and reported Cramer’s V as effect size. Otherwise, Fisher’s exact tests were used if > 20% of expected cell counts were less than 5. Results: Out of 3,738 participants who received invitations to join CEDAR, 364 (9.74 %) expressed interest in enrolling by clicking on the email study link, and 349 (9.34%) enrolled. 210 (5.62%) of enrolled participants completed the barriers and motivators survey, and 134 (3.58%) indicated interest in joining the CSPB. Compared to those who did not enroll in CEDAR, those who enrolled were significantly older (mean age in years = 58.29, SD 11.49 vs mean 54.08, SD 13.02), had higher educational attainment (mean education in years = 16.25, SD 2.4 vs mean 15.40, SD 2.52), and a higher percentage of self-reported family history of AD (41.83% vs 28.09%). Those who enrolled in CEDAR had significantly lower subjective cognitive decline (self-report ECog score) compared to those who did not enroll (mean 1.39, SD 0.44 vs mean 1.49, SD 0.52). Among all Black BHR participants invited to join CEDAR, 100% completed at least the BHR initial questionnaire, 4.12% completed all tasks, 53.18% completed at least one BHR cognitive test, 11.08% attempted to complete one BHR test but encountered technical difficulties, and 4.95% have an enrolled study partner. Compared to those who did not enroll, those enrolled in CEDAR had a significantly higher percentage of: participants completing all BHR tasks (22.42% vs 1.92%), participants completing at least one cognitive test (76.83% vs 49.66%), participants attempting a cognitive test but encountering technical difficulties (17.88% vs 10.12%) and participants with an enrolled study partner (17.88% vs 3.36%). The CSPB convened on a quarterly basis and consists of 19 BHR members, 6 CEDAR investigators, and 1 marketing professional. The CSPB provided guidance and iterative feedback on URP recruitment and engagement strategies, participant communications, and methods for building trust and relationships with community-based organizations. Conclusion: These findings demonstrate that culturally informed strategies created through a CER approach are a feasible, scalable strategy to increase engagement of Black participants in an online ADRD-related research registry. Future efforts should evaluate the effectiveness of the individual engagement strategies deployed. Furthermore, CEDAR participants were 84.53% female and had mean education of 16.25 years. Strategies should be developed for recruiting and engaging Black men and Black individuals with lower educational attainment.
LP108- QUESTIONNAIRE-BASED COMPUTER ASSISTED DIAGNOSIS (CADX) IS USEFUL FOR IDENTIFYING ALZHEIMER’S DISEASE. T. Daly1, D. Weisman2(1. Sorbonne Université - Paris (France), 2. Abington Neurological Associates - Abington (United States))
Background: Memory and cognitive disorders are underdiagnosed and the failure to recognize them is a missed opportunity for treatment, diagnosis and inclusion in research. Computer Assisted Diagnosis (CADx) may be a simple tool for assisting the identification of subjects with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) compared with normal elder controls. Objectives: Our study validated the diagnoses of memory complaints with a questionnaire-based CADx against gold standard same day diagnosis. Methods: The CADx is a web based memory/cognitive screening program (Cogminder.com). The study used prospective data entry from caregivers entering subject information into a computerized expert system that renders a report. We validate this report by comparing the report with standard diagnosis based on same day history and physical. All patients were seen in a private neurology office. Results: 319 patients with cognitive complaints who presented with a caregiver were included. Out of the 319, 253 (79.3%) were properly diagnosed and 31 (9.7%) were misdiagnosed by the system. Of the misdiagnoses, a total of 10 (3.1%) were considered “near misses” (for example, a clinical diagnosis DLB and AD overlap vs a CADx of AD only) and 21 (6.6%) were considered wrong (clinical diagnosis of normal cognition, CADx of MCI). Indeterminate results occurred in 27 (8.5)% of cases (computer data was at odds with itself, leading to indeterminate CADx) and the results were appropriately held in 8 (2.5%) cases due to the presence of suicidality. Features independently associated with increased misdiagnosis and near misses were presence of any historical confounder (odds ratio, 3.49; 95% confidence interval, 1.58 to 7.73, sig P= 0.0020) including psychiatric background, severe neuro-psychiatric symptoms, medical comorbidities, and English as second language. The clinical diagnosis of Alzheimer’s disease was associated with better CADx performance (Odds ratio 0.41, 95% CI: 0.18 to 0.95, P = 0.0383) compared to normal, MCI, DLB. Conclusion: The CADx was particularly efficient at assisting clinical diagnosis of AD, suggesting its usefulness as an extender support system within general practice. Confounders and non-AD clinical diagnoses were associated with misdiagnoses and future studies will be necessary to help refine the accuracy of CADx and improve its implementation in clinical practice.
LP109- ADVANCING MEASUREMENT IN ALZHEIMER’S DISEASE AND RELATED DISORDERS THROUGH DIGITIZING ASSESSMENT OF MEANINGFUL ASPECTS OF HEALTH. P. Griffiths1, C.Y. Wu2, D. Stefko3, L. Cesnakova4, J. Goldsack5(1. The Digital Medicine Society - Saumur (France), 2. The Digital Medicine Society - Portland (United States), 3. The Digital Medicine Society - Nashville (United States), 4. The Digital Medicine Society - Prague (Czech Republic), 5. The Digital Medicine Society - Sarasota (United States))
Background: To assess the impact of an intervention on a patient’s life, measurement must go beyond biological and clinical assessment of Alzheimer’s Disease and Related Dementias (ADRD). Alongside this important work, the impact on the patient’s lived experience needs to be appraised. Meaningful aspects of health (MAH) are the elements of the disease that a patient wants to prevent, does not want to worsen, or wants to improve. MAHs are typically expressed in the patient’s own words and the context of their daily life. MAHs are the basis for measuring what is important to patients. In the case of ADRD, it is critical to understand what the care partner and the clinician consider meaningful. This will allow researchers to find an intersection between all three stakeholders, allowing for measurement of ADRD which is directly translatable to the patient’s lived experience. Furthermore, given the global nature of clinical research, identifying MAHs that transcend language, culture, and place is essential. Objectives: To perform a systematic literature review of existing qualitative studies and summarize the frequently mentioned MAH at ADRD disease stages across people with different roles. To provide the basis for ongoing work led by a pre-competitive collaboration hosted by the Digital Medicine Society (DiMe) to develop a core set of high-value, globally relevant digital measures of ADRD. Methods: A systematic literature search was conducted using the PubMed and Embase databases (PROSPERO: CRD42022342748). The searches were limited to articles published from 2002 to present (past 20 years). A total of 2,113 titles and abstracts were reviewed independently by 2 researchers for screening. A third reviewer reconciled discrepancies between the 2 screeners. Of the 2,113 titles and abstracts, 65 publications were selected for the full-text review. From the full-text screening, 32 articles were identified for the final data extraction, including 2 systematic review articles, 1 non-English article, and 4 articles hand-searched from the included systematic review articles. Results: Most articles were on Alzheimer’s disease/mild cognitive impairment (MCI) (n = 19), followed by Lewy body disease (LBD) (n = 5) and mixed etiology disease (n = 3). No articles on frontotemporal dementia or vascular dementia alone were identified for inclusion. Most studies were conducted in North America (n = 9) and Europe regions (n = 9), followed by Asia (n = 3), mixed regions (n = 3), Africa (n = 1), Australia (n = 1), and South America (n = 1). Thirteen studies recruited dyads cohort (adults with ADRD and care partners), 13 studies recruited each role alone (n = 6 for adults with ADRD, n = 6 for care partners, n = 1 for clinicians), and only 2 studies recruited all three roles. Nearly half of the studies (48%) determined the ADRD diagnosis through hospitals and clinics (electronic medical records, physician referral etc). More than one-third of the studies (39%) recruited adults with mixed ADRD severities. Among the 30 original research articles, the most frequently reported meaningful outcomes were mental health (depression, anxiety et.; n = 21), followed by activities of daily living (n = 20), psychiatric symptoms (n = 15), communication/ conversations (n = 14), memory (n = 13), behavior problems (n = 13), sleep (n = 13), self-care/hygiene (n = 13), and behavior change (n = 13) across studies. While adults with ADRD had mentioned mobility/ physical health, socialization, and recognizing names/people as important concepts, caregivers did not mention them as often across studies. Instead, 67% of articles that recruited caregivers mentioned behavior problems as a relevant concept. Communication/conversations (67%), psychiatric symptoms (50%), and sleep (44%) were frequently reported in articles targeting adults with moderate/severe AD but sparsely reported in MCI/mild AD articles (38%; 13%; 13%). Safety, medication management, comorbidity, and visual problems were only mentioned in articles targeting moderate/ severe AD, but not MCI/mild AD. Conclusion: From the initial results arising from this literature review, we identified common elements of ADRD that 1) matter to patients, care partners and clinicians, and 2) transcend language, culture, and place. These relate to depression and anxiety, and sleep. We also discovered differences across these stakeholder groups. For example, patients place more emphasison mobility, physical health, socialization and recognizing names and people for patients, whereas care partners are more likely to prioritize behavior problems. There is limited available information for MAHs important to clinicians. This work will be used to develop a mixed methods survey to help address gaps in the MAH in ADRD for each of these three stakeholders and will be conducted across five countries. This work will allow us to understand which may be most appropriate to target with emerging digital health technologies, and to explore how these MAH could be parameterised for digital measurement in a way that is interpretable and useful for patients, care partners and clinicians. The overarching goal is to find meaningful digital measures that can be used to support drug development and clinical practice, the world over.
AD CLINICAL TRIALS AND COVID-19
LP110- SUSTAINED ACCELERATED COGNITIVE DECLINE IN OLDER ADULTS AS A RESULT OF THE COVID-19 PANDEMIC: ANALYSIS OF THE PROTECT UK STUDY DATA. A. Corbett1, C. Ballard1, B. Creese1, A. Hampshire2, D. Aarsland3, H. Brooker1(1. University of Exeter - Exeter (United Kingdom), 2. Imperial College London - London (United Kingdom), 3. King’s College London - London (United Kingdom))
Background: The full impact of the COVID-19 pandemic on public health is yet to be fully understood. Whilst the direct long-term health effects of SARS-CoV-2 infection are increasingly being recognised there is little understanding of the wider impacts of the pandemic conditions on public health. The societal restrictions during the first year of the pandemic hold the potential for considerable detriment to cognitive and mental health, particularly since major dementia risk factors such as exercise and dietary habits were impacted during this period. The longitudinal PROTECT study offers a unique means of exploring the impact of the pandemic on cognition in older adults. Methods: This is a longitudinal analysis of data from 3412 people aged 50 and over in the PROTECT study using computerised neuropsychology data and online self-report data collected before the pandemic (March 2019–2020) and during its first year (March 2020–March 2021) and second year (March 2021–2022). Cognitive trajectory was compared across the three time periods using ANCOVAs. Additional subgroup analyses were conducted in people with Mild Cognitive Impairment (n=147) and self-reporting Covid-19 infection (n=752), and an exploratory regression analysis identified lifestyle and medical factors associated with change in cognitive trajectory. Findings: Both executive function and working memory trajectories showed significant worsening across the whole cohort (p=0.0006) and sub-groups in the first year of the pandemic. This worsening was sustained in the second year (p=0.043). Regression analysis indicated that exercise, alcohol use and mental health significantly contributed to these declines, with sustained impacts in people with MCI and Covid-19 in the second year. Interpretation: The pandemic conditions have resulted in a significant worsening of cognition in older adults, driven by major dementia risk factors. The sustained decline highlights the need for public health interventions to mitigate the potential for dementia risk, particularly in people with MCI where conversion to dementia is likely within five years. The findings emphasise the need to consider long-term intervention for people with Covid-19 to support cognitive health in the long-term.
LETTER TO THE EDITOR: CASSAVA SCIENCES RESPONSE TO CTAD ABSTRACT LP105A. R. Barbier (Cassava Sciences, Inc., Austin, TX, (USA))
Dear Editor, We are developing simufilam, a novel drug candidate, for mild-to-moderate Alzheimer’s disease. We appreciate the opportunity to respond to CTAD abstract LP105A (J Prev Alz Dis 2022;9(S1):S51-S248). The Abstract Does Not Describe an Attempt to Replicate Prior Experiments: First, the title refers to the “replication” of experiments, but the authors do no such thing. Rather, they describe a one-off experiment using a different measurement technique. That is not “replication.” Second, the binding affinity of simufilam was previously established using two reliable techniques: competitive binding and direct binding to the full protein, either purified or in tissue (1). The authors describe a third technique, isothermal titration calorimetry (ITC). In their hands, ITC generated incongruous results. The authors’ incongruous result does not nullify two prior experiments. The meaning of the authors’ results is inconclusive, at best. The Reliability of Data Is in Doubt: First, the authors could only have used adulterated simufilam. Simufilam is a proprietary compound not authorized for manufacture, sale or use in the US and countries where it is patented. Any drug not manufactured in compliance with cGMP regulations is “adulterated” under the law. Adulterated simufilam may be sold illegally on-line, but an illegal manufacturer/seller of adulterated simufilam is unlikely to comply with FDA regulations that assure identity, strength, quality, and purity. In addition, a drug must be authenticated by independent, third-party certification to ensure manufacturing standards are met. The authors’ use of adulterated simufilam sourced from an unauthorized vendor raises questions about data reliability. Second, the abstract does not describe an appropriate positive control. A negative experimental result is significant and reliable if compared to a positive result from a positive control. The authors do not, however, describe a positive control showing a small molecule binding to a short peptide using ITC. Instead, they reference a small molecule binding to its whole protein target (carbonic anhydrase II). Third, ITC is a sensitive research technique, and results depend strongly on the chosen experimental parameters (2). Different values of enthalpies (the total heat energy of a system) can be obtained with different instruments and different setting parameters. ITC results are affected by numerous factors, including choice of buffer, solvent, pH and concentration; presence of impurities; equilibration temperature; saturation of the signal; and computational methodologies. Any one of these experimental factors can contribute variability to the data or lead to unclear results. Conclusion: Abstract LP105A does not nullify two prior experiments relating to simufilam. The authors used adulterated simufilam to conduct their experiment. Their experiment lacks an appropriate positive control. They engaged in patent infringement. They failed to disclose all conflicts of interest. The abstract must be read in this context. As recently highlighted by the Journal of Clinical Investigation, everyone should be concerned “when whistleblowers profit from allegations of scientific misconduct” (3). Conflict of Interest: Remi Barbier is President, CEO, Chairman and a shareholder of Cassava Sciences, Inc. Cassava Sciences has filed a defamation lawsuit against the authors of this abstract and other defendants in US federal court alleging dissemination of false information about simufilam. References: 1. Wang, HY, et al. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer’s disease pathogenesis. Neurobiol Aging 55, 99–114 (2017). 2. Medoš, Ž., Čobanov, I., Bešter-RogaČ, M. et al. Usually overlooked problems related with measurements of high-heat effects using power compensation isothermal titration calorimetry. J Therm Anal Calorim 145, 87–96 (2021). 10.1007/s10973-020-09663-2. 3. McNally EM. Conflicting interests: when whistleblowers profit from allegations of scientific misconduct, J Clin Invest. 2022;132(21):e166176. 10.1172/JCI166176
| 36471008 | PMC9734609 | NO-CC CODE | 2022-12-14 23:28:29 | no | J Prev Alzheimers Dis. 2022 Dec 3; 9(Suppl 1):51-248 | utf-8 | J Prev Alzheimers Dis | 2,022 | 10.14283/jpad.2022.97 | oa_other |
==== Front
J Fam Econ Issues
J Fam Econ Issues
Journal of Family and Economic Issues
1058-0476
1573-3475
Springer US New York
9878
10.1007/s10834-022-09878-5
Original Article
A Study on the Effects of Gendered Social Norms on the Tradeoff Between Paid and Unpaid Work in Korea
http://orcid.org/0000-0001-8323-7844
Kim Young-sook [email protected]
grid.467786.c 0000 0001 2113 4751 Korean Women’s Development Institute, Seoul, 03367 South Korea
6 12 2022
113
16 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
In this study, Korean time-use survey data for coupled households is analyzed to show that unpaid work time is endogenous in its relationship with paid work time because the views of traditional gender roles affect gender disparity in unpaid work time. The data not only includes time allocation between husbands and wives but also their views of traditional gender roles within their households, and this information can represent gendered social norms that can potentially explain the distribution of unpaid work between husbands and wives. The control function model is estimated to identify the tradeoff between unpaid work time and paid work time by solving the endogeneity problem. The results of this study show that wives’ unpaid work is likely to be affected by gendered social norms and that the effect can be larger for those having children. In addition, only in the case of wives, unpaid work time is found to be negatively associated with whether to work full-time, showing that wives’ burden of unpaid work could prevent them from working full time. The results indicate that it is crucial to recognize the need to change gendered social norms to address an asymmetric division of unpaid work between husbands and wives.
Keywords
Gendered social norms
Unpaid work
Gender gaps in labor participation
Control-function approach
JEL Classification
J16
J22
==== Body
pmcIntroduction
Women’s unpaid household work is invisible and undervalued but women contribute to GDP through the informal economy. Reducing women’s unpaid work could therefore increase national income as well as the income of women. Korea has been conducting national time-use surveys every 5 years since 1999 and publishing statistics for the household production satellite account. Calculations based on the data estimated that women’s unpaid work amounted to 25.5% of GDP in 2019.
According to the ILO (Addati et al., 2018), women do 3.2 times more unpaid work than men, ranging from 1.7 times in the Americas, to up to 4.7 times in the Arab states. In Asia and the Pacific, women conduct 4.1 times more. Korean men perform only 17.2 percent of the total volume of unpaid work while their Northern European counterparts perform over 40 percent. Meanwhile, the Economist’s annual glass-ceiling index 2022 shows that women had a 15.6 point lower labor force participation rate than men on the OECD average. The gender gap in the participation rate is 18.8 points in Korea, which is not only much larger than the average but also the second largest after Turkey.
In other words, Korean women seem to spend more time on unpaid work and less publicly on paid work compared to global averages. In the same vein, the 2022 glass-ceiling index shows that “four Nordic countries—Sweden, Iceland, Finland and Norway—top the index as the best places for working women” and “Japan and South Korea, where women must still choose between a family or a career, fill the bottom two places” (The Economist, Mar 7th, 2022).
This asymmetric division of unpaid and paid work between men and women in Korea should have been mitigated given that the education level of women has improved and publicly subsidized formal childcare has been expanded during the last decade. For example, according to the 2022 glass-ceiling index, the percentage of GMAT exams taken by women is around the OECD average while the net child-care costs are much lower than the average.
In fact, this gender gap in the labor market could have deleterious effects on the efficiency of the Korean economy. The country’s total fertility rate hit a record low of 0.84 in 2020 and for the first time, the government cited the gender gap in the labor market as one of the causes of the low birth rate in “The 4th Basic Plan on Low Birth Rates in an Aging Society (2021–2025).” Women in their 20s and 30s tend to prioritize their careers over child-rearing compared to the older generation, and men also prefer dual incomes. However, the majority of the care work is still undertaken mostly by women, which can lead to women interrupting their careers after childbirth or delaying their childbirth.1
In Korea, the gender gap in unpaid and paid work is likely to widen further because of gendered social norms which associate men and women with different ideal physical attributes and prescribed behaviors. For example, a gendered social norm, that regards unpaid work as a female prerogative, can make it difficult for working-age females to participate in the labor market. Given that women's roles were confined to domestic spheres in traditional Korean society, it would not be easy to change perceptions of the traditional role of women in parallel with the trajectory of Korea’s economic development. The 2021 Social Survey (Statistics Korea, 2021) clearly demonstrates that men tend to prioritize their work and women tend to prioritize their family although the share of people prioritizing their families over work has increased during the last decade. Compared to 2011, the share of people prioritizing their families over work rose from 11.5 to 48.2%. The share increased from 8.2 to 16.2% for men and from 16.4 to 21.1% for women, which shows that a gender gap in the proportion still remains.
The contribution of this study is its focus on a gendered social norm, that is, “men should work in the labor market and women should work at home”. This study aims to show how the level of approval of the traditional gender role affects the allocation of unpaid work time between husband and wife in Korea. To put it in another way, unpaid work time is assumed to be endogenous in its relationship with paid work time. Hence, the main purpose of this study is to investigate the tradeoff between time spent on unpaid work and time spent on paid work by husband and wife and analyze how the gendered social norm affects this tradeoff in Korea.
Background
Significant gender gaps in labor market outcomes, such as wages, hours of work, and occupational choices, exist in all countries. Altonji and Blank (1999) focus on two factors, differences in human capital accumulation and discrimination, as the main sources of these gender gaps. While these two factors have been studied extensively since that article was published, psychological and socio-psychological factors are also commonly discussed as possible explanations for gender differences in labor market outcomes (Blau & Kahn, 2017). One of the less-studied factors is a social norm about what actions are appropriate for men and women to undertake.
In this regard, Akerlof and Kranton (2000) propose a theoretical model where one’s identity enters the utility function and apply the identity model to both the decision to participate in the labor force and the allocation of unpaid work between spouses. The proposed utility function is:Uj=Ujaj,a-j,Ij.
j’s utility depends on j’s actions, aj, and others’ actions, a-j, and j’s identity,Ij. Ij depends on the social status of j’s assigned social category, the extent to which j’s characteristics match the ideal of j’s assigned category, and the extent to which j’s own and others’ actions correspond to the social norms of j’s assigned category.
When it comes to gender identity and labor force participation, a gendered social norm prescribing that “men should work in the labor market and women should work at home” could explain the gender gap in labor force participation. If women’s identity is enhanced by unpaid work at home, they will have lower labor force attachment than men. For example, women are traditionally considered the main providers of child care within the household and are more likely to be stay-at-home wives or to work part-time because of negative social attitudes toward working mothers. This can be a source of child penalty, the effect of having children on gender gaps. The child penalty effect remains significant in many studies (Goldin, 2014; Kleven & Landais, 2017; Kleven et al., 2019).
The gender identity model can explain why there is an asymmetric division of unpaid work between husband and wife, which can cause gender gaps in labor force participation. However, theories based on comparative advantage (for example Becker, 1965) do not predict this asymmetry. As husband and wife have the same utility function, that in decreasing paid work time and unpaid work time and increasing quantity of a household public good obtained from their joint work (Van Klaveren et al., 2008), more time will be spent on paid work, and less spent on housework, whether by the husband or the wife. On the other hand, in the gender identity model, the husband loses identity when he does unpaid work and when his wife earns more than half of the household income (Akerlof & Kranton, 2000). Hence, the utilities of husband and wife are equalized when the wife undertakes more unpaid work than her husband.
The relevance of the gender identity model for explaining women’s labor market outcomes has been tested in a number of empirical papers. The notion that the husband should be the breadwinner and the wife be the homemaker (Fortin, 2005, 2008), the men’s view of the gender role (Charles et al., 2009), the traditional gender role divide (Booth & van Ours, 2009), and family values (Gousse et al., 2017), all these factors have been found to relate to women’s labor market outcomes. However, it is not clear exactly through which channels gendered social norms affect women’s labor market participation.
Bertrand et al. (2015) analyzed how the behavioral prescription that “a man should earn more than his wife” affects social and economic outcomes, and found that the gender gap in home production is larger in couples where the wife earns more than her husband. Since unpaid work is considered a dependent variable in this study, the effect of unpaid work, which is easily influenced by gendered social norms, on labor market outcomes does not seem to be addressed. Could gender inequality in unpaid work be a missing link in the analysis of gender gaps in labor market outcomes (Ferrant et al., 2014)?
Based on the above discussion, my research hypothesis is that there exists endogeneity between unpaid work and paid work because gendered social norms affect the tradeoffs for husband and wife, which can imply that the gender identity model is relevant in explaining an asymmetric division of unpaid work between husband and wife.
Data and Empirical Strategy
Data
The empirical data on three key variables of this study—respondents’ paid work time, unpaid work time, and their view of gender roles—is derived from the Korean time use survey data in 2019, which is the most recent version. The 2019 Korean time use survey covers 12,435 households across the country and the respondents are asked to report what they did each 10-min interval of the previous 2 days. For the empirical data, a person’s daily average time on weekdays is used. Also, the survey includes data on the respondents’ socio-economic characteristics and household composition.
Time-use data have a great advantage over conventional household surveys for analyzing unpaid work (Esquivel et al., 2008; Dong & An, 2015). From the Korean time use data, I can get a daily average of each respondent’s time (in minutes) spent on both paid and unpaid work. According to the classification of activities in time use data, paid work time is defined as the amount of time spent on “employment”. Unpaid work time is defined as the amount of time spent on unpaid care work for household members, which includes “caring for a household: preparing food, cleaning, arrangement, shopping, etc.”, “family and household member care: child care, etc.”, and “traveling related to the managing of a household and caring”.
The definition of unpaid work is based on the scope of care activities formulated by the ILO (Addati et al., 2018). Care activities comprise two broad kinds. First, those that consist of direct, face-to-face, personal care activities, such as feeding a baby, nursing a sick partner, helping an older person take a bath, carrying out health check-ups, or teaching young children. Second, those involving indirect care activities, which do not necessarily entail face-to-face personal care, such as cleaning, cooking, doing the laundry, and other household maintenance tasks, that provide the preconditions for personal caregiving.
The Korean time-use data not only includes respondents’ time allocation but also their views of gender roles within their households. The level of approval on the traditional gender role, “men should work in the labor market and women work at home”, is measured on a 4-point ordinal scale (strongly agree, agree, disagree, and strongly disagree). This information can represent gendered social norms and stereotypes that can potentially explain the distribution of responsibilities for care and housework between husbands and wives. Considering the purpose of the study, married couples living together are selected for analysis.
Descriptive Statistics of three key variables are given in Table 1. On average, wives spend more than 60% of total work time on unpaid work while husbands spend only less than 30%. In Korea, women’s employment rate is lower than men’s while part-time employment rate is higher among women.2 Therefore, this seems to indicate a tradeoff between paid and unpaid work.Table 1 Descriptive Statistics of Three Key Variables (n = 11,040 people, 5520 households)
Traditional gender role # Of households Husbands Wives
Paid work(min) Unpaid work(min) % of unpaid work Paid work(min) Unpaid work(min) % of unpaid work
Total 5520 342.5 61.0 26.4 182.7 266.3 65.7
Husbands Strongly disagree 932 374.3 78.8 24.7 238.3 248.8 55.9
Disagree 2308 343.0 60.6 26.4 189.9 263.6 64.4
Agree 1922 332.9 53.5 26.7 155.8 274.8 70.4
Strongly agree 358 307.5 57.8 28.9 136.0 284.1 73.8
Wives Strongly disagree 1859 380.5 67.0 22.4 234.6 257.0 57.2
Disagree 2332 330.7 58.1 27.5 171.5 271.5 67.6
Agree 1134 309.3 58.8 30.3 129.2 273.9 74.1
Strongly agree 195 313.6 51.5 28.8 134.2 249.7 74.1
# of children under 10 0 4140 313.2 56.2 29.2 192.5 222.6 62.9
1 752 427.5 70.5 17.5 154.3 372.2 73.3
Over 2 628 433.6 81.3 18.5 152.1 428.0 74.9
Full-time working couples 918 445.0 53.8 12.3 385.0 162.4 30.4
The level of approval on the traditional gender role, “men should work in the labor market and women should work at home,” is surveyed on an ordinal scale, such as strongly agree, agree, disagree, and strongly disagree
However, Table 1 shows that this ratio tends to depend on the level of approval on the traditional gender role. Among wives, the higher the level of approval, the higher the share of unpaid work. Also, the wives’ ratio of unpaid work tends to increase as the husbands’ level of approval becomes higher. While wives seem to behave according to the gender norm, husbands appear to do the opposite, which shows that husbands are likely to be more “cooperative” when women ascribe to the gender norm. This can be explained in the identity model, where Ij depends on the social status of j’s assigned social category and, to some extent an individual may also choose the category assignment. In terms of gender, the assignment differences between men and women have diminished over time, and prescribed behavior has changed as well. Table 1 shows that the wives’ ratio of agreeing with the traditional gender role, 24.1%, is much lower than the husbands’, 41.3%. Even if a wife indicates a positive attitude toward the traditional gender role, she wouldn’t gain in her identity as much as her husband would gain in his identity because she recognizes the traditional gender role is a controversial issue. Hence, equality of utility is likely to be restored when the husband undertakes more housework than he used to.
Also, the number of children aged under 10 is more likely to affect the wives’ ratio of unpaid work rather than the husbands,’ which could reveal the child penalty in the labor market. Even in the case of full-time working couples, an asymmetric division of unpaid work between husband and wife is observed. The wives’ ratio of unpaid work is more than twice the husbands’ despite the fact that both are working full time.
Empirical Strategy
A key motivation for the research question is to identify the tradeoff between paid work time (y1) and unpaid work time (y2) by solving the endogeneity problem. A linear structural form for paid work time (y1) and a linear reduced form for unpaid work time (y2), which is in turn an endogenous regressor of y1, can be proposed as below.y1=αy2+x1β1+u1,E(x1′u1)=0,
y2=xγ+u2=x1γ1+x2γ2+u2,Ex′u2=0
All equations are estimated separately for wives and husbands. x1 includes unity and is an n by K1 subvector of x=(x1,x2) and the rank condition holds if and only if x2≠0. The level of approval on the traditional gender role and the need for child care can be included in covariates x2 and the endogeneity of y2 is due to COR (u1,u2)≡ρ≠0.
The control function method solves the problem of endogenous explanatory variables in linear models and Heckman's two-stage least squares can be derived using this approach. As u1=ρσ1σ2u2+ε, where the new error term ε∼N0,σε2 is distributed independently of u2, y1 can be explained by exogenous regressors which are y2, x1, and u2^. This way of explicitly accounting for the part of the error term causing endogeneity is called the “control-function (CF) approach” and u2^ is a control function for the endogeneity of y2 (Lee, 2010).y1=αy2+x1β1+ρσ1σ2u2^+ε,
E(u2^ε)=0
Compared with the two-stage least squares approach, the control function method produces a heteroskedasticity-robust Hausman test of the null hypothesis (H0:ρ=0), which means that y2 is exogenous (Wooldridge, 2015). This test for no endogeneity (H0:ρ=0) can be done with the t-value for u2^ ignoring the correction terms (σ1σ2). Since using u2^ instead of u2 affects the asymptotic distribution of ε, the standard errors for the control function estimates are based on bootstrap replications. The linear reduced form for unpaid work time (y2) can be estimated by OLS.
The linear structural form for paid work time (y1) can be applied to the case where both husbands and wives participate in the labor market. Hence, the equation can be estimated by OLS and the purpose is to estimate the effect of unpaid work time (y2) on paid work time (y1), which is the intensive margins of labor supply for husbands and wives.
When it comes to the full-sample analysis including people who are not in the labor force, y1 can be set as a dummy variable for measuring whether or not the respondent is working full-time.3 A significant number of Koreans tend to work part-time because they are unable to find a full-time job and may not be fully protected by the social security net. In this case, the y1 equation is a binary response model, for which a Probit model is an appropriate specification. Compared to the OLS analysis involving working couples only, the purpose of the Probit analysis is to estimate the effects of unpaid work time (y2) on whether to work full-time (y1), which is the extensive margins of full-time labor supply for husbands and wives.y1=1αy2+x1β1+u1>0,u1∼Normal(0,1)
P(y1=1|y2,x1)=Φ(αy2+x1β1)
where Φ· is the standard normal cumulative distribution function.
Explanatory Variables
Based on the empirical strategy, x2 are assumed to affect only unpaid work time (y2). In the empirical data, x2 measures the need for family care and the views on the traditional gender role, “men should work in the labor market and women should work at home”. These are variables that make unpaid work time (y2) endogenous in its relationship with paid work time (y1).
The level of approval on the traditional gender role is measured on an ordinal scale, such as strongly agree, agree, disagree, and strongly disagree. This information can represent gendered social norms and stereotypes that should be addressed to redistribute responsibilities for care and housework between husband and wife while it does not seem to indicate gendered social norms prevailing in society, which can affect paid work. That is why the views on the traditional gender role are assumed to affect paid work only through unpaid work in the empirical model.
Referring to the need for family care, we included ‘# family’, ‘65 older’, ‘Children4 10 and over’, and ‘Children under 10.’ The variable ‘# family’ is the number of family members, ‘65 older’ is a dummy variable indicating whether or not there are any household members over the age of 65, ‘Children 10 and over’ is a dummy variable for having children aged 10 and over, and ‘Children under 10’ is a dummy variable for having children under the age of 10. ‘Children 10 and over’ and ‘Children under 10’ are included to capture the need for child care and their estimates can be interpreted as the child penalty in the labor market.
Because the decision of having children and the experience of raising young children could be impacted by the views on the traditional gender role, the effect of the views on unpaid work time might depend on whether they have children or not. Households having no children are compared with those having children, which are limited to those households with children aged 10 and over5 in order to consider the experience of raising young children. It appears that the two groups are quite different with respect to their views on the traditional gender role (Table a7 in Appendix) and the % of time devoted to unpaid work according to the views (Table a8 in Appendix). Based on the results, not only ‘Children 10 and over’ but also the interaction terms with the views are included in x2, which only affects unpaid work time (y2).
Regarding the level of approval on the traditional gender role, “men should work in the labor market and women should work at home”, the 4-point ordinal scales are collapsed into binary responses, i.e., agree (including “agree” or “strongly agree”) vs. disagree (including “disagree” or “strongly disagree”). The variables ‘FAV_NORM_R’ and ‘FAV_NORM_S’ are defined as shown in Table 2. The level of approval is collapsed to binary responses for two reasons. First, the gender norm was self-reported by respondents who decide whether or not they agreed with the norm and rank the level of approval/disapproval. Unlike the former decision, each respondent, in the latter decision, may interpret the scale differently (Chevalier & Fielding, 2011). However, the empirical data doesn’t include anchoring vignettes linked to self-reported assessments of the norm for improving comparability across individuals. Second, there will be too many dummy variables that are transformed in Table 2 if the 4-point scale is applied, which can make empirical results harder to interpret.Table 2 Transformation of the Level of Approval on the Traditional Gender Role
Respondent
Husbands Wives
Agree Disagree Agree Disagree
Spouse Agree FAV_NORM_R = 1 FAV_NORM_R = 0 FAV_NORM_R = 0 FAV_NORM_R = 1
FAV_NORM_S = 1 FAV_NORM_S = 1 FAV_NORM_S = 0 FAV_NORM_S = 0
Disagree FAV_NORM_R = 1 FAV_NORM_R = 0 FAV_NORM_R = 0 FAV_NORM_R = 1
FAV_NORM_S = 0 FAV_NORM_S = 0 FAV_NORM_S = 1 FAV_NORM_S = 1
‘FAV_NORM_R’ is a dummy variable for the respondent having a favorable view of the traditional gender norm concerning their own unpaid work time. For example, if the respondent is a wife and disagrees or strongly disagrees with the traditional gender role, then ‘FAV_NORM_R’ is 1. Thus, having a favorable view of the norm as a wife means that it decreases her unpaid work time. On the other hand, if the respondent is a husband and agrees or strongly agrees with the traditional gender role, then ‘FAV_NORM_R’ is 1. Thus, having a favorable view of the norm as a husband means that it decreases his unpaid work time. ‘FAV_NORM_S’ is a dummy for the respondent’s spouse having a favorable view of the traditional gender norm concerning the respondent’s unpaid work time. If the respondent is a wife and her husband disagrees or strongly disagrees with the traditional gender role, then ‘FAV_NORM_S’ is 1, as this decreases the wife’s unpaid work time. On the other hand, if the respondent is a husband and his wife agrees or strongly agrees with the traditional gender role, then again, ‘FAV_NORM_S’ is 1, as this should decrease the husband’s unpaid work time. This conversion is required since the effects of the level of approval on unpaid work time could depend on whether the respondent is a wife or husband. It would be hard to interpret the estimates if the level of approval is used as it is.
Information on the variables can be found in Tables 3 and 4. All explanatory variables besides the need for family care and the level of approval on the traditional gender role are also included in the y1 equation. Variables (x1) that are commonly included in both y1 and y2 equations are those that measure individual and household characteristics. An individual variable ‘Age’ is the age of respondent and ‘Junior college or above’ is a dummy variable of graduating from junior college or above. A household variable ‘Rural’ is a dummy for living in a rural area, ‘House size(m2)’ is the size of the house measured in square meters, ‘Own house’ is a dummy variable for owning a house, and ‘Fam. Inc’ measures respondent’s household income in ranges (Korean Won; $1≃KRW 1300). ‘House size (m2)’ and ‘Own house’ are included in x1 as they can represent the amount of household assets as well as the need for housing maintenance.Table 3 Descriptive Statistics of the Full Sample (n = 11,040)
Husbands Wives
Mean SD Min Max Mean SD Min Max
y2 Unpaid work(min) 60.97 84.83 0 735 266.34 171.11 0 970
y1 Whether to work full time 0.48 0.50 0 1 0.25 0.43 0 1
x2 FAV_NORM_R 0.41 0.49 0 1 0.76 0.43 0 1
FAV_NORM_RxChildren 10 and over 0.15 0.36 0 1 0.29 0.46 0 1
FAV_NORM_S 0.24 0.43 0 1 0.59 0.49 0 1
FAV_NORM_Sx Children 10 and over 0.07 0.26 0 1 0.21 0.41 0 1
Children 10 and over 0.37 0.48 0 1 0.37 0.48 0 1
Children under 10 0.25 0.43 0 1 0.25 0.43 0 1
# family 3.04 1.05 2 9 3.04 1.05 2 9
65 older 0.29 0.46 0 1 0.29 0.46 0 1
x1 Age 54.51 13.72 21 94 51.60 13.11 19 90
Junior college or above 0.50 0.50 0 1 0.42 0.49 0 1
Rural 0.23 0.42 0 1 0.23 0.42 0 1
House size (m2) 87.03 40.32 9 660 87.03 40.32 9 660
Own house 0.75 0.43 0 1 0.75 0.43 0 1
Fam. Inc
2 ~ 3 Million Won 0.15 0.36 0 1 0.15 0.36 0 1
3 ~ 4 Million Won 0.16 0.37 0 1 0.16 0.37 0 1
4 ~ 5 Million Won 0.16 0.36 0 1 0.16 0.36 0 1
5 ~ 6 Million Won 0.11 0.32 0 1 0.11 0.32 0 1
6 million Won or more 0.24 0.43 0 1 0.24 0.43 0 1
Table 4 Descriptive Statistics of Working Couples (n = 5316)
Husbands Wives
Mean SD Min Max Mean SD Min Max
y2 Unpaid work(min) 48.76 69.11 0 735 189.72 130.16 0 820
y1 Paid work(min) 409.52 163.12 0 980 331.02 170.20 0 960
x2 FAV_NORM_R 0.36 0.48 0 1 0.82 0.39 0 1
FAV_NORM_Rx Children 10 and over 0.15 0.36 0 1 0.36 0.48 0 1
FAV_NORM_S 0.19 0.39 0 1 0.64 0.48 0 1
FAV_NORM_Sx Children 10 and over 0.06 0.24 0 1 0.28 0.45 0 1
Children 10 and over 0.43 0.50 0 1 0.43 0.50 0 1
Children under 10 0.24 0.43 0 1 0.24 0.43 0 1
# Family 3.15 1.07 2 8 3.15 1.07 2 8
65 oLder 0.22 0.41 0 1 0.22 0.41 0 1
x1 Age 52.13 12.24 21 86 49.28 11.68 22 86
Junior college or above 0.31 0.46 0 1 0.26 0.44 0 1
Rural 0.26 0.44 0 1 0.26 0.44 0 1
House size (m2) 85.35 38.16 9 660 85.35 38.16 9 660
Own house 0.75 0.44 0 1 0.75 0.44 0 1
Fam. Inc
2 ~ 3 Million Won 0.11 0.32 0 1 0.11 0.32 0 1
3 ~ 4 Million Won 0.15 0.36 0 1 0.15 0.36 0 1
4 ~ 5 Million Won 0.18 0.38 0 1 0.18 0.38 0 1
5 ~ 6 Million Won 0.15 0.36 0 1 0.15 0.36 0 1
6 Million Won or more 0.32 0.47 0 1 0.32 0.47 0 1
Industry
Manufacturing 0.20 0.40 0 1 0.12 0.32 0 1
Construction 0.09 0.28 0 1 0.02 0.13 0 1
Wholesale and retail trade 0.12 0.32 0 1 0.14 0.34 0 1
Accommodation and food service activities 0.05 0.21 0 1 0.10 0.31 0 1
Public administration and defense 0.07 0.25 0 1 0.03 0.18 0 1
Education 0.04 0.21 0 1 0.14 0.34 0 1
Human health and social work activities 0.03 0.16 0 1 0.15 0.35 0 1
Occupation
Managers 0.05 0.23 0 1 0.01 0.11 0 1
Professionals and related Workers 0.14 0.34 0 1 0.22 0.41 0 1
Clerks 0.17 0.38 0 1 0.16 0.37 0 1
Service workers 0.06 0.24 0 1 0.19 0.39 0 1
Sales workers 0.09 0.28 0 1 0.13 0.34 0 1
Skilled agricultural, forestry, and fishery workers 0.13 0.34 0 1 0.11 0.31 0 1
Craft and related trades workers 0.12 0.32 0 1 0.02 0.15 0 1
Equipment, machine operating, and assembling workers 0.13 0.34 0 1 0.03 0.18 0 1
When analyzing working couples, industry and occupation classifications are added to the explanatory variables. When it comes to industry classification, all industries with 5% or more respondents are included except for ‘Agriculture, forestry and fishing’ which is likely to correlate with ‘Rural.’
Results
OLS Estimates: Unpaid Work Time Equation
Table 5 presents the OLS estimates for the unpaid work time (y2) equation. For the full sample, while husbands’ view, ‘FAV_NORM_R’, has a significant negative effect of − 13.48 min on their unpaid work time, their wives’ view, ‘FAV_NORM_S’, is not significant. The interaction terms with ‘Children 10 and over’ are not significant as well. This means that husbands’ unpaid work time seems to be affected by their own views rather than those of their wives and the effect of their views does not depend on whether or not they have children aged 10 and over.Table 5 OLS Estimates of Unpaid Work Time Equation (y2)
Variables Full sample (n = 11,040) Working couples (n = 5316)
Husbands Wives Husbands Wives
Estimates t-Values Estimates t-Values Estimates t-Values Estimates t-Values
Intercept 68.45*** 3.40 190.28*** 5.22 112.28*** 4.06 231.21*** 5.71
x2 FAV_NORM_R − 13.48*** − 4.18 − 11.07a − 1.95 − 12.92*** − 3.31 − 5.55 − 0.75
FAV_NORM_Rx Children 10 and over 2.10 0.47 − 24.39* − 2.38 − 0.12 − 0.02 6.41 0.53
FAV_NORM_S − 4.49 − 1.24 − 18.26*** − 3.40 4.70 1.05 − 12.50a − 1.95
FAV_NORM_Sx Children 10 and over − 2.02 − 0.41 − 19.91* − 2.27 − 3.39 − 0.54 − 12.25 − 1.26
Children 10 and over − 13.24*** − 3.33 23.81* 2.19 − 9.71* − 2.15 − 4.03 − 0.31
Children under 10 26.70*** 6.36 152.12*** 18.52 26.60*** 5.75 93.54*** 10.96
# Family 1.50 0.84 26.37*** 6.75 2.26 1.08 24.63*** 5.65
65 Older 6.78 1.56 − 18.24** − 2.64 1.11 0.21 − 27.37*** − 3.49
x1 Age − 0.16 − 0.21 0.51 0.39 − 2.06a − 1.88 − 2.95a − 1.80
Age2 0.01 0.82 0.00 − 0.16 0.02 1.58 0.04* 2.11
Junior college or above 10.55*** 4.17 17.56*** 3.40 10.20** 3.02 16.97** 2.56
Rural − 0.96 − 0.35 − 11.32* − 2.41 3.95 1.16 3.51 0.62
House size (m2) 0.06a 1.90 0.09a 1.87 0.02 0.46 − 0.06 − 1.05
Own house − 3.13 − 1.16 2.26 0.44 − 0.84 − 0.27 − 3.97 − 0.67
Fam. Inc
2 ~ 3 Million Won − 20.40*** − 4.38 − 9.98 − 1.42 − 8.38 − 1.28 − 33.84** − 3.26
3 ~ 4 Million Won − 32.33*** − 6.58 − 34.23*** − 4.49 − 13.92* − 2.11 − 37.42*** − 3.43
4 ~ 5 Million Won − 36.19*** − 7.25 − 56.60*** − 6.97 − 8.85 − 1.29 − 40.74*** − 3.53
5 ~ 6 Million Won − 31.20*** − 5.60 − 92.47*** − 10.50 − 2.66 − 0.35 − 64.67*** − 5.33
6 Million Won or more − 39.08*** − 7.66 − 101.4*** − 12.34 − 6.47 − 0.91 − 74.81*** − 6.44
The standard errors are robust to heteroskedasticity
Regarding working couples, the coefficients of industry and occupation classifications are omitted here
ap < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001
Meanwhile, all of the wives’ variables regarding the view, which are ‘FAV_NORM_R’, ‘FAV_NORM_S’, and the two interaction terms with ‘Children 10 and over’, have significant negative effects from − 11.07 to −24.39 min. This indicates that wives’ unpaid work time appears to be affected not only by their own views but also by their husbands’ views and the effects become larger when they have children aged 10 and over.
In the case of working couples, the results for husbands regarding the view are nearly the same as those from the full sample. For wives, only ‘FAV_NORM_S’ has a significant negative effect, which means that wives of working couples are more likely to be affected by their husbands’ views rather than their own views.
In both samples, the presence of young children, ‘Children under 10’, significantly increases unpaid work time for both husbands and wives, but the magnitude of the effect is much greater among wives, 152.12 and 93.54 min, than husbands, 26.7 and 26.6 min for each sample. The presence of young children appears to be the main factor that increases unpaid work time the most for both husbands and wives. Also, ‘65 older’ decreases only wives’ unpaid work time by 18.24 and 27.37 min for each sample, showing that household members over the age of 65 might act as informal caregivers rather than recipients of care. In contrast, ‘# family’ has positive significant effects on wives’ unpaid work time, which means that the greater the number of family members, the more time is spent by wives on unpaid work.
‘Junior college or above’ has significant positive effects across the board, so a higher level of education seems to increase unpaid work time significantly in both samples. This might be because people with higher education tend to invest more time in child education. In the empirical data, there is little difference in average unpaid work time by education level. However, looking at the child care time included in the unpaid work time, for people graduating junior college or above, it is revealed that husbands spend 2.8 times more and women 3.8 times more on average than their lower educated counterparts respectively.
Except for the husbands of working couples, ‘Fam. Inc’s have significant negative effects on all other occasions. For wives, the size of the effect increases as the income bracket increases. In other words, a higher level of household income reduces unpaid work time especially for wives regardless of their employment status. Given that income is a commonly used indicator of family economic well-being (Xiao, 2013), various services can be purchased in the market if the household income is sufficient. However, the opposite case is also conceivable. Let us suppose that an unemployed mother and her husband worry about their family’s economic well-being. Rao (2020) asks: “how do college-educated, heterosexual, married mothers experience involuntary unemployment?” and finds that “the experience of job loss is tempered for mothers as they derive a culturally valued identity from motherhood which also anchors their lives” (p. 299).
PROBIT/OLS Estimates: Whether to Work Full-Time/Paid Work Time Equation
Table 6 presents the estimates for y1 equation: y1 is whether to work full-time for the full sample and the amount of paid work time for the working couples, respectively. First of all, the Probit estimates for whether to work full-time can be interpreted as the effects of unpaid work time and other variables on the extensive margins of full-time labor supply. The t statistic on the control function ‘u2^’ is significant only for wives, which rejects the null that wives’ unpaid work time (y2) is exogenous. To rephrase it, wives’ unpaid work time seems to be endogenous in its relationship with whether to work full time because their unpaid work time is affected by x2 as can be seen in Table 5. Also, ‘Unpaid work’ of wives has a small but significant negative effect on whether they work full-time.Table 6 Estimates of Whether to Work Full-Time/Paid Work Time Equation (y1)
Full sample (n = 11,040)
y1: whether to work full-time (PROBIT) Working couples (n = 5316)
y1: paid work(min) (OLS)
Husbands Wives Husbands Wives
Variables (x1) Estimates t-Values Estimates t-Values Estimates t-Values Estimates t-Values
Intercept 0.431 0.908 − 0.212 − 0.496 287.7*** 5.123 246.6*** 5.513
Unpaid work(min) − 0.002 − 1.150 − 0.004*** − 11.070 − 0.143 − 0.731 − 0.487*** − 9.397
u2^ − 0.001 − 0.570 − 0.001*** − 3.003 − 0.861*** − 4.257 − 0.376*** − 6.584
Age 0.000 0.016 0.021 1.276 7.942*** 4.163 6.557*** 4.249
Age2 0.000** − 2.610 − 0.001** − 3.200 − 0.101*** − 5.641 − 0.081*** − 5.285
Junior college or above 0.373*** 7.225 0.173** 3.200 − 16.949* − 2.461 − 10.008 − 1.451
Rural − 0.185*** − 3.633 0.045 0.764 − 7.904 − 1.117 15.340* 2.486
House size (m2) − 0.001** − 2.315 − 0.001* − 2.130 − 0.059 − 0.674 − 0.012 − 0.180
Own house − 0.053 − 1.017 − 0.002 − 0.028 − 0.942 − 0.141 16.001** 2.587
Fam. Inc
2 ~ 3 Million won 0.517*** 5.218 0.212a 1.800 15.482 1.107 17.342 1.420
3 ~ 4 Million won 0.790*** 7.405 0.492*** 4.425 25.111a 1.694 23.911a 1.934
4 ~ 5 Million won 0.915*** 8.034 0.800*** 6.976 15.672 1.036 27.473* 2.149
5 ~ 6 Million won 1.009*** 8.795 1.031*** 8.502 31.391* 2.090 47.547*** 3.612
6 Million won or more 1.104*** 9.537 1.075*** 9.473 15.405 1.039 42.959** 3.216
The standard errors for the CF estimates are based on 1000 bootstrap replications
Regarding working couples, the coefficients of industry and occupation classifications are omitted here
ap < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001
As for the OLS estimates presenting the effects on the intensive margins of labor supply, the control function ‘u2^’ is significant both for husbands and wives. However, ‘Unpaid work’ has a significant effect only on wives’ paid work time. In a nutshell, only in the case of wives, unpaid work time is negatively associated with paid work time after controlling for the endogenous predictor and the same is also true for the decision on whether to work full time.
Among other variables, ‘Age’ seems to increase paid work time of the working couples while the higher education level, ‘Junior college or above’, increases the chance of working full time but decreases paid work time of husbands from the working couples. Household income, ‘Fam. Inc.’, tends to increase both the chance of working full time and the amount of paid work time, but the effects are more significant in the former equation for the full sample. Considering Table 5 showing that the income brackets have more significant negative effects on unpaid work time of the full sample, it seems that various services related to unpaid work can be purchased in the market as long as family economic well-being does not change much, which leads to a higher chance of working full time.
Conclusions
This study finds that women’s unpaid work is more likely to be affected by views on the traditional gender roles within their households and the effect can be larger for those having children. Hence, this gendered social norm seems to affect wives’ tradeoff between unpaid and paid work time in Korea. This finding suggests that the gender identity model should be relevant for explaining the asymmetric division of unpaid and paid work between husbands and wives.
When it comes to unpaid work time, husbands seem to be more affected by their own views on traditional gender roles rather than those of their wives. Wives, meanwhile, are more likely to behave according to their spouses’ views, rather than their own. This raises the possibility that women could be more susceptible to gendered social norms. As a matter of fact, such a situation has been observed during the COVID-19 pandemic and related closures of daycare centers and schools. Jessen et al. (2021) finds in Germany that there has been a significant increase in the number of couples with the mother solely undertaking care work. Further, Alon et al. (2022) shows that the global recession triggered by the pandemic had a disproportionate impact on women’s employment, demonstrating larger employment declines among women with micro survey data gathered around six countries: the United States, Canada, Germany, the Netherlands, Spain, and the United Kingdom. These results establish that were it not for the essential care infrastructure, women’s employment could be prone to be swayed by gendered social norms even in western countries.
In addition, only in the case of wives, unpaid work time is found to be negatively associated with the chance of working full-time, showing that wives’ burden of unpaid work could prevent them from working full time. When the samples are restricted to working couples, there also exists a negative correlation between unpaid work time and paid work time. Parental leave is an employee benefit available in this matter, and it is supposed to incentivize labor market attachment for women before and after childbirth. However, this benefit can make the situation worse as long as the traditional gender role affects the allocation of unpaid work within the household. This is because male employees could fear they might be stigmatized by their employers and be disadvantaged at work by taking parental leave, which can make women more likely to take parental leave and spend more time on unpaid work than men.
The results presented in this paper show that it is critical to recognize the need to change gendered social norms to address an asymmetric division of unpaid work between husbands and wives. In the framework of the gender identity model in the Background section, policies may change favorable attitudes towards the traditional gender role into a more gender-equal one. This may make the asymmetric division of unpaid work between men and women more loathsome to household members, leading to lower values of their identity (Ij) and a deviation from the prescriptions of the traditional gender role. For example, government programs to improve work-life balance, such as parental leaves and flexible work arrangements, need to ensure that the programs are not used only by women. Also, we need to incentivize men to use the programs because there still exist gendered social norms that penalize men who choose to take parental leaves or flexible work arrangements.
To address this issue, the Korean government has implemented policies encouraging gender-equal use of parental leave over the past 10 years. Not only have they raised the income replacement rate during parental leave and but also offered financial incentives for men taking parental leave. The percentage of men on parental leaves has increased from 2% in 2010 to 21.2% in 2019. However, male parental leave is still not considered to be as common as female parental leave. Also, the duration of leave depends on gender. From September 2017 to August 2018, 52% of female parental leave users took leaves for the entire year and only 15% of leaves were less than 3 months. However, only 25% of male parental leave users took the entire year and 41% of leaves were less than 3 months (Park et al., 2020).
This study analyzes data consisting only of married couples living together, and it does not consider the fact that the decision of whom to marry is also endogenous and varies with the views on gender roles. Also, the child penalty could be detrimental to wives’ unpaid work time if society and schools continue to demand more from mothers than from fathers when it comes to child care. The empirical data do not have the relevant variables capturing gendered social norms prevailing in society and schools and therefore the study has limitations in this respect.
In future research, it would be interesting to test whether the gender gaps in the labor market are due to gendered social norms of society and education system that emphasizes the role of mothers in child-rearing. The comparison between different countries regarding gendered social norms and the structure of society and education may be helpful in this regard.
Appendix
(See Tables 7 and 8).Table 7 Views of the Traditional Gender Role (unit: %)
Traditional gender role Full sample
(n = 5520) No children 10 and over
(n = 3494) Having children 10 and over
(n = 2026)
Husbands Strongly disagree 16.88 16.89 16.88
Disagree 41.81 42.22 41.12
Agree or strongly agree 41.30 40.90 42.00
Wives Strongly disagree 33.68 31.34 37.71
Disagree 42.25 42.10 42.50
Agree or strongly agree 24.08 26.56 19.79
The level of approval on the traditional gender role, “men should work in the labor market and women should work at home,” is surveyed on an ordinal scale, such as strongly agree, agree, disagree, and strongly disagree
Pearson's chi-squared for the hypothesis that the view of the gender role and whether having children 10 and over are independent: for wives, chi2(2) = 39.8925 (Pr = 0.000) and for husbands: chi2(2) = 0.7502 (Pr = 0.687)
Table 8 The % of Time Devoted to Unpaid Work According to the Views of the Traditional Gender Role
Full sample
(n = 5520) No children 10 and over
(n = 3494) Having children 10 and over
(n = 2026)
Traditional gender role Husband Wife Husband Wife Husband Wife
Total 26.4 65.7 32.2 68.7 16.3 60.4
Husbands Strongly disagree 24.7 55.9 28.1 60.7 18.9 47.5
Disagree 26.4 64.4 32.1 68.1 16.4 58.0
Agree or strongly agree 27 70.9 34.1 72.7 15.1 68.0
Wives Strongly disagree 22.4 57.2 26.5 61.2 16.4 51.4
Disagree 27.5 67.6 33.6 70.3 16.9 63.0
Agree or strongly agree 30.1 74.1 36.8 75.0 14.6 72.1
Full-time working couples (n = 918) (n = 486) (n = 432)
12.3 30.4 14.0 32.8 10.4 27.8
Acknowledgements
This work was completed while the author was visiting Aarhus University Department of Economics and Business Economics as a guest researcher in Fall 2021. Helpful comments from Leslie S. Stratton, Nabanita Datta Gupta, and Taek-Meon Lee are dearly appreciated.
Funding
No funding was received for conducting this study.
Data Availability
The data that support the findings of this study are publicly available from microdata integrated service of Statistics Korea (refer to https://mdis.kostat.go.kr/eng/pageLink.do?link=mdisService).
Declarations
Conflict of interest
The author has no competing interests to declare that are relevant to the content of this article.
Ethical Approval
This study is a secondary data analysis that does not involve human participants or animals.
Consent for participants
Since my study involves only secondary analysis of anonymized data, participant consent was not required.
Consent for publication
Publication concent is not applicable since my study involves only secondary analysis of anonymized data.
1 In Korea, the average age at which women give birth to their first child has increased from 29.8 years old in 2009 to 32.2 in 2019.
2 As of 2019, the employment rate in Korea was 70.8% for men and 51.9% for women. On the other hand, the share of employment in part-time employment was 8.9% for men and 20.8% for women (refer to OECD. Stat(https://stats.oecd.org/)).
3 y1=0 means working part-time or not working.
4 Children refer to unmarried children living together in the empirical data.
5 This is because the empirical data doesn’t have the age of children and only offers whether their child is 10 years old and over.
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References
Addati, L., Cattaneo, U., Esquivel, V., & Valarino, I. (2018). Care work and care jobs for the future of decent work. Geneva, Switzerland: ILO. Retrieved August 8, 2022, from http://hdl.voced.edu.au/10707/459243
Akerlof GA Kranton RE Economics and identity The Quarterly Journal of Economics 2000 115 3 715 753 10.1162/003355300554881
Alon T Coskun S Doepke M Koll D Tertilt M From mancession to shecession: Women’s employment in regular and pandemic recessions NBER Macroeconomics Annual 2022 36 1 83 151 10.1086/718660
Altonji JG Blank RM Ashenfelter OC Card D Race and gender in the labor market Handbook of labor economics 1999 Elsevier 3143 3259
Becker GS A theory of the allocation of time Economic Journal 1965 75 299 493 517 10.2307/2228949
Bertrand M Kamenica E Source JP Gender identity and relative income within households The Quarterly Journal of Economics 2015 130 2 571 614 10.1093/qje/qjv001
Blau FD Kahn LM The gender wage gap: Extent, trends, and explanations Journal of Economic Literature 2017 55 3 789 865 10.1257/jel.20160995
Booth AL Van Ours JC Hours of work and gender identity: Does part-time work make the family happier? Economica 2009 76 301 176 196 10.1111/j.1468-0335.2007.00670.x
Charles, K., Guryan, J., & Pan, J. (2009). Sexism and women’s labor market outcomes. [Unpublished manuscript], Booth School of Business, University of Chicago. Retrieved August 8, 2022, from https://www.chicagofed.org/~/media/others/research/research-calendar-attachments/seminars-2009/sem-guryan101909-pdf.pdf
Chevalier A Fielding A An introduction to anchoring vignettes Royal Statistical Society A 2011 174 3 569 574 10.1111/j.1467-985X.2011.00703.x
Dong X An X Gender patterns and value of unpaid care work: Findings from China’s first large-scale time use survey Review of Income and Wealth 2015 61 3 540 560 10.1111/roiw.12119
Esquivel V Budlender D Folbre N Hirway I Explorations: Time-use surveys in the south Feminist Economics 2008 14 3 107 152 10.1080/13545700802075135
Fortin N Gender role attitudes and women’s labour market outcomes across OECD countries Oxford Review of Economic Policy 2005 21 3 416 438 10.1093/oxrep/gri024
Fortin, N. (2008). Gender role attitudes and women’s labor market participation: Opting out and the persistent appeal of housewifery. [Unpublished manuscript], University of British Columbia. Retrieved August 8, 2022, from https://kooperationen.zew.de/fileadmin/user_upload/Redaktion/DFGFLEX/ws08fortin.pdf
Ferrant, G., Pesando, L. M., & Nowacka, K. (2014). Unpaid Care Work: The missing link in the analysis of gender gaps in labour outcomes. Boulogne Billancourt: OECD Development Center. Retrieved August 8, 2022, from https://www.oecd.org/dev/development-gender/Unpaid_care_work.pdf
Goldin C A grand gender convergence: Its last chapter American Economic Review 2014 104 4 1091 1119 10.1257/aer.104.4.1091
Gousse M Jacquemet N Robin J Marriage, labor supply, and home production Econometrica 2017 85 6 1873 1919 10.3982/ECTA11221
Jessen, J., Spiess, C. K., Waights, S., & Wrohlich, K. (2021). Sharing the caring? The gender division of care work during the Covid-19 pandemic in Germany. [IZA Discussion Paper 14457], IZA. Retrieved August 8, 2022, from https://ssrn.com/abstract=3870188
Kleven H Landais C Gender inequality and economic development: Fertility, education, and norms Economica 2017 84 334 180 209 10.1111/ecca.12230
Kleven H Landais C Søgaard JE Children and gender inequality: Evidence from Denmark American Economic Journal: Applied Economics 2019 11 4 181 209 10.1257/app.20180010
Lee MJ Micro-econometrics: Methods of moments and limited dependent variables 2010 Springer
Park, S., Kim, Y., Kim, B., Kim, H., & Kwon, D. (2020). The analysis of the effect of the government budget for childcare support. Ministry of Gender Equality and Family of Korea (in Korean).
Rao AH From professionals to professional mothers: How college-educated married mothers experience unemployment in the US Work, Employment and Society 2020 34 2 299 316 10.1177/0950017019887334
Statistics Korea. (2021). Report on the 2021 Social Survey (in Korean).
The Economist. (Mar 7th, 2022). The Economist’s annual glass-ceiling index. https://www.economist.com/graphic-detail/glass-ceiling-index.
Van Klaveren C Van Praag B van den Brink HM A public good version of the collective household model: An empirical approach with an application to British household data Review of Economics of the Household 2008 6 2 169 191 10.1007/s11150-007-9028-8
Wooldridge JM Control function methods in applied econometrics The Journal of Human Resource 2015 50 2 420 445 10.3368/jhr.50.2.420
Xiao JJ Peterson G Bush K Family economic well-being Handbook of marriage and the family 2013 Boston, MA Springer
| 0 | PMC9734610 | NO-CC CODE | 2022-12-14 23:28:29 | no | J Fam Econ Issues. 2022 Dec 6;:1-13 | utf-8 | J Fam Econ Issues | 2,022 | 10.1007/s10834-022-09878-5 | oa_other |
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J Biosci
J Biosci
Journal of Biosciences
0250-5991
0973-7138
Springer India New Delhi
36503907
312
10.1007/s12038-022-00312-4
Review
Effects of immunosuppressants on T-cell dynamics: Understanding from a generic coarse-grained immune network model
Nayak Sonali Priyadarshini 12
Bagchi Biman [email protected]
3
http://orcid.org/0000-0001-6411-4347
Roy Susmita [email protected]
4
1 grid.18048.35 0000 0000 9951 5557 Department of Systems and Computational Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
2 grid.7450.6 0000 0001 2364 4210 Max Planck School Matter to Life, University of Göttingen, Friedrich-Hund-Platz 1, 37077 Göttingen, Germany
3 grid.34980.36 0000 0001 0482 5067 Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru, 560012 India
4 grid.417960.d 0000 0004 0614 7855 Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, 741246 India
Communicated by Mohit Kumar Jolly.
10 12 2022
2022
47 4 7010 1 2022
22 9 2022
© Indian Academy of Sciences 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Long-term immunosuppressive therapy is a drug regimen often used to lower aggressive immune responses in various chronic inflammatory diseases. However, such long-term therapy leading to immune suppression may trigger other adverse reactions in the immune system. The rising concern regarding the optimal dose and duration of such treatment has motivated us to understand non-classical immunomodulatory responses induced by various immunosuppressive steroid and secosteroid drugs such as glucocorticoid and vitamin D supplements. The immunomodulatory actions of such immunosuppressants (that govern the adaptive immune response) are often mediated through their characteristic control over CD4+ T-cells involving pro- and anti-inflammatory T-cells. Several early studies attempted to decode temporal and dose-dependent behaviors of such pro- and anti-inflammatory T-cells using the chemical dynamics approach. We first summarize these early works. Then, we develop a minimal coarse-grained kinetic network model to capture the commonality in their immunomodulatory functions. This generic model successfully reproduces the characteristic dynamical features, including the clinical latency period in long-term T-cell dynamics. The temporal behavior of T-cells is found to be sensitive to specific rate parameters and doses of immunosuppressants. The steady-state analysis reflects the transition from an early classified weakly regulated (autoimmune-prone) immune state to a strongly regulated state (immunocompromised state), separated by an intervening state of moderate/balanced regulation. An optimal dose and duration are essential in rescuing balanced immune regulation. This review elucidates how developing a simple generic coarse-grained immune network model may provide immense information that helps diagnose inefficacy in adaptive immune function before and after administering immunosuppressants such as glucocorticoid or vitamin D.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12038-022-00312-4.
Keywords
Chemical dynamics
glucocorticoid
immune network
T-cell
steroid
vitamin D
http://dx.doi.org/10.13039/501100001407 Department of Biotechnology , Ministry of Science and Technology BT/12/IYBA/2019/12 Roy Susmita http://dx.doi.org/10.13039/501100001843 Science and Engineering Research Board SRG/2020/001295 Roy Susmita issue-copyright-statement© Indian Academy of Sciences 2022
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pmcIntroduction: A brief overview of the human immune system and its components
We continuously encounter many bacteria, viruses, fungi, and other complex organisms during our lifetime. While some are not harmful to us, like the commensal bacteria inhabiting our gut, others are considered pathogenic, leading to severe health ailments. To maintain physiological homeostasis, we have a cellular and humoral system that is able to control and get rid of these foreign organisms from our bodies – the immune system. Distinguishing self from non-self is one of the primary functions of the immune system. The immune system has two interconnected arms, i.e., innate immunity and adaptive immunity. Innate immunity corresponds to a non-specific defense mechanism present in our body at birth, whereas adaptive immunity is acquired immunity that the body develops upon encountering pathogens.
The innate immune system mainly consists of two types of barriers against infection: the anatomical barrier, both physical and chemical, and the cellular immune response. In most cases, the innate immune system provides the first line of defense against foreign pathogens after the physical barriers, i.e., the skin and mucosal epithelia. The chemical barrier includes chemokines and anti-microbial substances. Cells expressing innate immune recognition receptors are macrophages, dendritic cells, mast cells, natural killer (NK) cells, neutrophils, and eosinophils. After recognizing the microbial trespasser in the body, phagocytes are the specialized cells that quickly engulf the microbe through phagocytosis (Perelson 1989; Chaplin 2010; Brodin and Davis 2017; Mayassi et al. 2021; Nayak and Roy 2021).
Some innate immunity components have very similar structural blocks across species, not only in mammals and other vertebrates but also in insects and plants. This indicates that innate immunity is well preserved through the course of evolution, presenting an active distinction between self and non-self (Hoffmann et al. 1999). Moreover, it has been observed that animals or plants which depend only upon innate immunity have no instance of autoimmunity, allergy, or organ transplant rejection (Janeway et al. 2002; Cebula et al. 2019).
Adaptive immunity, on the other hand, is a subsystem of the immune system which comprises specialized, systemic cells and processes that help in the elimination of pathogens by preventing their growth. Compared with innate immunity, adaptive immunity is a slow response process. One significant advantage of the adaptive immune system is producing long-term memory cells. These memory cells get quickly activated on the second encounter with the same pathogen, resulting in a quicker and more efficient response against that pathogen. The different lymphocyte populations of the adaptive immune system constitute T-cells and B-cells. T-cells act via cell-mediated responses, and B-cells are responsible for the production of antibodies. The B-cell is produced and undergoes maturation in the bone marrow. B-cells have a significant role in antigen presentation. The diversity of antibodies produced by B-cells is vast, but each B-cell produces only one type of antibody with a unique antigen-binding site. B-cells recognize antigens through the immunoglobulins (Igs), which are cell membrane-bound proteins uniquely expressed by B-cells, also termed B-cell receptors (BCRs). When a B-cell is fully differentiated, it becomes a plasma cell that secretes immunoglobulin with the same antigen specificity as their BCR, called antibodies. Antibodies bind to pathogens or their products. This leads to their phagocytosis by cells of the innate immunity system (Cyster and Allen 2019; Liu et al. 2020).
T-cells are a group of lymphocytes produced in the bone marrow, mature in the thymus gland, and play a significant role in immune system response. The interaction of the T-cell receptor (TCR) and CD4 or CD3 as co-receptors with the antigen-MHC II complex, which is presented by antigen presentation cells, causes the antigenic stimulation that triggers the first stage of differentiation of the naïve T-cells. Naïve T-cell proliferation and differentiation into particular effector cells are ultimately activated by a network of downstream signaling pathways induced by combined TCR and CD3 activation (Fouchet and Regoes 2008; Roy et al. 2014). Lineage-specific differentiation is influenced by the micro-environment cytokine milieu, antigen concentration, antigen-presenting cell (APC) type, and co-stimulatory molecule levels. Dendritic cells are considered the most significant APC due to their efficient role in the activation process of naïve T-cells (Chaplin 2010).
Experimental overview of dynamic behaviors of CD4+ T-cells: Team behavior
CD4+ T-cells play a significant role in the immune responses throughout the host’s defense against the pathogen. However, an extension of their critical functions of being helper cells sometimes leads to action against self-cells, leading to autoimmune disorders and allergies (Jones and Diamond 1995; Smith and Germolec 1999). T-cells that express co-receptor CD4+ are considered helper T-cells. These cells have a crucial role in immune regulation, mainly in the adaptive immune system. Regulatory cells are another class of CD4+ T-cells involved in the immune system’s modulation or regulation. In addition to the critical roles as helper cells, CD4+ T-cells may cause some autoimmune diseases and allergies.
Homeostasis maintains a stable internal environment between various physiological variables. Any quantity, either lower or in surplus, causes imbalance. It was earlier believed that the helper T-cells were only limited to two significant subsets: Th1 and Th2 cells. The Th1/Th2 paradigm (Elenkov 2004) is a simplistic yet classical approach to defining the immune response, governed by a balance between Th1 and Th2 cells. However, in the pathogenesis of inflammatory arthritis, it is observed that both Th1 and Th2 cytokines can be pro- or anti-inflammatory in varied circumstances (Elenkov 2004). A new concept about how the disease condition is induced by CD4+ T-cells is summarized in the study by Hirahara and Nakayama (2016). It entails the association between inflammatory diseases and the complexity of the helper T-cell subsets, which include Th1, Th2, Th17, Th9, Th22, T follicular-helper (Tfh) cells, and T-regulatory (Treg) cells. Several such studies articulated that the outcome of this cell fate decision is complex and depends on various parameters like cell–cell interactions and the cellular environment (Nurieva and Chung 2010; Schmidt et al. 2012; Srivastava et al. 2018).
In 1901, Paul Ehrlich observed that in some scenarios, the immune system might attack its own cells (Bordon 2016). In such situations, the immune system attacks the host’s self-cells instead of carrying out its classical work of protecting the body against foreign antigens by reacting against them, creating a condition that Paul Ehrlich termed ‘horror autotoxicus’. This may result in a clinical syndrome called autoimmunity. He coined the term ‘horror autotoxicus’ to highlight that autoimmunity contradicts nature’s disinclination towards self-injury. In some instances, injury to self-cells or organs is prompted by antibodies, whereas in other cases, T-cells are the chief culprits resulting in fatal autoimmune diseases (Margo and Harman 2016) such as rheumatoid arthritis, multiple sclerosis, and some types of diabetes.
Tolerance or self-tolerance is the mechanism present in our bodies to prevent a self-immune attack. Self-tolerance is a complicated process that involves the elimination of the immune cells that can react against self-antigens, and the active inhibition of the immune response against self-proteins (Margo and Harman 2016; Kaufmann 2019). T-cells that express CD8 are recognized as cytotoxic T-cells or killer T-cells. As the name suggests, they is directly involved in killing the infected cell (Fagnoni et al. 2002; Cowley et al. 2005). CD4+ T-cells can also be classified into different subsets, such as Th1, Th2, Th3, Th17, Th9, Th22, Tfh cells, and Treg cells (Nurieva and Chung 2010; Deenick et al. 2011; Schmidt et al. 2012; Scurr et al. 2014; Golubovskaya and Wu 2016; Srivastava et al. 2018; Chemin et al. 2019). Among these CD4+ T-cells, it has been observed that some act as pro-inflammatory cells (Th1, Th2, Th17, Th9, Th22, and Tfh cells), and others work as anti-inflammatory cells (Th 3 and Treg cells) (Lei et al. 2021; Nayak and Roy 2021).
Immunomodulatory effects of immunosuppressants on CD4+ T-cell population dynamics
As discussed above, CD4+ T-cells have two subpopulations: pro-inflammatory T-cells and anti-inflammatory T-cells. As the name suggests, pro-inflammatory T-cells promote inflammation. In some scenarios, they attack self-cells to cause autoimmune disorders and allergies (Sakaguchi and Sakaguchi 2005; Orihara et al. 2008; Murdoch and Lloyd 2010). In contrast, anti-inflammatory T-cells adopt a downregulatory mechanism acting on the population of pro-inflammatory T-cells. Thus, they can prevent autoimmunity (Grossman et al. 2004; Cao et al. 2007).
Vitamin D and glucocorticoid (GC) are well-known immunosuppressants (Chun et al. 2014). Both are effective in downregulating pro-inflammatory T-cells, i.e., the effector T-cell population, and upregulating anti-inflammatory T-cells, i.e., the regulatory T-cell population. The role of vitamin D in autoimmunity (Cutolo et al. 2011) gained much attention after the discovery of the vitamin D receptor (VDR) and other essential vitamin D-metabolizing enzymes expressed by the immune system cells. The role of vitamin D is discrete both in the case of innate and adaptive immunity (Kongsbak et al. 2013). Several experimental and clinical studies (Bouillon et al. 2021) have shown that the endogenously produced active vitamin D (1,25(OH)2D3) in macrophages increases the production rate of anti-microbial peptides like cathelicidin and β-defensins, which promote innate immune response. Consequently, the conversion of 25(OH)D3 into its functional form, i.e., 1,25(OH)2D3 (active vitamin D) in antigen-presenting cells (APCs), exerts a beneficial effect on the adaptive immune system. Correale et al. (2009) also observed a similar phenomenon. They showed that effector T-cells can convert inactive vitamin 25(OH)D3 into biologically active 1,25(OH)2D3 with the help of the enzyme 1α-hydroxylase, which is present in them (Mora et al. 2008; Chun et al. 2014).
Experimental studies (Chun et al. 2014) based on the immunomodulatory traits of vitamin D showed that autoimmunity is principally guided by the increase in the number of helper T-cells that attack several self-tissues in the body. Some studies (Mora et al. 2008; Marcinowska-Suchowierska et al. 2018) suggest that vitamin D has an adverse effect on the activation, proliferation, and differentiation of helper T-cells and a promoter effect on regulatory T-cells. It has also been observed that both vitamin D and regulatory T-cells have an inhibitory effect on the conversion of resting APC to active APC (Chun et al. 2014; Charoenngam and Holick 2020). With the above notion, vitamin D is expected to have a substantial role in T-cell population dynamics.
Glucocorticoids are also beneficial and cost-effective drugs. They have been in use for more than 60 years. They exert their primary anti-inflammatory and immunosuppressive effects on innate and adaptive immune responses. In several earlier studies, it has been found that glucocorticoids have suppressive effects on eosinophils, basophils, NK cells, monocytes, macrophages, and T-cells, whereas glucocorticoids support growth of regulatory T-cells (Cain and Cidlowski 2017; Timmermans et al. 2019). Glucocorticoids cause apoptosis of T-cells and impact T-cell differentiation by regulating the cytokines affecting the differentiation of T-cell subsets. One such case is where GCs inhibit the production of Th2-mediated cytokines. GCs are known to decrease circulating monocytes/macrophages, synthesis of pro-inflammatory cytokines and prostaglandins, and expression of their MHC class II molecules and Fc receptors (Elenkov 2004; Coutinho and Chapman 2011).
Several steroid hormones, including testosterone, and vitamin D are produced and released into the systemic circulation as precursor molecules, mainly in bio-inactive form. These circulating precursors are then converted to end-organ metabolized products (their most bioactive forms) by tissue- and organ-specific enzymes (Bereshchenko et al. 2018). In contrast, GCs are produced and released by the adrenal gland in their bioactive forms that can be metabolized by tissue-specific 11-hydroxysteroid dehydrogenase (11-HSD) enzymes. However, the 11-keto metabolites (cortisone and 11-DHC) can diffuse into the cells without restriction. It is reported that lymphocytes can produce bioactive GCs from their physiologically inactive 11-keto (cortisone and 11-DHC) metabolites (Zhang et al. 2005). They have reported that 11-HSD1 mRNA and protein are expressed in murine CD4+ and CD8+ lymphocytes. The complete conversion of cortisone (inactive) to cortisol (bioactive) occurs in lymphocytes (Cain and Cidlowski 2017; Weinstein et al. 2017). Hence, GCs can also play a vital role in modulating T-cell dynamics.
Mathematical models capturing T-cell dynamics of the human immune system
Modeling immune networks through an ordinary differential equation (ODE)-based model is inspired by the seminal work of Perelson and co-workers, who developed, among others, immune models of HIV progression (Rong and Perelson 2009; Perelson and Ribeiro 2013). By carefully fitting the models to patient data and inspecting the dynamics of CD4+ T-cells, they designed optimal therapeutic dosing strategies to keep the disease at bay. Such approaches have saved lives and continue to be fruitful, for instance, in the current times, by modeling disease progression in COVID-19 (Perelson and Ke 2021). An immune system is often classified into various regulation regimes: recurrent infection, persistent non-infectious inflammation, and healthy oscillations (Kumar et al. 2004). Kumar et al. (2004) have shown this in a study through a bifurcation diagram. In the same line of thought, a study by Garcia et al. (2020) has pointed out the crucial role of bistability in therapeutic success. Nonlinearity and the emergence of bistability have also been widely studied in the context of physiology and pathology. Through the hysteresis effect, the appearance of bistability in biological systems has been characterized experimentally (Malka et al. 2010). In the context of cancer–immune system interplay, one may consider a nonlinear system having mutual inhibitory components (Sahoo et al. 2021), and here, the system can even attain multistability (both bistability and tristability) (Lu et al. 2013). T-cells are reported to exhibit phenotypic heterogeneity and multistability in an adaptive immune system (Duddu et al. 2020).
A specific phenomenon that a model captures is often parameter-dependent. In system-based modeling, bifurcation theory is an efficient method for capturing critical biological interaction-driven phenomena (Kumar et al. 2004; Lu et al. 2013; Duddu et al. 2020). In the T-cell-mediated immune system context, such theoretical concepts help characterize different immunoregulatory states and their modulation under different environmental situations (Roy et al. 2014; Roy and Bagchi 2020; Nayak and Roy 2021). T-cell-mediated immune regulations are often classified into weak, strong, and moderate regulation regimes based on the ratio and relative concentration of pro-inflammatory T-cells and anti-inflammatory T-cells. The characteristics of these categories (Fouchet and Regoes 2008; Roy et al. 2014) are depicted in figure 1 and are described below:Weak regulation: The ratio between pro-inflammatory T-cells and anti-inflammatory T-cells is >1. As the population of pro-inflammatory T-cells is high, the immune system is more autoimmune-prone. The pathogenic load under this regulation is low.
Moderate regulation: The ratio between the pro-inflammatory T-cells and the anti-inflammatory T-cells is balanced or =1. Interestingly, here the immune system may hold the characteristics of bistability. Moreover, this regime is likely to be sensitive to therapies. Our previous work, including several other studies, has highlighted the importance of bistability and therapeutic sensitivity in a moderate regulation regime (Fouchet and Regoes 2008; Roy and Bagchi 2020; Garcia et al. 2020).
Strong regulation: The ratio of pro-inflammatory and anti-inflammatory T-cell concentrations is <1. Pathogen load is higher, which can lead to an immunocompromised condition.
Figure 1 Classification of T-cell regulation based on theoretical models. The immune system can transit from a weak regulation regime to a moderate regulation regime and then to a strong regulation regime and vice versa depending on the concentration and composition of pro-inflammatory T-cells (Tpro) and anti-inflammatory T-cells (Tanti) (refer to Roy et al. 2014; Roy and Bagchi 2020; Nayak and Roy 2021 for more details).
Immunomodulatory role of vitamin D from a theoretical perspective
The dynamic role of vitamin D in the immune system has been elaborated from an experimental perspective in the above sections. On the other hand, mathematical models in understanding the role of immunosuppressants, especially focusing on Vitamin D, are limited. A few modeling efforts have been made to distinguish the role of serum vitamin D as a metabolite, providing critical new insights into vitamin D and human health (Chun et al. 2012). In recent times, Roy et al. (2014) have developed a theoretical coarse-grained kinetic network model based on some relevant experimental observations, as shown in figure 2, which depicts the interaction of vitamin D with the adaptive immune system. The details of the immunological processes are described in an event-wise manner in the supplementary material. The study finds that the opposing role of regulatory T-cells and effector T-cells in the regulation of the immune system is dependent on the concentration of vitamin D in the body, along with several known/unknown factors determining the strength of immune regulation and the ultimate fate of a disease.Figure 2 A schematic representation of the adaptive immune responses at a cellular level. This includes the interaction of naïve T-cells, pathogen, pro-inflammatory T-cells, anti-inflammatory T-cells, and vitamin D. It is a derivative and a coarse-grained form of our previous work (Roy et al. 2014). In this design, the significant events are the following: (a) The primary step after the infection setting is to eliminate the pathogen by pro-inflammatory T-cells. Invasion of pathogens leads to the conversion of naïve T-cells to (b) pro-inflammatory T-cells and (c) anti-inflammatory T-cells. Vitamin D adds to the maturation of anti-inflammatory T-cells. Moreover, the mature pro-inflammatory T-cells and anti-inflammatory T-cells have a role in inducing naïve T-cells to produce more of themselves. However, controlling the over-explosion of pro-inflammatory T-cells is an exaggerated immune response: vitamin D and anti-inflammatory T-cells cause (d) the downregulation of pro-inflammatory T-cells. (e) The presence of pro-inflammatory T-cells facilitates the transformation of inactive vitamin D into its active form.
In an early study, Fouchet and Regoes (2008) also classified the T-cell-mediated immune network into three regulation regions (weak, moderate, and strong), where they investigated the boundaries between any two regions. The model predicted that the role of APC is crucial in the emergence of a restricted bistable region. They did not account for the effects of vitamin D in their model. However, in the presence of vitamin D, expansion of the bistable region signifies the importance of vitamin D in immune regulation and how it prevents over-explosion of effector T-cells, thereby preventing the autoimmune condition (Roy et al. 2014).
Immunomodulatory role of glucocorticoids from a theoretical perspective
Among others, GCs are well-known immunosuppressants that control T-cell-mediated adaptive immune response similar to vitamin D. Although there are several classes of synthetic glucocorticoids, dexamethasone (Dex) is the most widely used steroid due to its higher binding affinity to GC receptors (GRs) compared with natural cortisol. In addition, it has minimal mineralocorticoid activity. Again, the immunomodulatory functions of GCs are also quite similar to vitamin D. The immunomodulatory actions of GC-mediated adaptive immune response are mainly exerted on the CD4+ T cell. Specifically, those are pro-inflammatory and anti-inflammatory by nature. To better understand the immunomodulatory role of GC, a recent mathematical model by Yakimchuk (2020) used a saturation function with six kinetic rate equations. The saturation function presents a one-time external dose (GC) intake mode. Nayak and Roy (2021) have also developed a kinetic network-based model to understand the direct and indirect effects of GCs on the immune system and anti-inflammatory immune response. In the model of Yakimchuk (2020), the saturation function leads the system to saturate towards a constant dose value. As a result, after a certain concentration, the GC coupling effect is lost. Nayak and Roy (2021), on the other hand, used pharmacokinetic constants accounting for the normal metabolism of GC.
A generic coarse-grained kinetic network model for understanding the impact of immunosuppressants on T-cell regulation
From the above sections, we have seen that the immune system is indeed a complex network where its cells continuously interact and clash with foreign invaders/pathogens to maintain homeostasis. There is a continuous predator/prey-like tussle between the pro-inflammatory T-cells and the pathogen, where the pro-inflammatory T-cells are the predators. On the other end, the pathogen, being the prey, tries to escape from its predator, with assistance from anti-inflammatory T-cells. However, functional balance between pro-inflammatory T-cells and anti-inflammatory T-cells is necessary for maintaining a healthy state. An immunosuppressant like vitamin D or GC governs that. With this generic view, here we present a generic coarse-grained kinetic network model. It is noteworthy that since the immune system comprises many players, for designing a mathematical model, a coarse-graining approach helps filter essential nodes of a network so as to understand a particular phenomenon or mechanism. Here, the generic model is constructed based on a careful survey of published experimental and theoretical literature, described in the supplementary material and detailed in other references (Roy et al. 2014; Roy and Bagchi 2020; Nayak and Roy 2021). A more straightforward, albeit refined, correlation among the various elements of the immune system and their interplay with immunosuppressants is proposed and presented in figure 3, which accounts for the complexities present at a molecular level by coarse-graining them at the cellular level.Figure 3 A generic coarse-grained kinetic network model to decipher the impact of immunosuppressants on T-cell dynamics. This model is the skeletal framework of the schematic representations depicted in figure 2. The black arrows indicate conversion, and the blue and red arrows represent the activation and inhibition processes, respectively. The significance of each network parameter is described in table 1. Additional details are described in supplementary table 1.
Table 1 Definition of representative symbols of rate parameters used in figure 3
Definition Symbol
1 Rate of pathogen killing by pro-inflammatory T-cells (Tpro) kp
2 Rate of differentiation of naïve T-cells to Tpro/Tanti cells which is induced by the antigen krp
3 Rate of differentiation of naïve T-cells to Tpro cells which is induced by the pro-inflammatory T-cell itself (autocatalytic) kpro
4 Rate of differentiation of naïve T-cell to the pro-inflammatory T-cell which is induced by the pro-inflammatory T-cell itself (autocatalytic) kanti
5 Rate of inhibition of pro-inflammatory T-cell by anti-inflammatory T-cell kpa
6 Rate of inhibition of pro-inflammatory T-cell by the active immunosuppressant kpI∗
7 Rate of anti-inflammatory T-cell reactivation by an active immunosuppressant kaI∗
Once the developed network appears to be simple and effective, a system of coupled differential equations is used to first model the system without the influence of any immunosuppressants (vitamin D or GC). A detailed method is presented in the supplementary material. The critical elements considered in our coarse-grained model are the following:Pathogen/antigen/self-antigen (P)
Naïve T-cell (precursor T-cell) (TNa)
Pro-inflammatory T-cell (Tpro)
Anti-inflammatory T-cell (Tanti)
Under any pathogen attack, a healthy immune system always aims to disarm the foreign antigen by enhancing its pro-inflammatory T-cell proliferation and differentiation rate. However, an exceeding number of pro-inflammatory T-cells often fail to differentiate between self-cells and foreign peptides. Moreover, pro-inflammatory T-cells may begin damaging self-tissues. Therefore, a healthy immune system has to operate under a balanced regulation. This signifies that the concentration of pro-inflammatory T-cells must increase to overcome the pathogenic stimulation by resisting its explosive growth efficiently. Herein lies the role of vitamin D and GCs. Their optimum level effectively maintains a balanced immune regulation by inhibiting anti-inflammatory T-cells and downregulating pro-inflammatory T-cells.
Dynamic phases of CD4+ T-cell: Emergence of a characteristic lag time or clinical latency
Let us first consider a system free of immunosuppressants in the generic coarse-grained Model-I described in the supplementary material. Here, we have four coupled rate equations. By solving these four coupled differential equations, we find the dynamical behavior of pro-inflammatory T-cells and anti-inflammatory T-cells throughout their time evolution, as depicted in figure 4. A unique dynamical period known as the latent period is identified here. It is the time range within which there is a steady-state-like condition, i.e., the concentration of almost all the cell populations (pro-inflammatory T-cells, anti-inflammatory T-cells, naïve T-cells, and the pathogen) are not changing with time. After that, there is a jump to the real long-term steady-state condition. In this period, the pathogenic load is significantly low, insufficient to cause ailment. It is considered an asymptomatic phase, or clinical latency in clinical terminology. The pro-inflammatory and anti-inflammatory T-cells maintain highly balanced concentrations in this latent period. The pathogen population is too small to cause symptoms. This phase where the pathogen remains latent is called the latent period. Finally, after a long time, the system reaches the final long-term steady-state, i.e. a lower number of pro-inflammatory T-cells depicting a scenario in which symptoms resurface in the patient. In the long term, the system reaches a steady state with a higher number of anti-inflammatory T-cells and a lower number of pro-inflammatory T-cells in the post-latent period, depicting the antagonistic nature of pro-inflammatory T-cells and anti-inflammatory T-cells. Such steady-state behavior in T-cell dynamics over a longer time period is shown in figure 4. Our previous study (Nayak and Roy 2021) and many other studies (Mindikoglu et al. 2006; Gonzalez and Perrillo 2016) have pointed out that there is a probability of pathogenic reactivation as one of the side effects of long-term immunosuppressant therapy.Figure 4 Time evolution of immune response of CD4+ T-cells in the absence of any immunosuppressive drug. (a) The log-scale plot represents a regime of the immune phase regulation that contains a latent period (the time range within which there is no change in the concentration of Tpro cells and Tanti cells). During the post latent period, there is a jump to the steady-state condition. (b) Distinctive dynamical phases of immune response mediated by antigen-specific pro-inflammatory T-cells are depicted, where three phases of the immune response (expansion, contraction, and memory) are indicated. Here, the time evolution of pro-inflammatory T-cells and anti-inflammatory T-cells are plotted by solving coupled kinetic equations shown in Model I. We reproduce the T-cell dynamics considering kpro=30, and the other rate values are the same as given in Nayak and Roy (2021). In the plot, red and blue lines represent Tpro and Tanti, respectively. Note: 1.66×10−5 nmol/L corresponds to 1000 T-cells.
The initial phase of pro-inflammatory T-cell time evolution has three sub-phases: expansion, contraction, and memory (figure 4b). After the onset of infection, pro-inflammatory T-cells increase clonally in number. Figure 4b shows some fundamental phenomena during that time. Day 0 to Day 1, i.e., within 24 h, is the time during which infection is set by the pathogen. This peak of T-cell expansion on Day 1 post-infection is a limitation of this model. Adaptive response sets in after a few hours of pathogen incursion (Kaech et al. 2002). The pathogen annihilation process starts after recognizing the pathogen, followed by T-cell activation. Soon after the pathogen load decreases, the contraction phase begins. The population of pro-inflammatory T-cells reduces due to apoptosis. After the contraction phase, the number of pro-inflammatory T-cells reaches its pre-steady state value and is maintained for a significant period, representing the memory phase. Several other studies have also observed similar immune phases (Wang et al. 2015; Bertrand 2019).
Generic effects of immunosuppressants on CD4+ T-cell population: Immune state transition from weak to moderate to strong regulation
The general immunomodulatory effects of immunosuppressants on T-cell population dynamics can be described by a generic model framework (Model II discussed in the supplementary information). When the system encounters a pathogen of weak to moderate strength, it immediately switches on the activation process of effector pro-inflammatory T-cells. Subsequently, the upregulation of anti-inflammatory T-cells and pro-inflammatory counterparts plays a crucial role in setting up a competitive dual switch that can trigger either a strong or weakly regulated state (Roy and Bagchi 2020). This competing behavior of anti-inflammatory T-cells and pro-inflammatory T-cells may never end in the presence of a pathogen because our immune system is constantly exposed to some pathogenic load. Thus, it may stay moderately activated by pathogenic stimulation, which we call a moderately regulated state (Roy and Bagchi 2020). As we found earlier, the effects of immunosuppressants become essential when the system falls into a condition where the number of pro-inflammatory T-cells is more than the anti-inflammatory T-cells, transitioning the system into a weakly regulated immune state that is more prone to cause autoimmune disorders. Such a risky state can be shifted to a moderately regulated immune state depending on an optimal dose of immunosuppressant. However, if the dose of immunosuppressant exceeds that optimal level, the system may further shift to another disease-prone immune state classified as a strongly regulated state. Our generic coarse-grained Model II involves those essential and general effects of immunosuppressants that capture the shift of different immune regulation states from strong to moderate to weak regulations, as shown in figure 5d–f.Figure 5 Time evolution of the T-cell population in all three classified regulations regimes, both in the absence and presence of an immunosuppressant, GC. Time evolution of pro-inflammatory T-cells and anti-inflammatory T-cells are plotted by solving coupled kinetic equations using a deterministic approach. These three regulations are obtained by varying a single rate parameter, kpro, an autocatalytic activity of pro-inflammatory T-cells. kpro values are very sensitive towards determining the strong, moderate, and weak regulation of pro-inflammatory T-cells. In the absence of any immunosuppressant (a) a weak regulation state appears around kpro = 50, (b) a moderate regulation appears around kpro = 30, and (c) a strong regulation appears around kpro = 10. In the presence of GC (d) a weak regulation state appears around kpro = 70, (e) a moderate regulation appears around kpro = 56, and (f) a strong regulation appears again around kpro = 10. Apart from kpro , other parameter values are taken from Nayak and Roy (2021). The dose of Dex (synthetic glucocorticoid dexamethasone) is taken to be optimal, which is 38.21 nmol/L. This calculation and figure are reproduced from Nayak and Roy (2021) (Reprinted (calculations/figure) with permission from Sonali Priyadarshini Nayak and Susmita Roy, Phys. Rev. E 103, 062401 – Published 3 June 2021 (https://doi.org/10.1103/PhysRevE.103.062401). Copyright 2022 by the American Physical Society). In the plot, the red and blue lines represent Tpro and Tanti respectively. Note: 1.66 × 10−5 nmol/L corresponds to 1000 T-cells.
In an early study, Fouchet and Regoes (2008) analyzed the steady-state values of T-cells in these three regulation regimes. As shown in our earlier work (Roy and Bagchi 2020), in the absence of vitamin D, a bistable region is found in this generic model, where both strong and weak regulation can coexist. However, we find that in the presence of even a minute vitamin D level, a weakly regulated state can be converted to a strongly regulated state intervened by a moderate regulation regime as the dose intake increases. At a very high dose limit, even when a simulation starts with an initial state of weak regulation, feedback makes this weak regulation stronger. The system mounts the required effective regulation depending on the vitamin D dose variation, as shown in figure 6. The dose-dependent dynamics of the system are captured from a theoretical model in figure 6a–c. From a modeling perspective, vitamin D dose dependence of T-cell population dynamics has been shown by Roy et al. (2014) In this work, in the bistable region, both the variation of T-cell and pathogen levels remain intimately connected and help to determine an optimal vitamin D range (Roy and Bagchi 2020). A similar T-cell variation pattern was obtained experimentally by Jeffery et al. (2012), as shown in figure 6d–e. In both cases, with an increase in vitamin D dose level, there is a concomitant increase in anti-inflammatory T-cell concentration and a decrease in pro-inflammatory T-cell concentration. Moreover, similar to the effect of GC, the system reverts to a weakly regulated state at a low vitamin D dose level as the pro-inflammatory T-cells again increase in population size. At the other extreme, when the vitamin D dose is very high, the system reaches a strongly regulated state as the anti-inflammatory T-cells are abundant and suppress the pro-inflammatory T-cell concentration.Figure 6 Time evolution of the T-cell population in the presence of a secosteroid vitamin D from a theoretical model, followed by experimental validation (Roy et al. 2014). Time evolution of pro-inflammatory T-cells and anti-inflammatory T-cells are plotted by solving coupled kinetic equations from Model II at varying vitamin D concentrations. Strong regulation, moderate regulation, and weak regulation are very sensitive to vitamin D concentration. (a) A weak regulation state appears close to vitamin D dose of 10 nM/L. (b) Moderate regulation state starts to appear around vitamin D dose of 50 nM/L. (c) Strong regulation state appears around vitamin D dose of 900 nM/L, which is an extremely high dose. Other parameter values are taken from Roy et al. (2014), apart from variable active vitamin D concentration ([I*]) (Roy et al. 2014) to solve Model II. Note: 1.66 × 10−5 nmol/L corresponds to 1000 T-cells. (d–e) Experimental validation of our model adapted from Jeffery et al. (2012). (d) An increase in Tanti concentration and (e) decrease in Tpro concentration with an increase in the concentration of active vitamin D. For review purposes, the data for (d–e) are obtained from Jeffery et al. (2012). The details regarding the experimental study can be found in Jeffery et al. (2012). In the plot, the red and blue lines represent Tpro and Tanti respectively.
Summarizing the immunomodulatory role of immunosuppressants and future aspects to comprehend their responses
Beyond their classical role, glucocorticoids (GCs) and vitamin D impact the immune system as immunomodulators. However, as the immune system is a highly complex network, we have generalized a theoretical coarse-grained kinetic model based on a T-cell-mediated interaction network to obtain an insight into the immune regulation exerted by such immunosuppressants. We solved this complex network problem using a chemical dynamics approach. The interaction network dynamically connects different immune components involved in the relevant immune responses. The expressed kinetic design illustrates the time evolution of all critical components, including pro-inflammatory T-cells and anti-inflammatory T-cells. The steady-state analyses of the proposed kinetic equations infer tangled relations between the GC or vitamin D dose and anti-inflammatory T-cells maintained by homeostasis, wherein such immunosuppressants have a significant regulatory role. The absence or presence of a lower concentration of GC (lower than optimum) corresponds to a weak regulatory regime. At the optimal concentration of such immunosuppressants, the system may enable the characteristics of bistability. In this phase, one may observe a unique dynamical phase similar to the clinical latent period (Nayak and Roy 2021). At a concentration higher than optimal, the system moves towards a strong regulation with a decrease in latent time, accounting for the importance of monitoring the appropriate dose of immunosuppressant administered for autoimmune disease or cancer treatment. Hence, it is essential to closely monitor an appropriate dose of an immunosuppressant administrated during the treatment. This helps prevent potential side effects such as compromised immunity or easy pathogen target. At low GC concentration, if any pathogen enters the body, the immune response’s nature would be more inflammatory, which can finally lead to an autoimmune condition.
GCs are observed to have a significant role in keeping the immune system in a moderate/bistability regime for a very long time. As shown in figure 4, the immune system has a latent period of very high value at specific concentrations of GCs, which we consider an optimal range. In that phase, the pathogen population is low, and the pro-inflammatory T-cell concentration is also under control. These findings show that at a meager value or in the absence of GC, the latent period is significantly shorter; there is a risk of autoimmune disease due to the uncontrolled growth of pro-inflammatory T-cells. While these phenomena and the optimal range of GC (Dex) are in accordance with the experimental finding (Becker 2013), the dependence of the clinical latency on vitamin D is yet to be explored.
For an immunosuppressant, one may identify one/many sensitive parameters. For instance, take the example of kpro. kpro is the rate at which pro-inflammatory T-cells can induce naive T-cells to produce more of themselves, which is primarily a self-regulatory mechanism. kpro represents how pro-inflammatory T-cells produce more of themselves. The kpro value is not fixed. It may vary from person to person. Moreover, it has been known that the cytokine level does not have a particular value, and it varies over a physiological range (Kim et al. 2011; Roy and Bagchi 2020; Nayak and Roy 2021). The range of kpro is dependent on the cytokine level. Thus, to incorporate such effects one may also account for the variability of rate parameters by including a relevant distribution function of rate parameters.
Another essential concern is to address specific responses hosted by various interactions with key immunological components in different physiological conditions. In practice, we investigate the regulation mentioned above and their cross-over by time evolution analysis of each participating element after the pathogen attack to study their long-time steady-state behavior. One may ask, how do we find this co-existence line between any two immune regulation regimes? Clinical and experimental studies also use some standard values of pro- and anti-inflammatory T-cells; more often, the ratio of these T-cells cells serves as the predictor of the patients’ immune profile. However, other related studies or experimental results frequently challenge such standardized ratios or numbers. Often, we ignore the fact that these standard numbers can be personalized and may vary among patients carrying the same disease. Under such circumstances, experimental and theoretical investigations should find suitable parameters to quantify person-specific immune responses. An early study (Roy and Bagchi 2020) accounted for the fluctuations in the number/concentration of active participants along stochastic trajectories. A relevant fluctuating quantity serves as a crucial order parameter capturing a divergent-like behavior that might evoke a characteristic of criticality near the cross-over line of immune phases (Roy and Bagchi 2020). The study also addresses the adverse long-term effects of any analogue of vitamin D or other immunosuppressants with their overdose limit in treating autoimmune diseases. The mean-square fluctuation-mediated response parameter is so sensitive that it can efficiently capture the signature of an immune breakdown in the presence of the overdose limit of immunosuppressant by a significant drop in essential fluctuation of pro-inflammatory T-cells. It also demonstrated that the presence of an optimal level of vitamin D rather than its lower concentration limit assists in broadening the tolerance limit. A bistable condition emerges with strong anticorrelated fluctuations between pro- and anti-inflammatory T-cell subsets. The broad fluctuation profile and a significant reduction in the relative fluctuation of effector T-cells in the presence of an immune-modulator like vitamin D suggest that the fluctuation of the active T-cell subset can be more responsive as often found in clinical studies. Hence, these fluctuations can be used as a tool for future diagnostics and therapeutics. We strongly believe that more findings will help shed light and also help explain several clinical results associated with the dose effectiveness of various immunosuppressants used as a critical remedy under emergency conditions.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 671 KB)
Acknowledgements
BB thanks the Science and Engineering Research Board (SERB), India, for the National Science Chair Professorship and the Department of Science and Technology. SR acknowledges support from the Department of Biotechnology (DBT) (Grant No. BT/12/IYBA/2019/12) and Science and Engineering Research Board (SERB), Department of Science and Technology (DST), India (Grant No. SRG/2020/001295).
This article is part of the Topical Collection: Emergent dynamics of biological networks.
Corresponding editor: Mohit Kumar Jolly
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References
Becker DE Basic and clinical pharmacology of glucocorticosteroids Anesth. Prog. 2013 60 25 32 10.2344/0003-3006-60.1.25 23506281
Bereshchenko O Bruscoli S Riccardi C Glucocorticoids, sex hormones, and immunity Front. Immunol. 2018 9 1332 10.3389/fimmu.2018.01332 29946321
Bertrand RL Lag phase is a dynamic, organized, adaptive, and evolvable period that prepares bacteria for cell division J. Bacteriol. 2019 201 e00697 e718 10.1128/JB.00697-18 30642990
Bordon Y The many sides of Paul Ehrlich Nat. Immunol. 2016 17 S6 S6 10.1038/ni.3601
Bouillon R Manousaki D Rosen C The health effects of vitamin D supplementation: evidence from human studies Nat. Rev. Endocrinol. 2021 18 96 110 10.1038/s41574-021-00593-z 34815552
Brodin P Davis MM Human immune system variation Nat. Rev. Immunol. 2017 17 21 29 10.1038/nri.2016.125 27916977
Cain DW Cidlowski JA Immune regulation by glucocorticoids Nat Rev. Immunol. 2017 17 233 247 10.1038/nri.2017.1 28192415
Cao X Cai SF Fehniger TA Song J Granzyme B and perforin are important for regulatory T-cell-mediated suppression of tumor clearance Immunity 2007 27 635 646 10.1016/j.immuni.2007.08.014 17919943
Cebula A, Kuczma M, Szurek E, et al. 2019 Dormant pathogenic CD4+ T cells are prevalent in the peripheral repertoire of healthy mice. Nat. Commun. 10 4882
Chaplin DD Overview of the immune response J. Allergy Clin. Immunol. 2010 125 S3 S23 10.1016/j.jaci.2009.12.980 20176265
Charoenngam N Holick MF Immunologic Effects of Vitamin D on human health and disease Nutrients 2020 12 2097 10.3390/nu12072097 32679784
Chemin K Gerstner C Malmström V Effector functions of CD4+ T-cells at the site of local autoimmune inflammation—Lessons from rheumatoid arthritis Front. Immunol. 2019 10 353 10.3389/fimmu.2019.00353 30915067
Chun RF Peercy BE Adams JS Hewison M Vitamin D binding protein and monocyte response to 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D: Analysis by mathematical modeling PLoS One 2012 7 e30773 10.1371/journal.pone.0030773 22292037
Chun RF Liu PT Modlin RL Adams JS Hewison M Impact of vitamin D on immune function: lessons learned from genome-wide analysis Front. Physiol. 2014 5 151 10.3389/fphys.2014.00151 24795646
Correale J Ysrraelit MC Gaitán MI Immunomodulatory effects of Vitamin D in multiple sclerosis Brain 2009 132 1146 1160 10.1093/brain/awp033 19321461
Coutinho AE Chapman KE The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights Mol. Cell. Endocrinol. 2011 335 2 13 10.1016/j.mce.2010.04.005 20398732
Cowley SC Hamilton E Frelinger JA CD4-CD8-T-cells control intracellular bacterial infections both in vitro and in vivo J. Exp. Med. 2005 202 309 319 10.1084/jem.20050569 16027239
Cutolo M Pizzorni C Sulli A Vitamin D endocrine system involvement in autoimmune rheumatic diseases Autoimmun. Rev. 2011 11 84 87 10.1016/j.autrev.2011.08.003 21864722
Cyster JG Allen CDC B-cell responses: Cell interaction dynamics and decisions Cell 2019 177 524 540 10.1016/j.cell.2019.03.016 31002794
Deenick EK Ma CS Brink R Tangye SG Regulation of T follicular helper cell formation and function by antigen presenting cells Curr. Opin. Immunol. 2011 23 111 118 10.1016/j.coi.2010.10.007 21115333
Duddu AS Sahoo S Hati S Jhunjhunwala S Jolly MK Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators J. R. Soc. Interface 2020 17 20200631 10.1098/rsif.2020.0631 32993428
Elenkov IJ Glucocorticoids and the Th1/Th2 balance Ann. N. Acad. Sci. 2004 1024 138 1346 10.1196/annals.1321.010
Fagnoni FF T-cell dynamics after high-dose chemotherapy in adults: elucidation of the elusive CD8+ subset reveals multiple homeostatic T-cell compartments with distinct implications for immune competence Immunology 2002 106 27 37 10.1046/j.1365-2567.2002.01400.x 11972629
Fouchet D Regoes R A population dynamics analysis of the interaction between adaptive regulatory T-cells and antigen presenting cells PloS One 2008 3 e2306 10.1371/journal.pone.0002306 18509463
Garcia V Bonhoeffer S Fu F Cancer-induced immunosuppression can enable effectiveness of immunotherapy through bistability generation: A mathematical and computational examination J. Theor. Biol. 2020 492 110185 10.1016/j.jtbi.2020.110185 32035826
Golubovskaya V Wu L Different subsets of T-cells, memory, effector functions, and CAR-T immunotherapy Cancers 2016 8 36 10.3390/cancers8030036 26999211
Gonzalez SA Perrillo RP Hepatitis B virus reactivation in the setting of cancer chemotherapy and other immunosuppressive drug therapy Clin. Infect. Dis. 2016 62 S306 S313 10.1093/cid/ciw043 27190320
Grossman WJ Verbsky JW Barchet W Human T regulatory cells can use the perforin pathway to cause autologous targeT-cell death Immunity 2004 21 589 601 10.1016/j.immuni.2004.09.002 15485635
Hirahara K Nakayama T CD4+ T-cell subsets in inflammatory diseases: beyond the T h 1/T h 2 paradigm Int. Immunol. 2016 28 163 171 10.1093/intimm/dxw006 26874355
Hoffmann JA Kafatos FC Janeway CA Ezekowitz RA Phylogenetic perspectives in innate immunity Science 1999 284 1313 1318 10.1126/science.284.5418.1313 10334979
Janeway CA Jr and Medzhitov R 2002 Innate immune recognition. Annu. Rev. Immunol. 20 197–216
Jeffery LE Wood AM Qureshi OS Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T-cell responses J. Immunol. 2012 189 5155 10.4049/jimmunol.1200786 23087405
Jones DE Diamond AG The basis of autoimmunity: an overview J. Clin. Endocrinol. Metab. 1995 9 1 24
Kaech SM Wherry EJ Ahmed R Effector and memory T-cell differentiation: implications for vaccine development Nat. Rev. Immunol. 2002 2 251 262 10.1038/nri778 12001996
Kaufmann SHE Immunology’s coming of age Front. Immunol. 2019 10 684 10.3389/fimmu.2019.00684 31001278
Kim HO Kim H-S Youn J-C Shin E-C Park S Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays J. Transl. Med. 2011 9 113 10.1186/1479-5876-9-113 21774806
Kongsbak M Levring T Geisler C von Essen M The vitamin D receptor and T-cell function Front. Immunol. 2013 4 148 10.3389/fimmu.2013.00148 23785369
Kumar R Clermont G Vodovotz Y Chow CC The dynamics of acute inflammation J. Theor. Biol. 2004 230 145 155 10.1016/j.jtbi.2004.04.044 15321710
Lei T-Y Ye Y-Z Zhu X-Q The immune response of T-cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke J. Neuroinflam. 2021 18 25 10.1186/s12974-020-02057-z
Liu W Tolar P Song W Kim TJ Editorial: BCR Signaling and B-cell activation Front. Immunol. 2020 11 45 10.3389/fimmu.2020.00045 32063903
Lu M Jolly MK Levine H Onuchic JN Ben-Jacob E MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination Proc. Natl. Acad. Sci. USA 2013 110 18144 18149 10.1073/pnas.1318192110 24154725
Malka R Shochat E Rom-Kedar V Bistability and bacterial infections PLoS One 2010 5 e10010 10.1371/journal.pone.0010010 20463954
Marcinowska-Suchowierska E Kupisz-Urbańska M Łukaszkiewicz J Płudowski P Jones G Vitamin D toxicity–A clinical perspective Front. Endocrinol. 2018 9 550 10.3389/fendo.2018.00550
Margo CE Harman LE Autoimmune disease: Conceptual history and contributions of ocular immunology Surv. Ophthalmol. 2016 61 680 688 10.1016/j.survophthal.2016.04.006 27131478
Mayassi T Barreiro LB Rossjohn J Jabri B A multilayered immune system through the lens of unconventional T-cells Nature 2021 595 501 510 10.1038/s41586-021-03578-0 34290426
Mindikoglu AL Regev A Schiff ER Hepatitis B virus reactivation after cytotoxic chemotherapy: The disease and its prevention Clin. Gastroenterol. Hepatol. 2006 4 1076 1081 10.1016/j.cgh.2006.05.027 16861051
Mora JR Iwata M von Andrian UH Vitamin effects on the immune system: vitamins A and D take centre stage Nat. Rev. Immunol. 2008 8 685 698 10.1038/nri2378 19172691
Murdoch JR Lloyd CM Resolution of allergic airway inflammation and airway hyperreactivity is mediated by IL-17-producing γδ T-cells Am. J. Respir. Crit. Care Med. 2010 182 464 476 10.1164/rccm.200911-1775OC 20413629
Nayak SP Roy S Immune phase transition under steroid treatment Phys. Rev. E 2021 103 62401 10.1103/PhysRevE.103.062401
Nurieva RI Chung Y Understanding the development and function of T follicular helper cells Cell. Mol. Immunol. 2010 7 190 197 10.1038/cmi.2010.24 20383172
Orihara K, Nakae S, Pawankar R and Saito H 2008 Role of regulatory and pro-inflammatory T-cell Populations in allergic diseases World Allergy Organ. J. 1 9–14
Perelson AS Immune network theory Immunol. Rev. 1989 110 5 36 10.1111/j.1600-065X.1989.tb00025.x 2477327
Perelson AS Ke R Mechanistic modeling of SARS-CoV-2 and other infectious diseases and the effects of therapeutics Clin. Pharmacol. Ther. 2021 109 829 840 10.1002/cpt.2160 33410134
Perelson AS Ribeiro RM Modeling the within-host dynamics of HIV infection BMC Biol. 2013 11 96 10.1186/1741-7007-11-96 24020860
Rong L Perelson AS Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy PLoS Comput. Biol. 2009 5 e1000533 10.1371/journal.pcbi.1000533 19834532
Roy S Bagchi B Fluctuation theory of immune response: A statistical mechanical approach to understand pathogen induced T-cell population dynamics J. Chem. Phys. 2020 153 45107 10.1063/5.0009747
Roy S Shrinivas K Bagchi B A stochastic chemical dynamic approach to correlate autoimmunity and optimal Vitamin D range PLoS One 2014 9 e100635 10.1371/journal.pone.0100635 24971516
Sahoo S Nayak SP Hari K Immunosuppressive traits of the hybrid epithelial/mesenchymal phenotype Front. Immunol 2021 12 5347 10.3389/fimmu.2021.797261
Sakaguchi S Sakaguchi N Regulatory T-cells in immunologic self-tolerance and autoimmune disease Int. Rev. Immunol. 2005 24 211 226 10.1080/08830180590934976 16036375
Schmidt A Oberle N Krammer P Molecular mechanisms of Treg-mediated T-cell suppression Front Immunol. 2012 3 51
Scurr M Highly prevalent colorectal cancer-infiltrating LAP+ Foxp3− T-cells exhibit more potent immunosuppressive activity than Foxp3+ regulatory T-cells Mucosal Immunol. 2014 7 428 439 10.1038/mi.2013.62 24064667
Smith DA Germolec DR Introduction to immunology and autoimmunity Environ. Health Perspect. 1999 107 661 665 10502528
Srivastava RK Dar HY Mishra PK Immunoporosis: Immunology of osteoporosis—role of T-cells Front. Immunol 2018 9 657 10.3389/fimmu.2018.00657 29675022
Timmermans S Souffriau J Libert C A general introduction to glucocorticoid biology Front. Immunol 2019 10 1545 10.3389/fimmu.2019.01545 31333672
Wang L Fan D Chen W Terentjev EM Bacterial growth, detachment and cell size control on polyethylene terephthalate surfaces Sci. Rep. 2015 5 15159 10.1038/srep15159 26464114
Weinstein RS Hogan EA Borrelli MJ The pathophysiological sequence of glucocorticoid-induced osteonecrosis of the femoral head in male Mice Endocrinol. 2017 158 3817 3831 10.1210/en.2017-00662
Yakimchuk K Mathematical modeling of immune modulation by glucocorticoids Bio Syst. 2020 187 104066
Zhang TY Ding X Daynes RA The Expression of 11β-Hydroxysteroid Dehydrogenase Type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities J. Immunol. 2005 174 879 10.4049/jimmunol.174.2.879 15634910
| 36503907 | PMC9734612 | NO-CC CODE | 2022-12-14 23:47:22 | no | J Biosci. 2022 Dec 10; 47(4):70 | utf-8 | J Biosci | 2,022 | 10.1007/s12038-022-00312-4 | oa_other |
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Review
Effects of immunosuppressants on T-cell dynamics: Understanding from a generic coarse-grained immune network model
Nayak Sonali Priyadarshini 12
Bagchi Biman [email protected]
3
http://orcid.org/0000-0001-6411-4347
Roy Susmita [email protected]
4
1 grid.18048.35 0000 0000 9951 5557 Department of Systems and Computational Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
2 grid.7450.6 0000 0001 2364 4210 Max Planck School Matter to Life, University of Göttingen, Friedrich-Hund-Platz 1, 37077 Göttingen, Germany
3 grid.34980.36 0000 0001 0482 5067 Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru, 560012 India
4 grid.417960.d 0000 0004 0614 7855 Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, 741246 India
Communicated by Mohit Kumar Jolly.
10 12 2022
2022
47 4 7010 1 2022
22 9 2022
© Indian Academy of Sciences 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Long-term immunosuppressive therapy is a drug regimen often used to lower aggressive immune responses in various chronic inflammatory diseases. However, such long-term therapy leading to immune suppression may trigger other adverse reactions in the immune system. The rising concern regarding the optimal dose and duration of such treatment has motivated us to understand non-classical immunomodulatory responses induced by various immunosuppressive steroid and secosteroid drugs such as glucocorticoid and vitamin D supplements. The immunomodulatory actions of such immunosuppressants (that govern the adaptive immune response) are often mediated through their characteristic control over CD4+ T-cells involving pro- and anti-inflammatory T-cells. Several early studies attempted to decode temporal and dose-dependent behaviors of such pro- and anti-inflammatory T-cells using the chemical dynamics approach. We first summarize these early works. Then, we develop a minimal coarse-grained kinetic network model to capture the commonality in their immunomodulatory functions. This generic model successfully reproduces the characteristic dynamical features, including the clinical latency period in long-term T-cell dynamics. The temporal behavior of T-cells is found to be sensitive to specific rate parameters and doses of immunosuppressants. The steady-state analysis reflects the transition from an early classified weakly regulated (autoimmune-prone) immune state to a strongly regulated state (immunocompromised state), separated by an intervening state of moderate/balanced regulation. An optimal dose and duration are essential in rescuing balanced immune regulation. This review elucidates how developing a simple generic coarse-grained immune network model may provide immense information that helps diagnose inefficacy in adaptive immune function before and after administering immunosuppressants such as glucocorticoid or vitamin D.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12038-022-00312-4.
Keywords
Chemical dynamics
glucocorticoid
immune network
T-cell
steroid
vitamin D
http://dx.doi.org/10.13039/501100001407 Department of Biotechnology , Ministry of Science and Technology BT/12/IYBA/2019/12 Roy Susmita http://dx.doi.org/10.13039/501100001843 Science and Engineering Research Board SRG/2020/001295 Roy Susmita issue-copyright-statement© Indian Academy of Sciences 2022
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pmcIntroduction: A brief overview of the human immune system and its components
We continuously encounter many bacteria, viruses, fungi, and other complex organisms during our lifetime. While some are not harmful to us, like the commensal bacteria inhabiting our gut, others are considered pathogenic, leading to severe health ailments. To maintain physiological homeostasis, we have a cellular and humoral system that is able to control and get rid of these foreign organisms from our bodies – the immune system. Distinguishing self from non-self is one of the primary functions of the immune system. The immune system has two interconnected arms, i.e., innate immunity and adaptive immunity. Innate immunity corresponds to a non-specific defense mechanism present in our body at birth, whereas adaptive immunity is acquired immunity that the body develops upon encountering pathogens.
The innate immune system mainly consists of two types of barriers against infection: the anatomical barrier, both physical and chemical, and the cellular immune response. In most cases, the innate immune system provides the first line of defense against foreign pathogens after the physical barriers, i.e., the skin and mucosal epithelia. The chemical barrier includes chemokines and anti-microbial substances. Cells expressing innate immune recognition receptors are macrophages, dendritic cells, mast cells, natural killer (NK) cells, neutrophils, and eosinophils. After recognizing the microbial trespasser in the body, phagocytes are the specialized cells that quickly engulf the microbe through phagocytosis (Perelson 1989; Chaplin 2010; Brodin and Davis 2017; Mayassi et al. 2021; Nayak and Roy 2021).
Some innate immunity components have very similar structural blocks across species, not only in mammals and other vertebrates but also in insects and plants. This indicates that innate immunity is well preserved through the course of evolution, presenting an active distinction between self and non-self (Hoffmann et al. 1999). Moreover, it has been observed that animals or plants which depend only upon innate immunity have no instance of autoimmunity, allergy, or organ transplant rejection (Janeway et al. 2002; Cebula et al. 2019).
Adaptive immunity, on the other hand, is a subsystem of the immune system which comprises specialized, systemic cells and processes that help in the elimination of pathogens by preventing their growth. Compared with innate immunity, adaptive immunity is a slow response process. One significant advantage of the adaptive immune system is producing long-term memory cells. These memory cells get quickly activated on the second encounter with the same pathogen, resulting in a quicker and more efficient response against that pathogen. The different lymphocyte populations of the adaptive immune system constitute T-cells and B-cells. T-cells act via cell-mediated responses, and B-cells are responsible for the production of antibodies. The B-cell is produced and undergoes maturation in the bone marrow. B-cells have a significant role in antigen presentation. The diversity of antibodies produced by B-cells is vast, but each B-cell produces only one type of antibody with a unique antigen-binding site. B-cells recognize antigens through the immunoglobulins (Igs), which are cell membrane-bound proteins uniquely expressed by B-cells, also termed B-cell receptors (BCRs). When a B-cell is fully differentiated, it becomes a plasma cell that secretes immunoglobulin with the same antigen specificity as their BCR, called antibodies. Antibodies bind to pathogens or their products. This leads to their phagocytosis by cells of the innate immunity system (Cyster and Allen 2019; Liu et al. 2020).
T-cells are a group of lymphocytes produced in the bone marrow, mature in the thymus gland, and play a significant role in immune system response. The interaction of the T-cell receptor (TCR) and CD4 or CD3 as co-receptors with the antigen-MHC II complex, which is presented by antigen presentation cells, causes the antigenic stimulation that triggers the first stage of differentiation of the naïve T-cells. Naïve T-cell proliferation and differentiation into particular effector cells are ultimately activated by a network of downstream signaling pathways induced by combined TCR and CD3 activation (Fouchet and Regoes 2008; Roy et al. 2014). Lineage-specific differentiation is influenced by the micro-environment cytokine milieu, antigen concentration, antigen-presenting cell (APC) type, and co-stimulatory molecule levels. Dendritic cells are considered the most significant APC due to their efficient role in the activation process of naïve T-cells (Chaplin 2010).
Experimental overview of dynamic behaviors of CD4+ T-cells: Team behavior
CD4+ T-cells play a significant role in the immune responses throughout the host’s defense against the pathogen. However, an extension of their critical functions of being helper cells sometimes leads to action against self-cells, leading to autoimmune disorders and allergies (Jones and Diamond 1995; Smith and Germolec 1999). T-cells that express co-receptor CD4+ are considered helper T-cells. These cells have a crucial role in immune regulation, mainly in the adaptive immune system. Regulatory cells are another class of CD4+ T-cells involved in the immune system’s modulation or regulation. In addition to the critical roles as helper cells, CD4+ T-cells may cause some autoimmune diseases and allergies.
Homeostasis maintains a stable internal environment between various physiological variables. Any quantity, either lower or in surplus, causes imbalance. It was earlier believed that the helper T-cells were only limited to two significant subsets: Th1 and Th2 cells. The Th1/Th2 paradigm (Elenkov 2004) is a simplistic yet classical approach to defining the immune response, governed by a balance between Th1 and Th2 cells. However, in the pathogenesis of inflammatory arthritis, it is observed that both Th1 and Th2 cytokines can be pro- or anti-inflammatory in varied circumstances (Elenkov 2004). A new concept about how the disease condition is induced by CD4+ T-cells is summarized in the study by Hirahara and Nakayama (2016). It entails the association between inflammatory diseases and the complexity of the helper T-cell subsets, which include Th1, Th2, Th17, Th9, Th22, T follicular-helper (Tfh) cells, and T-regulatory (Treg) cells. Several such studies articulated that the outcome of this cell fate decision is complex and depends on various parameters like cell–cell interactions and the cellular environment (Nurieva and Chung 2010; Schmidt et al. 2012; Srivastava et al. 2018).
In 1901, Paul Ehrlich observed that in some scenarios, the immune system might attack its own cells (Bordon 2016). In such situations, the immune system attacks the host’s self-cells instead of carrying out its classical work of protecting the body against foreign antigens by reacting against them, creating a condition that Paul Ehrlich termed ‘horror autotoxicus’. This may result in a clinical syndrome called autoimmunity. He coined the term ‘horror autotoxicus’ to highlight that autoimmunity contradicts nature’s disinclination towards self-injury. In some instances, injury to self-cells or organs is prompted by antibodies, whereas in other cases, T-cells are the chief culprits resulting in fatal autoimmune diseases (Margo and Harman 2016) such as rheumatoid arthritis, multiple sclerosis, and some types of diabetes.
Tolerance or self-tolerance is the mechanism present in our bodies to prevent a self-immune attack. Self-tolerance is a complicated process that involves the elimination of the immune cells that can react against self-antigens, and the active inhibition of the immune response against self-proteins (Margo and Harman 2016; Kaufmann 2019). T-cells that express CD8 are recognized as cytotoxic T-cells or killer T-cells. As the name suggests, they is directly involved in killing the infected cell (Fagnoni et al. 2002; Cowley et al. 2005). CD4+ T-cells can also be classified into different subsets, such as Th1, Th2, Th3, Th17, Th9, Th22, Tfh cells, and Treg cells (Nurieva and Chung 2010; Deenick et al. 2011; Schmidt et al. 2012; Scurr et al. 2014; Golubovskaya and Wu 2016; Srivastava et al. 2018; Chemin et al. 2019). Among these CD4+ T-cells, it has been observed that some act as pro-inflammatory cells (Th1, Th2, Th17, Th9, Th22, and Tfh cells), and others work as anti-inflammatory cells (Th 3 and Treg cells) (Lei et al. 2021; Nayak and Roy 2021).
Immunomodulatory effects of immunosuppressants on CD4+ T-cell population dynamics
As discussed above, CD4+ T-cells have two subpopulations: pro-inflammatory T-cells and anti-inflammatory T-cells. As the name suggests, pro-inflammatory T-cells promote inflammation. In some scenarios, they attack self-cells to cause autoimmune disorders and allergies (Sakaguchi and Sakaguchi 2005; Orihara et al. 2008; Murdoch and Lloyd 2010). In contrast, anti-inflammatory T-cells adopt a downregulatory mechanism acting on the population of pro-inflammatory T-cells. Thus, they can prevent autoimmunity (Grossman et al. 2004; Cao et al. 2007).
Vitamin D and glucocorticoid (GC) are well-known immunosuppressants (Chun et al. 2014). Both are effective in downregulating pro-inflammatory T-cells, i.e., the effector T-cell population, and upregulating anti-inflammatory T-cells, i.e., the regulatory T-cell population. The role of vitamin D in autoimmunity (Cutolo et al. 2011) gained much attention after the discovery of the vitamin D receptor (VDR) and other essential vitamin D-metabolizing enzymes expressed by the immune system cells. The role of vitamin D is discrete both in the case of innate and adaptive immunity (Kongsbak et al. 2013). Several experimental and clinical studies (Bouillon et al. 2021) have shown that the endogenously produced active vitamin D (1,25(OH)2D3) in macrophages increases the production rate of anti-microbial peptides like cathelicidin and β-defensins, which promote innate immune response. Consequently, the conversion of 25(OH)D3 into its functional form, i.e., 1,25(OH)2D3 (active vitamin D) in antigen-presenting cells (APCs), exerts a beneficial effect on the adaptive immune system. Correale et al. (2009) also observed a similar phenomenon. They showed that effector T-cells can convert inactive vitamin 25(OH)D3 into biologically active 1,25(OH)2D3 with the help of the enzyme 1α-hydroxylase, which is present in them (Mora et al. 2008; Chun et al. 2014).
Experimental studies (Chun et al. 2014) based on the immunomodulatory traits of vitamin D showed that autoimmunity is principally guided by the increase in the number of helper T-cells that attack several self-tissues in the body. Some studies (Mora et al. 2008; Marcinowska-Suchowierska et al. 2018) suggest that vitamin D has an adverse effect on the activation, proliferation, and differentiation of helper T-cells and a promoter effect on regulatory T-cells. It has also been observed that both vitamin D and regulatory T-cells have an inhibitory effect on the conversion of resting APC to active APC (Chun et al. 2014; Charoenngam and Holick 2020). With the above notion, vitamin D is expected to have a substantial role in T-cell population dynamics.
Glucocorticoids are also beneficial and cost-effective drugs. They have been in use for more than 60 years. They exert their primary anti-inflammatory and immunosuppressive effects on innate and adaptive immune responses. In several earlier studies, it has been found that glucocorticoids have suppressive effects on eosinophils, basophils, NK cells, monocytes, macrophages, and T-cells, whereas glucocorticoids support growth of regulatory T-cells (Cain and Cidlowski 2017; Timmermans et al. 2019). Glucocorticoids cause apoptosis of T-cells and impact T-cell differentiation by regulating the cytokines affecting the differentiation of T-cell subsets. One such case is where GCs inhibit the production of Th2-mediated cytokines. GCs are known to decrease circulating monocytes/macrophages, synthesis of pro-inflammatory cytokines and prostaglandins, and expression of their MHC class II molecules and Fc receptors (Elenkov 2004; Coutinho and Chapman 2011).
Several steroid hormones, including testosterone, and vitamin D are produced and released into the systemic circulation as precursor molecules, mainly in bio-inactive form. These circulating precursors are then converted to end-organ metabolized products (their most bioactive forms) by tissue- and organ-specific enzymes (Bereshchenko et al. 2018). In contrast, GCs are produced and released by the adrenal gland in their bioactive forms that can be metabolized by tissue-specific 11-hydroxysteroid dehydrogenase (11-HSD) enzymes. However, the 11-keto metabolites (cortisone and 11-DHC) can diffuse into the cells without restriction. It is reported that lymphocytes can produce bioactive GCs from their physiologically inactive 11-keto (cortisone and 11-DHC) metabolites (Zhang et al. 2005). They have reported that 11-HSD1 mRNA and protein are expressed in murine CD4+ and CD8+ lymphocytes. The complete conversion of cortisone (inactive) to cortisol (bioactive) occurs in lymphocytes (Cain and Cidlowski 2017; Weinstein et al. 2017). Hence, GCs can also play a vital role in modulating T-cell dynamics.
Mathematical models capturing T-cell dynamics of the human immune system
Modeling immune networks through an ordinary differential equation (ODE)-based model is inspired by the seminal work of Perelson and co-workers, who developed, among others, immune models of HIV progression (Rong and Perelson 2009; Perelson and Ribeiro 2013). By carefully fitting the models to patient data and inspecting the dynamics of CD4+ T-cells, they designed optimal therapeutic dosing strategies to keep the disease at bay. Such approaches have saved lives and continue to be fruitful, for instance, in the current times, by modeling disease progression in COVID-19 (Perelson and Ke 2021). An immune system is often classified into various regulation regimes: recurrent infection, persistent non-infectious inflammation, and healthy oscillations (Kumar et al. 2004). Kumar et al. (2004) have shown this in a study through a bifurcation diagram. In the same line of thought, a study by Garcia et al. (2020) has pointed out the crucial role of bistability in therapeutic success. Nonlinearity and the emergence of bistability have also been widely studied in the context of physiology and pathology. Through the hysteresis effect, the appearance of bistability in biological systems has been characterized experimentally (Malka et al. 2010). In the context of cancer–immune system interplay, one may consider a nonlinear system having mutual inhibitory components (Sahoo et al. 2021), and here, the system can even attain multistability (both bistability and tristability) (Lu et al. 2013). T-cells are reported to exhibit phenotypic heterogeneity and multistability in an adaptive immune system (Duddu et al. 2020).
A specific phenomenon that a model captures is often parameter-dependent. In system-based modeling, bifurcation theory is an efficient method for capturing critical biological interaction-driven phenomena (Kumar et al. 2004; Lu et al. 2013; Duddu et al. 2020). In the T-cell-mediated immune system context, such theoretical concepts help characterize different immunoregulatory states and their modulation under different environmental situations (Roy et al. 2014; Roy and Bagchi 2020; Nayak and Roy 2021). T-cell-mediated immune regulations are often classified into weak, strong, and moderate regulation regimes based on the ratio and relative concentration of pro-inflammatory T-cells and anti-inflammatory T-cells. The characteristics of these categories (Fouchet and Regoes 2008; Roy et al. 2014) are depicted in figure 1 and are described below:Weak regulation: The ratio between pro-inflammatory T-cells and anti-inflammatory T-cells is >1. As the population of pro-inflammatory T-cells is high, the immune system is more autoimmune-prone. The pathogenic load under this regulation is low.
Moderate regulation: The ratio between the pro-inflammatory T-cells and the anti-inflammatory T-cells is balanced or =1. Interestingly, here the immune system may hold the characteristics of bistability. Moreover, this regime is likely to be sensitive to therapies. Our previous work, including several other studies, has highlighted the importance of bistability and therapeutic sensitivity in a moderate regulation regime (Fouchet and Regoes 2008; Roy and Bagchi 2020; Garcia et al. 2020).
Strong regulation: The ratio of pro-inflammatory and anti-inflammatory T-cell concentrations is <1. Pathogen load is higher, which can lead to an immunocompromised condition.
Figure 1 Classification of T-cell regulation based on theoretical models. The immune system can transit from a weak regulation regime to a moderate regulation regime and then to a strong regulation regime and vice versa depending on the concentration and composition of pro-inflammatory T-cells (Tpro) and anti-inflammatory T-cells (Tanti) (refer to Roy et al. 2014; Roy and Bagchi 2020; Nayak and Roy 2021 for more details).
Immunomodulatory role of vitamin D from a theoretical perspective
The dynamic role of vitamin D in the immune system has been elaborated from an experimental perspective in the above sections. On the other hand, mathematical models in understanding the role of immunosuppressants, especially focusing on Vitamin D, are limited. A few modeling efforts have been made to distinguish the role of serum vitamin D as a metabolite, providing critical new insights into vitamin D and human health (Chun et al. 2012). In recent times, Roy et al. (2014) have developed a theoretical coarse-grained kinetic network model based on some relevant experimental observations, as shown in figure 2, which depicts the interaction of vitamin D with the adaptive immune system. The details of the immunological processes are described in an event-wise manner in the supplementary material. The study finds that the opposing role of regulatory T-cells and effector T-cells in the regulation of the immune system is dependent on the concentration of vitamin D in the body, along with several known/unknown factors determining the strength of immune regulation and the ultimate fate of a disease.Figure 2 A schematic representation of the adaptive immune responses at a cellular level. This includes the interaction of naïve T-cells, pathogen, pro-inflammatory T-cells, anti-inflammatory T-cells, and vitamin D. It is a derivative and a coarse-grained form of our previous work (Roy et al. 2014). In this design, the significant events are the following: (a) The primary step after the infection setting is to eliminate the pathogen by pro-inflammatory T-cells. Invasion of pathogens leads to the conversion of naïve T-cells to (b) pro-inflammatory T-cells and (c) anti-inflammatory T-cells. Vitamin D adds to the maturation of anti-inflammatory T-cells. Moreover, the mature pro-inflammatory T-cells and anti-inflammatory T-cells have a role in inducing naïve T-cells to produce more of themselves. However, controlling the over-explosion of pro-inflammatory T-cells is an exaggerated immune response: vitamin D and anti-inflammatory T-cells cause (d) the downregulation of pro-inflammatory T-cells. (e) The presence of pro-inflammatory T-cells facilitates the transformation of inactive vitamin D into its active form.
In an early study, Fouchet and Regoes (2008) also classified the T-cell-mediated immune network into three regulation regions (weak, moderate, and strong), where they investigated the boundaries between any two regions. The model predicted that the role of APC is crucial in the emergence of a restricted bistable region. They did not account for the effects of vitamin D in their model. However, in the presence of vitamin D, expansion of the bistable region signifies the importance of vitamin D in immune regulation and how it prevents over-explosion of effector T-cells, thereby preventing the autoimmune condition (Roy et al. 2014).
Immunomodulatory role of glucocorticoids from a theoretical perspective
Among others, GCs are well-known immunosuppressants that control T-cell-mediated adaptive immune response similar to vitamin D. Although there are several classes of synthetic glucocorticoids, dexamethasone (Dex) is the most widely used steroid due to its higher binding affinity to GC receptors (GRs) compared with natural cortisol. In addition, it has minimal mineralocorticoid activity. Again, the immunomodulatory functions of GCs are also quite similar to vitamin D. The immunomodulatory actions of GC-mediated adaptive immune response are mainly exerted on the CD4+ T cell. Specifically, those are pro-inflammatory and anti-inflammatory by nature. To better understand the immunomodulatory role of GC, a recent mathematical model by Yakimchuk (2020) used a saturation function with six kinetic rate equations. The saturation function presents a one-time external dose (GC) intake mode. Nayak and Roy (2021) have also developed a kinetic network-based model to understand the direct and indirect effects of GCs on the immune system and anti-inflammatory immune response. In the model of Yakimchuk (2020), the saturation function leads the system to saturate towards a constant dose value. As a result, after a certain concentration, the GC coupling effect is lost. Nayak and Roy (2021), on the other hand, used pharmacokinetic constants accounting for the normal metabolism of GC.
A generic coarse-grained kinetic network model for understanding the impact of immunosuppressants on T-cell regulation
From the above sections, we have seen that the immune system is indeed a complex network where its cells continuously interact and clash with foreign invaders/pathogens to maintain homeostasis. There is a continuous predator/prey-like tussle between the pro-inflammatory T-cells and the pathogen, where the pro-inflammatory T-cells are the predators. On the other end, the pathogen, being the prey, tries to escape from its predator, with assistance from anti-inflammatory T-cells. However, functional balance between pro-inflammatory T-cells and anti-inflammatory T-cells is necessary for maintaining a healthy state. An immunosuppressant like vitamin D or GC governs that. With this generic view, here we present a generic coarse-grained kinetic network model. It is noteworthy that since the immune system comprises many players, for designing a mathematical model, a coarse-graining approach helps filter essential nodes of a network so as to understand a particular phenomenon or mechanism. Here, the generic model is constructed based on a careful survey of published experimental and theoretical literature, described in the supplementary material and detailed in other references (Roy et al. 2014; Roy and Bagchi 2020; Nayak and Roy 2021). A more straightforward, albeit refined, correlation among the various elements of the immune system and their interplay with immunosuppressants is proposed and presented in figure 3, which accounts for the complexities present at a molecular level by coarse-graining them at the cellular level.Figure 3 A generic coarse-grained kinetic network model to decipher the impact of immunosuppressants on T-cell dynamics. This model is the skeletal framework of the schematic representations depicted in figure 2. The black arrows indicate conversion, and the blue and red arrows represent the activation and inhibition processes, respectively. The significance of each network parameter is described in table 1. Additional details are described in supplementary table 1.
Table 1 Definition of representative symbols of rate parameters used in figure 3
Definition Symbol
1 Rate of pathogen killing by pro-inflammatory T-cells (Tpro) kp
2 Rate of differentiation of naïve T-cells to Tpro/Tanti cells which is induced by the antigen krp
3 Rate of differentiation of naïve T-cells to Tpro cells which is induced by the pro-inflammatory T-cell itself (autocatalytic) kpro
4 Rate of differentiation of naïve T-cell to the pro-inflammatory T-cell which is induced by the pro-inflammatory T-cell itself (autocatalytic) kanti
5 Rate of inhibition of pro-inflammatory T-cell by anti-inflammatory T-cell kpa
6 Rate of inhibition of pro-inflammatory T-cell by the active immunosuppressant kpI∗
7 Rate of anti-inflammatory T-cell reactivation by an active immunosuppressant kaI∗
Once the developed network appears to be simple and effective, a system of coupled differential equations is used to first model the system without the influence of any immunosuppressants (vitamin D or GC). A detailed method is presented in the supplementary material. The critical elements considered in our coarse-grained model are the following:Pathogen/antigen/self-antigen (P)
Naïve T-cell (precursor T-cell) (TNa)
Pro-inflammatory T-cell (Tpro)
Anti-inflammatory T-cell (Tanti)
Under any pathogen attack, a healthy immune system always aims to disarm the foreign antigen by enhancing its pro-inflammatory T-cell proliferation and differentiation rate. However, an exceeding number of pro-inflammatory T-cells often fail to differentiate between self-cells and foreign peptides. Moreover, pro-inflammatory T-cells may begin damaging self-tissues. Therefore, a healthy immune system has to operate under a balanced regulation. This signifies that the concentration of pro-inflammatory T-cells must increase to overcome the pathogenic stimulation by resisting its explosive growth efficiently. Herein lies the role of vitamin D and GCs. Their optimum level effectively maintains a balanced immune regulation by inhibiting anti-inflammatory T-cells and downregulating pro-inflammatory T-cells.
Dynamic phases of CD4+ T-cell: Emergence of a characteristic lag time or clinical latency
Let us first consider a system free of immunosuppressants in the generic coarse-grained Model-I described in the supplementary material. Here, we have four coupled rate equations. By solving these four coupled differential equations, we find the dynamical behavior of pro-inflammatory T-cells and anti-inflammatory T-cells throughout their time evolution, as depicted in figure 4. A unique dynamical period known as the latent period is identified here. It is the time range within which there is a steady-state-like condition, i.e., the concentration of almost all the cell populations (pro-inflammatory T-cells, anti-inflammatory T-cells, naïve T-cells, and the pathogen) are not changing with time. After that, there is a jump to the real long-term steady-state condition. In this period, the pathogenic load is significantly low, insufficient to cause ailment. It is considered an asymptomatic phase, or clinical latency in clinical terminology. The pro-inflammatory and anti-inflammatory T-cells maintain highly balanced concentrations in this latent period. The pathogen population is too small to cause symptoms. This phase where the pathogen remains latent is called the latent period. Finally, after a long time, the system reaches the final long-term steady-state, i.e. a lower number of pro-inflammatory T-cells depicting a scenario in which symptoms resurface in the patient. In the long term, the system reaches a steady state with a higher number of anti-inflammatory T-cells and a lower number of pro-inflammatory T-cells in the post-latent period, depicting the antagonistic nature of pro-inflammatory T-cells and anti-inflammatory T-cells. Such steady-state behavior in T-cell dynamics over a longer time period is shown in figure 4. Our previous study (Nayak and Roy 2021) and many other studies (Mindikoglu et al. 2006; Gonzalez and Perrillo 2016) have pointed out that there is a probability of pathogenic reactivation as one of the side effects of long-term immunosuppressant therapy.Figure 4 Time evolution of immune response of CD4+ T-cells in the absence of any immunosuppressive drug. (a) The log-scale plot represents a regime of the immune phase regulation that contains a latent period (the time range within which there is no change in the concentration of Tpro cells and Tanti cells). During the post latent period, there is a jump to the steady-state condition. (b) Distinctive dynamical phases of immune response mediated by antigen-specific pro-inflammatory T-cells are depicted, where three phases of the immune response (expansion, contraction, and memory) are indicated. Here, the time evolution of pro-inflammatory T-cells and anti-inflammatory T-cells are plotted by solving coupled kinetic equations shown in Model I. We reproduce the T-cell dynamics considering kpro=30, and the other rate values are the same as given in Nayak and Roy (2021). In the plot, red and blue lines represent Tpro and Tanti, respectively. Note: 1.66×10−5 nmol/L corresponds to 1000 T-cells.
The initial phase of pro-inflammatory T-cell time evolution has three sub-phases: expansion, contraction, and memory (figure 4b). After the onset of infection, pro-inflammatory T-cells increase clonally in number. Figure 4b shows some fundamental phenomena during that time. Day 0 to Day 1, i.e., within 24 h, is the time during which infection is set by the pathogen. This peak of T-cell expansion on Day 1 post-infection is a limitation of this model. Adaptive response sets in after a few hours of pathogen incursion (Kaech et al. 2002). The pathogen annihilation process starts after recognizing the pathogen, followed by T-cell activation. Soon after the pathogen load decreases, the contraction phase begins. The population of pro-inflammatory T-cells reduces due to apoptosis. After the contraction phase, the number of pro-inflammatory T-cells reaches its pre-steady state value and is maintained for a significant period, representing the memory phase. Several other studies have also observed similar immune phases (Wang et al. 2015; Bertrand 2019).
Generic effects of immunosuppressants on CD4+ T-cell population: Immune state transition from weak to moderate to strong regulation
The general immunomodulatory effects of immunosuppressants on T-cell population dynamics can be described by a generic model framework (Model II discussed in the supplementary information). When the system encounters a pathogen of weak to moderate strength, it immediately switches on the activation process of effector pro-inflammatory T-cells. Subsequently, the upregulation of anti-inflammatory T-cells and pro-inflammatory counterparts plays a crucial role in setting up a competitive dual switch that can trigger either a strong or weakly regulated state (Roy and Bagchi 2020). This competing behavior of anti-inflammatory T-cells and pro-inflammatory T-cells may never end in the presence of a pathogen because our immune system is constantly exposed to some pathogenic load. Thus, it may stay moderately activated by pathogenic stimulation, which we call a moderately regulated state (Roy and Bagchi 2020). As we found earlier, the effects of immunosuppressants become essential when the system falls into a condition where the number of pro-inflammatory T-cells is more than the anti-inflammatory T-cells, transitioning the system into a weakly regulated immune state that is more prone to cause autoimmune disorders. Such a risky state can be shifted to a moderately regulated immune state depending on an optimal dose of immunosuppressant. However, if the dose of immunosuppressant exceeds that optimal level, the system may further shift to another disease-prone immune state classified as a strongly regulated state. Our generic coarse-grained Model II involves those essential and general effects of immunosuppressants that capture the shift of different immune regulation states from strong to moderate to weak regulations, as shown in figure 5d–f.Figure 5 Time evolution of the T-cell population in all three classified regulations regimes, both in the absence and presence of an immunosuppressant, GC. Time evolution of pro-inflammatory T-cells and anti-inflammatory T-cells are plotted by solving coupled kinetic equations using a deterministic approach. These three regulations are obtained by varying a single rate parameter, kpro, an autocatalytic activity of pro-inflammatory T-cells. kpro values are very sensitive towards determining the strong, moderate, and weak regulation of pro-inflammatory T-cells. In the absence of any immunosuppressant (a) a weak regulation state appears around kpro = 50, (b) a moderate regulation appears around kpro = 30, and (c) a strong regulation appears around kpro = 10. In the presence of GC (d) a weak regulation state appears around kpro = 70, (e) a moderate regulation appears around kpro = 56, and (f) a strong regulation appears again around kpro = 10. Apart from kpro , other parameter values are taken from Nayak and Roy (2021). The dose of Dex (synthetic glucocorticoid dexamethasone) is taken to be optimal, which is 38.21 nmol/L. This calculation and figure are reproduced from Nayak and Roy (2021) (Reprinted (calculations/figure) with permission from Sonali Priyadarshini Nayak and Susmita Roy, Phys. Rev. E 103, 062401 – Published 3 June 2021 (https://doi.org/10.1103/PhysRevE.103.062401). Copyright 2022 by the American Physical Society). In the plot, the red and blue lines represent Tpro and Tanti respectively. Note: 1.66 × 10−5 nmol/L corresponds to 1000 T-cells.
In an early study, Fouchet and Regoes (2008) analyzed the steady-state values of T-cells in these three regulation regimes. As shown in our earlier work (Roy and Bagchi 2020), in the absence of vitamin D, a bistable region is found in this generic model, where both strong and weak regulation can coexist. However, we find that in the presence of even a minute vitamin D level, a weakly regulated state can be converted to a strongly regulated state intervened by a moderate regulation regime as the dose intake increases. At a very high dose limit, even when a simulation starts with an initial state of weak regulation, feedback makes this weak regulation stronger. The system mounts the required effective regulation depending on the vitamin D dose variation, as shown in figure 6. The dose-dependent dynamics of the system are captured from a theoretical model in figure 6a–c. From a modeling perspective, vitamin D dose dependence of T-cell population dynamics has been shown by Roy et al. (2014) In this work, in the bistable region, both the variation of T-cell and pathogen levels remain intimately connected and help to determine an optimal vitamin D range (Roy and Bagchi 2020). A similar T-cell variation pattern was obtained experimentally by Jeffery et al. (2012), as shown in figure 6d–e. In both cases, with an increase in vitamin D dose level, there is a concomitant increase in anti-inflammatory T-cell concentration and a decrease in pro-inflammatory T-cell concentration. Moreover, similar to the effect of GC, the system reverts to a weakly regulated state at a low vitamin D dose level as the pro-inflammatory T-cells again increase in population size. At the other extreme, when the vitamin D dose is very high, the system reaches a strongly regulated state as the anti-inflammatory T-cells are abundant and suppress the pro-inflammatory T-cell concentration.Figure 6 Time evolution of the T-cell population in the presence of a secosteroid vitamin D from a theoretical model, followed by experimental validation (Roy et al. 2014). Time evolution of pro-inflammatory T-cells and anti-inflammatory T-cells are plotted by solving coupled kinetic equations from Model II at varying vitamin D concentrations. Strong regulation, moderate regulation, and weak regulation are very sensitive to vitamin D concentration. (a) A weak regulation state appears close to vitamin D dose of 10 nM/L. (b) Moderate regulation state starts to appear around vitamin D dose of 50 nM/L. (c) Strong regulation state appears around vitamin D dose of 900 nM/L, which is an extremely high dose. Other parameter values are taken from Roy et al. (2014), apart from variable active vitamin D concentration ([I*]) (Roy et al. 2014) to solve Model II. Note: 1.66 × 10−5 nmol/L corresponds to 1000 T-cells. (d–e) Experimental validation of our model adapted from Jeffery et al. (2012). (d) An increase in Tanti concentration and (e) decrease in Tpro concentration with an increase in the concentration of active vitamin D. For review purposes, the data for (d–e) are obtained from Jeffery et al. (2012). The details regarding the experimental study can be found in Jeffery et al. (2012). In the plot, the red and blue lines represent Tpro and Tanti respectively.
Summarizing the immunomodulatory role of immunosuppressants and future aspects to comprehend their responses
Beyond their classical role, glucocorticoids (GCs) and vitamin D impact the immune system as immunomodulators. However, as the immune system is a highly complex network, we have generalized a theoretical coarse-grained kinetic model based on a T-cell-mediated interaction network to obtain an insight into the immune regulation exerted by such immunosuppressants. We solved this complex network problem using a chemical dynamics approach. The interaction network dynamically connects different immune components involved in the relevant immune responses. The expressed kinetic design illustrates the time evolution of all critical components, including pro-inflammatory T-cells and anti-inflammatory T-cells. The steady-state analyses of the proposed kinetic equations infer tangled relations between the GC or vitamin D dose and anti-inflammatory T-cells maintained by homeostasis, wherein such immunosuppressants have a significant regulatory role. The absence or presence of a lower concentration of GC (lower than optimum) corresponds to a weak regulatory regime. At the optimal concentration of such immunosuppressants, the system may enable the characteristics of bistability. In this phase, one may observe a unique dynamical phase similar to the clinical latent period (Nayak and Roy 2021). At a concentration higher than optimal, the system moves towards a strong regulation with a decrease in latent time, accounting for the importance of monitoring the appropriate dose of immunosuppressant administered for autoimmune disease or cancer treatment. Hence, it is essential to closely monitor an appropriate dose of an immunosuppressant administrated during the treatment. This helps prevent potential side effects such as compromised immunity or easy pathogen target. At low GC concentration, if any pathogen enters the body, the immune response’s nature would be more inflammatory, which can finally lead to an autoimmune condition.
GCs are observed to have a significant role in keeping the immune system in a moderate/bistability regime for a very long time. As shown in figure 4, the immune system has a latent period of very high value at specific concentrations of GCs, which we consider an optimal range. In that phase, the pathogen population is low, and the pro-inflammatory T-cell concentration is also under control. These findings show that at a meager value or in the absence of GC, the latent period is significantly shorter; there is a risk of autoimmune disease due to the uncontrolled growth of pro-inflammatory T-cells. While these phenomena and the optimal range of GC (Dex) are in accordance with the experimental finding (Becker 2013), the dependence of the clinical latency on vitamin D is yet to be explored.
For an immunosuppressant, one may identify one/many sensitive parameters. For instance, take the example of kpro. kpro is the rate at which pro-inflammatory T-cells can induce naive T-cells to produce more of themselves, which is primarily a self-regulatory mechanism. kpro represents how pro-inflammatory T-cells produce more of themselves. The kpro value is not fixed. It may vary from person to person. Moreover, it has been known that the cytokine level does not have a particular value, and it varies over a physiological range (Kim et al. 2011; Roy and Bagchi 2020; Nayak and Roy 2021). The range of kpro is dependent on the cytokine level. Thus, to incorporate such effects one may also account for the variability of rate parameters by including a relevant distribution function of rate parameters.
Another essential concern is to address specific responses hosted by various interactions with key immunological components in different physiological conditions. In practice, we investigate the regulation mentioned above and their cross-over by time evolution analysis of each participating element after the pathogen attack to study their long-time steady-state behavior. One may ask, how do we find this co-existence line between any two immune regulation regimes? Clinical and experimental studies also use some standard values of pro- and anti-inflammatory T-cells; more often, the ratio of these T-cells cells serves as the predictor of the patients’ immune profile. However, other related studies or experimental results frequently challenge such standardized ratios or numbers. Often, we ignore the fact that these standard numbers can be personalized and may vary among patients carrying the same disease. Under such circumstances, experimental and theoretical investigations should find suitable parameters to quantify person-specific immune responses. An early study (Roy and Bagchi 2020) accounted for the fluctuations in the number/concentration of active participants along stochastic trajectories. A relevant fluctuating quantity serves as a crucial order parameter capturing a divergent-like behavior that might evoke a characteristic of criticality near the cross-over line of immune phases (Roy and Bagchi 2020). The study also addresses the adverse long-term effects of any analogue of vitamin D or other immunosuppressants with their overdose limit in treating autoimmune diseases. The mean-square fluctuation-mediated response parameter is so sensitive that it can efficiently capture the signature of an immune breakdown in the presence of the overdose limit of immunosuppressant by a significant drop in essential fluctuation of pro-inflammatory T-cells. It also demonstrated that the presence of an optimal level of vitamin D rather than its lower concentration limit assists in broadening the tolerance limit. A bistable condition emerges with strong anticorrelated fluctuations between pro- and anti-inflammatory T-cell subsets. The broad fluctuation profile and a significant reduction in the relative fluctuation of effector T-cells in the presence of an immune-modulator like vitamin D suggest that the fluctuation of the active T-cell subset can be more responsive as often found in clinical studies. Hence, these fluctuations can be used as a tool for future diagnostics and therapeutics. We strongly believe that more findings will help shed light and also help explain several clinical results associated with the dose effectiveness of various immunosuppressants used as a critical remedy under emergency conditions.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 671 KB)
Acknowledgements
BB thanks the Science and Engineering Research Board (SERB), India, for the National Science Chair Professorship and the Department of Science and Technology. SR acknowledges support from the Department of Biotechnology (DBT) (Grant No. BT/12/IYBA/2019/12) and Science and Engineering Research Board (SERB), Department of Science and Technology (DST), India (Grant No. SRG/2020/001295).
This article is part of the Topical Collection: Emergent dynamics of biological networks.
Corresponding editor: Mohit Kumar Jolly
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References
Becker DE Basic and clinical pharmacology of glucocorticosteroids Anesth. Prog. 2013 60 25 32 10.2344/0003-3006-60.1.25 23506281
Bereshchenko O Bruscoli S Riccardi C Glucocorticoids, sex hormones, and immunity Front. Immunol. 2018 9 1332 10.3389/fimmu.2018.01332 29946321
Bertrand RL Lag phase is a dynamic, organized, adaptive, and evolvable period that prepares bacteria for cell division J. Bacteriol. 2019 201 e00697 e718 10.1128/JB.00697-18 30642990
Bordon Y The many sides of Paul Ehrlich Nat. Immunol. 2016 17 S6 S6 10.1038/ni.3601
Bouillon R Manousaki D Rosen C The health effects of vitamin D supplementation: evidence from human studies Nat. Rev. Endocrinol. 2021 18 96 110 10.1038/s41574-021-00593-z 34815552
Brodin P Davis MM Human immune system variation Nat. Rev. Immunol. 2017 17 21 29 10.1038/nri.2016.125 27916977
Cain DW Cidlowski JA Immune regulation by glucocorticoids Nat Rev. Immunol. 2017 17 233 247 10.1038/nri.2017.1 28192415
Cao X Cai SF Fehniger TA Song J Granzyme B and perforin are important for regulatory T-cell-mediated suppression of tumor clearance Immunity 2007 27 635 646 10.1016/j.immuni.2007.08.014 17919943
Cebula A, Kuczma M, Szurek E, et al. 2019 Dormant pathogenic CD4+ T cells are prevalent in the peripheral repertoire of healthy mice. Nat. Commun. 10 4882
Chaplin DD Overview of the immune response J. Allergy Clin. Immunol. 2010 125 S3 S23 10.1016/j.jaci.2009.12.980 20176265
Charoenngam N Holick MF Immunologic Effects of Vitamin D on human health and disease Nutrients 2020 12 2097 10.3390/nu12072097 32679784
Chemin K Gerstner C Malmström V Effector functions of CD4+ T-cells at the site of local autoimmune inflammation—Lessons from rheumatoid arthritis Front. Immunol. 2019 10 353 10.3389/fimmu.2019.00353 30915067
Chun RF Peercy BE Adams JS Hewison M Vitamin D binding protein and monocyte response to 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D: Analysis by mathematical modeling PLoS One 2012 7 e30773 10.1371/journal.pone.0030773 22292037
Chun RF Liu PT Modlin RL Adams JS Hewison M Impact of vitamin D on immune function: lessons learned from genome-wide analysis Front. Physiol. 2014 5 151 10.3389/fphys.2014.00151 24795646
Correale J Ysrraelit MC Gaitán MI Immunomodulatory effects of Vitamin D in multiple sclerosis Brain 2009 132 1146 1160 10.1093/brain/awp033 19321461
Coutinho AE Chapman KE The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights Mol. Cell. Endocrinol. 2011 335 2 13 10.1016/j.mce.2010.04.005 20398732
Cowley SC Hamilton E Frelinger JA CD4-CD8-T-cells control intracellular bacterial infections both in vitro and in vivo J. Exp. Med. 2005 202 309 319 10.1084/jem.20050569 16027239
Cutolo M Pizzorni C Sulli A Vitamin D endocrine system involvement in autoimmune rheumatic diseases Autoimmun. Rev. 2011 11 84 87 10.1016/j.autrev.2011.08.003 21864722
Cyster JG Allen CDC B-cell responses: Cell interaction dynamics and decisions Cell 2019 177 524 540 10.1016/j.cell.2019.03.016 31002794
Deenick EK Ma CS Brink R Tangye SG Regulation of T follicular helper cell formation and function by antigen presenting cells Curr. Opin. Immunol. 2011 23 111 118 10.1016/j.coi.2010.10.007 21115333
Duddu AS Sahoo S Hati S Jhunjhunwala S Jolly MK Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators J. R. Soc. Interface 2020 17 20200631 10.1098/rsif.2020.0631 32993428
Elenkov IJ Glucocorticoids and the Th1/Th2 balance Ann. N. Acad. Sci. 2004 1024 138 1346 10.1196/annals.1321.010
Fagnoni FF T-cell dynamics after high-dose chemotherapy in adults: elucidation of the elusive CD8+ subset reveals multiple homeostatic T-cell compartments with distinct implications for immune competence Immunology 2002 106 27 37 10.1046/j.1365-2567.2002.01400.x 11972629
Fouchet D Regoes R A population dynamics analysis of the interaction between adaptive regulatory T-cells and antigen presenting cells PloS One 2008 3 e2306 10.1371/journal.pone.0002306 18509463
Garcia V Bonhoeffer S Fu F Cancer-induced immunosuppression can enable effectiveness of immunotherapy through bistability generation: A mathematical and computational examination J. Theor. Biol. 2020 492 110185 10.1016/j.jtbi.2020.110185 32035826
Golubovskaya V Wu L Different subsets of T-cells, memory, effector functions, and CAR-T immunotherapy Cancers 2016 8 36 10.3390/cancers8030036 26999211
Gonzalez SA Perrillo RP Hepatitis B virus reactivation in the setting of cancer chemotherapy and other immunosuppressive drug therapy Clin. Infect. Dis. 2016 62 S306 S313 10.1093/cid/ciw043 27190320
Grossman WJ Verbsky JW Barchet W Human T regulatory cells can use the perforin pathway to cause autologous targeT-cell death Immunity 2004 21 589 601 10.1016/j.immuni.2004.09.002 15485635
Hirahara K Nakayama T CD4+ T-cell subsets in inflammatory diseases: beyond the T h 1/T h 2 paradigm Int. Immunol. 2016 28 163 171 10.1093/intimm/dxw006 26874355
Hoffmann JA Kafatos FC Janeway CA Ezekowitz RA Phylogenetic perspectives in innate immunity Science 1999 284 1313 1318 10.1126/science.284.5418.1313 10334979
Janeway CA Jr and Medzhitov R 2002 Innate immune recognition. Annu. Rev. Immunol. 20 197–216
Jeffery LE Wood AM Qureshi OS Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T-cell responses J. Immunol. 2012 189 5155 10.4049/jimmunol.1200786 23087405
Jones DE Diamond AG The basis of autoimmunity: an overview J. Clin. Endocrinol. Metab. 1995 9 1 24
Kaech SM Wherry EJ Ahmed R Effector and memory T-cell differentiation: implications for vaccine development Nat. Rev. Immunol. 2002 2 251 262 10.1038/nri778 12001996
Kaufmann SHE Immunology’s coming of age Front. Immunol. 2019 10 684 10.3389/fimmu.2019.00684 31001278
Kim HO Kim H-S Youn J-C Shin E-C Park S Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays J. Transl. Med. 2011 9 113 10.1186/1479-5876-9-113 21774806
Kongsbak M Levring T Geisler C von Essen M The vitamin D receptor and T-cell function Front. Immunol. 2013 4 148 10.3389/fimmu.2013.00148 23785369
Kumar R Clermont G Vodovotz Y Chow CC The dynamics of acute inflammation J. Theor. Biol. 2004 230 145 155 10.1016/j.jtbi.2004.04.044 15321710
Lei T-Y Ye Y-Z Zhu X-Q The immune response of T-cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke J. Neuroinflam. 2021 18 25 10.1186/s12974-020-02057-z
Liu W Tolar P Song W Kim TJ Editorial: BCR Signaling and B-cell activation Front. Immunol. 2020 11 45 10.3389/fimmu.2020.00045 32063903
Lu M Jolly MK Levine H Onuchic JN Ben-Jacob E MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination Proc. Natl. Acad. Sci. USA 2013 110 18144 18149 10.1073/pnas.1318192110 24154725
Malka R Shochat E Rom-Kedar V Bistability and bacterial infections PLoS One 2010 5 e10010 10.1371/journal.pone.0010010 20463954
Marcinowska-Suchowierska E Kupisz-Urbańska M Łukaszkiewicz J Płudowski P Jones G Vitamin D toxicity–A clinical perspective Front. Endocrinol. 2018 9 550 10.3389/fendo.2018.00550
Margo CE Harman LE Autoimmune disease: Conceptual history and contributions of ocular immunology Surv. Ophthalmol. 2016 61 680 688 10.1016/j.survophthal.2016.04.006 27131478
Mayassi T Barreiro LB Rossjohn J Jabri B A multilayered immune system through the lens of unconventional T-cells Nature 2021 595 501 510 10.1038/s41586-021-03578-0 34290426
Mindikoglu AL Regev A Schiff ER Hepatitis B virus reactivation after cytotoxic chemotherapy: The disease and its prevention Clin. Gastroenterol. Hepatol. 2006 4 1076 1081 10.1016/j.cgh.2006.05.027 16861051
Mora JR Iwata M von Andrian UH Vitamin effects on the immune system: vitamins A and D take centre stage Nat. Rev. Immunol. 2008 8 685 698 10.1038/nri2378 19172691
Murdoch JR Lloyd CM Resolution of allergic airway inflammation and airway hyperreactivity is mediated by IL-17-producing γδ T-cells Am. J. Respir. Crit. Care Med. 2010 182 464 476 10.1164/rccm.200911-1775OC 20413629
Nayak SP Roy S Immune phase transition under steroid treatment Phys. Rev. E 2021 103 62401 10.1103/PhysRevE.103.062401
Nurieva RI Chung Y Understanding the development and function of T follicular helper cells Cell. Mol. Immunol. 2010 7 190 197 10.1038/cmi.2010.24 20383172
Orihara K, Nakae S, Pawankar R and Saito H 2008 Role of regulatory and pro-inflammatory T-cell Populations in allergic diseases World Allergy Organ. J. 1 9–14
Perelson AS Immune network theory Immunol. Rev. 1989 110 5 36 10.1111/j.1600-065X.1989.tb00025.x 2477327
Perelson AS Ke R Mechanistic modeling of SARS-CoV-2 and other infectious diseases and the effects of therapeutics Clin. Pharmacol. Ther. 2021 109 829 840 10.1002/cpt.2160 33410134
Perelson AS Ribeiro RM Modeling the within-host dynamics of HIV infection BMC Biol. 2013 11 96 10.1186/1741-7007-11-96 24020860
Rong L Perelson AS Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy PLoS Comput. Biol. 2009 5 e1000533 10.1371/journal.pcbi.1000533 19834532
Roy S Bagchi B Fluctuation theory of immune response: A statistical mechanical approach to understand pathogen induced T-cell population dynamics J. Chem. Phys. 2020 153 45107 10.1063/5.0009747
Roy S Shrinivas K Bagchi B A stochastic chemical dynamic approach to correlate autoimmunity and optimal Vitamin D range PLoS One 2014 9 e100635 10.1371/journal.pone.0100635 24971516
Sahoo S Nayak SP Hari K Immunosuppressive traits of the hybrid epithelial/mesenchymal phenotype Front. Immunol 2021 12 5347 10.3389/fimmu.2021.797261
Sakaguchi S Sakaguchi N Regulatory T-cells in immunologic self-tolerance and autoimmune disease Int. Rev. Immunol. 2005 24 211 226 10.1080/08830180590934976 16036375
Schmidt A Oberle N Krammer P Molecular mechanisms of Treg-mediated T-cell suppression Front Immunol. 2012 3 51
Scurr M Highly prevalent colorectal cancer-infiltrating LAP+ Foxp3− T-cells exhibit more potent immunosuppressive activity than Foxp3+ regulatory T-cells Mucosal Immunol. 2014 7 428 439 10.1038/mi.2013.62 24064667
Smith DA Germolec DR Introduction to immunology and autoimmunity Environ. Health Perspect. 1999 107 661 665 10502528
Srivastava RK Dar HY Mishra PK Immunoporosis: Immunology of osteoporosis—role of T-cells Front. Immunol 2018 9 657 10.3389/fimmu.2018.00657 29675022
Timmermans S Souffriau J Libert C A general introduction to glucocorticoid biology Front. Immunol 2019 10 1545 10.3389/fimmu.2019.01545 31333672
Wang L Fan D Chen W Terentjev EM Bacterial growth, detachment and cell size control on polyethylene terephthalate surfaces Sci. Rep. 2015 5 15159 10.1038/srep15159 26464114
Weinstein RS Hogan EA Borrelli MJ The pathophysiological sequence of glucocorticoid-induced osteonecrosis of the femoral head in male Mice Endocrinol. 2017 158 3817 3831 10.1210/en.2017-00662
Yakimchuk K Mathematical modeling of immune modulation by glucocorticoids Bio Syst. 2020 187 104066
Zhang TY Ding X Daynes RA The Expression of 11β-Hydroxysteroid Dehydrogenase Type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities J. Immunol. 2005 174 879 10.4049/jimmunol.174.2.879 15634910
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==== Front
Soft comput
Soft comput
Soft Computing
1432-7643
1433-7479
Springer Berlin Heidelberg Berlin/Heidelberg
7716
10.1007/s00500-022-07716-2
Application of Soft Computing
A prediction model of stock market trading actions using generative adversarial network and piecewise linear representation approaches
http://orcid.org/0000-0003-3494-5507
Wu Jheng-Long [email protected]
Tang Xian-Rong
Hsu Chin-Hsiung
grid.445078.a 0000 0001 2290 4690 Department of Data Science, Soochow University, Taipei, Taiwan
9 12 2022
114
27 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Supervised learning applied stock prediction tasks and obtained satisfactory performance. The trading strategies are very complex and diverse but supervised learning is only learned and fitted by gold standard trading strategies. Supervised learning approaches often have over-fitting problems. To learn distribution of gold standard answers, the generative adversarial network (GAN) models can generate extra similar samples to improve performance. Therefore, the paper proposes a generative GAN-based frameworks with the piecewise linear representation (PLR) approach to learn three trading actions, namely buying, selling, and holding. The proposed framework consists of two parts: first, PLR approach uses to detect historical prices to form trading sequences with three actions, PLR can provide a guided trading strategy to discriminator of GAN. Second, the generator of GAN is used to generate/predict daily trading actions, and the discriminator is used to detect the real/fake trading actions from the PLR/generator of GAN. Experimental results indicate that the proposed GAN-based frameworks outperform the long short-term memory network.
Keywords
Generative adversarial network
Trading action
Piecewise linear regression
Long short-term memory
Stock forecasting
http://dx.doi.org/10.13039/501100004663 Ministry of Science and Technology, Taiwan MOST 110-2221-E-031-004 MOST-107-2218-E-031-002-MY2 MOST-109-2221-E-031-003 Wu Jheng-Long National Science and Technology Council, TaiwanMOST 111-2221-E-031-004-MY3 Wu Jheng-Long
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pmcIntroduction
Quantitative trading is supported by mathematical statistics, and it can be used to quickly process large amounts of financial information. Machine learning (ML) of supervised learning approach has been developed to solve financial prediction problems using a set of historical stock prices as features to predict future stock prices (Lee et al. 2020). Recent deep learning (DL) models have outperformed the traditional statistical and ML approaches on many stock market prediction tasks. Most ML approaches based on the optimization algorithms to obtain the best model parameters or rules, different optimization algorithms will lead to the model performances (Liu et al. 2021; Ozcalici and Bumin, 2022). However, the ML and DL algorithms have been used to learn and predict the stock prices or trading actions, but the overfitting problem still happens in the training stage and cannot adapt in the future. Advanced models based on generative adversarial networks (GANs), in which a generator and a discriminator are used to compete in a game, are different from traditional supervised learning models. The GAN model is subjected to a two-stage learning process involving real data and fake data (Gulrajani et al. 2017; Abraham, 2021). The generator in GAN model is required to generate an output that is close to the real data, and the discriminator must be able to discriminate whether the input is real or from the generator. In many studies, GANs models can generate more training samples for model training and enhance model performance in terms of price prediction (Xu et al. 2022; Kumar et al. 2022). According to the aforementioned studies, GAN models outperform supervised learning approaches. Therefore, GAN models can be built a powerful forecasting model for use in the financial field. GAN models adapted for stock trade forecasting can converge from multiple directions; this is different from the traditional supervised learning approach. But the GAN needs a lot of real data of high quality because the distribution of real data is a learning target of the discriminator to recognize. Therefore, the high-quality trading action sequence as real data in historical stock prices should be obtained for the GAN model. In addition, a piecewise linear representation (PLR) approach can be used to identify a series of bottom and peak points from time series data (Wu and Chang 2012). PLR can identify many of the turning points required to guide trading actions such as buying and selling.
GAN model can used to generate the similar examples such as trading actions, and the similar trading actions may avoid the overfitting problem because the GAN is learning by adversarial mechanism, instead of the directly fit the target of the trading actions. To obtain the high quality of trading actions in training stage, the PLR can provide the seed trading actions for GAN model because of optimization searching from historical stock prices. Therefore, the final predicted trading actions by the GAN based on PLR approaches will give the more diverse trading action sequence. The paper proposes a GAN-based framework that can learn and generate trading actions based on historical trading information and technical indices. The objectives of this paper include (1) the PLR approach uses to generate suitable trading points as a referenced trading strategy. (2) (GAN)-based framework proposes to train model which using generator to generate predicted stock trading action sequence, and discriminator to detect whether is the real sequence from PLR or fake sequence from GAN’s generator. (3) GAN-based framework can improve the prediction performance compared with other DL models. In addition, we apply other GAN-based frameworks, namely the least squares GAN (LSGAN) (Mao et al. 2017) and the Wasserstein GAN (WGAN) with gradient penalty (Gulrajani et al. 2017) to achieve superior convergence effects to the DL model. We aim to use the capabilities of the proposed GAN to generate stock trading action sequences that can yield high returns on investment (ROI).
The rest of the paper is organized as follows. Literature review is in Sect. 2. The methodology is introduced in Sect. 3, followed by the introduction of the data and result in Sect. 4. Finally, we discuss the theoretical and practical implications of this work in Sect. 6.
Related work
In this section, we review the literature on the development and application trends in stock prediction, machine learning, deep learning, and generative adversarial networks.
Technical analysis and indicator
According to the efficient market hypothesis, only in an inefficient market is it possible to use technical analysis and historical prices to predict future prices and achieve returns. In Taiwan, even if the stock market is extremely liquid and dominated by high-tech industries, it is an inefficient market when tested using Wald’s weak efficiency market detection model, cross-sectional standard deviation, and cross-sectional absolute deviation. Therefore, in the case of the Taiwan Stock Exchange, by using historical prices to generate stock trade predictions, rewards higher than those obtainable from the broader market may be obtained (Nguyen et al. 2012). Technical analysis involves using historical trading information such as historical prices and trading volume as the basis for trading strategies, and many studies have focused on the development or use of technical analysis tools or indicators to obtain the profits from stock market. Therefore, the technical indicators as features for model training are no longer limited to stock price and volume. For example, candlesticks are calculated based on the opening, highest, lowest, and closing prices, and they facilitate easy observation of price changes in each time interval. Moving average observes the price trend during a certain period, which is the average of the price of a stock at several points in the past. Many technical indicators are used for solving stock prediction problems, such as candlestick charts (Thammakesorn and Sornil, 2019), different types of MA (Detzel et al. 2021; Dai et al. 2021), Bollinger bands, and RSI (Pramudya and Ichsani, 2020; Pramudya, 2020). In sum, technical indicators facilitate the observation of current market trends, and they have certain effects on stock prediction tasks.
Applications of deep learning in finance
The DL framework is based on the neural network model, which is a nonlinear model with uses multiple neurons. Vijh et al. (2020) proposed that the multi-layer neural networks have been used to obtain predictions of stock closed price. In terms of price prediction, the backpropagation algorithm to optimize model that can have better validity and superiority in price prediction issues. Recurrent neural networks (RNNs) are designed to process sequential or time series data, and have been used to predict stock prices on the stock market (Saud and Shakya 2020). Long short-term memory (LSTM) networks are advanced RNN models that are composed of input, output, and forget gates to determine whether to retain past features or refresh the feature list. In general, LSTM outperform RNN models (Lee et al. 2020). Another convolutional neural network (CNN) model, which was first developed for image classification, can also be applied to the financial field. A convolutional LSTM model has combined CNN and LSTM to predict prices on multiple cryptocurrencies (Alonso-Monsalve et al. 2020). In summary, DL can capture useful features by itself, and has a flexible structure that can be used to predict stock prices or generate trading rules.
Generative adversarial networks
GANs are based on deep learning, and they can be applied to unsupervised learning problems such as data, images, audio, and text generation. The original GAN model was proposed and composed of two neural network models, namely a generator and discriminator (Goodfellow et al. 2014). GAN was first used for image generation with CNN as the basic structure of the model. Now GAN has been applied to various fields, including problems related to time series. A VAE-GAN model which using LSTM to encoder, generator and discriminator to detect abnormal conditions of IOT (Niu et al. 2020). A random sampling from the latent space as the input of the generator to train the discriminator and generator, and calculates the difference between the result generated by the generator and the actual data (Bashar and Nayak, 2020). However, the original GAN model is limited by the gradient disappearance problem, which makes it difficult for the model to converge. A WGAN model (Arjovsky et al. 2017) has proposed that used Jensen–Shannon divergence to measure the deviation between the distributions of generated data and actual data. The WGAN model proposed to implement model training with weight clipping. If the model weight exceeds the value range, network weights will readjust boundary. Moreover, the weight clipping method with the gradient penalty method to enforce the Lipschitz constraint for GAN model (WGAN-GP) which converged more easily and yielded better image generation results than the weight clipping method (Gulrajani et al. 2017). In the least squares GAN (LSGAN) model proposed that the loss function was changed from cross entropy to mean square error (MSE) (Mao et al. 2017). When applied to picture generation, this model converged faster and in a more stable manner than did the WGAN.
Applications of GANs in finance
GOH and Lai (2019) used a GAN to establish an association network between the US dollar and 15 other currencies. The network used to generate data which closer to actual currency, and can observe annual changes in the correlations of various currencies. Moreover, Marti (2020) used GAN model to Sampling realistic financial correlation matrices from 1-year data of randomly selected stocks from the SandP500 as a sample and attempted to generate a new covariance matrix with the same distribution. Zhou et al. (2018) proposed a GAN to generate historical information for every minute. Wiese et al. (2020) combined a temporal convolutional network with a GAN to develop the Quant GAN model for generating new samples of SandP500 index prices. Their results displayed that the Quant GAN model was superior to other methods. In addition, GANs also have been used to generate financial data for training other models. For example, Abraham (2021) uses GAN to increase samples of stocks to improve the accuracy of the classification model for predicting the future price of stocks. Yoon et al. (2019) developed the time-series generative adversarial networks model, in which the generator and the discriminator were composed of LSTM model, to generate extra samples that approximated real data. Moreover, the stock-GAN model proposed by Li et al. (2020), which combining WGAN-GP and conditional GAN models, and was used to generate order-by-order data in the stock market to simulate the actual stock order-by-order scenario. Compared with the variational autoencoder and deep convolutional generative adversarial network models, the difference between the stock-GAN-generated data and the original data was smaller, meaning that the order data generated by the stock-GAN was closer to the real data. Most financial applications for generating confrontation networks use existing price and volume information to generate more price and volume information and use the generated price and volume information to train predictive models. The generated price and volume information can be input into deep learning models, which require large volumes of data for training. In addition, the WGAN-GP model has been used to simulate the generation of future stock price series. To avoid model overfitting, Lezmi et al. (2020) used the WGAN-GP model to generate daily changes in financial indicators, such as SandP500 and VIX. The WGAN-GP model can generate sample data that exhibit the statistical characteristics of real data.
Methodology
In this study, we develop a GAN-based framework which combining PLR approach, LSTM, and three GAN models to generate trading actions with high performance. The overall process is illustrated in Fig. 1, and it can be divided into three stages as follows:Stage I: Data preprocessing:Step 1: Create input features for model training including daily opening price, closing price, highest price, lowest price, trading volume, and technical indices.
Step 2: Employ the PLR approach to generate real output targets such as trading actions by identifying trading points (trading timing) based on the adjusted closing price. Subsequently, transform all trading points to trading actions, such as buying, selling or holding.
Step 3: Merge the features and trading actions to obtain sample data by date.
Stage II: GAN-based framework building:Step 1: Build a generator in the GAN-based framework to predict trading sequences based on features.
Step 2: Build a discriminator in the GAN-based framework to determine whether an input trading sequence is the real trading sequence obtained using PLR or the trading sequence predicted by the GAN’s generator.
Stage III: Model training and optimizationEnsure the convergence of all model parameters of the GAN-based framework according to the different loss function, namely cross entropy and MSE.
Stage IV: Performance evaluationUse cumulative return on investment (CR), the Sharpe ratio (SR), and winning percentage (WPTC) to evaluate the performance of each of the GAN-based frameworks.
Fig. 1 Process flow of the proposed GAN-based framework
The detailed process flow of the proposed GAN-based framework is as follows:
Data preprocessing
The process of generating training samples involves three steps, namely feature generation, trading sequence generation, and training sample generation.
Feature generation as input
The daily opening price, closing price, highest price, lowest price, adjusted closing price (P¯), and trading volume are used to calculate technical indices as input features, which consist of a total of 152 technical indicators generated using 97 technical analysis methods.1 A total of 157 features are used, including 152 technical indicators and 5 pieces of stock trading data (open, close, high, low, volume). The final input feature for each day is denoted as F.
Trading sequence generation as target
The PLR approach is used to generate a known turning point sequence D=[d1,d2,⋯,dTtrain] from historical data P¯=[p¯1,p¯2,⋯,p¯Ttrain], where Ttrain is the length of the trading period in the training data. Then, the turning point sequence is transformed into a trading action sequence A=[a1,a2,⋯,aTtrain]. The steps involved in trading sequence generation are as follows:Step 1: Set the start and end points on the sequence for training data segmentation.
Step 2: Compute a simple linear regression function by using the least squares method.
Step 3: Find point t with the maximum deviation between the actual price of a stock and the price predicted using the linear regression function in the entire segmentation. This point represents the new segmented point t; set dt=1.
Step 4: Perform recursive segmentation at the newly segmented point, which has left and right segments. Repeat steps 1–4 for each new segment until a stopping threshold γ is satisfied, which is times multiplicate standard deviation of the entire segmentation. Finally, the final turning point sequence D is obtained upon completion of the aforementioned step 1–4, and the index of turning point DI is obtained as {argtdt,ifdt=1}.
Step 5: Transform the final tuning point sequence D into a trading action sequence A, which is 0 by default. The types of final trading actions on these turning points are as follows:1 aDIq=1,andifapDIq<apDIq-12,andifapDIq≥apDIq-1
where aDIq refers to the action type on the qth index of the turning point DI.
For model training, the trading action sequence is converted into a matrix of the training target with one-hot encoding as follows:2 A′=one_hot(A)
where A′∈Ttrain×3 is the training target, and one_hot is the one-hot encoding function.
Training sample generation
In this section, a special training sampling process is considered. A trading period length TP and a number of historical data days S are considered for predictions for each trading day. A complete sample data X is composed of X with length TP from F:3 X=[X1,⋯Xk⋯,XTP]
where Xk denotes the features on the kth trading day. Each X contains S features:4 Xk=Fk-S,Fk-S+1,⋯,F1
where Fk-S denotes the feature of the previous k-S day. For the training target, the same sampling process is applied:5 Y=a1′,⋯ak′⋯,aTP′
For the validation and test data, the adjusted closing price is not used to calculate the target trading actions, and sampling of the TP length is not performed.
GAN-based framework building
The proposed GAN-based model is composed of a generator and a discriminator. The generator predicts the trading sequence Y~ based on the features X of the training samples; the discriminator distinguishes whether the trading sequence is the predicted trading sequence Y~ or the real trading sequence Y.
Generator
The generator comprises two LSTM layers and two linear layers, where the first layer G1 estimates the hidden feature of a day based on the features of the previous day, the second layer G2 estimates the sequential hidden features by using the output of the first layer, and the third layer G3 predicts the probabilities of trading actions by using the two linear layers. First, we input all X into the first LSTM layer G1 to obtain the hidden features of each day hs,k1 through the s-th time point feature xks:6 hs,k1=G1xks,s∈[1,⋯,S]
Subsequently, we use the last hidden feature at the Sth point to represent the final state of each day. Therefore, the final state vectors [hS,11,⋯,hS,k1⋯,hS,TP1] from G1 are input into the second LSTM layer G2 to obtain the sequential hidden features hk2 as follows:7 hk2=G2hS,k1,k∈[1,⋯,TP]
The output hk2 of the second layer is passed through G3 to predict trading actions. In G3, pipeline estimation is performed using first linear layer with a leaky ReLU function and second linear layer with a softmax function:8 y~k=G3(hk2)
where y~k contains y~k0, y~k1, and y~k2 for each trading day; these represent the probabilities of holding, buying, and selling, respectively:9 Y~=[y~1,⋯y~k⋯,y~TP]
where Y~ represents the predicted trading action sequences on all trading days over the entire trading period. The proposed generator is also called the hierarchical-LSTM (H-LSTM) model.
Discriminator
The discriminator comprises three LSTM layers. The first LSTM layer Dp estimates the hidden feature of each day hkp at the k-th time point based on the adjusted closing price P¯ in a training sample, where k∈[1,⋯,TP]:10 hkp=Dpp¯k
The trading action sequence Y~, which is either the real Y or the predicted Y^, is input into another LSTM layer Da to obtain the hidden feature of daily action as follows:11 hka=DaY~k
The hkp and hka of each trading day are concatenated from the Dp layer and the Da layer to the third LSTM layer to estimate the sequential hidden feature of each trading day:12 hk′=D1hkp,hka
The last output hTP′ at time point TP of the third layer is input into the layer D2 to determine whether it is the real target trading sequence or the predicted trading sequence. In layer D2, pipeline estimation is performed using a linear layer with a leaky ReLU function and another linear layer with a softmax function:13 Z=D2(hTP′)
Model training and optimization
Zfake Is the discriminator output obtained by inputting the real stock price P¯ and the predicted trading action sequence Y~ generated by the generator. Zreal is the discriminator output obtained by inputting the real stock price P¯ and the target trading action sequence Y generated using the PLR approach. The model parameters of the generator are updated using only Zfake to obtain gradients. The model parameters of the discriminator are updated using both Zfake and Zreal to obtain gradients. In addition, the model parameters of all of the GAN-based framework are optimized using the Adam optimizer.
Loss functions in the simple GAN framework
In the simple GAN framework, the generator loss L_G^GAN is calculated using the binary cross entropy function:14 LGGAN=log(1-Zfake)
where log denotes the logarithm function. Similarly, the discriminator loss LDGAN is calculated using the categorical cross entropy function:15 LDGAN=log2Zfake+log(1-Zreal)
Loss function in the LSGAN framework
According to training concept of the LSGAN algorithm, the generator loss LGGAN in the LSGAN framework is calculated using the MSE function:16 LGLSGAN=(Zfake-1)2
The discriminator loss LDLSGAN in the LSGAN framework is calculated using the MSE function:17 LDLSGAN=12(Zfake-0)2+12(Zreal-1)2
Loss function in the WGAN framework
In the WGAN framework, the generator loss LGWGAN is calculated using the binary cross entropy function, which is the same as that in the case of the simple GAN framework. The discriminator loss LDWGAN in the WGAN framework is computed using the WGAN-GP algorithm developed by Gulrajani et al. (2017). The gradient L2 norm uses the loss function of the discriminator in the WGAN framework; therefore, LDWGAN is presented as follows:18 LDWGAN=-Zreal+Zfake+λ(‖∇YmixZYmix‖2-1)2
where λ denotes the weight of the penalty on the output ZYmix, and λ is set to 0.1. ZYmix is the output of the discriminator in the WGAN framework, and it is obtained by inputting the real stock price P¯ and the mixed trading action sequence Ymix. The weighting approach is used to obtain the mixed trading action sequence Ymix, which includes Y~ and Y:19 Ymix=ϵY+1-ϵY~,0≤ϵ≤1
where ϵ denotes a random value from 0 to 1.
Loss functions of H-LSTM, GAN-S, LSGAN-S, and WGAN-S frameworks
In addition, we use only the H-LSTM model as the generator to develop the prediction model by applying supervised learning to the target trading actions. The loss of the of H-LSTM model LH-LSTM enhances the model convergence of the generators of each GAN-based framework. The loss function of the H-LSTM model uses the categorical cross entropy function as follows:20 LH-LSTM=∑k=1TP∑a=02-ykalog(y~ka)
where yka denotes the ath type of target trading action, and y~ka denotes the ath type of predicted trading action. The loss function of the generators of the GAN-S and WGAN-S models is as follows:21 LDGAN-S,LDWGAN-S=log1-Zfake+LH-LSTM2
In this case, the average weights of both the H-LSTM model and the GAN-based models are considered. The loss function of the generator of the LSGAN-S model is as follows:22 LDLSGAN-S=(Zfake-1)2+LH-LSTM2
Performance evaluation
There are three indicators such as CR, SR, and WPCT to evaluate predicting performance for each framework. The probabilities that the daily predicted trading actions Y~=[y~1,y~2,⋯,y~N] are converted into the daily predicted action type A~=[a~1,a~2,⋯,a~N] and a~n as follows:23 a~n=argmaxny~nu
We suppose that all cash is used to buy or sell stocks. In this case, if the continuous predicted buying or selling actions appear in A~, only the first buying or selling action is considered. If the last action is to buy on the last trading day, the action of the last trading day is converted into a selling action. For example, for the predicted trading action sequence A~=[0,2,1,1,0,0,2,2,1,0] covering 10 trading days, the converted trading action is A′=[0,0,1,0,0,0,2,0,1,2]. Therefore, the final buying actions occur on the third and the ninth days, and the final selling actions occur on the seventh and tenth days. To compute the ROI, A′ is converted into two lists of actual trading positions IBUY and ISELL. The trading position of IBUY is24 IBUY=argn,an′∈A′an′,ifan′=1,
and the trading position of ISELL is25 ISELL=argn,an′∈A′an′,ifan′=,
where IBUY means that the buy position in A′ represents a buying action, and ISELL means that the sell position in A′ represents a selling action. In this case, the lengths of IBUY and ISELL are equal, and each corresponding position on IBUY and ISELL is a trading pair. Therefore, the returns R = [r1,r2,⋯,rM], and the rate of return of the m-th trading pair can be expressed as follows:26 rm=p¯ImSELL-1p¯ImBUY
where p¯ImSELL denotes the sell price corresponding to the mth sell action, and p¯ImBUY denotes the buy price corresponding to the mth buy action. The final cumulative rate of return on investment CR is as follows:27 CR=∏M=1M(1+rM)-1
In addition, the SR during the holding period of the model is computed as follows:28 SR=avg_dr-fixed_drstd_dr
where fixed_dr is the daily interest rate on the fixed deposit, and avg_dr and std_dr denote the average and standard deviation of the daily excess return, respectively. avg_dr can be computed as follows:29 avg_dr=∑m=1M∑l=ImBuyImSELL-1p¯l+1-p¯lp¯l∑m=1MImSELL-ImBuy
where std_dr can be computed as follows:30 std_dr=∑m=1M∑l=ImBuyImSELL-1p¯l+1-p¯lp¯l-Fixed_dr2
where Fixed_dr can be computed as follows:31 Fixed_dr=(1+Semi-fixed_r)1/125-1
where fixed_r denotes the annualfixeddepositinterestrate. In addition, we compute the WPCT to evaluate each model as follows:32 WPTC=‖R>0‖M
where ‖R>0‖ denotes the number of positive return rates on trading pairs.
Experimental results
This section describes the datasets, experimental setting and results including the collected dataset, comparative predictors, evaluation metrics and trading performance comparisons.
Datasets
A set of top 20 stocks represent the highest proportion of the Taiwan Stock Exchange Capitalization Weighted Stock Index (TAIEX). The proportion of stock in TAIEX is equivalent to the ratio of the capital stock value to the Taiwan market. Therefore, this data set contains the 20 most representative companies in Taiwan. These 20 companies encompass a wide variety of industries. All stock trading information, including date, opening price, closing price, highest price, lowest price, trading volume, and adjusted closing price, are collected using the Yahoo Finance API. The null value of a feature is set to 0. To balance the scale differences of different features, all of the features are subjected to min–max normalization, and all of the training data are normalized between 0 and 1. The validation and test data are adjusted according to the zoom scale of the training data. Due to COVID-19 epidemic affects the price trends very fierce, so this study collects the experimental data before 2020. The period of the training data is from October 20, 2016 to December 17, 2018; the periods of the validation and test data are from December 17, 2018 to July 1, 2019 and from July 1, 2019 to December 31, 2019, respectively.
Descriptive statistics
According to Table 1, data from the semiconductor industry, finance and insurance industry, plastic industry, communication networks industry, and others are used.Table 1 Stocks and industry
Industry Company name (stock ID) Count
Semiconductor Taiwan Semiconductor Manufacturing (2330.TW), MediaTek (2454.TW), ASE Holdings (3711.TW) 3
Finance and insurance Cathay Pacific Financial Holdings (2882.TW), Mega Financial Holding (2886.TW), Fubon Financial Holdings (2881.TW), CTBC Financial Holdings (2891.TW), Yushan Financial Holdings (2884.TW) 5
Plastic Formosa Plastics (1301.TW), Nan Ya Plastics (1303.TW), Formosa Petrochemical (1326.TW) 3
Communications network Chunghwa Telecom (6505.TW), Taiwan Mobile (3045.TW) 2
Other Hon Hai (2317.TW), Formosa Petrochemical Corporation (6505.TW), Delta Electronics (2308.TW), Largan Precision (3008.TW), Uni-President Enterprises (1216.TW), Hotai Motor (2207.TW), Quanta Computer (2382.TW) 7
Table 2 displays the statistical results for the adjusted closing prices of each stock in the training data, validation data, and test data. All adjusted closing prices were calculated on August 12, 2020. The stock IDs 2330.TW, 2454.TW, 6505.TW, 3045.TW exhibited rise trends in the training, validation, and test data. The average prices of the semiconductor stocks in the test data are higher than those in the training data, and the average prices of the semiconductor stocks in the validation data are lower than those in the training data. The average prices of the plastics stocks in the validation data are higher those in the training data, but the average prices of the plastics stocks in the test data are lower than those in the validation data. The financial industry stocks exhibit different trends across the three data periods.Table 2 Descriptive statistics of the adjusted closing prices of 20 stocks
Stock ID Training data Validation data Test data
Mean St. D Min Max Mean St. D Min Max Mean St. D Min Max
1216.TW 57.1 8.8 43.8 74.6 69.9 3.8 63.1 77.3 72.9 2.4 69.1 77.6
1301.TW 83.5 9.7 68.4 106.0 95.8 4.4 85.9 103.7 92.6 3.4 85.8 103.7
1303.TW 65.2 6.9 51.4 77.5 69.4 1.5 65.6 71.9 68.5 1.7 63.8 71.3
1326.TW 86.6 11.8 70.7 115.2 96.3 2.3 89.4 101.3 85.3 3.9 80.8 96.9
2207.TW 294.4 39.7 192.9 355.1 364.2 89.3 235.0 502.6 505.2 79.9 403.3 693.8
2308.TW 127.8 17.2 93.0 153.2 141.5 9.2 118.5 156.1 139.6 6.5 123.3 150.9
2317.TW 99.5 16.2 61.2 134.1 68.2 5.7 61.1 83.0 76.4 7.3 68.1 88.3
2330.TW 199.0 25.0 155.7 248.3 223.1 13.5 194.9 252.0 274.9 30.0 234.3 336.5
2382.TW 51.1 5.3 42.7 64.4 51.2 2.4 45.4 55.2 55.8 3.0 51.1 61.7
2412.TW 93.7 4.7 84.5 102.2 101.2 2.3 98.1 105.5 106.5 2.2 102.6 109.9
2454.TW 245.0 40.0 182.7 333.4 262.5 27.8 207.1 301.6 368.8 45.3 296.6 452.2
2881.TW 43.3 2.6 35.9 47.9 41.1 1.2 38.3 43.6 42.6 1.2 39.8 45.0
2882.TW 44.0 3.5 32.8 49.5 40.2 1.7 36.6 43.6 39.3 1.0 37.3 40.9
2884.TW 15.6 2.1 12.7 20.1 20.8 2.0 17.7 24.3 25.5 1.1 22.9 27.2
2886.TW 19.7 1.7 16.3 23.3 23.9 1.6 21.4 27.1 27.7 0.9 26.2 29.3
2891.TW 17.2 1.7 13.8 20.9 18.8 0.4 17.9 19.8 20.1 0.7 19.0 21.4
3008.TW 4179.1 735.9 2842.1 5684.3 3900.4 509.5 2797.7 4670.8 4221.0 346.8 3656.3 4960.1
3045.TW 93.9 3.5 84.1 101.1 102.8 4.1 97.4 112.1 108.3 2.1 104.0 112.1
3711.TW 66.9 5.5 52.8 82.5 59.2 5.0 51.5 70.7 71.6 6.2 60.0 83.0
6505.TW 99.3 10.7 83.0 137.9 104.9 3.3 95.7 110.1 96.3 4.0 91.9 106.5
Figure 2 depicts the numbers of trades corresponding to the three actions generated by the PLR approach under γ = 0.01, 0.05, 0.1, and 0.5. For smaller γ, a large number of trading points is obtained; for example, when γ = 0.01, 19 stocks have more than 100 trading pairs. For γ = 0.5, none of the stocks have more than 20 trading pairs.Fig. 2 Number of trading actions for 20 stocks as determined by the PLR approach under different γ
Predictor
In the experiments, we used one supervised learning model and six GAN-based frameworks:H-LSTM: This is the traditional supervised learning approach for generator training without the GAN-based framework.
GAN: This model trains the generator and the discriminator by using the original GAN model developed by Goodfellow et al. (2014).
GAN-S: The convergence of this model is the same as that of the GAN model, but the loss function is combined with the loss LH-LSTM of H-LSTM model.
LSGAN: The convergence of this model is the same as that of the LSGAN model developed by Mao et al. (2017).
LSGAN-S: The convergence of this model is the same as that of the LSGAN model, but the loss function is combined with the loss LH-LSTM of H-LSTM model.
WGAN: The convergence of the discriminator is the same as that in the case of the WGAN-GP model developed by Gulrajani et al. (2017), but the loss function of the generator is computed using the binary cross entropy method.
WGAN-S: The convergence of this model is the same as that of the WGAN model, but the loss function is combined with the loss LH-LSTM of H-LSTM model.
The best predictor in each experiment is selected based on positive CRs in the training and validation data and the maximum CRs in the validation data.
Hyperparameter setting
The detailed hyperparameter settings are summarized in Table 3, and hidden size is applied to the generator and the discriminator at the same time.Table 3 Explanation of hyperparameters
Parameter Value Explanation
Ttrain 500 The length of training data
Tval 125 The length of validation data
Ttest 125 Total testing data length
S 2,10,20 How many trading information of historical trading days as features
TP 50 Number of trading days on train data for sampling
γ 0.01, 0.05, 0.1, 0.5 The segmenting threshold for PLR approach
hs 200, 400 The hidden size for the generator and discriminator model
lr 10–3, 10–4, 10–5 The learning rate used for training model
epoch 4000 The number of rounds that the model is trained with all data
Comparison of cumulative returns of seven models
The best models are selected based on their return rates when applied to the validation data. As summarized in Table 4, the GAN model yields the best return rates for stocks 6505.TW, 1301.TW, and 2207.TW. The GAN-S yields the best return rates for stocks 2454.TW, 6505.TW, 2882.TW, 3008.TW, and 3711.TW. The LSGAN yields the best return rates for stocks 2317.TW, 2886.TW, and 2881.TW. The LSGAN-S yields the best return rates for stocks 1216.TW and 2382.TW. The WGAN yields the best return rates for stocks 2330.TW and 2308.TW. The WGAN-S yields the best return rates for stocks 1303.TW, 1326.TW, 2891.TW, and 2884.TW. The H-LSTM yields the best return rate only for stock 3045.TW. In addition, none of the predictors yield positive return rates for stocks 2308.TW, 1216.TW, and 3045.TW.Table 4 Comparison of CRs of the seven predictors when applied to testing data
Stock ID H-LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
2330.TW 0.0385 0.0150 0.0547 0.0221 0.0858 0.2249 0.0700
2454.TW – 0.0112 0.2038 0.3082 0.1143 0.2004 0.1049 0.0291
2317.TW 0.0000 0.1702 0.0029 0.1935 0.0194 0.1468 0.0855
2412.TW 0.0000 0.0375 0.0047 – 0.0226 – 0.0044 0.0233 0.0371
6505.TW – 0.0851 0.0000 0.0676 0.0000 – 0.0633 0.0000 0.0186
2882.TW – 0.0352 – 0.0070 0.0477 0.0192 – 0.0140 0.0034 0.0230
2308.TW – 0.0188 – 0.0291 – 0.1192 – 0.0456 – 0.0136 0.0000 – 0.1143
3008.TW 0.1319 0.0000 0.1995 0.1261 0.1128 0.1859 0.1914
1301.TW – 0.0241 0.0567 – 0.0737 – 0.0195 – 0.0840 – 0.0468 0.0212
1303.TW 0.0000 0.0274 0.0027 0.0204 0.0145 0.0278 0.0525
2886.TW 0.0936 – 0.0100 0.0000 0.1214 0.0353 0.1016 0.0853
2881.TW – 0.0844 – 0.0163 0.0000 0.0625 – 0.0021 0.0518 – 0.0471
1216.TW – 0.0488 – 0.0843 – 0.0398 – 0.0355 – 0.0153 – 0.0535 – 0.0703
1326.TW – 0.0127 – 0.0199 – 0.0873 – 0.1065 – 0.0057 0.0000 0.0711
2891.TW 0.0719 0.0493 0.0973 0.0486 0.0240 0.0582 0.1082
3045.TW – 0.0046 – 0.0131 – 0.0511 – 0.0126 – 0.0753 – 0.0075 – 0.0293
2207.TW 0.0000 0.3231 0.2455 0.0000 0.0385 0.0000 0.2035
2884.TW 0.1276 0.1158 0.0502 0.0940 0.0000 0.1320 0.1466
3711.TW – 0.0010 0.1717 0.1995 0.0264 0.0000 0.0000 0.1685
2382.TW 0.0656 0.0931 0.0898 0.1628 0.3107 0.0000 – 0.0038
As summarized in Table 5, the GAN-S yields the highest rewards on five stocks, and its average CR is 0.0500. However, the GAN has the highest average CR of 0.0542 among the seven models. The WGAN-S is ranked second with an average CR of 0.0523, and the H-LSTM is ranked last with an average CR of 0.0102. In addition, the GAN-S and WGAN-S are superior to the GAN and WGAN in terms of providing the best returns. However, in terms of the average CR, only WGAN-S is superior to WGAN.Table 5 Counting of stock CRs of seven predictors and average CR
Item H– LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
Count of CR 1 3 5 3 2 2 4
Average CR 0.0102 0.0542 0.0500 0.0384 0.0282 0.0476 0.0523
Table 6 displays the count of positive CRs (pCR), the count of negative CRs (nCR), the count of zero CRs, and the positive ratio CR (prCR) for each model when applied to the test data, where pr is calculated as pCR/(pCR + nCR). In the case of the WGAN-S, 15 stocks fall under pCR, and it is the best predictor given its prCR of 0.75. In the case of the H-LSTM, only six stocks fall under pCR, and it is the worst model given its prCR of 0.38. The performance of the other predictors in terms of prCR are between those of the H-LSTM and WGAN-S. On the basis of a comparison of the GAN-S, LSGAN-S, and WGAN-S in terms of supervised loss, only the LSGAN-S exhibits no improvement. However, all of the models outperform the fixed deposit return rate of 0.004.Table 6 Numbers of positive returns, negative returns, and no trades for 20 stocks
Item H-LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
Count on positive CR 6 11 13 12 9 11 15
Count on zero CR 4 2 2 2 2 6 0
Count on negative CR 10 7 5 6 9 3 5
Positive rate 0.38 0.61 0.72 0.67 0.50 0.78 0.75
Investment risk comparison of seven predictors
The annual interest rate for 6-month fixed deposits is 0.00795 according to the Bank of Taiwan’s New Taiwan Dollar Deposit (Lending) interest rate on July 1, 2019, and the interest rate for a half year is 0.004, which is used as the benchmark for SR comparisons. To evaluate investment risk, Table 7 displays the semi-annual fixed deposit interest rate as the basis to calculate the SRs of each predictor and each stock. The H-LSTM has the worst SR compared with the other GAN-based predictors. The WGAN-S yields the best SRs on 5 out of 20 stocks. The GAN yields the best SRs on 4 out of 20 stocks. The WGAN, LSGAN-S, and LSGAN yield the best SRs on 3 out of 20 stocks. The H-LSTM yields the best SRs on 2 out of 20 stocks.Table 7 Comparison of SRs of the seven predictors when applied to testing data
Stock ID H-LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
2330.TW 0.0409 0.0684 0.1028 0.1910 0.0969 0.2772 0.4263
2454.TW 0.1432 0.1947 – 0.0302 0.1442 0.1918 0.3292 0.0788
2317.TW 0.1361 0.0128 – 0.2225 0.1755 0.1744 0.1301
2412.TW 0.4468 0.4830 – – 0.1727 – 1.0144 0.0896 0.0648
6505.TW – 0.0822 – 0.0961 – – 0.0576 – 0.0268
2882.TW – 0.3749 0.1851 – 0.3790 0.0206 – 0.0244 0.0036 0.0316
2308.TW – 0.2659 – 0.1155 – 0.1945 – 0.0343 – 0.0106 – – 0.1742
3008.TW – 0.1975 0.0764 0.0598 0.0820 0.0763 0.2030
1301.TW 0.0743 – 0.1943 – 0.1631 – 0.0146 – 0.0881 – 0.1488 0.0583
1303.TW 0.0642 0.0051 – 0.0282 0.0455 0.0646 0.0740
2886.TW – 0.0269 – 0.1024 0.2688 0.1311 0.1320 0.1387
2881.TW – 0.0615 – – 0.1883 0.1167 – 0.5565 0.1366 – 0.1574
1216.TW – 0.0952 – 0.0469 – 0.0617 – 0.3059 – 0.0190 – 0.0587 – 0.0771
1326.TW – 1.0785 – 0.4177 – 0.0296 – 0.2103 – 0.0086 – 0.1110
2891.TW 0.0917 0.1436 0.1166 0.0965 0.0558 0.0776 0.3708
3045.TW – 0.0420 – 0.0931 – 0.0226 – 0.0271 – 0.1587 – 0.0127 – 0.0431
2207.TW 0.4728 0.1214 – – 0.0378 – 0.1614
2884.TW 0.2049 0.6938 0.4491 0.2751 – 0.1957 0.1464
3711.TW 0.1479 0.2171 – 0.0038 0.2755 – – 0.1230
2382.TW 0.1241 0.1090 0.1619 0.2597 0.3018 – – 0.0032
Table 8 displays the count of the best SRs of each predictor on the test data as well as the average SRs. The WGAN-S is the best one in terms of the count of the best SR scores; it has five best SR scores. The WGAN is the best one in terms of average SR; its average SR of 0.0955. In addition, the H-LSTM and LSGAN-S have negative average SRs; the H-LSTM is the worst one. Moreover, these GAN-based predictors have better SRs than the simple GAN and H-LSTM.Table 8 Best stock SR counts and average SRs of different predictors
Item H-LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
Count of best SR 0 2 4 3 3 3 5
Average SR – 0.0100 0.0001 0.0915 0.0663 – 0.0455 0.0955 0.0845
WPCT comparison of seven predictors
Table 9 displays the WPCT performance of each predictor. All of the predictors have a positive WPCT on many of the stocks. However, the WGAN-S has at least one trading pair on each stock, and only on stock 2308.TW and 3045.TW belong to WPCT of 0.Table 9 WPCT performance on test data
Stock H– LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
2330.TW 0.4545 0.5000 0.5000 1.0000 0.7143 0.5455 0.5000
2454.TW 0.5556 1.0000 0.8571 1.0000 1.0000 0.7500 0.7500
2317.TW – 1.0000 0.5000 1.0000 1.0000 1.0000 0.5333
2412.TW – 0.5000 0.3333 0.0000 0.0000 1.0000 1.0000
6505.TW 0.5000 – 0.5714 – 0.5238 – 0.4783
2882.TW 0.0000 0.0000 0.5000 0.5000 0.3846 1.0000 0.4444
2308.TW 0.3333 0.2500 0.4286 0.5000 0.4000 – 0.0000
3008.TW 0.5556 – 0.4706 0.5000 1.0000 1.0000 1.0000
1301.TW 0.5714 0.4615 0.3158 0.0000 0.3333 0.6667 0.3333
1303.TW – 0.6000 0.5000 0.6667 0.4878 0.6000 0.5556
2886.TW 1.0000 0.5000 – 0.5000 0.6667 0.7500 0.6154
2881.TW 0.2308 0.3333 – 1.0000 0.0000 0.6667 0.3333
1216.TW 0.2500 0.3333 0.4615 0.2500 0.2857 0.1667 0.1818
1326.TW 0.4286 0.0000 0.5000 0.0000 0.2000 – 0.6000
2891.TW 0.7500 0.6000 0.5625 0.8000 0.3750 1.0000 0.8750
3045.TW 0.3182 0.0000 0.4286 0.3750 0.3000 0.6667 0.0000
2207.TW – 0.3333 0.7000 – 0.5294 – 0.6667
2884.TW 1.0000 1.0000 1.0000 0.4848 – 0.6667 0.3333
3711.TW 0.3333 0.8000 0.5556 1.0000 – – 1.0000
2382.TW 1.0000 0.2500 0.4000 0.6667 0.7333 0.5455 0.4000
Table 10 displays WPCT counts in terms of WPCT counts. If WPCT≥0.5, all of the predictors satisfy 7–14 stocks; if WPCT=1, all of the predictors satisfy 1–6 stocks. In summary, the average WPCT of the WGAN is 0.7485, which is the highest among the seven models. However, all of the predictors have acceptable performance, with average WPCT values being between 47.01 and 64.73%.Table 10 Average WPCT of each model on all stocks
Item H– LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
Count of WPTC≥0.5 7 9 11 11 8 14 11
Count of WPTC=1 3 3 1 5 3 6 3
Average WPTC 0.5176 0.4701 0.5325 0.5691 0.4963 0.7485 0.5300
Performance summary
Table 11 displays the overall performance of the seven predictors. Overall, the WGAN outperforms the five GAN-based predictors and the deep learning predictor. The performance of the GAN-S and WGAN-S is similar and high. The performance of the H-LSTM and LSGAN-S is similar and poor; their overall ranks are 18 and 19, respectively.Table 11 Performance comparison of the seven models on three evaluation metrics
Item H-LSTM GAN GAN-S LSGAN LSGAN-S WGAN WGAN-S
Average CR 0.0102 0.0542 0.0500 0.0384 0.0282 0.0476 0.0523
Average SR – 0.0100 0.0001 0.0915 0.0663 – 0.0455 0.0955 0.0845
Average WPTC 0.5176 0.4701 0.5325 0.5691 0.4963 0.7485 0.5300
Overall rank (∑) 18 13 8 11 19 6 9
Discussion
Experimental results present the proposed GAN-based framework used to generate more acceptable trading actions according to three evaluation metrics. The MSE loss function used in LSGAN and LSGAN-S is not a reliable convergence approach because the difference between actual value and predicted value is not a real distance. Therefore, GAN, GAN-S, WGAN, and WGAN-S models using binary cross entropy function obtain high performances because the task of trading action prediction belongs to multi-class classification problems which are buying, selling, and holding. Another hand, in the stock prediction task, the WPCT is the most important indicator since if to do trading-pair (buy in and sell out) which always get positive return, in this case, people will obtain high confidence for the prediction model such as WGAN.
Conclusion
The paper has proposed the GAN-based frameworks to improve the prediction performances of trading strategy. The experimental results indicate that the GAN-based frameworks yield excellent performance; in particular, the WGAN and WGAN-S predictors yield high average CRs and counts of positive CRs. However, the GAN-based predictors also outperform the traditional supervised learning models such as the H-LSTM predictor. The generator has predicted the more effective trading actions, and the discriminator has distinguished whether these trading actions originate from the PLR or the generator. In addition, the PLR approach provides a reliable training target for GAN-based frameworks and improves stock market trading performance. Therefore, the GAN-based framework has generated the more diverse trading strategies and has decrease the overfitting problem.
There are few limitations in the paper, buying and selling actions are all-in or all-out on the stock market. In practice, there are fixed units for stock trading. Moreover, herein, trading fees and transaction levies are not considered when ROI is computed, and traders may be required to pay larger amounts when executing trades frequently. In the future work, seed trading action sequences for GAN models can apply multiple methods, such as the buy and hold strategy and the stock ticker strategy. Therefore, the discriminator of the GAN-based framework will be able to obtain more real trading action sequences from historical trading information to detect whether a sequence is real or fake.
Author’s contribution
JLW: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Supervision, Validation, and Visualization, Roles/Writing—original draft. X-RT: Conceptualization, Methodology, Experiment, and Writing. C-HH: Conceptualization, Validation, and Writing. All the authors read and approved the final manuscript.
Funding
This research work was partially funded by funds from the Ministry of Science and Technology (MOST) and National Science and Technology Council (NSTC), Taiwan, ROC, under Grant No. MOST 107–2218-E-031–002-MY2, MOST 109–2221-E-031–003, MOST 110–2221-E-031–004, and MOST 111–2221-E-031–004-MY3.
Data availability
Enquiries about data availability should be directed to the authors.
Declarations
Conflict of interest
The authors have no conflicts of interest to declare.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
There are no human subjects in this article and informed consent is not applicable.
1 The pandas-ta package is used in the paper for compute 157 technical analysis indicators.
Publisher's Note
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References
Abraham JB Improving stock price prediction with GAN-based data augmentation Indonesian J Artif Intell Data Mining 2021 4 1 1 10
Alonso-Monsalve S Suárez-Cetrulo AL Cervantes A Quintana D Convolution on neural networks for high-frequency trend prediction of cryptocurrency exchange rates using technical indicators Expert Syst Appl 2020 149 113250 10.1016/j.eswa.2020.113250
Arjovsky M, Chintala S, Bottou L (2017) Wasserstein generative adversarial networks. In: Proceedings of the 34th International Conference on Machine Learning (ICML), pp. 214–223.
Bashar MA, Nayak R (2020) TAnoGAN: Time series anomaly detection with generative adversarial networks. In: Proceedings of the 2020 IEEE Symposium Series on Computational Intelligence (SSCI), pp. 1778–1785.
Dai Z Zhu H Kang J New technical indicators and stock returns predictability Int Rev Econ Financ 2021 71 127 142 10.1016/j.iref.2020.09.006
Detzel A Liu H Strauss J Zhou G Zhu Y Learning and predictability via technical analysis: Evidence from bitcoin and stocks with hard-to-value fundamentals Financ Manage 2021 50 1 107 137 10.1111/fima.12310
Goh YK Lai AC Financial network construction of a set of coupled stochastics differential equations using generative adversarial network AIP Conf Proc 2019 2138 1 030016 10.1063/1.5121053
Goodfellow I, Pouget-Abadie J, Mirza M, Xu B, Warde-Farley D, Ozair S, Courville A, Bengio Y (2014) Generative adversarial nets. In: Proceedings of the 2014 Advances in neural information processing systems, pp. 2672–2680.
Gulrajani I, Ahmed F, Arjovsky M, Dumoulin V, Courville AC (2017) Improved training of Wasserstein GANs. In: Proceedings of the 2019 31rd Conference on neural information processing systems, pp. 5767–5777.
Kumar A Alsadoon A Prasad PW Abdullah SH Rashid TA Pham DT Nguyen TQ Generative adversarial network (GAN) and enhanced root mean square error (ERMSE): deep learning for stock price movement prediction Multim Tools Appl 2022 81 3995 4013 10.1007/s11042-021-11670-w
Lee MC, Liao JS, Yeh SC, Chang JW (2020) Forecasting the short-term price trend of Taiwan stocks with deep neural network. In: Proceedings of the 2020 11th International Conference on E-Education, E-Business, E-Management, and E-Learning, pp. 296–299.
Lezmi E Roche J Roncalli T Xu J Improving the robustness of trading strategy backtesting with boltzmann machines and generative adversarial networks SSRN Electronic J 2020 25 3645473
Li J, Wang X, Lin Y, Sinha A, Wellman M (2020) Generating realistic stock market order streams. In: Proceedings of the AAAI Conference on Artificial Intelligence, pp. 727–734.
Liu M Luo KZ Chen S A stock selection algorithm hybridizing grey wolf optimizer and support vector regression Expert Syst Appl 2021 179 115078 10.1016/j.eswa.2021.115078
Mao X, Li Q, Xie H, Lau RY, Wang Z, Smolley, SP (2017) Least squares generative adversarial networks. In: Proceedings of the 2017 IEEE International Conference on Computer Vision, pp. 2794–2802.
Marti G (2020) CorrGAN: Sampling realistic financial correlation matrices using generative adversarial networks. In: Proceedings of the 2020 IEEE International Conference on Acoustics, Speech and Signal Processing, pp. 8459–8463.
Nguyen CV Chang CH Nguyen TD Testing the weak-form efficient market hypothesis: using panel data from the emerging Taiwan stock market Int J Bus Soc Sci 2012 3 18 192 198
Niu Z Yu K Wu X LSTM-based VAE-GAN for time-series anomaly detection Sensors 2020 20 13 3738 10.3390/s20133738 32635374
Ozcalici M Bumin M Optimizing filter rule parameters with genetic algorithm and stock selection with artificial neural networks for an improved trading: the case of Borsa Istanbul Expert Syst Appl 2022 208 118120 10.1016/j.eswa.2022.118120
Pramudya R Technical analysis to determine buying and elling signal in stock trade Int J Financ Bank Stud 2020 9 1 58 67
Pramudya R Ichsani S Efficiency of technical analysis for the stock trading Int J Financ Bank Stud 2020 9 1 58 67
Saud AS Shakya S Analysis of look back period for stock price prediction with RNN variants: a case study on banking sector of NEPSE Proc Computer Sci 2020 167 788 798 10.1016/j.procs.2020.03.419
Thammakesorn S Sornil O Generating trading strategies based on candlestick chart pattern characteristics J Phys: Conf Ser 2019 1195 012008
Vijh M Chandola D Tikkiwal VA Kumar A Stock closing price prediction using machine learning techniques Proc Computer Sci 2020 167 599 606 10.1016/j.procs.2020.03.326
Wiese M Knobloch R Korn R Kretschmer P Quant GANs: deep generation of financial time series Quantit Financ 2020 20 1 22 10.1080/14697688.2020.1730426
Wu JL Chang PC A trend-based segmentation method and the support vector regression for financial time series forecasting Math Probl Eng 2012 25 871
Xu H Cao D Li S A self-regulated generative adversarial network for stock price movement prediction based on the historical price and tweets Knowl Based Syst 2022 247 108712 10.1016/j.knosys.2022.108712
Yoon J, Jarrett D, van der Schaar M (2019). Time-series generative adversarial networks. In: Proceedings of the 2019 33rd Conference on Neural Information Processing Systems (NeurIPS), pp. 5508–5518.
Zhou X Pan Z Hu G Tang S Zhao C Stock market prediction on high-frequency data using generative adversarial nets Math Probl Eng 2018 2018 1 11
| 0 | PMC9734618 | NO-CC CODE | 2022-12-14 23:28:29 | no | Soft comput. 2022 Dec 9;:1-14 | utf-8 | Soft comput | 2,022 | 10.1007/s00500-022-07716-2 | oa_other |
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AIDS Behav
AIDS Behav
AIDS and Behavior
1090-7165
1573-3254
Springer US New York
36463390
3938
10.1007/s10461-022-03938-5
Original Paper
Acceptability and Feasibility of Online, Asynchronous Photovoice with Key Populations and People Living with HIV
http://orcid.org/0000-0002-4147-3301
Earnshaw Valerie A. [email protected]
1
Cox Jon 2
Wong Pui Li 3
Saifi Rumana 34
Walters Suzan 5
Azwa Iskandar 3
Omar Sharifah Faridah Syed 3
Collier Zachary K. 6
Hassan Asfarina Amir 4
Lim Sin How 7
Wickersham Jeffrey 8
Haddad Marwan S. 9
Kamarulzaman Adeeba 34
Altice Frederick L. 8
1 grid.33489.35 0000 0001 0454 4791 Department of Human Development and Family Sciences, University of Delaware, 111 Alison Hall West, Newark, DE 19716 USA
2 grid.33489.35 0000 0001 0454 4791 Department of Art and Design, University of Delaware, Newark, DE USA
3 grid.10347.31 0000 0001 2308 5949 Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
4 grid.10347.31 0000 0001 2308 5949 Centre of Excellence for Research in AIDS, Universiti Malaya, Kuala Lumpur, Malaysia
5 grid.137628.9 0000 0004 1936 8753 School of Global Public Health, New York University, New York, NY USA
6 grid.33489.35 0000 0001 0454 4791 School of Education, University of Delaware, Newark, DE USA
7 grid.10347.31 0000 0001 2308 5949 Department of Social and Preventive Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
8 grid.47100.32 0000000419368710 School of Medicine, Yale University, New Haven, CT USA
9 grid.428181.6 Center for Key Populations, Community Health Center, Inc., New Britain, CT USA
3 12 2022
115
14 11 2022
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Photovoice is an action-oriented qualitative method involving photography and story-telling. Although photovoice yields a powerful form of data that can be leveraged for research, intervention, and advocacy, it has arguably been underutilized within HIV research. Online, asynchronous photovoice methods represent a promising alternative to traditional in-person methods, yet their acceptability and feasibility with key populations and people living with HIV (PLWH) have yet to be explored. The current study describes the methods and evaluation of an online, asynchronous photovoice project conducted with 34 members of key populations and PLWH in Malaysia in 2021. A HIPAA-compliant website incorporating a series of instructional videos was created to facilitate participant engagement and data collection. Quantitative and qualitative indicators suggest that participants found the project to be highly acceptable and feasible. Online, asynchronous photovoice methods hold potential for increasing the scale of this powerful and versatile qualitative research method with key populations and PLWH.
Resumen
La fotovoz es un método cualitativo orientado a la acción que usa fotografía y narración de historias. Aunque la fotovoz produce una poderosa forma de datos que se puede utilizar para la investigación, la intervención y la promoción, podría decirse que ha sido poca aplicada en la investigación del VIH. Los métodos de fotovoz asincrónicos en línea representan una alternativa prometedora a los métodos en persona tradicionales, pero aún no se ha explorado su aceptabilidad y viabilidad con los grupos de población clave y las personas que viven con el VIH (PLWH por sus siglas en inglés). El estudio actual describe los métodos y la evaluación de un proyecto de fotovoz asincrónico en línea realizado con 34 miembros de grupos de población clave y PLWH en Malasia en 2021. Se creó un sitio web compatible con HIPAA que incorpora una serie de videos instructivos para facilitar la participación y la recopilación de datos. Los indicadores cuantitativos y cualitativos sugieren que los participantes encontraron el proyecto altamente aceptable y realizable. La fotovoz asincrónica en línea es un poderoso y versátil método cualitativo de investigación la cual tiene potencial para usarse más con los grupos de población clave y PLWH.
Keywords
HIV
Key populations
Photovoice
Qualitative methods
http://dx.doi.org/10.13039/100000025 National Institute of Mental Health R34MH124390 Earnshaw Valerie A. http://dx.doi.org/10.13039/100000026 National Institute on Drug Abuse K01DA053159 Walters Suzan
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pmcIntroduction
The use of photovoice has been increasing in health research generally, as well as HIV research specifically, in recent years [1, 2]. Photovoice is a qualitative research method that enables individuals to represent their lives and communities through photographs and stories [3]. Photovoice, which has long been used as a method to engage communities affected by HIV in participatory action research [4], has recently been gaining in popularity among HIV researchers [1]. Scholarly publications referring to HIV and photovoice have more than doubled in the past decade (see Fig. 1), reflecting a trend that has been observed with photovoice research more generally [2]. Photovoice may be increasing in popularity, in part, because it is a culturally- and trauma-responsive method [2] that yields an insightful form of data that can be leveraged for several purposes. Photovoice can be used to answer descriptive research questions [5] and has yielded insight into the needs and experiences of diverse people living with HIV (PLWH1) [1]. Photovoice can also be used in interventions to contribute to attitude and behavior change. As examples, photovoice has been used to build empowerment [8, 9] and support disclosure processes [10] among PLWH as well as to reduce stigma towards key populations among clinicians [11]. Finally, photovoice can be used for advocacy to promote social change [1, 3, 12]. Photovoice projects are often shared with communities, including via public exhibits, which can facilitate consciousness raising, community building, and action planning [9].Fig. 1 Number of scholarly publications referencing “HIV photovoice” in Google Scholar, 2012–2021
Teti et al., who recently reviewed photovoice studies with PLWH, concluded that although photovoice has been successfully used as a research method with PLWH and has potential to transform practice and policy, it is currently underutilized within HIV research [1]. Photovoice projects have traditionally been conducted in person and synchronously. Yet, this format may not always be feasible and acceptable due to participant locations and/or concerns related to confidentiality (e.g., in places with strong HIV-related stigma) or safety (e.g., during COVID-19 surges). Conducting photovoice projects online and asynchronously (i.e., not live or in real time) represents a promising alternative to confidentially and safely engage more members of key populations [e.g., men who have sex with men (MSM), transgender women (TGW), female sex workers (FSW), and people who inject drugs (PWID)] and PLWH in photovoice projects and responds to calls to engage in “responsive innovation” in photovoice methods [2]. The current study describes the methods as well as acceptability and feasibility of an online, asynchronous photovoice project to contribute to increasing the scale of this highly versatile and action-oriented qualitative method for HIV research.
In-Person, Synchronous Photovoice: Traditional Method
Photovoice projects traditionally involve in-person, synchronous interactions between facilitators, participants, and other stakeholders such as community members and policymakers. Key elements and steps for photovoice projects have been described by Wang and Burris [3], who first introduced the method in 1997, and others who have reviewed the use of photovoice since its introduction [5, 12, 13]. Photovoice projects often begin with in-person trainings where facilitators and participants interact. Trainings vary in duration and content, with most addressing photography skills and some additionally addressing issues of research methods, safety, ethics, and social power. Trainings represent an opportunity for reciprocity between researchers and participants. In addition to receiving a stipend for their time, participants can build photography and other skills via these trainings. Participants then take photographs in their communities that are related to the goal of the project. Next, facilitators and participants typically re-convene to select significant photographs, add captions to photographs, and identify themes and issues captured by the photographs and captions via discussion. Finally, photovoice projects that aim to engage in advocacy or social change may culminate in a public exhibit that could include the facilitators, participants, and other stakeholders such as community members and policymakers. Such public events also have the potential to facilitate dissemination.
Photovoice projects have yielded valuable insights into the lives, needs, assets, and priorities of a wide range of populations over the past 25 years, including key populations and PLWH. Golden argued that photovoice is well-aligned with health equity goals and is well-suited for research that engages with stigmatized topics and vulnerable populations [2]. In their review of photovoice studies in the health and public health literatures, Catalani and Minkler found that photovoice as a research methodology has been almost exclusively applied to descriptive research questions and analysis typically involves triangulating several forms of data (e.g., photographs, written reflections, and group discussions) [5]. They concluded that photovoice projects yield improved understanding of community needs and assets. In their review of photovoice studies with PLWH, Teti et al. found that this is also the case for HIV research [1]. As examples, photovoice projects have yielded insights into aging and HIV among Latino/a activists-artists living with HIV [14]; challenges, resilience, and hope among women living with HIV [15]; disclosure among PLWH [10]; priorities for HIV/STI prevention among rural American Indian communities [16]; and situations and locations that place rural, African youth at risk for HIV [17]. Over half of the studies reviewed by Teti et al. involved an advocacy or action component, most often occurring via an exhibit of participants’ work [1].
In-person, synchronous photovoice may not always be acceptable to or feasible for key populations and/or PLWH. In places where key populations and PLWH are geographically dispersed, it may not be feasible to physically gather for a multi-phase in-person project. Barriers to in-person care experienced by rural key populations and PLWH, such as transportation [18], are also often barriers to participation in research. Additionally, traditional photovoice methods may not be feasible during COVID-19 or other similar infectious disease surges, when in-person gatherings could threaten the health and safety of key populations and PLWH. Finally, in-person photovoice may not be acceptable to key populations and PLWH in places with strong cultural or structural stigma associated with HIV, sexual and gender diversity, drug use, and/or sex work. Key populations and PLWH may decline participation because they fear consequences ranging from gossip to arrest if their key population or HIV status were to become known due to their participation in a project related to HIV or key populations. In these places, it may not be safe to hold in-person photovoice projects and/or individuals who fear gathering in person may not participate, threatening the generalizability of results. Indeed, disclosure of HIV, illicit drug use and/or sexual activities, and stigmatized statuses has been identified as an ethical challenge for photovoice projects involving key populations and PLWH [19].
Online, Asynchronous Photovoice: New Method
The widespread, global uptake of smartphones (i.e., internet-enabled mobile phones with computing functionality) and engagement in social media may create new opportunities for photovoice. Over 80% of people worldwide were estimated to have smartphones as of 2022 [20]. Global disparities in smartphone access persist; yet, smartphone access is increasing in low- and middle-income countries [21] and are becoming increasingly popular resources for HIV interventions in these settings [22, 23]. The global uptake of smartphones means that many key populations and PLWH now have access to and experience with a camera and an internet-enabled device, the key tools needed for online, asynchronous photovoice projects. Moreover, rates of social media engagement are also increasing worldwide [21]. Instagram, one of the world’s most popular social media sites, revolves around sharing photographs and captions. Many key populations and PLWH globally have experience with taking, captioning, and sharing photographs via social media platforms.
Researchers have begun to explore the possibility of conducting online photovoice projects. Lichty et al. found an online photovoice project to be acceptable and feasible with American youth [24]. This project involved both synchronous and asynchronous components: training workshops were held with participants synchronously, whereas participants uploaded and commented on photographs asynchronously. Researchers identified benefits of online photovoice, including increasing the scale of the project by involving more participants and preserving project resources. To our knowledge, the methods for conducting asynchronous, online photovoice projects as well as the acceptability and feasibility of these methods with key populations and PLWH have yet to be described.
Current Study
Online, asynchronous photovoice methods offer a promising alternative to in-person, synchronous photovoice methods in cases when members of key populations and PLWH cannot gather due to geographic constraints and/or concerns regarding confidentiality or safety. Yet, online, asynchronous photovoice methods with key populations and PLWH have yet to be described, representing a barrier to the adoption of this methodology. Therefore, the first goal of this manuscript is to describe the methods that our team used to conduct an online, asynchronous photovoice project with sufficient detail that they could be replicated by other research teams. The second goal is to assess the feasibility and acceptability of the online photovoice project, as indicated by responses to an online survey and completion of photovoice submissions.
Methods
The photovoice project was part of a program of research focused on addressing HIV-related stigma among clinicians in Malaysia. This program of research involved a partnership between clinicians, social scientists, and community members from Malaysia and the United States. The project was designed to serve two purposes, including (1) answering descriptive research questions regarding key populations’ and PLWH’s experiences of stigma in healthcare settings, and (2) providing intervention content to reduce HIV-related stigma among clinicians in the context of a longitudinal randomized controlled trial. The project was conducted in Malaysia in the fall of 2021. Below, we provide information about the study context. To achieve the first goal of the current study, we describe our methods for conducting this online, asynchronous photovoice project. To achieve the second goal, we describe our methods for assessing perceived acceptability and feasibility of online, asynchronous photovoice.
Context
Malaysia is a high, middle-income country in Southeast Asia. The national language is Bahasa Malay, and English is the common language spoken by multi-ethnic, multi-lingual Malaysians. HIV is concentrated among Malaysian key populations, including MSM, PWID, TGW, and FSW, and prevalence ranges from 15.8 to 54.0 times those of the general population [25]. Yet, members of these key populations are, at best, half as likely as members of the general population to know their HIV status [25]. Stigma towards key populations is structurally sanctioned in Malaysia, where secular and/or Shariah laws criminalize same-sex sexual practices, gender expression of transgender persons, drug possession and use, and sex work [26–28]. Protecting the identities of key populations and PLWH is therefore critically important. The project took place in 2021 when in-person data collection was challenging due to the COVID-19 pandemic. To curb the spread of COVID-19, periodic Movement Control Orders issued by the government restricted movement and public assembly within Malaysia. Although our team had initially planned to conduct a traditional, in-person photovoice project, the pandemic made it challenging to safely gather participants. We therefore conducted the photovoice project online.
Photovoice
The online photovoice project was conducted in four phases. First, we built a custom website to host the project and facilitate data collection. Second, we collected data by recruiting participants as well as monitoring participant engagement in the study and submissions of photographs and captions. Third, we reviewed and de-identified submissions to ensure confidentiality. Fourth, we disseminated the photovoice submissions. These phases are described in detail below.
Phase 1: Website Design
The project website served three main purposes, including to: (1) introduce participants to the photovoice project and facilitate the informed consent process, (2) teach participants photography skills and an understanding of visual literacy, and (3) collect photovoice submissions from participants. We created a series of short videos to accomplish these goals and facilitate participant connection, comprehension, and engagement with the project [29]. These videos featured 10 Malaysian clinicians, a photographer (i.e., a professional photographer and professor of photography) who was a member of the study team, and an exemplar participant. The website included a password-protected participant portal. After entering their password, participants landed at the homepage. From the homepage, participants could navigate to a series of pages designed to introduce them to the project and photography, and facilitate completion of the photovoice submissions. Prompts for the photovoice submissions were framed as “challenges” to enhance engagement by gamifying participation [30]. The webpages and videos are described in Appendix 1.
The website was accessible in both Bahasa Malay and English. Participants could switch between the two languages using a toggle button at the top of the website. On the Malay version of the website, all text and downloadable forms (e.g., consent forms, photograph recipe card) were translated from English to Malay by a member of the study team. Most clinicians and the photographer spoke in English in the videos. The videos on the Malay version of the website included either written Malay captions or Malay voice-overs. One clinician spoke in Malay in the videos, and their video segments included English captions on the English version of the website.
Participant confidentiality was prioritized in website design. The website was compliant with the U.S. Health Insurance Portability and Accountability Act (HIPAA) [31]. Data were encrypted at rest and in transit. Participants did not have to create an account for the website; therefore, they did not have to provide their name or any other identifying information to use the website. They were given dummy email addresses and passwords to log into the site so that they would not have to use their personal email addresses. Additionally, the website instructed participants to not submit photographs of their own or other people’s faces.
Phase 2: Data Collection
Participant recruitment and data collection occurred on a rolling basis and lasted for 5 weeks, starting in early October and lasting through mid-November 2021. Our recruitment strategy was developed in partnership with members of our Scientific and Community Advisory Board, and leveraged approaches that our team has successfully used to recruit key populations and PLWH for previous studies in Malaysia. Participants were recruited through digital flyers that were shared via social media and WhatsApp by local community organizations serving key populations and PLWH. Flyers were shared in Bahasa Malay and English. Eligibility criteria included: 18 years or older, access to a camera phone with internet connection, and belonging to a key population group (i.e., MSM, TGW, FSW, PWID) or living with HIV. Interested individuals contacted a research assistant via a study-specific WhatsApp number. The research assistant, who spoke Bahasa Malay and English, screened individuals for study eligibility.
The research assistant scheduled appointments with eligible individuals to introduce the project and complete the consenting process by phone. During this appointment, the research assistant shared a dummy email address and password with each participant so that they could log into the website. The research assistant then prompted participants to watch the project introduction video and reviewed the consent form with participants. Participants were also asked whether they would like to have their photographs shared with general audiences for advocacy purposes. After participants consented to the study and indicated whether they were willing to share their photographs for advocacy purposes, the research assistant introduced participants to the rest of the website. Participants were given the option to watch the photography introduction videos during the appointment with the research assistant or at a later time on their own. The research assistant additionally showed participants how to access the six photovoice challenges. Participants were encouraged to respond to one challenge per day over the course of a week but were told that they could complete the challenges faster or slower. After the call, the research assistant sent participants a COVID-19 safety sheet over WhatsApp that included tips to avoid COVID-19 exposure while engaging in the project (e.g., wear a face mask, practice social distancing, avoid crowded areas).
The research assistant monitored participant engagement and submissions daily. They sent participants messages to encourage engagement. As examples, they messaged participants who were not uploading submissions to ask if they had questions or problems with the website and they messaged participants who were uploading submissions with compliments about submissions. The research assistant additionally screened the photographs for identifiers, including people’s faces, and asked participants to upload new submissions if photographs included identifiers.
Participants were compensated for each step of the project, including completing the introductory call with the research assistant and for each photovoice submission. Photovoice submissions were compensated on an increasing scale, with each submission compensated at a higher rate than the previous submission. Participants were eligible for a bonus if they completed all aspects of the project. Participants could earn 400 Malaysian Ringgit (approximately $100 U.S. Dollars) for participating in all aspects of the project. The monthly minimum wage in Malaysia is 1500 Malaysian Ringgit (approximately $375 U.S. Dollars). Participants could choose to receive their compensation via an online bank transfer or by collecting it from the research site.
Phase 3: Submission Review
A photograph de-identification protocol was developed based on HIPAA guidance and recommendations for de-identifying photographs in medical settings [32]. Using a photograph de-identification form (see Appendix 2), two members of the study team independently screened each photograph for four different categories of identifiers. Categories included: any facial photography, identifiers intrinsic to the participant (e.g., anatomic anomalies, birthmark, scar), identifiers on the participant (e.g., unique clothing, jewelry, piercings, tattoos), and identifiers around the participant (e.g., unique setting, surrounding, location). Photographs were characterized as: (1) not including identifiers and thus eligible for inclusion in photovoice presentations, (2) including identifiers that cannot be edited out and thus must be permanently deleted, or (3) including identifiers that can be edited out and thus would be edited and re-reviewed.
After completing their independent screenings, the two team members met with an additional team member to discuss the screenings as a panel. Consensus regarding screenings was achieved through panel discussion. Photographs that were determined to include identifiers that could be edited out were then edited by a member of the team. The panel then re-convened and re-reviewed the edited photographs according to the de-identification protocol.
Phase 4: Dissemination
Our dissemination plan prioritized sharing results of the photovoice study with several audiences: clinicians enrolled in our randomized controlled trial, members of the key population and PLWH communities, and members of the general public. The dissemination plan was developed and executed in partnership with members of our Scientific and Community Advisory Board. To disseminate results to clinicians in our randomized controlled trial, we created a series of videos that featured montages of participant submissions. Each video featured one key population (i.e., MSM, PWID, TGW, or FSW) or PLWH group and lasted approximately 3 min. To disseminate results to members of the key population and PLWH communities, we created two brief videos that could be shared via social media. To disseminate results to members of the general public, we posted photovoice submissions to a university website that could also be shared via social media. Photovoice submissions from participants who agreed to share their photographs with general audiences for advocacy purposes were featured in the videos and website.
Assessment
Data used to assess the feasibility and acceptability of the project were drawn from several sources, including participant responses to surveys and open-ended questions embedded in the website as well as the photovoice submissions. Information regarding whether participants belonged to a key population group or were a person living with HIV were collected to determine study eligibility. Data regarding participant socio-demographic characteristics, however, were not collected during this study. As noted in the introduction, key populations and PLWH are highly stigmatized and often criminalized in Malaysia. Any information that could be used to identify participants was therefore carefully considered by the study team and Institutional Review Boards in Malaysia and the U.S. Moreover, collecting socio-demographic characteristics could increase participants’ perceived threat to confidentiality, even if this threat were to be minimized with data management. Ultimately, given that data regarding socio-demographic characteristics were not needed to achieve study aims, the risk of collecting socio-demographic data was deemed to outweigh potential benefits.
Measures and Indicators
Acceptability and feasibility were measured using quantitative and qualitative methods. Data regarding participants’ perceived quality of the videos and website were collected given that they were hypothesized to be associated with participants’ perceived acceptability and feasibility of the project overall. Indicators of fidelity included measures of photovoice completion and confidentiality of photovoice submissions. All self-report measures are included in Appendix 3.
Acceptability and Feasibility
Acceptability and feasibility of the project was assessed using a validated implementation outcome scale [33], which participants completed after the final photovoice challenge. Scale items were adapted to refer to the photovoice challenges and rated on 5-point Likert-type scales ranging from strongly disagree (1) to strongly agree (5). Acceptability was measured with three items (Cronbach’s alpha = 0.79), and feasibility was measured with two items (Cronbach’s alpha = 0.81). Mean scores were created to represent acceptability and feasibility. Participants were also asked two open-ended questions about the photovoice challenges, including: “What did you like about the photovoice challenges?” and “What should we change about the photovoice challenges?”.
Video and Website Quality
Ratings of video quality were developed for the current study and included following videos introducing the project and photography. Scale items were rated on 5-point Likert-type scales ranging from strongly disagree (1) to strongly agree (5). Video quality was assessed with three items for both the introduction to project video (Cronbach’s alpha = 0.82) and introduction to photography videos (Cronbach’s alpha = 0.85). Ratings of website quality were assessed using items from a validated measure of quality of website user experience [34]. Ratings of website quality were completed after the final photovoice challenge, alongside ratings of project acceptability and feasibility. Three items assessed usability of the website (Cronbach’s alpha = 0.94), three items assessed trust in the website (Cronbach’s alpha = 0.92), and three items assessed the appearance of the website (Cronbach’s alpha = 0.87). Mean scores were created to represent video and website quality. Participants were additionally asked two open-ended questions about the website, including: “What did you like about the website?” and “What should we change about the website?”.
Fidelity
As a measure of fidelity, we examined the number of photovoice submissions completed by participants. There were a total of six photovoice prompts, and a higher rate of photovoice completion was considered an indicator of greater fidelity. We additionally explored the number of participants who engaged in the English versus Malay versions of the website, as well as the number of participants who volunteered to have their photographs shared with general audiences for advocacy purposes in addition to research purposes.
Submission Confidentiality
A central question was whether this online, asynchronous form of photovoice would yield non-identifiable submissions that could be used in photovoice presentations for intervention and advocacy purposes. Therefore, the number of non-identifiable photovoice submissions was determined following photovoice submission review.
Analysis
To analyze the quantitative data, we explored descriptive statistics and correlations between key variables. To analyze the qualitative data, we employed elements of Rapid Qualitative Inquiry methods [35]. Rapid Qualitative Inquiry was chosen for several reasons. First, it focuses on developing an insider’s perspective on an issue. We sought to understand our participants’ perspectives on and experiences with online, asynchronous photovoice. Second, Rapid Qualitative Inquiry requires teamwork. We prioritized a team-based approach given that our team included individuals with unique perspectives and expertise (e.g., key population, clinician, photographer) that we believed were invaluable to the analysis process. Third, it is recommended for evaluation, and our goal was to evaluate the acceptability and feasibility of online, asynchronous photovoice. Finally, Rapid Qualitative Inquiry is a targeted qualitative method designed to reduce lengthiness of qualitative research. Given the timeline of our overall program of research, we sought a method that would reduce our time on this phase of the project without sacrificing analysis quality.
Analyses were iterative and team-based. Initial findings were summarized and then discussed with members of the team. Team members focused on reaching consensus around conclusions, and triangulating qualitative and quantitative data. Findings were re-summarized and again discussed with members of the team, and conclusions were refined. As a trustworthiness check, results were then shared with members of the project’s Scientific and Community Advisory Board as well as community partners from a local community-based advocacy organization to verify the team’s conclusions.
Results
Thirty-four participants completed the photovoice challenges, with 12 (35.3%) identifying as MSM, 8 (23.5%) as PLWH, 7 (20.6%) as TGW, 7 (20.6%) as FSW, and 6 (17.6%) as PWID. Five participants (14.7%) identified as MSM and PLWH, and one participant (2.9%) identified as TGW and PLWH. Two individuals (n = 1 PLWH, n = 1 PWID) met with the research assistant to learn about the project and provide consent to participate, but then did not engage in the project or respond to the research assistant.
Acceptability and Feasibility
Responses to the final survey demonstrate that the photovoice project was viewed as both acceptable and feasible by participants, with mean scores for acceptability and feasibility both above 4.5 out of 5 (see Table 1). Participants evaluated the photovoice project positively in response to the open-ended questions. Participants enjoyed the opportunity to express themselves through photography, with one noting: “I love it because it gives me the opportunity to convey my heart and words through pictures, in a unique way.” Several participants liked that the challenges were anonymous, with one stating that they appreciated “expressing who we are without revealing ourself.” Participants enjoyed learning new photography skills. For example, one participant stated “I like how the challenges help us exercise our minds and how we are able to learn new skills.” Several participants reported that the challenges were fun, with one stating: “Unlike an ordinary survey, the photovoice allows participants to do something fun.”Table 1 Participant assessments of indicators of acceptability and feasibility, and quality of videos and website (n = 34)
Construct Mean (SD) Correlations
Acceptability Feasibility
Photovoice implementation outcomes
Acceptability 4.65 (0.46) – –
Feasibility 4.56 (0.56) 0.60** –
Video quality ratings
Introduction to project 4.46 (0.53) 0.55** 0.61**
Introduction to photography 4.38 (0.52) 0.59** 0.56**
Website quality ratings
Usability 4.63 (0.52) 0.74** 0.72**
Trust 4.52 (0.63) 0.71** 0.64**
Appearance 4.47 (0.53) 0.56** 0.71**
All constructs were evaluated on 1–5 point Likert-type scales, with higher scores indicating greater approval of construct
**p < 0.001
When asked what could be done to improve the photovoice project, many participants responded that nothing should change. For example, one suggested that the team “proceed without changing what is already there.” Yet, several participants provided valuable ideas to improve on future photovoice projects. Participants requested more challenges focused on religion, stigma, and HIV and STI treatment. One participant suggested that participants choose questions themselves, noting: “Maybe in the future, we should give flexibility to participants to make 1 or 2 questions.” Two participants requested the option to submit responses using videos, with one stating: “Making the challenge of recording video to make the message easier to convey.” One participant suggested that the project be offered via an app instead of a website. Finally, one participant suggested that the challenges be leveraged to empower individuals and communities, stating: “Photovoice projects entail the opportunity for empowering participants. Future research using photovoice should assess the influence it has on participants’ empowerment changes and how to sustain those individuals and social changes.”
Video and Website Quality
Participants rated the quality of the videos introducing the project and photography as high, and agreed that the website was usable, trustworthy, and pleasing in appearance (see Table 1). Participant ratings of video and website quality were positively correlated with their ratings of project acceptability and feasibility, suggesting that participants who viewed the videos and websites as higher in quality also found the project to be more acceptable and feasible. Participants also evaluated the website positively in response to the open-ended questions. They appreciated that the website was simple and easy to use, with one participant noting that: “It’s very simple and clean. It’s very easy to navigate.” Several participants who completed the project in Malay reported that the two language options facilitated understanding, with one stating: “Easy to understand because you can choose two languages, namely English and Malay.” Participants additionally noted that they enjoyed learning about photography, with one stating that the website was “packed with knowledge.” One participant liked that they did not have to share any identifying information to participate, stating: “I do not have to fill in any details about myself to register. I feel comfortable and safe.”
When asked what could be done to improve the website, many participants again responded that nothing should change. One participant stated: “I like the website, nothing should change.” Participants gained access to photovoice challenge prompts one at a time. For example, they were able to view the webpage describing the fourth photovoice challenge only after viewing the webpage describing the third challenge. Two participants requested the ability to view a summary of all of the photovoice challenge prompts at the beginning of the project. One of these participants stated that:It would be nice if we could have the whole idea of how we should answer all our questions with being able to access all the challenges before answering them. That will give me [a] better view on how to select my photo and write [my] captions.
Fidelity
All participants completed all photovoice challenges (i.e., 100% completion rate), indicating a very high degree of fidelity. Half of participants (n = 17) engaged in the Malay version of the website, and half engaged with the English version. Most participants (n = 27, 79.4%) volunteered to share their photographs with general audiences for advocacy purposes. Participants who preferred to have their photographs used only for research purposes included 3 PWID, 2 TGW, 1 PLWH, and 1 PLWH/MSM participant.
Submission Confidentiality
There were 204 total photovoice submissions (i.e., 34 participants completed 6 photovoice submissions; see Fig. 2). Thirteen (10.3%) of the photovoice submissions were flagged as identifiable by the research assistant during the data collection period (e.g., an identification card that included a photograph of a participant, a tattoo, people’s faces). All of these submissions were replaced by participants, resulting in 204 submissions for the panel review. The majority of submissions (n = 183, 89.7%) were rated as unidentifiable by the panel and eligible for inclusion in photovoice presentations. Of the remaining 21 (10.3%) submissions, 4 (19.01%) were rated as including identifiers that could not be edited out (e.g., unique houses in identifiable settings, a distinctive silhouette of a person), 9 (42.8%) were rated as including identifiers that could possibly be edited out (e.g., a distinctive watch on an arm, a license plate number, address numbers on a building), and 8 (38.01%) were rated as not identifiable. The editable photographs were edited by blurring identifiable aspects of the photographs, and all of the edited photographs were subsequently rated by the panel as unidentifiable. This process resulted in 200 total photographs (n = 191, 95.5% unedited; n = 9, 4.5% edited) that were considered appropriate for inclusion in the final photovoice analysis. In sum, the vast majority of photographs submitted by participants were either not identifiable or were easily editable to protect confidentiality, yielding a rich final dataset for analysis and dissemination. Examples of photovoice submissions are included in Fig. 3.Fig. 2 Submission confidentiality screen (n = 34 participants)
Fig. 3 Photovoice examples
Discussion
Results of this project suggest that online, asynchronous photovoice methods are acceptable to and can be feasibly used with key populations and PLWH in Malaysia and perhaps more broadly, potentially holding promise to increase the scale of this highly versatile and action-oriented qualitative method within the field of HIV research. This approach was especially feasible and acceptable during stringent lockdowns in Malaysia during the COVID-19 pandemic. Supporting the acceptability of this method, participants enjoyed expressing themselves through photography and learning new skills, and noted that photovoice was more fun than other commonly used data collection methods such as surveys. Participants reviewed several features of the website positively, including its simple design, dual language options, and content about photography. Participants’ ratings of the videos and website quality were positively correlated with their ratings of project acceptability and feasibility. It is possible that an online interface that is perceived as high quality and easy to use may contribute to the acceptability and feasibility of online, asynchronous photovoice projects. Further supporting feasibility, participants completed 100% of the photovoice assignments and several participants noted that they would have liked to respond to more assignments. Additionally, almost all photographs (98%) were either non-identifiable when submitted or easily editable to remove identifiers. In total, this project yielded many photovoice submissions (n = 200) that could be used for research, intervention, and advocacy purposes.
Online, asynchronous photovoice methods may enhance participant safety and address confidentiality concerns, particularly in places with pronounced stigma towards key populations and PLWH. Previous researchers have highlighted the importance of carefully considering ethical concerns when engaging in photovoice projects with communities affected by HIV [19]. Online methods address some of these concerns given that participants do not have to physically gather—they can remain anonymous to other participants and will not be observed going to a study site for key populations or PLWH. Participant safety was additionally promoted in several ways through the design of the website and project protocol. First, the website was designed so that participants did not need to use their own email address to register or login, and no identifying information (including socio-demographic characteristics) were collected from participants during the study. Participants reported that they appreciated the ability to maintain anonymity on the website. Second, the website was HIPAA-compliant, with data encrypted both at rest and in transit. This ensured a high level of protection for participant data, comparable to that afforded to private health-related data in the U.S. Third, measures were taken to ensure that identifiable photographs were not taken or kept. Participants were instructed and reminded to not submit photographs of faces. Photographs were screened as they were submitted, and participants were asked to resubmit photographs with identifiable content. Additionally, all submissions were reviewed and de-identified following a protocol based on HIPAA guidance.
Strengths, Limitations and Future Directions of Online, Asynchronous Photovoice
There are both strengths and limitations of online, asynchronous photovoice methods that researchers, community members, and other stakeholders may consider as they decide whether to adopt this method for research, intervention, and advocacy purposes. Strengths include the high levels of confidentiality afforded to participants, which is important in places with substantial stigma towards and criminalization of key populations and PLWH. Additionally, online methods can enable individuals to participate from dispersed geographic locations. This may be particularly advantageous when trying to engage individuals from rural locations, where key populations and PLWH may experience barriers to transportation to research sites. Online methods may also be safer during COVID-19 surges, when gathering in person may threaten the health of participants. Online, asynchronous photovoice projects additionally have potential to engage participants at large scales, allowing for larger reach in implementation. Although this study was relatively modest in size, with 34 participants, a recent online photovoice project engaged 120 participants across one U.S. state [24]. Finally, findings from this study suggest that online, asynchronous photovoice methods are highly acceptable to and feasible for participants.
Despite these benefits, there are limitations of online, asynchronous photovoice methods that may lead researchers and community partners to choose in-person, synchronous methods. Individuals needed to have a camera phone with internet connection to participate in the current study. Although smartphones have been increasing in popularity worldwide, this inclusion criteria may have excluded some individuals without smartphone access. The markedly high reach and use of smartphone ownership, including among key populations and in emerging economies, may make this limitation less concerning [21–23]. Future studies may explore the feasibility of providing camera phones with internet connection to participants. Designing a HIPAA-compliant website including instructional videos for one study can be resource-intensive and may not be feasible for projects with limited budgets or personnel. Strack et al. describe the development of a web-based tool that could be used by multiple studies [36]. Such a resource may be very useful for increasing the scale of photovoice studies within HIV research. Moreover, some participants may prefer formats other than websites, such as apps. As researchers develop infrastructure for such online data collection, they will have to continue to grapple with evolving data privacy issues (e.g., handling meta-data associated with digital photographs [32]).
An additional limitation of this study was that participants did not engage in participatory analysis after submitting their photographs and captions. Depending on the aims of photovoice projects, this can be a critically important component of photovoice methods [2, 3]. Our team met with members of our Scientific and Community Advisory Board as well as community partners from a local community-based organization to reflect on themes that emerged from the data and design a dissemination strategy for advocacy purposes. Other studies have facilitated online engagement of participants in the analysis stage, including via blogs [24]. Future studies employing online, asynchronous photovoice methods may continue to explore strategies for participatory analysis that maintain participant confidentiality and safety. Future studies may additionally explore strategies for facilitating participant engagement and interaction at other stages of photovoice projects, including choosing the photovoice prompts, engaging with the website content (e.g., instructional videos), and directing the dissemination strategy.
Conclusions
Although photovoice is a unique and powerful form of participatory action research, it is currently underutilized within HIV research [1]. Online, asynchronous methods have potential to substantially enhance the scale of this method. The acceptability and feasibility of online photovoice methods have been explored with other populations [24], and this study suggests that these methods may also be acceptable to and feasible for key populations and PLWH. Researchers, community partners, and other stakeholders may balance the strengths (e.g., high levels of confidentiality) and limitations (e.g., barriers to participatory analysis) of this approach in relation to their study aims and context. The development, testing, and use of diverse photovoice methods may ultimately better contribute to qualitative HIV research, interventions, and advocacy.
Appendix 1: Outline of Website
Participants accessed the following website pages in sequential order.Homepage (one page): the homepage featured a 2-min video with four Malaysian clinicians who welcomed participants to the project, introduced themselves, and described why they chose to become infectious disease clinicians. From the homepage, participants could navigate to a series of pages designed to introduce them to the project and photography, and facilitate completion of the photovoice submissions.
Introductions (two pages): two pages introduced participants to the project and photography.Project: included a 3-min video of a clinician who further welcomed participants. The clinician described the purpose of the project as to help doctors connect with and understand the lives of patients from key populations and/or living with HIV. The clinician additionally introduced the concept of photovoice and invited participants to share their experiences with doctors by responding to a series of photovoice prompts. This page also included the project consent form and a form where participants could indicate whether they agreed to share their photovoice submissions with clinicians and other audiences outside of the project (e.g., local community advocacy groups).
Photography: included four videos featuring the photographer teaching about photography. Individual videos focused on composition, color, and light. Videos included example photographs and brief animations to demonstrate concepts, and lasted 3–5 min. The page also included a photo recipe card summarizing tips from the videos, which participants could download and reference as they took photographs for the project.
Photovoice prompts (six pages): six pages introduced participants to specific photovoice prompts. Each prompt was accompanied by a brief video (length = 1.5–2.5 min) featuring up to three clinicians responding to the prompt verbally and one clinician stating why learning about participants’ responses would help them provide better care to patients. Videos additionally featured an exemplar participant sharing their own photovoice submission in response to the prompt and the photographer reinforcing photography techniques from the introductory videos. Below the videos were places for participants to upload photographs and enter accompanying captions. Prompts included:What makes you happy?
What makes you sad?
What is important to you?
What challenges do you face?
How do doctors see you?
What do you want doctors to know about you?
Appendix 2: Photograph De-identification Form
Reviewer ID:
Photo ID:
Date:
Instructions: Two independent reviewers will screen each photograph for identifiers. Their reviews will be compared, and discrepancies will be discussed as a team.
Each reviewer should follow the following steps:Step 1: Review the photograph for identifiers.
Step 2: Check any boxes that apply and make note of the identifier.
Step 3: Mark the location of the identifier in the photograph.
Step 4: Check recommendation regarding whether photograph includes identifier.
Identifier Notes
Any facial photography
Face
Intrinsic to the participant
Anatomic anomalies
Birthmark
Scar
Other
On the participant
Unique clothing
Jewelry
Piercings
Tattoos
Other
Around the participant
Unique setting
Unique surrounding
Unique location
Other
Recommendation:Category 1: Photo does not include identifiers.
Category 2: Photo includes identifiers that cannot be edited out.
Category 3: Photo includes identifiers that may be edited out—this photograph may be eligible for inclusion in photovoice presentation after editing and re-review.
Next steps:Compare reviewers’ category assignments. Disagreements to be resolved via discussion.
The following steps will be taken with photographs from each category:Category 1 photographs can be included in photovoice presentations.
Category 2 photographs will be permanently deleted.
Category 3 photographs should be sent to the photographer for editing. Edited photographs will be assigned a new photo ID and then re-reviewed following this protocol.
Appendix 3: Self-report Measures
Participants responded to the following items:Photovoice implementation outcomes: Acceptability
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree
I liked doing the photovoice challenges 1 2 3 4 5
I would recommend the photovoice challenges to a friend 1 2 3 4 5
The photovoice challenges were enjoyable 1 2 3 4 5
2. Photovoice implementation outcomes: Feasibility
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree
The photovoice challenges took the right amount of time 1 2 3 4 5
The photovoice challenges were possible to do in my everyday life 1 2 3 4 5
3. Video quality ratings: Introduction to the project
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree
This video was clear 1 2 3 4 5
This video was the right length, or amount of time 1 2 3 4 5
I understand the goals of the project 1 2 3 4 5
4. Video quality ratings: Introduction to photography
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree
These videos were clear 1 2 3 4 5
These videos were the right length, or amount of time 1 2 3 4 5
I learned about photography from these videos 1 2 3 4 5
5. Website quality ratings: Usability
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree
The website is easy to use 1 2 3 4 5
It is easy to move around on the website 1 2 3 4 5
It is easy to submit photographs and captions through the website 1 2 3 4 5
6. Website quality ratings: Trust
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree
I feel comfortable sending my photographs through the website 1 2 3 4 5
I trust the website 1 2 3 4 5
I’m not worried about other people seeing my photographs and captions 1 2 3 4 5
7. Website quality ratings: Appearance
Strongly disagree Disagree Neither agree nor disagree Agree Strongly agree
I like how the website looks 1 2 3 4 5
The website has a clean and simple look 1 2 3 4 5
The videos were well-made 1 2 3 4 5
Acknowledgements
The authors would like to thank all of the study participants and the Malaysian AIDS Council for their partnership, as well as Jordan Silberman for his partnership on website development.
Author Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by VAE, JC, PLW, RS, SW, and AAH. All authors read, revised, and approved the final manuscript.
Funding
This work was supported by the National Institute of Mental Health (Grant No. R34MH124390) and National Institute on Drug Abuse (Grant No. K01DA053159). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data Availability
Data may be available from the corresponding author upon request.
Declarations
Conflict of interest
The authors declare no conflicts of interest.
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study received institutional review board approval from the University of Delaware (1588354) and University of Malaya Medical Centre.
Consent to Participate
All participants provided informed consent.
Consent for Publication
In addition to consenting to the study, participants consented to have their photographs shared via publication.
1 We recognize that preferred terminology within the HIV field evolves. As recommended by the current UNAIDS Terminology Guidelines [6] and National Institute of Allergy and Infectious Diseases HIV Language Guide [7], we use the term people living with HIV (PLWH) in this manuscript.
Publisher's Note
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References
1. Teti M Koegler E Conserve DF Handler L Bedford M A scoping review of photovoice research among people with HIV J Assoc Nurses AIDS Care 2018 29 504 527 10.1016/j.jana.2018.02.010 29576252
2. Golden T Reframing photovoice: building on the method to develop more equitable and responsive research practices Qual Health Res 2020 30 960 972 10.1177/1049732320905564 32081060
3. Wang C Burris MA Photovoice: concept, methodology, and use for participatory needs assessment Health Educ Behav 1997 24 369 387 10.1177/109019819702400309 9158980
4. Rhodes SD Hergenrather KC Wilkin AM Jolly C Visions and voices: indigent persons living with HIV in the southern United States use photovoice to create knowledge, develop partnerships, and take action Health Promot Pract 2008 9 159 169 10.1177/1524839906293829 17563400
5. Catalani C Minkler M Photovoice: a review of the literature in health and public health Health Educ Behav 2010 37 424 451 10.1177/1090198109342084 19797541
6. United Nations Programme HIV/AIDS. UNAIDS terminology guidelines 2015. Geneva: UNAIDS. Available at: https://www.unaids.org/sites/default/files/media_asset/2015_terminology_guidelines_en.pdf. Accessed 26 July 2022.
7. National Institute of Allergy and Infectious Diseases. NIAID HIV language guide. Available at: https://www.hptn.org/sites/default/files/inline-files/NIAID%20HIV%20Language%20Guide%20-%20March%202020.pdf. Accessed 26 July 2022.
8. Teti M Pichon L Kabel A Farnan R Binson D Taking pictures to take control: photovoice as a tool to facilitate empowerment among poor and racial/ethnic minority women with HIV J Assoc Nurses AIDS Care 2013 24 539 553 10.1016/j.jana.2013.05.001 24064314
9. Budig K Diez J Conde P Sastre M Hernán M Franco M Photovoice and empowerment: evaluating the transformative potential of a participatory action research project BMC Public Health 2018 18 1 9 10.1186/s12889-018-5335-7
10. Teti M Conserve D Zhang N Gerkovich M Another way to talk: exploring photovoice as a strategy to support safe disclosure among men and women with HIV AIDS Educ Prev 2016 28 43 58 10.1521/aeap.2016.28.1.43 26829256
11. Flanagan EH Buck T Gamble A Hunter C Sewell I Davidson L “Recovery speaks”: a photovoice intervention to reduce stigma among primary care providers Psychiatr Serv 2016 67 566 569 10.1176/appi.ps.201500049 26766754
12. Suprapto N Sunarti T Suliyanah Wulandari D Hidayaatullaah HN Adam AS Mubarok H A systematic review of photovoice as participatory action research strategies Int J Eval Res Educ 2020 9 675 683
13. Lorenz LS Kolb B Involving the public through participatory visual research methods Health Expect 2009 12 262 274 10.1111/j.1369-7625.2009.00560.x 19754690
14. Witkowski K Valerio R Samad A Matiz-Reyes A Padilla M Aging and thriving with HIV: a photovoice project with long-term HIV survivors in Miami, Florida Arts Health 2021 13 329 346 10.1080/17533015.2020.1821386 32951532
15. Lennon-Dearing R Price J Women living with HIV tell their stories with photovoice J Hum Behav Soc Environ 2018 28 588 601 10.1080/10911359.2018.1443867
16. Markus SF Photovoice for healthy relationships: community-based participatory HIV prevention in a rural American Indian community Am Indian Alsk Native Ment Health Res 2012 19 102 123 10.5820/aian.1901.2012.102 22569727
17. Lofton S Norr KF Jere D Patil C Banda C Developing action plans in youth photovoice to address community-level HIV risk in rural Malawi Int J Qual Methods 2020 19 1 12 10.1177/1609406920920139
18. Pellowski JA Barriers to care for rural people living with HIV: a review of domestic research and health care models J Assoc Nurses AIDS Care 2013 24 422 437 10.1016/j.jana.2012.08.007 23352771
19. Teti M Murray C Johnson LS Binson D Photovoice as a community-based participatory research method among women living with HIV/AIDS: ethical opportunities and challenges J Empir Res Hum Res Ethics 2012 7 34 43 10.1525/jer.2012.7.4.34 23086046
20. O’Dea S. Number of smartphone subscriptions worldwide from 2016 to 2027. Statista; 2022. Available at: https://www.statista.com/statistics/330695/number-of-smartphone-users-worldwide/. Accessed 26 July 2022.
21. Poushter J, Bishop C, Chwe H. Social media use continues to rise in developing countries but plateaus across developed ones. Pew Research Center; 2018. Available at: https://www.pewresearch.org/global/2018/06/19/social-media-use-continues-to-rise-in-developing-countries-but-plateaus-across-developed-ones/. Accessed 26 July 2022.
22. Feroz AS Ali NA Khoja A Asad A Saleem S Using mobile phones to improve young people sexual and reproductive health in low and middle-income countries: a systematic review to identify barriers, facilitators, and range of mHealth solutions Reprod Health 2021 18 1 1 13 10.1186/s12978-020-01059-7 33388066
23. Shrestha R Lim SH Altice FL Copenhaver M Wickersham JA Saifi R Ab Halim MA Naning H Kamarulzaman A Use of smartphone to seek sexual health information online among Malaysian men who have sex with men (MSM): implications for mHealth intervention to increase HIV testing and reduce HIV risks J Community Health 2020 45 10 19 10.1007/s10900-019-00713-x 31375976
24. Lichty L Kornbluh M Mortensen J Foster-Fishman P Claiming online space for empowering methods: taking photovoice to scale online Glob J Community Psychol Pract 2019 10 3 26
25. UNAIDS Country Factsheets: Malaysia. Available at: https://www.unaids.org/en/regionscountries/countries/malaysia. Accessed 26 July 2022.
26. Syariah Criminal Offences Enactment 1997. Available at: http://www2.esyariah.gov.my/esyariah/mal/portalv1/enakmen2011/Eng_enactment_Ori_lib.nsf/f831ccddd195843f48256fc600141e84/3f7f4673a90e5f2c48257679000ddf32?OpenDocument. Accessed 7 July 2022.
27. Barmania S Reiss MJ Islam and health policies related to HIV prevention in Malaysia 2018 Cham Springer International Publishing
28. Barmania S Aljunid SM Transgender women in Malaysia, in the context of HIV and Islam: a qualitative study of stakeholders’ perceptions BMC Int Health Hum Rights 2017 17 1 10 10.1186/s12914-017-0138-y 28052765
29. Hsin W-J Cigas J Short videos improve student learning in online education J Comput Sci Coll 2013 28 253 259
30. Looyestyn J Kernot J Boshoff K Ryan J Edney S Maher C Does gamification increase engagement with online programs? A systematic review PLoS ONE 2017 12 3 e0173403 10.1371/journal.pone.0173403 28362821
31. HIPAA Vault: HIPAA Compliant Hosting. Available at: https://www.hipaavault.com/. Accessed 24 Mar 2022.
32. Nettrour JF Burch MB Bal BS Patients, pictures, and privacy: managing clinical photographs in the smartphone era Arthroplast Today 2019 5 57 60 10.1016/j.artd.2018.10.001 31020023
33. Weiner BJ Lewis CC Stanick C Powell BJ Dorsey CN Clary AS Boynton MH Halko H Psychometric assessment of three newly developed implementation outcome measures Implement Sci 2017 12 1 12 10.1186/s13012-017-0635-3 28057027
34. Sauro J SUPR-Q: a comprehensive measure of the quality of the website user experience J Usability Stud 2015 10 68 86
35. Beebe J Rapid qualitative inquiry: a field guide to team-based assessment 2014 2 Lanham Rowman & Littlefield
36. Strack RW Orsini MM Fearnow-Kenney M Herget J Milroy JJ Wyrick DL Developing a web-based tool using information and communication technologies to expand the reach and impact of photovoice Am J Health Educ 2015 46 192 195 10.1080/19325037.2015.1044585 27642378
| 36463390 | PMC9734619 | NO-CC CODE | 2022-12-14 23:28:29 | no | AIDS Behav. 2022 Dec 3;:1-15 | utf-8 | AIDS Behav | 2,022 | 10.1007/s10461-022-03938-5 | oa_other |
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Article
Ratio-cum-product Type Estimators for Rare and Hidden Clustered Population
Singh Rajesh
http://orcid.org/0000-0002-5721-198X
Mishra Rohan [email protected]
grid.411507.6 0000 0001 2287 8816 Institute of Science, Department of Statistics, Banaras Hindu University, Varanasi, India
8 12 2022
121
19 1 2022
28 10 2022
© Indian Statistical Institute 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The use of multi-auxiliary variables helps in increasing the precision of the estimators, especially when the population is rare and hidden clustered. In this article, four ratio-cum-product type estimators have been proposed using two auxiliary variables under adaptive cluster sampling (ACS) design. The expressions of the mean square error (MSE) of the proposed ratio-cum-product type estimators have been derived up to the first order of approximation and presented along with their efficiency conditions with respect to the estimators presented in this article. The efficiency of the proposed estimators over similar existing estimators have been assessed on four different populations two of which are of the daily spread of COVID-19 cases. The proposed estimators performed better than the estimators presented in this article on all four populations indicating their wide applicability and precision.
Keywords and phrases
COVID-19
adaptive cluster sampling
ratio estimator
product estimator
regression estimator
combining estimators.
AMS (2000) subject classification
Primary 62-XX; Secondary 62D05
==== Body
pmcIntroduction
The type of sampling design to be used depends on the population under study and when that population is rare and hidden clustered, the conventional sampling designs cannot be used to estimate the population’s parameter of interest as most of the sampled units will provide a heavily biased estimate of the population’s parameter of interest. This has been one of the major issues in survey sampling theory. However, Thompson (1990) proposed a sampling design that gives an edge to the researcher by allowing them to fix a criterion or condition according to which the units will be selected in the sample. This sampling design is called Adaptive cluster sampling (ACS). Due to its flexibility and wide applications, ACS design have been used in various disciplines such as Ecological science (e.g., Acharya et al., 2000; Conners and Schwager 2002), Environmental science (e.g., Correll, 2001), Epidemiological study and Social science (Thompson, 1997; Thompson and Collins, 2002).
It is common in sample surveys that information regarding a variable related to the survey variable is known in advance from past surveys. If it is highly correlated with the survey variable then the use of such a variable increases the precision of the estimator. Such a variable is called an auxiliary variable. Researchers in sample surveys have been utilising auxiliary variables for a long time and many transformed estimators utilising them have been proposed (PRS INDIA, 2021; Acharya et al. 2000; Latpate and Kshirsagar, 2020; WHO, 2022). Using a single auxiliary variable, one of the most widely used and efficient estimator is the ratio estimator. However, in adaptive designs, the final sample size is not fixed in advance and thus the use of ratio estimators is somewhat restricted. This issue was addressed by Dryver and Chao (2007). As per their proposed methodology, classical sampling designs such as SRSWOR or SRSWR can be applied if we use observed network means for estimation. Since then, many modified and transformed ratio estimators have been proposed under ACS.
Using a single auxiliary variable many researchers have proposed highly efficient estimators in ACS design. Dryver and Chao (2007) proposed a ratio estimator and examined its properties, Yadav et al. (2016), proposed their estimator using a single auxiliary variable along with other known population parameters. Singh and Mishra (2021) proposed their improved exponential ratio estimator and studied its characteristics. Singh and Mishra (2022) proposed improved exponential ratio estimators for estimating cases of COVID-19 and studied its efficiency. Latpate and Kshirsagar (2020) proposed their two stage inverse ACS design.
As per WHO (2022), COVID-19 is caused by the SARS-CoV-2 virus. The virus spreads in various ways, some of them include, spreading between people who are in close proximity with each other or in a poorly ventilated indoor setting or getting infected by touching a surface contaminated by the virus and then touching own’s eye, nose or mouth without cleaning the hands. As a result, localities followed by cities and then entire states or provinces become a hotspot of the virus putting an immense burden on the limited healthcare system of a country.
At first, when the virus starts to spread, the cases are highly clustered or rare and at different places depending on the carrier of the virus. In such a situation using classical sampling designs to estimate the average number of cases would result in extremely biased estimates which would prove to be catastrophic. To deal with this, ACS becomes the only viable option (Chandra et al. 2021).
The use of two auxiliary variables will result in a further increase in the efficiencies of the estimators and this will be highly beneficial particularly in the case of adaptive designs (for instance, the ACS design) where getting a representative sample is difficult as the researchers are dealing with a population which is rare or highly clumped. In spite of that, there are only a handful of estimators in the ACS design for instance Chaudhry and Hanif (2015) where they proposed their estimator using two auxiliary variables to estimate the unknown population mean. This article aims to address this problem.
In this article, we have proposed four ratio-cum-product type estimators using two auxiliary variables. The estimators proposed are flexible and allows incorporation of negatively and positively correlated auxiliary variables. The performance of these estimators are examined on four different populations. The methodology of the ACS design has been presented in Section 2. Section 3 contains some related estimators which are already proposed under the ACS design along with their expressions of mean squared error (MSE). Section 4, contains the proposed ratio-cum-product type estimators and the derivations of their respective MSEs up to the first order of approximations. In Section 5, we derived the conditions in which the proposed estimator will be efficient over the other estimators presented in this article. In Section 6 the performance of the proposed estimators have been assessed on four different populations. To highlight the novelty and real life applicability of the ACS design, two of the four populations considered are of daily new cases of COVID-19 during its initial days of spread (between 27th March 2020 to 4th July 2020 COVID 2021) in the Indian state of Goa and union territory of Andaman & Nicobar islands as they are corelated and have similar pattern of spread of disease. Rest of the populations are taken from Thompson (2012). Section 7 contains a discussion over the results obtained on the four different populations and Section 8 contains the concluding remarks of this article.
Methodology of Adaptive Cluster Sampling
Adaptive cluster sampling (ACS), first proposed by Thompson (1990) in 1990 is a type of sampling scheme which is used for sampling rare and hidden clustered populations. In ACS, before conducting the survey, the researcher has to precisely define two things, namely: the neighbourhood of a unit (or observation)
the pre-defined condition (C)
The neighbourhood of an ith unit consists of other units, which are immediately adjacent in East, West, North and South directions to the ith unit. The pre-defined condition (C) is a criterion decided by the researcher according to which units are selected for estimating the population’s parameter of interest. Both of these definitions depend on the researcher but, usually the pre-defined condition (C) is yi > 0 where yi represents the ith unit or the ith observation on the survey variable and the neighbourhood which is generally considered in ACS, is the four-unit first-order neighbourhood. In ACS, an initial sample of size n is drawn using any probability sampling method (in this article the initial sample of size n is drawn using simple random sampling without replacement (SRSWOR)) from a population of size N. After the initial sample has been drawn, we draw the adaptive sample based on what has been drawn in the initial sample. For all the observations or units in the initial sample which satisfies the pre-defined condition (C), we draw their four-unit first-order neighbourhood, which includes that ith unit and its four adjacent units in the East, West, North and South directions. If any unit selected in the adaptive sample satisfies the condition of interest yi > 0, then its four-unit first-order neighbourhood is selected as well. This process of drawing the adaptive samples is repeated till there is no unit left satisfying the pre-defined condition (C).
There will be some observations in the neighbourhood satisfying the pre-defined condition (C) and there will be some observations in the neighbourhood, not satisfying the pre-defined condition (C). Observations satisfying it are called networks and those observations not satisfying it are called edge units. The edge units are considered as networks of size one. The selection of any observation or unit from a network leads to the selection of the entire network. These networks and edge units together form a cluster (Fig. 1). Figure 1 This is an example of a hypothetical cluster. The pre-defined condition (C) yi > 0. The units having y-values 1, 2, 4, 5 and 1 form a network of size five. The edge units are the units with y values 0, adjacent to the y values greater than 0. Together they form a cluster
The clusters are not necessarily disjoint due to overlapping edge units but the networks are disjoint and thus the entire population can be partitioned into exhaustive sets of networks. So the final sample consists of the initial sample and the adaptive samples.
Some Related Existing Estimators in ACS
An unbiased estimator for population mean under ACS was proposed by Thompson (1990) which was a modification of the Hansen and Hurwitz (1943). Thompson’s estimator is as follows: 3.1 tTh=(1n)∑i=1nwyi,
where wyi denotes the network means of network ψi containing the ith unit, so 3.2 wyi=1mi∑j𝜖Ψiyj,
where ψi is the network containing the ith unit and mi be the number of units in the network ψi. The variance of Thompson’s estimator is 3.3 V(tTh)=1n−1NY¯2Cwy2=fY¯2Cwy2,
where f=nN, Cwy2=Swy2Y¯2 and Swy2=1N−1∑i=1N(wyi−Y¯)2.
A modified ratio estimator was proposed by Dryver and Chao (2007) as 3.4 tDC=∑i=1nwyi∑i=1nwxiX¯,
where wyi=∑j𝜖Ψi(yj) and wxi=∑j𝜖Ψi(xj) denote the network means of a network containing the ith unit, where ψi is the network containing the ith and mi be the number of units in the network ψi.
The Mean Square Error of Dryver and Chao’s estimator t6 up to the first order of approximation is 3.5 MSE(tDC)=1n−1Nwy2¯[Cwy2+Cwx2−2ρwxwyCwxCwy].
Chaudhry and Hanif (2015) proposed regression-cum-exponential ratio estimators in adaptive cluster sampling: 3.6 tCH1=w¯y+β(Z¯−wz¯)expX¯−wx¯X¯+wx¯,
3.7 tCH2=w¯y+β(Z¯−wz¯)expX¯−wx¯X¯,
where β=SwywzSwx2.
The MSE of estimator tCH1 as per Chaudhry and Hanif (2015) is MSE(tCH1)=Y¯2𝜃Cwy2+14Y¯2𝜃Cwx2−β2Z¯2𝜃Cwz2−Y¯2𝜃ρwxwyCwyCwx−2βY¯Z¯𝜃ρwywzCwyCwz+βY¯Z¯𝜃ρwxwyCwxCwz.
However the correct expression of tCH1 is 3.8 MSE(tCH1corrected)=Y¯2𝜃Cwy2+14Y¯2𝜃Cwx2+β2Z¯2𝜃Cwz2−Y¯2𝜃ρwxwyCwyCwx−2βY¯Z¯𝜃ρwywzCwyCwz+βY¯Z¯𝜃ρwxwyCwxCwz.
The MSE of the estimator tCH2 is: 3.9 MSE(tCH2)=Y¯2𝜃Cwy2+Y¯2𝜃Cwx2+β2Z¯2𝜃Cwz2−2βY¯Z¯𝜃ρwzwy−2βY¯2𝜃ρwxwyCwxCwy+2βY¯Z¯𝜃ρwxwzCwxCwz.
Proposed Estimators
Motivated by Raj (1965), Singh (1967) and Perri (2005), we propose the following ratio-cum-product type estimators in Adaptive Cluster Sampling. 4.1 ta=w¯yl2∗l1∗X¯Z¯,
4.2 tb=w¯yX¯l1∗Z¯l2∗,
4.3 tc=w¯yl1∗X¯l2∗Z¯,
4.4 td=w¯yl1∗l2∗Z¯X¯,
where l1∗=w¯x+α1(X¯−w¯x) and l2∗=w¯z+α2(Z¯−w¯z).
The MSE up to the first order of approximations of the proposed estimators are: 4.5 MSE(ta)=1−fn(Swy2+γwx∗2+γwz∗2−2(γwyx∗−γwyz∗+γxz∗)),
4.6 MSE(tb)=1−fn(Swy2+γwx∗2+γwz∗2−2(γwyx∗+γwyz∗−γxz∗)),
4.7 MSE(tc)=1−fn(Swy2+γwx∗+γwz∗+2(γyx∗+γyz∗+γxz∗)),
and 4.8 MSE(td)=1−fn(Swy2+γwx∗+γwz∗+2(γyx∗−γyz∗−γxz∗))
respectively, (For detailed derivations, please see Appendix).
where Swy2=1N−1∑i=1N(wyi−Y¯)2, γwx∗2=R12Swx2,R1=Y¯X¯,Swx2=1N−1∑i=1N(wxi−X¯)2,
γwz∗2=R22Swz2,R2=Y¯Z¯,Swz2=1N−1∑i=1N(wzi−Z¯)2,
γwyx∗=(1−α1)R1Swywx,Swywx=1N−1∑i=1N(wyi−Y¯)(wxi−X¯),γwyz∗=(1−α2)R2Swywz,
Swywz=1N−1∑i=1N(wyi−Y¯)(wzi−Z¯),γwxz∗=(1−α1)(1−α2)R1R2Swxwz,
Swxwz=1N−1∑i=1N(wxi−X¯)(wzi−Z¯).
Using Cramer’s rule (2020), the optimum values of α1 and α2 which minimizes the MSE of estimators ta−d are: 4.9 α1=1−SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1−β1R1=α1−ta∗(say),
4.10 α2=δ2δ=1+SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2)=1+β2R2=α2−ta∗(say),
4.11 α1=1−SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1−β1R1=α1−tb∗(say),
4.12 α2=δ2δ=1−SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2)=1−β2R2=α2−tb∗(say),
4.13 α1=1+SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1+β1R1=α1−tc∗(say),
4.14 α2=δ2δ=1+SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2)=1+β2R2=α2−tc∗(say),
4.15 α1=1+SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1+β1R1=α1−td∗(say),
and 4.16 α2=δ2δ=1−SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2)=1−β2R2=α2−td∗(say).
Substituting the obtained α∗ in expressions of MSEs of estimators ta, tb, tc and td, we get 4.17 MSE(tj)=1−fnSwy2(1−Rwy.wxwz2)
where j = a,b,c,d for estimators ta, tb, tc and td and Rwy.wxwz2=ρwxwy2ρwywz2−2ρwxwyρwywzρwxwz1−ρwxwz2.
Efficiency Comparisons
In this section we have compared the proposed estimators with some existing estimators as under: I. The proposed estimators will perform better than Thompson’s estimator tTh when 1−fnSwy2(1−Rwy.wxwz2)<(1n−1N)Y¯2Cwy2,
N−nn(1−Rwy.wxwz2)<f,
(1−Rwy.wxwz2)<1N,
Δ<1N,
where Δ=(1−Rwy.wxwz2).
II. The proposed estimators will perform better than estimator tCH1corrected when 1−fnSwy2(1−Rwy.wxwz2)<Y¯2𝜃Cwy2+14Y¯2𝜃Cwx2+β2Z¯2𝜃Cwz2−Y¯2𝜃ρwxwyCwyCwx−2βY¯Z¯𝜃ρwywzCwyCwz+βY¯Z¯𝜃ρwxwyCwxCwz,
Δ<1+14Y¯2X¯2Swx2Swy2+β2Swz2Swy2−Y¯X¯ρwxwySwxSwy−2βρwywzSwzSwy+βY¯X¯ρwxwzSwxSwySwzSwy,
Δ<1+14γwx∗21Swy2+β2γwywz2−R1ρwxwyγwxwy−2βρwywzγwzwy+βR1ρwxwzγwxwyγwzwy,
where γwywz=SwzSwy, γwxwy=SwxSwy, γwywz=SwySwz, γwx∗2 and R1 are the same as defined in Section 4.
III. The proposed estimators will perform better than estimator tCH2 when 1−fnSwy2(1−Rwy.wxwz2)<Y¯2𝜃Cwy2+Y¯2𝜃Cwx2+β2Z¯2𝜃Cwz2−2βY¯Z¯𝜃ρwzwy−2βY¯2𝜃ρwxwyCwxCwy+2βY¯Z¯𝜃ρwxwzCwxCwz,
Δ<1+γwx∗21Swy2+β2γwywz2−2βρwywzγwzwy−2R1ρwxwyγwxwy+2βR1ρwxwzγwxwyγwzwy.
where γwywz=SwzSwy, γwxwy=SwxSwy, γwywz=SwySwz, γwx∗2 and R1 are the same as defined in Section 4.
Numerical Study
In this section, we will examine the performance of the proposed estimators over the existing estimators presented in this article on four different populations.
Numerical Study on Cases of COVID-19
The initial spread of COVID-19 is highly clustered, rare and limited to a few localities which are termed as hotspots of the virus. Trying to get a representative sample using a conventional design to get an estimate on the average number of cases will lead to an extremely biased estimate. So, we propose using ACS design in such a case.
Here, the new cases of COVID-19 per day in the Indian state of Goa and union territory of Andaman & Nicobar island between 27th March 2020 and 4th July 2020 (PRS INDIA, 2021) are taken as auxiliary variables x and z respectively. Using them, the survey variable y is generated from the following two models
6.1 yi=xi+zi+6ei,
where ei∼N(0,xi+zi) and 6.2 yi=wxi+wzi+6ei,
where ei∼N(0,wxi+wzi) respectively.
The survey variable y generated from (6.1) depends on the auxiliary variables x and z but in the case of (6.2), it depends on the network means of the auxiliary variables x and z respectively.
Numerical Study on Thompson’s Population
In this section, the performance of the estimators are examined by taking the auxiliary variables x and z from Thompson (2012) and generating the values of the survey variable y from the same models in Eqs. A.14 and A.15 respectively.
Discussion
The values of survey variable y for both Sections 6.1 and 6.2 are presented in Figs. 2 and 4 respectively. The generated y-values in the case of the model in Eq. A.15 depends on the network means of auxiliary variables x and z (for both the studies) and thus has less variations (Figs. 3 and 4) . For the model in Eq. A.14 in both Sections 6.1 and 6.2, we have 3 networks of size more than one and in the case of model in Eq. A.15, we have four networks of size more than one. We compared the performance of our proposed estimators with Thompson’s (1990) estimator tTh, Dryver and Chao’s (2007) ratio estimator tDC and after correction, with Chaudhry and Hanif’s (2015) regression-cum-ratio estimator tCH1corrected and tCH2 on four different populations based on MSEs obtained from five different sample sizes (see Tables 1, 2, 3 and 4). Figure 2 Figure highlighting the different networks obtained in the y-values generated from both the models
Figure 3 Proposed estimators resulting in lowest MSE in case of both the populations of COVID-19
Figure 4 Figure highlighting the different networks obtained in the y-values generated from both the models
Table 1 MSE of all estimators for model in Eq. 27
n tTh tDC tCH1corrected tCH2 ta tb tc td
20 35.6294 96.9537 179.4504 232.4137 29.9935 29.9935 29.9935 29.9935
25 28.1284 76.5424 141.6714 183.4845 23.6790 23.6790 23.6790 23.6790
30 23.1278 62.9348 116.4854 150.8650 19.4694 19.4694 19.4694 19.4694
35 19.5559 53.2152 98.4953 127.5654 16.4626 16.4626 16.4626 16.4626
40 16.8770 45.9254 85.0028 110.0907 14.2074 14.2074 14.2074 14.2074
Table 2 MSE of all estimators for model in Eq. 28
n tTh tDC tCH1corrected tCH2 ta tb tc td
20 4.2361 12.8280 19.4234 26.2475 3.6210 3.6210 3.6210 3.6210
25 3.3443 10.1274 15.3343 20.7217 2.8587 2.8587 2.8587 2.8587
30 2.7497 8.3269 12.6082 17.0378 2.3505 2.3505 2.3505 2.3505
35 2.3250 7.0409 10.6609 14.4065 1.9875 1.9875 1.9875 1.9875
40 2.0065 6.0764 9.2005 12.4330 1.7152 1.7152 1.7152 1.7152
Table 3 MSE of all estimators for model in Eq. 27
n tTh tDC tCH1corrected tCH2 ta tb tc td
10 3.2804 3.3740 10.3926 10.8824 3.2434 3.2434 3.2434 3.2434
15 2.1589 2.2205 6.8396 7.1619 2.1345 2.1345 2.1345 2.1345
20 1.5981 1.6437 5.0631 5.3017 1.5801 1.5801 1.5801 1.5801
25 1.2617 1.2977 3.9971 4.1855 1.2474 1.2474 1.2474 1.2474
30 1.0374 1.0670 3.2865 3.4414 1.0257 1.0257 1.0257 1.0257
Table 4 MSE of all estimators for model in Eq. 28
n tTh tDC tCH1corrected tCH2 ta tb tc td
10 3.8088 3.9723 5.6027 5.9854 3.8030 3.8030 3.8030 3.8030
15 2.5066 2.6142 3.6872 3.9391 2.5028 2.5028 2.5028 2.5028
20 1.8555 1.9352 2.7295 2.9159 1.9352 1.9352 1.9352 1.9352
25 1.4649 1.5278 2.1548 2.3020 1.4626 1.4626 1.4626 1.4626
30 1.2045 1.2562 1.7717 1.8928 1.2026 1.2026 1.2026 1.2026
In the study on COVID-19 cases Section 6.1, tCH2 and tDC resulted in the highest MSE while the proposed estimators resulted in the lowest MSE for all sample sizes (see Fig. 3). In the study on Thompson’s population Section 6.2, tCH1corrected and tCH2 resulted in the highest MSE and the proposed estimators resulted in the lowest MSE (see Fig. 5). In all the four studies conducted, the proposed estimator resulted in a MSE which is much lower than the estimators considered in this article. Figure 5 Proposed estimators resulting in lowest MSE in case of both the populations of Thompson
Conclusion
In this paper, we have addressed the problem of lack of multi-auxiliary estimators in the ACS desigs by proposing four ratio-cum-product type estimators. The estimators proposed are flexible such that they allow incorporation of multi-auxiliary variables which are negatively and positively correlated with the survey variable. Our proposed estimators resulted in a lower MSE not only on a theoretical population but on the real COVID-19 population as well which shows their wide applicability and precision therefore when the population under study is highly rare or hidden clustered we propose that our proposed ratio-cum-product type estimators should be used.
Some fruitful future research areas in this direction include developing flexible methods to identify clusters, developing different designs under the ACS design like Stratified ACS, Systematic ACS and proposing efficient estimators with application to real data.
Appendix:
Derivations of MSE
To obtain the MSE of the estimator ta, we expand (10) as follows:
A.1 ta=Y¯(ēwy+1)X¯Z¯(ēwz+1)Z¯+α2Z¯−α2Z¯(ēwz+1)(ēwx+1)X¯+α1X¯−α1X¯(ēwx+1)
on simplifying, we get A.2 ta=Y¯(ēwy+1)(ēwz+1−α2ēwz)(1+ēwx−α1ēwx)−1
On further expanding (A.2) and simplifying, we get: ta=Y¯ēwz−ēwxēwz+α1ēwxēwz+1−ēwx+α1ēwx+ēwx2+α12ēwx2−2α1ēwx2
−α2ēwz+α2ēwxēwz−α1α2ēwxēwz+ēwyēwz+ēwy+α1ēwyēwx−α2ēwyēwz−ēwyēwx
Subtracting Y¯ from both sides, squaring and taking expectation on both sides, we get A.3 MSE(ta)=1−fn(Swy2+γwx∗2+γwz∗2−2(γwyx∗−γwyz∗+γxz∗))
,
To obtain the MSE of the estimator tb, we expand (11) as follows: A.4 tb=w¯yX¯Z¯(w¯x+α1(X¯−w¯x))(w¯z+α2(Z¯−w¯z))
On simplyfing, we get A.6 tb=Y¯(ēwy+1)[(1−ēwx+α1ēwx+ēwx2+α12ēwx2−2α1ēwx2)(1−ēwz−α2ēwz+ēwz2+α22ēwz2−2α2ēwz2)]
Subtracting Y¯ from both the sides in Eq. A.6, squaring and taking expectation on both sides, we get A.6 MSE(tb)=1−fn(Swy2+γwx∗2+γwz∗2−2(γwyx∗+γwyz∗−γxz∗))
Similarly, the MSE of proposed estimators tc and td are as follows A.7 MSE(tc)=1−fn(Swy2+γwx∗+γwz∗+2(γyx∗+γyz∗+γxz∗)),
and A.8 MSE(td)=1−fn(Swy2+γwx∗+γwz∗+2(γyx∗−γyz∗−γxz∗)),
respectively.
In order to obtain the optimum values of α1 and α2 which minimises the MSE of estimator ta, we first partially differentiate equation (A.3) with respect to α1 and α2 and get: A.9 ∂MSE(ta)∂α1=1−fn(−2(1−α1)R12Swx2+2SwywxR1+2SwxwzR1R2(1−α2)),
and A.10 ∂MSE(ta)∂α2=1−fn(−2(1−α2)R22Swz2−2SwywzR2+2SwxwzR1R2(1−α1)).
Now, to obtain the steady state solution, we equate Eqs. A.9 and A.10 to zero and we get: A.11 α1R1Swx2−α2SwxwzR2=R1Swx2−Swywx−R2Swxwz,
and
A.12 α1R1Swxwz−α2R2Swz2=R1Swxwz−R2Swz2−Swywz.
Equations A.11 and A.12 takes the form: A.13 R1Swx2−R2SwxwzR1Swxwz−R2Swz2α1α2=R1Swx2−Swywx−R2SwxwzR1Swxwz−R2Swz2−Swywz.
Using Cramer’s rule (2020) we get: δ=R1Swx2−R2SwxwzR1Swxwz−R2Swz2,
δ1=R1Swx2−Swywx−R2Swxwz−R2SwxwzR1Swxwz−R2Swz2−Swywz−R2Swz2,
δ2=R1Swx2R1Swx2−Swywx−R2SwxwzR1SwxwzR1Swxwz−R2Swz2−Swywz,
A.14 α1=δ1δ=R1R2(Swxwz2−Swx2Swz2)+R2SwywxSwz2−SwxwzSwywzR2R1R2(Swxwz−Swx2Swz2).
On simplifying equation (A.14), we get: A.15 α1=1−SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1−β1R1=α1−ta∗(say)
Similarly, α2=δ2δ=1+SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2),
A.16 α2=1+β2R2=α2−ta∗(say)
Similarly to obtain the optimum values of α1 and α2 which minimises the MSE of estimator tb, we partially differentiate equation (A.6) with respect to α1 and α2 and get: A.17 ∂MSE(tb)∂α1=1−fn(−2(1−α1)R12Swx2+2SwywxR1−2SwxwzR1R2(1−α2)),
and A.18 ∂MSE(tb)∂α2=1−fn(−2(1−α2)R22Swz2+2SwywzR2SwxwzR1R2(1−α1)).
Equating equations (A.17) and (A.18) to zero to get steady state solution we get: A.19 α1R1Swx2+α2SwxwzR2=R1Swx2−Swywx+R2Swxwz,
and A.20 α1R1Swxwz+α2R2Swz2=R1Swxwz+R2Swz2−Swywz,
respectively.
Similar to the previous case, Eqs. A.19 and A.20 can be written as: A.21 R1Swx2R2SwxwzR1SwxwzR2Swz2α1α2=R1Swx2−Swywx+R2SwxwzR1Swxwz+R2Swz2−Swywz.
Using Cramer’s rule we get: δ=R1Swx2R2SwxwzR1SwxwzR2Swz2,
δ1=R1Swx2−Swywx+R2SwxwzR2SwxwzR1Swxwz+R2Swz2−SwywzR2Swz2,
δ2=R1Swx2R1Swx2−Swywx+R2SwxwzR1SwxwzR1Swxwz+R2Swz2−Swywz.
α1=δ1δ,
and α2=δ2δ.
On simplification, we get A.22 α1=1−SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1−β1R1=α1−tb∗(say),
and α2=δ2δ=1−SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2),
A.23 α2=1−β2R2=α2−tb∗(say).
Similarly the optimum values of α1 and α2 which minimises the MSE of estimator tc and td are A.24 α1=1+SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1+β1R1=α1−tc∗(say),
A.25 α2=δ2δ=1+SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2)=1+β2R2=α2−tc∗(say),
A.26 α1=1+SwywxSwz2−SwxwzSwywzR1(Swx2Swz2−Swxwz2)=1+β1R1=α1−td∗(say),
and A.27 α2=δ2δ=1−SwywzSwx2−SwxwzSwywxR2(Swx2Swz2−Swxwz2)=1−β2R2=α2−td∗(say).
Substituting the obtained α∗ in expressions of MSEs of estimators ta, tb, tc and td, we get A.28 MSE(tj)=1−fnSwy2(1−Rwy.wxwz2)
where j = a,b,c,d for estimators ta, tb, tc and td and Rwy.wxwz2=ρwxwy2ρwywz2−2ρwxwyρwywzρwxwz1−ρwxwz2.
Funding
There is no funding provided. Conflict of Interests. There is no conflict of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Acharya B Bhattarai G De Gier A Stein A Systematic adaptive cluster sampling for the assessment of rare tree species in Nepal For. Ecol. Manage. 2000 137 1-3 65 73 10.1016/S0378-1127(99)00318-7
Chandra G Tiwari N Nautiyal R Adaptive cluster sampling-based design for estimating covid-19 cases with random samples Curr. Sci. 2021 113891 120 7
Chaudhry, M.S. and Hanif, M. (2015). Regression-cum-exponential ratio estimators in adaptive cluster sampling. Journal of Statistics 22(1).
Conners ME Schwager SJ The use of adaptive cluster sampling for hydroacoustic surveys ICES J. Mar. Sci. 2002 59 6 1314 1325 10.1006/jmsc.2002.1306
Correll RL The use of composite sampling in contaminated sites—a case study Environ. Ecol. Stat. 2001 8 3 185 200 10.1023/A:1011395422397
Dryver AL Chao C-T Ratio estimators in adaptive cluster sampling Environmetrics: The Official Journal of the International Environmetrics Society 2007 18 6 607 620 10.1002/env.838
Hansen MH Hurwitz WN On the theory of sampling from finite populations Ann. Math. Stat. 1943 14 4 333 362 10.1214/aoms/1177731356
Thompson SK Adaptive cluster sampling J. Am. Stat. Assoc. 1990 85 412 1050 1059 10.1080/01621459.1990.10474975
Thompson SK Adaptive sampling in behavioral surveys NIDA Res. Monogr. 1997 167 296 319 9243567
Thompson, S.K. (2012). Sampling, 2nd edn. Wiley.
Thompson SK Collins LM Adaptive sampling in research on risk-related behaviors Drug. Alcohol. Depend. 2002 68 57 67 10.1016/S0376-8716(02)00215-6
Latpate RV Kshirsagar JK Two stage inverse adaptive cluster sampling with stopping rule depends upon the size of cluster Sankhya. B 2020 82 1 70 83 10.1007/s13571-018-0177-y
Perri, P.F. (2005). Combining two auxiliary variables in ratio-cum-product type estimators. Proceedings of Italian Statistical Society, Intermediate Meeting on Statistics and Environment, p. 193–196.
PRS INDIA (2021). https://prsindia.org/covid-19/cases. Accessed: 2021-08-01.
Raj D On a method of using multi-auxiliary information in sample surveys J. Am. Stat. Assoc. 1965 60 309 270 277 10.1080/01621459.1965.10480789
Singh M Ratio cum product method of estimation Metrika 1967 12 1 34 42 10.1007/BF02613481
Singh R Mishra R Improved exponential ratio estimators in adaptive cluster sampling J. Stat. Appl. Probab. Lett. 2021 9 1 19 29
Singh R Mishra R Transformed ratio type estimators under adaptive cluster sampling: An application to covid-19 J. Stat. Appl. Probab. Lett. 2022 9 2 1 8
WHO (2022). https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-covid-19-how-is-it-transmitted https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-covid-19-how-is-it-transmitted. Accessed: 2022-01-01.
Yadav SK Misra S Mishra SS Chutiman N Improved ratio estimators of population mean in adaptive cluster sampling J. Stat. Appl. Probab. Lett. 2016 3 1 1 6
Zill, D.G. (2020). Advanced Engineering Mathematics, 7th edn. Jones & Bartlett Learning.
| 0 | PMC9734625 | NO-CC CODE | 2022-12-14 23:28:29 | no | Sankhya B (2008). 2022 Dec 8;:1-21 | utf-8 | Sankhya B (2008) | 2,022 | 10.1007/s13571-022-00298-x | oa_other |
==== Front
Curr Dermatol Rep
Curr Dermatol Rep
Current Dermatology Reports
2162-4933
Springer US New York
378
10.1007/s13671-022-00378-1
Covid-19 in Dermatology (J. M. Gelfand, Section editor)
Impact of the COVID-19 Pandemic on the Delivery of Dermatological Care
Kimball Alexa B. 12
Porter Martina L. [email protected]
12
1 grid.239395.7 0000 0000 9011 8547 Clinical Laboratory for Epidemiology and Applied Research in Skin (CLEARS), Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 USA
2 grid.38142.3c 000000041936754X Department of Dermatology, Harvard Medical School, Boston, MA 02115 USA
9 12 2022
2022
11 4 313317
23 10 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose of Review
We review several important changes affecting dermatology during the COVID-19 pandemic, beginning in March 2020. Specifically, we focus on the impact of the COVID-19 pandemic on physician trends in employment, delivery of care via teledermatology, and burnout, resilience, and wellness.
Recent Findings
More physicians are now employed by corporate entities than prior to the pandemic. Teledermatology can be utilized effectively and integrated into current care models; however, the continued use of teledermatology will largely depend on financial compensation. The COVID-19 pandemic was a source of burnout for all physicians, including dermatologists, and impacted how many people view their work.
Summary
The COVID-19 pandemic pushed physicians to change their employment, required them to implement telehealth rapidly, and forced them to re-evaluate their priorities. Prior to the pandemic, more physicians transitioned into employed positions as compared to physician-owned practices. Multiple reasons for consolidation exist, but the trend accelerated during the COVID-19 pandemic for all medical specialties. Similarly, teledermatology was utilized prior to the pandemic, but its use exploded in the early days of the COVID-19 pandemic and continues to this day. The future of teledermatology though depends primarily on insurance reimbursement for these visits as well as both patient and physician preferences for continued usage. Lastly, wellness became a major focus in medicine as the pandemic took a significant toll on physicians, including dermatologists.
Keywords
COVID-19
Private practice
Workforce
Health workforce
Professional practice
Employment
Teledermatology
Telehealth
Telemedicine
Delivery of healthcare
Burnout
Stress
Wellness
Resilience
issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2022
==== Body
pmcIntroduction
The practice of dermatology has been incredibly dynamic over the past few decades, but nothing prepared us for what the COVID-19 pandemic would bring. As we rushed to implement telehealth, improvised on how to care for the patients that needed to be seen in person, deployed into other areas, discovered new associations and therapies, and tried to keep our practices afloat, the pandemic accelerated a number of important existing trends and created new changes. Specifically, increasing physician employment by corporate entities hastened due to financial pressures on practices, new ways of accessing care including consumerism and telehealth were driven by the conversion to remote interactions, and last, magnification of burnout from the stresses of the experience followed by the need for recuperation and rejuvenation affected all of our physicians and all of our staff, including nurses, medical assistants, techs, and administrative help. The fundamentals of our field have probably changed forever—but one thing that the history of dermatologists has shown us is that we are highly adaptable and very resilient.
Physician Trends in Employment
As in every area in medicine, dermatologists have been increasingly employed over the past two decades, although at lower levels than most other medical specialties [1–3]. However, prior to the pandemic, it was clear that dermatologists were starting to change location and employment at an accelerated rate. A recent article in JAMA Dermatology showed that 50% of dermatologists have changed their practice setting over the past 5 years, primarily those early or late in practice [4].
While this movement was fairly new for dermatology, it had been preceded by trends in the rest of medicine. The American Medical Association reported that for the first time, in 2020, less than half of physicians worked in physician-owned practices [5]. Other sources have reported that almost 75% of physicians are now employed by corporate groups (which may be physician owned) [6]. In recent times, the rate of conversion to employment had been steady at about 1–2% a year but accelerated in the pandemic with around a 10% absolute increase in the proportion of physicians employed by hospitals, networks, or corporate entities over the past 2 years.
What is driving these incredible changes and consolidation? The answer is that scope and scale matter. They matter because in order to manage the complicated regulatory, information technology (IT), compliance, and payor environment, MDs of all types have moved into employment to reduce costs and decrease personal financial risk. When groups come together, they have more leverage in negotiating for benefits as well as contracting and gain efficiencies in expenses. Compliance also becomes easier when there is a dedicated trained group to manage it, rather than the default of the MD leader. Large groups can also do more marketing, close networks, and spend capital on IT systems and buildings. Hospitals are, of course, merging quickly as well for all the same reasons.
The move to value-based contracting has also made it harder for practices to remain small. In a small practice, a single patient who has an incredibly expensive event, like a transplant, can completely change how much money that patient has used during the course of the year and then affect how a group would perform in any value-based contracts. This profound risk led to major issues for small practices in the 1990s and can only be avoid if groups are large.
Despite these changes, why would dermatologists be suddenly willing to trade autonomy for employment? Twenty years ago when we documented that dermatologists were in shortage [7], practices had little value. At that time, that realization was severely disappointing for senior physicians who had invested in their practices for years and who anticipated that the sale of their practice would be valuable in their retirement. Yet because there were minimal barriers to entry and a reasonable expense to start one’s own practice, practices themselves had limited value. However, in the past 5 to 10 years, private equity (PE), with its focus on consolidation of practices, began valuing dermatology practices at very high multiples, so it is understandable why people might find the sale of their practice to be an important opportunity for them. Between 2012 and 2018, approximately 381 dermatology clinics were acquired by private equity [8]. While PE remains a relatively small proportion overall for all of medicine, it also is increasing pretty dramatically and has disproportionately affected our field, as well orthopedics, ophthalmology, and a few specialties where the engagement with the hospital on a daily basis can be more minimal. The financial strains of COVID, which were very acute in dermatology [9] on these PE practices, did lead to some performing poorly [10]. The investment in dermatology may now be slowing, but this ownership model in dermatology is likely to be indelible.
Teledermatology in the Pandemic
Telehealth, or teledermatology, evolved significantly during the COVID-19 pandemic with widespread use across our specialty. Attitudes toward teledermatology remain mixed much as it was prior to the pandemic; however, our ability to provide significant dermatologic services via telehealth remains impressive.
Prior to march 2020, teledermatology, or the delivery of dermatology care at a distance, existed in a limited capacity but was primarily asynchronous, employing the “store and forward” technique, where medical information, most commonly clinical photographs, was transmitted to a dermatologist for review at a different time and location [11]. This technique could be used to triage patients, provide input to primary care providers or general practitioners, and provide services to underserved countries or rural areas—primarily addressing issues related to equity for dermatologic care. By providing reimbursement and decreasing regulatory barriers, including significantly altering medical licensing requirements for out of state patients, the pandemic brought about greater usage of synchronous teledermatology where virtual (or video) and telephone visits with live interaction between physician and patient occurred—sometimes with a hybrid method of asynchronously sharing photographs prior to the live visit.
A significant limitation to employment of teledermatology prior to the pandemic was insurance reimbursement. Although asynchronous teledermatology allowed dermatologists to practice telehealth on their own time outside of clinical visits, the time investment required for this practice offered little to no financial incentive for the dermatologist providing the services. Additionally, utilization of a Health Insurance Portability and Accountability Act (HIPAA) compliant platform and requirements for interstate licensure also posed problems. Thus, the majority of teledermatology services, approximately 50%, was being provided by academic centers [12]. Pre-pandemic Medicare payments for telehealth were originally limited to rural areas and required patients to leave their homes to receive services at a designated medical facility [13]. Although these services were expanded somewhat to include payment for brief communications with healthcare practitioners, such as virtual check-ins, they still required explicit consent from patients to be billed for these services and reimbursed minimally.
On March 17, 2020, the Centers for Medicare and Medicaid Services (CMS) announced an expansion of telehealth and telemedicine, including teledermatology, to allow for parity between in person and telehealth visits that could be conducted in a healthcare facility or a patient’s home [11]. Additionally, almost all states modified their licensure requirements for physicians to allow for delivery of telehealth across state lines. This allowed physicians to either easily obtain temporary licenses, often at no cost, or to obtain waivers for licensure to provide care via telehealth. Prior to the pandemic, physicians were required to hold a medical license in the state where services were rendered, which was determined by the physical location of the patient (not physician). These changes, paired with “stay at home” orders to minimize COVID-19 transmission, allowed for a rapid and necessary uptake of synchronous visits with some surveys estimating > 85% of dermatologists utilizing telehealth in 2020 [14]. For practices that utilized teledermatology during the spring of 2020, as many as 99% of their total visits were a mix of synchronous and asynchronous teledermatology visits [15].
Over 500 teledermatology publications from 2020 to 2022 also provided an abundance of information on practical and best case utilization of teledermatology as well as its limitations. Visits most suitable for teledermatology were acne, including isotretinoin-related visits, and dermatitis—conditions that were diagnosed and managed remotely and asynchronously—as well as complex medical dermatology patients, including many on immunosuppressive and immunomodulatory therapy, who benefited from hybrid or synchronous visits [16–19]. Visits for total body skin examinations, specific skin lesions suspected to be malignant or requiring a procedural intervention (i.e., cryotherapy or skin biopsy), and lesions or rashes in difficult to photograph or sensitive areas were difficult to assess remotely and often required follow-up in person visits [20]. Additionally, older patients, non-English speakers, and those with limited access to technology were not ideal candidates for teledermatology visits regardless of chief complaint [17].
The expansion of telehealth during the pandemic also accelerated remote alternative, often-cash-based, options for care that were already being tried, such as subscription prescription products. There are also providers, many of whom are not dermatologists, offering the opportunity to get a virtual visit for cosmetic prescriptions and acne. Whether patients will pay cash in significant numbers for this kind of service remains to be tested—and it has never been a huge part of medical dermatology, but it could chip around the edges of cosmetic practices. Already, some concerns about fraud have been come to pass, and there are expectations that CMS will be carefully monitoring for misuse. Notably since 2021, almost all states rescinded their modified telehealth medical licensing waivers, reverting back to pre-COVID requirements and often costly fee structures for obtaining medical licenses. Thus, dermatologists or physicians who do engage in these virtual platforms, or any telehealth services, are again required to hold medical licenses in all states where services are rendered.
Finally, how patients view and engage in their care has also likely changed dramatically. A dramatically increased number of patients now know how to test for medical conditions at home, do self-monitoring (i.e., O2 saturation testing), read CDC guidance, and participate more robustly in self-management of their medical conditions with support. Physicians are describing a sometimes overwhelming increase in patient portal questions, and we will need to manage that additional work. But, it is nonetheless positive to see patients more engaged in their care and reaching out with questions or clarifications.
Although dermatologists can use teledermatology to provide care for patients, it remains to be seen how teledermatology will be incorporated into future practice models and will likely largely depend on financial reimbursement, its convenience for dermatologists, and the expectations of patients who have come to rely on virtual interactions to limit travel and time spent on medical appointments. Fortunately, we as a specialty have the experience and access to technology to employ these telehealth services as we see fit in the future.
Burnout, Resilience, and Wellness
Turning to the last topic: burnout, resilience, recuperation, and rejuvenation. There was a pandemic of burnout in dermatology prior to the COVID-19 pandemic [21]. Over the past 2 years, of course, physicians went through an incredible maelstrom of emotional, physical, and environmental impacts that affected them in really different ways, and it was universally hard on everyone.
How should we get past these past few years—to recuperate, rest, and repair?
COVID has heralded a great realignment of how many people view their work. Some are reassessing priorities, some are changing what they do, and others are retiring. It’s too early yet to understand the impact on our workforce, but the effects could be substantial. That said, the pipeline continues to be full of eager new trainees; the number of applicants increased 5% between 2020 and 2021 to over 1300 [22]. Our workforce could become younger—and we are also continuing to try to make it more diverse and reflective of the patients we serve.
It's important to go back and find meaning in what to do, how to organize, and how to practice and to make sure that there is fulfillment, happiness, and finding career objectives. The good news is that dermatologists remain a very happy group. While our satisfaction waned during the peak of the IT transformations brought about by Meaningful Use, it has rebounded. In a recent Medscape survey of some 18,000 physicians, 96% of dermatologists would choose the same specialty again, followed only by the orthopedists [23]. It is worth noting that these two specialties are among the most autonomous of any of the groups in medicine. How employment affects satisfaction could substantially affect dermatology—about a quarter of physicians who become employed are interested in returning to self-employment, and physicians in large independent groups are less satisfied than smaller independents [24]. Some have even speculated that one impact of consolidation is a rise in physician unions.
Conclusion
COVID has changed many things, including where we work, who employs us, how we deliver care, and how we respond to adversity. Fortunately, the COVID-19 pandemic has not changed the most fundamental one: dermatology is a great career. It is endlessly interesting, we have amazing colleagues and collegiality, and most importantly, it has meaning and purpose as we make people’s lives better.
Declarations
Conflict of Interest
Alexa Kimball, MD, MPH, is on the Board of Directors of BILahey Health and Beth Israel Deaconess Medical Center and CEO of Harvard Medical Faculty Physicians. Martina Porter, MD, serves as a member of the American Academy of Dermatology’s Patient Safety and Quality Committee. She has no relevant financial declarations.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Covid-19 in Dermatology
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Ehrlich A Kostecki J Olkaba H Trends in dermatology practices and the implications for the workforce J Am Acad Dermatol 2017 77 4 746 752 10.1016/j.jaad.2017.06.030 28784330
2. Porter ML Kimball AB Predictions, surprises, and the future of the dermatology workforce JAMA Dermatol 2018 154 11 1253 1255 10.1001/jamadermatol.2018.2925 30193360
3. Parthasarathy V, Pollock JR, McNeely GL, Hogan JS, Bordeaux ZA, Trinh P, Deng J, Swanson DL, Sharfstein JM, Semenov YR, Kwatra SG. A cross-sectional analysis of trends in dermatology practice size in the United States from 2012 to 2020. Arch Dermatol Res. 2022. 10.1007/s00403-022-02344-0. Epub ahead of print. PMID: 35287181.
4. Cwalina TB Mazmudar RS Bordeaux JS Scott JF Dermatologist workforce mobility: recent trends and characteristics JAMA Dermatol 2022 158 3 323 325 10.1001/jamadermatol.2021.5862 35138354
5. PRP: Recent Changes in Physician Practice Arrangements: Private Practice Dropped to Less Than 50 percent of Physicians in 2020 (ama-assn.org). Accessed August 29, 2022.
6. http://www.physiciansadvocacyinstitute.org/PAI-Research/Physician-Employment-and-Practice-Acquisitions-Trends-2019-21. Accessed August 29, 2022.
7. Kimball AB Dermatology: a unique case of specialty workforce economics J Am Acad Dermatol 2003 48 2 265 270 10.1067/mjd.2003.108 12582399
8. Tan S Seiger K Renehan P Mostaghimi A Trends in private equity acquisition of dermatology practices in the United States JAMA Dermatol 2019 155 9 1013 1021 10.1001/jamadermatol.2019.1634.PMID:31339521;PMCID:PMC6659155 31339521
9. Benlagha I, Nguyen BM. Impact of the Paycheck Protection Program on dermatology practices during the COVID-19 pandemic. J Am Acad Dermatol. 2021;84(3):775–777. 10.1016/j.jaad.2020.11.064. Epub 2020 Dec 10. PMID: 33310110; PMCID: PMC7833840.
10. Memon R Memon A Francis J Konda S Trends in debt valuations of private equity–backed dermatology groups before and during the COVID-19 pandemic JAMA Dermatol 2022 158 4 395 403 10.1001/jamadermatol.2022.0009 35262637
11. Yeboah CB, Harvey N, Krishnan R, Lipoff JB. The impact of COVID-19 on teledermatology: a review. Dermatol Clin. 2021;39(4):599–608. 10.1016/j.det.2021.05.007. Epub 2021 May 28. PMID: 34556249; PMCID: PMC8162710.
12. Yim KM Florek AG Oh DH McKoy K Armstrong AW Teledermatology in the United States: an update in a dynamic era Telemed J E Health 2018 24 9 691 697 10.1089/tmj.2017.0253 29356616
13. Centers for Medicare & Medicaid Services Medicare telemedicine healthcare provider fact sheet: Medicare coverage and payment of virtual services. Available at: https://www.cms.gov/newsroom/fact-sheets/medicare-telemedicine-health-care-provider-fact-sheet?inf_contact_key1/438ca3f198618fc3aeba4091611f5b055680f8914173f9191b1c0223e68310bb1. Accessed July 16, 2022
14. Sharma A, Jindal V, Singla P, Goldust M, Mhatre M. Will teledermatology be the silver lining during and after COVID-19? Dermatol Ther. 2020;33(4):e13643. 10.1111/dth.13643. Epub 2020 Jun 4. PMID: 32441373; PMCID: PMC7267127.
15. Su MY, Das S. Expansion of asynchronous teledermatology during the COVID-19 pandemic. J Am Acad Dermatol. 2020;83(6):e471-e472. 10.1016/j.jaad.2020.08.054. Epub 2020 Aug 18. PMID: 32822793; PMCID: PMC7434450.
16. Bergamo S, Calacione R, Fagotti S, Finizio L, Scaini M, Schiesari L, Gatti A. Teledermatology with general practitioners and pediatricians during COVID-19 outbreak in Italy: preliminary data from a second-level dermatology department in North-Eastern Italy. Dermatol Ther. 2020;33(6):e14040. 10.1111/dth.14040. Epub 2020 Aug 12. PMID: 32696492; PMCID: PMC7404363.
17. Kazi R Evankovich MR Liu R Liu A Moorhead A Ferris LK Falo LD Jr English JC 3rd Utilization of asynchronous and synchronous teledermatology in a large health care system during the COVID-19 pandemic Telemed J E Health 2021 27 7 771 777 10.1089/tmj.2020.0299 33074786
18. Das S Su MY Kvedar JC Smith GP Asynchronous telemedicine for isotretinoin management: a direct care pilot J Am Acad Dermatol 2022 86 1 184 186 10.1016/j.jaad.2021.01.039 33484765
19. McGee JS, Reynolds RV, Olbricht SM. Fighting COVID-19: Early teledermatology lessons learned. J Am Acad Dermatol. 2020;83(4):1224–1225. 10.1016/j.jaad.2020.06.027. Epub 2020 Jun 15. PMID: 32553677; PMCID: PMC7294281.
20. Perkins S Cohen JM Nelson CA Bunick CG Teledermatology in the era of COVID-19: experience of an academic department of dermatology J Am Acad Dermatol 2020 83 1 e43 e44 10.1016/j.jaad.2020.04.048 32305442
21. Helm MF Kimball AB Butt M Stuckey H Costigan H Shinkai K Nagler AR Challenges for dermatologists during the COVID-19 pandemic: a qualitative study Int J Womens Dermatol 2022 8 1 e013 10.1097/JW9.0000000000000013.PMID:35620026;PMCID:PMC9112396 35620026
22. https://www.aamc.org/data-reports/interactive-data/eras-statistics-data. Accessed August 29, 2022.
23. https://www.medscape.com/slideshow/2022-lifestyle-happiness-6014665. Accessed August 29, 2022.
24. Physician employment in the COVID-19 era | McKinsey. Accessed August 29, 2022.
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Wireless Networks
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Springer US New York
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10.1007/s11276-022-03197-1
Original Paper
Secure user authentication and key agreement scheme for IoT device access control based smart home communications
Uppuluri Sirisha [email protected]
Sirisha Uppuluri
received the Masters degree from Jawaharlal Nehru technological university, Hyderabad in 2013. She is currently pursuing Ph.D. (PT) in the GITAM University. She is currently working as Assistant Professor in Narsimha Reddy Engineering College. Her research interests includes the security, internet of things and machine learning
Lakshmeeswari G. Dr.G. Lakshmeeswari
received Ph. D. in Computer Science and Engineering from GITAM Deemed to be University, Visakhapatnam, Andhra Pradesh, India in 2013.She is currently working as Associate Professor in GITAM Deemed to be University. She has more than 20 years of experience in teaching. She published research articles various national and international journals and conferences. Her research areas include Cloud Computing, Security, internet of things and visual cryptography.
grid.411710.2 0000 0004 0497 3037 GITAM University, Visakhapatnam, Andhra Pradesh 530045 India
3 12 2022
122
18 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The upcoming paradigm in Internet of Things (IoT) based applications is to afford effective interactional communication strategies between the devices in the smart home system. With the rapid growth of IoT services, the incorporation of security measures becomes a vital concern. The general issue faced in the security of the intercommunication between the devices and the users is improper authentication between them. Also, the access control of devices must be ensured with reliable features for establishing secure communication between the users and devices. Hence, we propose a protocol called Modified Honey Encryption using Inverse Sampling-Conditional Probability Model Transform (MHE-IS-CPMT) with Elliptic Curve Cryptography (ECC) to authenticate and perform the key agreement. Here, we employ the following steps: (1) Initialization, (2) Registration, (3) Login and data access Request, (4) Authentication and Session key agreement, and (5) Key update. At the commencement of the session, the users (u), Mobile Users (MU), and the other devices participating in the smart home system are initialized to the Home network head (H). Then, for the registration process, the user and the devices register them into H via the smart gateway (SG) by providing their own identities. The user details and the data about the devices are secured using the MHE-IS-CPMT with the ECC method. Next, during the login process, the registered users connect to the smart home system and send a request to SG to gain access to the devices. After verification, the user is authenticated and the system enables them to acquire the device access control by providing them with the private key of the device. In addition, the proposed system facilitates the secure key change procedure for the legitimate user to update their key whenever required. Hence, the performance of the model is secured against different types of attacks and also obtains more security features than existing methods.
Keywords
Internet of things (IoT)
Authentication
Key agreement
Smart home
Security
Device access control
Attacks
==== Body
pmcIntroduction
In today’s world, there has been a huge development in superior integrated services for smart home automation systems. With the rapid integration of the Internet of Things (IoT), the internet-enabled smart services are connected with the operation of controlled software and hardware components that communicate with each smart device to facilitate a high-tech lifestyle [1]. Due to the wide availability of the internet, intelligent devices are tremendously increased and reach 50 to 100 billion by the year 2020 [2]. In the IoT ecosystem, the physical devices include actuators and sensor networks, and other software settings are used in different applications such as medical, industrial, civic, etc., [3]. The embedded devices are integrated with IoT to connect with a large number of devices and provide users trusted gain in the smart environment [4]. Mostly, the consumers focused on “smart home” devices like cameras, video door locks, light bulbs, motion sensors, smoke detectors, thermostats, etc. [5] These devices are responsible for safety–critical functionality built-in web servers that allow accessing its information online for daily requirements. So, the application of device-to-device and app-to-device or user-to-device access control information is sensitive for the third-party servers [6, 7]. However, accessing the services of IoT based smart home device assessment methods needs security due to its heterogeneous nature at each operation.
Likewise, the constrained devices are lying to renowned attacks such as Denial of Service (DoS) attacks, replay attacks, and cryptography attacks [8, 9]. These security attacks are solved with cryptographic solutions to achieve the goals of data integrity, confidentiality, and availability [10]. Recently, access control and device authentication mechanism are some of the main security problems in smart home-based IoT environments. In the access control system, the capability-based access control model ensures end-to-end security by Internet Protocol Security (IPsec), and accessing devices in the group are supported using a single token. The accessed groups are determined using Unique Local Address (ULA) [11]. Also, the type of different access levels is provided to different agents using the user-managed access model [12]. But in large scale networks, the distributed network uses an attribute-based cryptography method in which the attributes are assigned with user permissions and changed easily with the absence of access structure [13, 14].
In the authentication mechanism, the three-level Kerberos secure mechanism uses Advanced Encryption Standard (AES) and SHA-1 hash algorithm for constrained smart home-based IoT devices [15]. The verified controller node identity minimizes handshake overhead and secures man-in-the-middle attack using Threshold Cryptography based Group Authentication (TCGA) scheme [16]. For secure communication, the shared key security mechanism is used with the digital certificate supported by the certificate authority to make the authentication more robust between the devices [17]. Moreover, the mobile IoT devices run on Wi-Fi gateway node and network for users to device configuration that initiates authentication process from the gateway to IoT device. This process is integrated with ECC for a key generation [18–20]. The above-presented methods of authentication and access control mechanism face problems in data transmission to the server. Also, an attacker can invade the user’s private information connected with smart devices by eavesdropping and DoS attack. The existing approaches suffer from a lack of security between the users and smart devices. Therefore, a secure key agreement based encryption mechanism should be designed that needs to supply further attention in IoT connected devices and provide security between users and devices at low cost.
Motivation
The current research on IoT is an interesting field of concern in smart home automation systems in which authentication and access control mechanisms are a major challenge to deal with several applications such as the smart devices that are used can include smart lights, air control, washing machine, smoke detector, door sensor, surveillance cameras, smart media, central AC etc. [21]. For example, IoT technology can be used to identify devices, users, or natural people’s access control such as attempted logins, service requests, access durations, and location, based on both IP and Bluetooth at smart homes, reducing strain on resources while monitoring people continuously and enabling them to stay at home longer, connected over the internet. In order to access services and manage IoT devices, users communicate with IoT networks through their end devices. The smart devices only transmit signals when the home owner is not at home. Limiting access to authorized entities (data owner, mobile user, IoT devices) is critical for ensuring data confidentiality against various types of attacks. Attackers can gain access to a system and steal information when user authentication is not secure [22].
Several existing methods, such as lightweight encryption [23], cryptography algorithms [24], and lightweight mutual authentication [25], perform data assessment on IoT devices, raising many security threats as well as efficiency issues in the system. The existing techniques concern the home server trust factor, which has complete access control to secure the user's private information on smart home platforms. But it cannot be leveraged on a secure access service. Moreover, the requested services gather the inside and outside information and encrypt the data before sending it to the server, which leads to security problems when using multiple requesting services to the server. Problems encountered in home communication between the device and user accessing data have been addressed in many existing methods. But an attacker can access the data in between the device and user communication. Motivated by these facts and existing studies, there is a need to overcome the security issues using key agreement and authentication algorithms that address the enforcement of IoT devices and access services of user-to-device applications.
The major contributions are summarized as follows
For secure authentication and key agreement in the smart home system, MHE-IS-CPMT with ECC is proposed in access control of IoT devices present in the smart home. Here, the user and device data are secured by the MHE with the keys generated using the ECC scheme.
The security of the protocol is evaluated for different commonly occurring attacks in the IoT environment and hence the proposed protocol is resilient to different types of attacks. The proposed protocol confuses the adversaries in the system by sending them plausible data instead of the original sensitive smart home data.
Moreover MHE-IS-CPMT with ECC protocol is simulated using the Python tool and then its performance efficiency is compared with other recent approaches.
The paper structure is organized as listed as follows. Section 2 provides a brief description of the existing works. Next, Sect. 3 provides the preliminaries of the system used in smart home security. A detailed description of the system model is provided in Sect. 4. In Sect. 5, the security of the proposed MHE-IS-CPMT is analyzed in detail. Section 6 conveys the comparative analysis for the performance efficiency of the proposed system. The limitations of the proposed work is presented in Sect. 7. The entire working process is concluded in Sect. 8.
Related works
Many research scholars have done a different aspect of authentication and key agreement methods and its issues on recent smart home systems are discussed below.
Chifor et al. [26], presented a lightweight authorization scheme for secure communication between the users and smart devices in IoT platforms. In this approach, a security stack scenario is used to interact between the web services and embedded devices for establishing the infrastructure through the IoT connected devices. The deployed smart home infrastructure has heterogeneous IoT devices where connected devices are accessed by a digital identity and communicate the response to another device service for authorization. This IoT based security architecture is considered a trusted module. After authorization, the user to device-centric data is secured by a Fast IDentity Online (FIDO) protocol. Thus the approach preserves user anonymity among the information linked by the user and the outcome shows a low impact on smart applications.
Shen et al. [27], introduced a key agreement and secure transport strategy for Home Area Networks (HAN). The smart home system faces security issues such as data integrity for data upload and smart gateway in data monitoring. For this purpose, the approach uses a secure data uploading scheme to verify whether any malicious gateway monitors the data or not. In this, the uploaded data is accessed by a home gateway based session key from the smart home environment. Hence the approach prevents malicious gateways while uploading the data. Furthermore, the security analysis proves that the approach ensures efficient security for uploading data. Similarly, verification of data integrity is also required for secure data uploading.
Anthi et al. [28], mentioned an IoT infrastructure system that incorporates a supervised approach called a 3-layer system for intrusion detection to determine security flaws on smart home-based IoT platforms. This system involves three entities: the first entity describes that the normal behavior of the IoT device profile and type is classified, and each device is connected to the smart home network-based IoT devices. Secondly, the network system determines that the transmitted packets are malicious on the network. Lastly, the deployed network classifies the type of attack in the system. Thus, the performance is evaluated with the machine learning approach for the network activity and automated function from real testbed parameters. This concludes that the IDS detects the attack deployed on the networks. However, the network does not support automatic detection.
Yan et al. [29], introduced a function-based access control authentication scheme between the home gateways and smart devices in IoT (FBAC-IoT). Each smart device has a unique ID with a number of functions for fine-grained access control in the home environment. In this, the varying number of function generates different data agrees with the hub. This scheme uses the Identity Based Encryption (IBE) method to access encrypted data before uploading it to the server, which ensures data privacy. Using this approach, only the authorized data is accessed and obtains the ciphertext to decrypt the function, else it will terminate the request. Since the FBAC-IoT scheme computational cost is constantly maintained for each operation and security proofs analyzed that the FBAC-IoT approach prevents privilege access among the devices.
Alshahrani et al. [30], presented a lightweight mutual authentication for edge devices with secure resource constraints in the IoT environment. In this case, the key exchange protocol and authentication method depend on the cumulative keyed-hash function and temporary identity. The authenticated nodes with the session are established by dynamic identities. Moreover, a virtual domain segregation setup ensures the security policy for the transmission and reception capability of nodes commands for inside attacks. The cumulative keyed-hash function is responsible for verifying the identity of the sender by a challenging command. In addition, this approach improves identity guarantee by using the concept of fog computing. Hence the performance is estimated using AVISPA toolkit and informal security analysis is proofed using BAN logic.
Punithavathi et al. [31], presented a secure lightweight authentication scheme based on cancelable biometric system (CBS) in the cloud environment. Initially, the biometric image processing step involves, Region of Interest (ROI), thinning, Binarisation, and histogram localization. Then the general process of the feature extraction step is obtained. Lastly, the matched templates are recovered and retrieved in the Cancelable Template Database (CTD). Then the new transformation of the authenticated key is generated by a new cancelable template. The evaluation considers real-world settings to authenticate the device data with less overhead and high accuracy. Furthermore, this approach is supported in smart IoT surroundings.
Naik et al. [32], presented an IoT based smart house management system that combines microcontrollers, actuators, smartphones, and web services. This method is cost effective and energy efficient, but time consumption is more. Furthermore, Gochhayat et al. [33] suggested a distributed key management solution for IoT security. This technique effectively secures IoT devices by transferring the majority of resource-intensive cryptographic operations to a local entity. This method has less communication overhead and generation time. However, storage cost is high.
Mansoor et al. [34], introduced an improved lightweight authentication protocol to secure Radio Frequency Identification (RFID) systems against known attacks in IoT networks. Each RFID system consists of three entities (database server, reader device, and tags) using Burrows Abadi-Needham (BAN) logic to analyze the security features. From the simulation of informal and formal security analysis, this protocol is suitable for practical IoT applications. However, this protocol is time consuming during transaction.
Shahid et al. [35], presented a Proficient Security over Distributed Storage (PSDS) method to solve the data security issues during data transmission on multi cloud. For this purpose, the cloud database splits the data into two sections: sensitive and normal. The normal data formation was encrypted and uploaded by a single cloud whereas the sensitive data is also encrypted and distributed via multi-cloud. Hence the PSDS method stores the data securely against multiple attacks. But the PSDS method cannot promote to validate the key agreement by trusted authority between user and cloud service.
Samuel et al. [36], presented a privacy infrastructure based on federated learning and blockchain technology to manage and reduce the risk of healthcare centers during transmission in Internet of Medical Things (IoMT). This privacy model was used to improve public communication and resolve large data silos when the data owner privacy was preserved, particularly for COVID-19 patients. Overall, the privacy infrastructure model was resistant to security-based attacks, but it cannot guarantee that the patient has been verified by the data owner.
The summary of several approaches involved in IoT based smart home device applications is shown in the Table 1.Table 1 Summary of existing approaches in IoT based smart home applications
Author/year Technique used Goal Advantage Limitations
Chifor et al. [26], 2018 Lightweight authorization scheme To preserve user anonymity among the information linked by the user and smart devices in IoT platforms Device to device access data is secured Low impact on smart applications
Shen et al. [27], 2018 Key agreement and secure transport strategy To upload the access data by a home gateway based session key for HAN Ensures efficient security while uploading data Less probable on data integrity
Anthi et al. [28], 2019 3-layer IDS method To determine security flaws on smart home based IoT platforms This scheme detects attacks on the networks The networks does not support automatic detection
Yan et al. [29], 2019 FBAC-IoT To access control in fine-grained resources from home environment This scheme protects smart applications from unauthorized accessing functions Only the device privilege is secured
Alshahrani et al. [30], 2019 Lightweight mutual authentication scheme To secure edge devices using cumulative keyed-hash function and temporary identity Less probable on inside attacks High computational cost
Punithavathi et al. [31], 2019 Lightweight authentication scheme based on CBS To secure device authentication using biometric process in cloud environment Low overhead
High accuracy
High execution time
Naik et al. [32], 2018 Smart house management system To manage the system devices Cost effective and energy efficient High computation time
Gochhayat et al. [33], 2020 Distributed key management solution To effectively secures IoT devices by transferring the majority of resource-intensive cryptographic operations Less communication overhead and generation time High storage cost
Mansoor et al. [34], 2019 Improved lightweight authentication protocol To secure RFID systems against known attacks in IoT networks Suitable for practical IoT applications High running time during transaction
Shahid et al. [35], 2020 PSDS To solve the data security issues during data transmission on multi cloud Stores the data securely against multiple attacks Cannot promote to validate the key agreement
Samuel et al. [36], 2022 Federated learning and blockchain technology To manage and reduce the risk of healthcare centers during transmission in IoMT Resists security based attacks Cannot guarantee that the patient has been verified by the data owner
The above-mentioned schemes discuss the advantages and drawbacks which is most viable to smart home-based IoT applications. On analyzing the presented mechanism, it is prone to several disadvantages such as it is less effective in accessing the device control, less privacy due to repeated request services, and less secure due to several attacks. Also, the system raises issues in communication that concerns delay, throughput, cost, and complexity. Therefore, there is an efficient secure authentication mechanism is required in IoT based smart home environment to address all issues determined in the existing systems.
Preliminaries
In this section, the details regarding the basic functionalities of the secure authentication and key agreement schemes is presented.
Smart home
It is a home that is fully equipped with automated device control applications that can be managed or supervised from a remote location using a computer or smartphone device. The attributes of the home such as the temperature sensors, lightings, appliances, entertainment systems, alarm systems, etc. are connected through the internet. For enabling the control over these devices, the system use web interface, applications in mobile phone, desktop computers, etc. However, these automation face issues due to the inadequacy in the standards of security measures provided to the system. The current state of smart home automation requires a considerable capacity to exchange data between the members of the family or only on the trusted individuals.
Adversarial model
The model assumes that an adversary tries to attack the smart home system and breaches the system to launch attacks. The assumptions of the adversary model are described as follows.Any internal or external attacks on the system may compromise an adversary β. This type of attack justifies that the attacker can steal the traffic data access center files (content of request files) between the connection of the home network head and the smart gateway sent by the user.
An attacker can acquire access to data over the communication channel. This type of attack can destroy the access data of the smart device and extract the sensitive information of user entities stored in the home network head.
The identities of the user, device, SG, and H are known to the attacker. This type of attack can falsify each entity's network access data over the network.
Adversaries do not have the ability to change, replay, or shift any user data content. This attack is sufficiently absent in strong login passwords due to hacker login between the user terminals.
An adversary can gain access through the links (link-ability attack) between the communication of a user and the home server. In this, unauthenticated access allows threat actors to gain access to an IoT device, which makes it easy to exploit device data.
Honey encryption (HE)
HE is a security tool to secure the data between the user and devices present in the smart home system [37]. This encryption process divides the user data into a set of sequences called the message set and stores them in the message space. Before encryption of the user data, the required message space must be predicted. Then, the message sequence is arranged in some order and the probability of occurrence of the message in the space is predicted. Next, an encoder is used to map the sequences into the seed space. Also, it is ensured that the number of mapped sequences of user data is equal to the number of spaces occupied by them in the space. The seed space must be large enough such that the message is mapped to a minimum of one seed. The major benefits of using the HE process is used to protect data stored on password manager services that will confuse the intruders or adversaries by sending plausible data similar to the original data for secure transmission.
Elliptic curve cryptography (ECC)
The most common method for key generation is the Elliptic Curve Cryptography (ECC) [38] that is used widely due to its easier working process. ECC generates a public–private key pair for the encryption. The public key is transferred to all the users and servers of the system whereas the private key is known only to the user. The key exchange mechanism is secured using the Diffie Helman Key exchange process. For the generation of the private key, the secret parameters are computed in the system from the ASCII encoding of the user id and password. This key generation assists in secure data transmission in the smart system. The seed generated by the HE process is XORed with the keys to generate a ciphertext for storing the valuable user data.
Proposed MHE-IS-CPMT framework
In the proposed methodology, we present a session key agreement and authentication scheme based upon Modified Honey Encryption using Inverse Sampling-Conditional Probability Model Transform (MHE-IS-CPMT) and Elliptic Curve Cryptography (ECC) that secures access data for a large number of IoT devices, which is more vulnerable to attacks from different sources. This algorithm helps in protecting smart home applications from attackers by generating plausible data. This plausible data generation will confuse the attackers as the provided data is similar to the real one. First, the device and user installation steps are performed to initiate all parameters. Then, the registration step is performed between the mobile user and IoT devices for registration request submission and device activation in the home network head. Next, the login and data access request step is performed between the home network head and user to verify the request data through the home gateway. Then the authentication and session key agreement steps are secured by concatenating the seed obtained from the honey encryption and the key is generated by ECC and only the ciphertext is sent to the users. The data accessed by the device is provided only to the authenticated user at the time of the request. Lastly, the key update step is performed based on the authenticated user with the valid secret key of each parameter for the mobile user and devices. Thus, the proposed security architecture is a reliable communication network and the accessed data allows only registered users to participate in the data transmission and also mitigate attacks. The smart home system model is shown in Fig. 1, and the flowchart of the proposed model is shown in Fig. 2.Fig. 1 Smart home system model
Fig. 2 Flowchart of proposed model
System model
There are five different entities such as Users (u), Smart gateway (SG), Mobile user (MU), IoT devices (N), and Home network head (H). The process flow of the proposed system is categorized into five phases.Installation Phase of IoT Devices and Users: This is the initial phase in the device access control of IoT. Here, u, MU, and N are initialized to H.
Registration Phase: In this, each user sends a request for registration and activate the device function.
Login and Data Access Request Phase: Here, legitimate users are allowed to login and request access control of the different IoT devices.
Authentication and Session Key Agreement Phase: The system allows only legitimate users to access the devices through an authentication mechanism using a key-based agreement scheme.
Key Updating Phase: Users can change and update the keys provided to them by selecting their own secret parameters. The overlay of the proposed security architecture graphical model for IoT device-based home communication is shown in Fig. 3.
Fig. 3 Proposed graphical model
The symbols used and its description is provided in Table 2.A. Installation phase of IoT devices and users
Table 2 Symbols used and their notations
Symbols Description
ux/MUx Users/mobile users
H Home network head
SG Smart gateway
C Certificate
UC User credentials
n Number of devices
u_id User identity
udx User details
Hux Sequence user details
CPdHux Conditional probability of sequence user details
pw_user User password
u_req User request key
χ Device activation function
dev_idi Device identity
ran_keyw Random keyword
pwdev_idi Device password
pub_key,pri_key Private key and Public key
req_key, Sess_key Request key and session key
tst Timestamp
eui, rui,wi,oi Secret parameters
Lmax String y of length
yii String for y-bits
ψi Random fields
k,,j Random parameter
y Storage overhead
S Message space
P Probabilistic random generator
k Random number
The basic requirement of providing smart facilities in the home involves the installation of smart devices. The installations follow the setup procedure for the devices in the smart home. This is the process of making the smart devices prepared for activation and execution of routine activities in the smart home environment. Consider n be the number of devices in the smart home system.User Installation
Step 1: The users u1,u2,..ux or the mobile users MU1,MU2,..MUx are initialized into the smart home system with their name and the membership in the family. Then, H issues u_id and password of the user pw_user to every initialized users u1,u2,..ux.
Step 2: A key for encrypting the requests made by the user req_key is maintained by the network. These pre-shared parameters are secretly stored into the internal memory by the producers P of the device to help in future communication. After initialization, H issues a certificate (C) to (n) devices in the system.
Device Installation
Step 1: Initially, the installation step is carried out in the H that requires the inherent of device id (dev_idi) with a random keyword (ran_keyw) and a password (pwdev_idi), this can be expressed as,1 P→devidev_idi,ran_keyw,pwdev_idi
Step 2: Here, pwdev_idi is considered to be secret such that P computed as,2 pwdev_idi==hashdev_idi||k⊕ran_keyw
where k is considered as a random number generated using the probabilistic random generator.
Step 3: Consider the parameters for future evaluations of Elliptic curve EC under random fields (ψi). Then choose j as a random generator in a group H with order l.
Step 4: Choose a private key such that keyεHl∗ and then predict the public key,pub_key=pk∗j.
The process flow of the proposed scheme is illustrated in Fig. 4.B. Registration phase
Fig. 4 Process flow of proposed scheme
Registration involves gathering the details about the entities and further enrolling them in the system to achieve the activation of the device and acquire services from them. In this phase, a user request (u_req) is send for registration and device activation (χ) is achieved. Here, each entity in the system (u, SG, N, and MU) are registered into SG using their credentials. Two types of registrations are carried out in the system, such as user registration and device registration. For secure storage and utility of the smart service, modified honey encryption algorithm is employed. Here, we propose the IS-CPMT process in honey encryption for user data encryption, which is incorporated with the keys generated using the ECC. It employs a strong fixed field for the generation of cryptography and proceeds with the signature and verification mechanisms of the user.a. User registration
Users of the smart home is confined to the members of the family since leakage of the smart home data is a serious issue affecting the privacy of the user. SG has the ability to store some information about user details because of convergence to the randomized strategy point of the internal network. It also enables users to securely aggregate, process, and filter data based on the connection of Wi-Fi and ZigBee. Then, it transfers the user details to H for encryption using HE. In between the encryption process, the user login terminals frame the public key using another secret parameter incorporated with the generated private key using the Diffie–Helman ephemeral key exchange mechanism. Therefore, only the initialized users are allowed to actively participate in the registration process.
Step 1: For ‘x’ number of users (u1,u2,..ux), compute the user details such as identity of the user (u_id), password of the user (pw_user) which is computed with the randomized strategy (rand∗pw) for storage into SG.
Step 2: SG transfers the user details (ud1,ud2,..udx) into H for encryption. ECC is applied to develop a public and private key pair. Frame suitable private key (pri_key) for the user using the parameter (eui) framed corresponding to the ASCII encoding of the user password (pw_user), which is expressed as,3 pri_key=eui||pw_user
Step 3: Then, frame the public key Pub_key using another secret parameter (rui) incorporated with the generated private key expressed as,4 pub_key=rui||pri_key
where the pri_key is distributed only to the registered ui and also kept secured in H via SG using the Diffie–Helman Ephemeral key exchange mechanism and ui provides the signature for the key using the secret parameter (eui).
Step 4: Apply modified honey encryption algorithm that employs IS-CPMT for encryption and secure the storage of user details. Consider the storage overhead parameter to be y. Determine the possible number of message space (S) to store ud1,ud2,..udx in H. Sample user details into several units (Hu1,Hu2,Hu3,..Hux) and acquire the possible generating sequences (Hu1,Hu2,Hu3,..Hux)-1.
Step 5: Find the conditional probability CPdHux for each sequenced unit Hux-1 and perform discretization of the sequence CPHui|Hu1,Hu2,..HuX. Unlike the other methods conditional probability needs a condition for encoding the user data.
The condition is defined for each sequence before encoding them. Here, the transformation model is suggested for the conditional probability model that involves the shifted factor to the user data. Then, select any sequence at random seq_rand in Hux-1 with CPdHux-1|ux is computed as,5 CPdHux-1|ux=CP(d)(Hux-1)⊕(Hux↦Hux+a)∑i∈1..nCP(d)(Hux-1)⊕(Hux′↦Hux′+a)
where CPdHux-1|ux involves shifting the stored message and enables padding of zeros between them. Here, Hux↦Hux+a is the shift in data bits of the user.
Step 6: Sort the units based upon suitable order and map the data into suitable seed space. Then, choose a sequence with more probability and encode each sequence with IS-CPMT. Encode each sequence by the IS-CPMT |Hu1,Hu2....Hux to y-bit string (str_ux).
Step 7: Concatenate the strings yii then pad the string with string y of length (Lmax) with random bits and output G seed.
Step 8: Choose an arbitrary number (Di) in the field ψi and multiply it with G. Then, XOR the seed with pri_key and pub_key of the user and output the cipher to u such that cipher←G∘pub_key||pri_key. The process of IS-CPMT is shown in Fig. 5.b. Device registration
Fig. 5 Process involved in IS-CPMT
Step 1: Initialized devices sends a request (req_reg) to SG into the system. For ‘n’ devices dev_id1,dev_id2,.....dev_idn, SG acquires dev_IP,U_code,Pro_code from the device. Also, the certificate C is uploaded into SG. The collected details are transferred to H and it verifies the C sent by the device to match with the C issued by H during initialization.
Step 2: If C is matched, for every device (devi) the public key and private key generation is performed using ECC and sends the accept message accept_msg along with Pub_key to the device and enables them to get registered into H.
Step 3: The details about the device is secured by employing the same procedure followed for encrypting the user details using the modified honey encryption.C. Login and data access request phase
In this phase, the users of the IoT system (u1,u2,..ux) or any registered mobile user login to get access of any devices dev_id1,dev_id2,.....dev_idn present in H. Any user ui inputs the cipher and pub_key along with a access_req message to SG.
Step 1: The login is initiated after verification of the keys and cipher of the user. Only the registered user can participate and access data from the IoT devices. For this, the user credentials (UC) are given to H.
Step 2: H verifies the user data by deciphering the user input using the pub_key. Here, the inverse of XOR is carried out to extract the seed G. Then, G is decoded to extract the rules and the bits for padding is neglected. Next, the user details are acquired from the decoded sequence.
Step 3: If ui is found to match with the user entities stored in H, the request made by ui is considered valid and allowed to proceed to the next step. This is intimated by ack_message to ui.Otherwise, the request is aborted and the user is detached from the system.D. Authentication and Session Key agreement phase
Authentication is the process through which the identities of the entities participating in the system are verified and thus enable them to take part in the smart access of devices in the smart home. When the login is successful, the user is confirmed with the system, authentication is carried out in the system with the registered user for attaining services from the IoT devices.
Step 1: For this, consider a session key (sess_key) which is computed using the two secret parameters such as wi and oi, expressed as,6 Sess_keyi←wi||oi||pub_keyi
Step 2: SG issues a timestamp (tst) and the sess_key encrypted using pub_key of the user to every requesting user (u1,u2,..ux) and to get authenticated to the system for utilizing the services offered by the IoT devices.
Step 3: Every user in the system receives tst and sends a response to the SG after decrypting the sess_key by their own pub_key with the reply_message←tst,Sess_keypri_key encrypted by their own private key. Then, SG transfers the message to H and it verifies the timestamp by decrypting the reply_message using pri_key of the user and checks for legitimacy. If it is found to be valid the user is allowed to get authenticated to the system. This is indicated by a ack_auth message to the user.
Step 4: pri_key of the device is sent to req_user for getting access over the device and enables monitoring from remote instance.E. Key updating phase
In this phase, only legitimate users are allowed to participate in the process. Here, the pre-shared key and the secret key are vital for the update of the key. The key update is carried out in a user-friendly manner since u can directly approach the SG to make alterations in its key. The system allows faster verification of the user entities and ensures the secure change of the keys.
Step 1: For the key update process, any registered user (u1,u2,..ux) in the system can login to the system and change his/her secret keys by sending a chang_key message to the SG.
Step 2: The legitimacy of the user is verified such that input ux matches with the value of ux stored in H. If matching is genuine, user can modify the keys by choosing their own secret parameter required in the generation of the keys.
The process flow of the proposed MHE-IS-CPMT is shown in Fig. 6.Fig. 6 Process flow of MHE-IS-CPMT
Security analysis
The capability of the proposed system to withstand the attacks from its environment is listed as follows.
Proposition 1
MHE-IS-CPMT is resistive against a replay attack.
Proof
In this attack, the adversary may try to occur the session key to gain access over the device. Considering this attack, the authentication and key agreement mechanism require the time stamp validity in order to get access to a device present in H. Here, the Sess_key is sent to the user after encrypting the time stamp with the user’s pub_key. The user receives the message and decrypts the message and gain the Sess_key and time stamp. Then, the reply is sent to H by encrypting the Sess_key and time stamp with the user’s own pri_key. When an adversary tries to gain access over the device fails in such a case since the system needs to encrypt the reply_message with their own pri_key.
Proposition 2
The proposed scheme is more resilient to impersonation attacks from the mobile user.
Proof
In such attacks, an adversary β tries to register himself as a legitimate user uβ dynamically during runtime. In such a case, the adversary submits its own fake u_id and pw_user to SG. H verifies the user credentials before enabling user registration. When the verification outputs a counterfeit result, H marks β as an adversary but issues the cipher. Therefore, if β struggles to gain access to the devices, H makes a tragic play on the user by issuing a plausible data similar to the original data. This diverts β from the system and hence prevents the leakage of the original data.
Proposition 3
The proposed scheme is safeguarded from the eavesdropping attack.
Eavesdropping attack: An adversary β tries to find the secret parameters of ui and compute the keys to get access over the devices. In this case, the proposed scheme generates the keys for authentication using this parameter. Therefore, it is vital that the generation of the secret parameter must be trustworthy in the system. This smart home system incorporates the ASCII encoding mechanism that chooses at random the bits of the pw_user to establish secure generation of eui. This makes it tedious for the intruder to compute the secret parameter used in the key generation process. Hence, our system is resilient to this type of attack by adversaries.
Proposition 4
The proposed scheme is sheltered from the Man-in-the-middle attack.
Proof
To initiate this attack, β intercepts the reply_message sent by the user ui to SG in order to get access over the device. In our scheme, the users are authenticated to the system and acquire the pri_key earlier. During the device access process, the user encrypts the Sess_key with his/her pri_key which is unknown to β or any external person. Therefore, it is impossible for β to indulge the message transmitted by ui. Hence, the contents cannot be modified in any circumstances and thus enabling secure access control features.
Proposition 5
The user relishes anonymity in the system and the system assures un-traceability.
Proof
In any circumstances β tries to acquire the timestamp tst to get authenticated and gain access over the devices. Under such requirements the proposed system is robust enough to withstand the impact of β into the system. For this, the system generates inimitable timestamp and the Sess_key for every device activation and access control. Moreover, the secret parameters required for the computation of Sess_key is altered during every sessions. Due to this unique nature, the proposed system is said to preserve the properties of anonymity and un-traceability.
Proposition 6
The proposed scheme is resistant to the de-synchronization or jamming attacks.
Proof
This sort of attack is committed by β when the system involves two parties such as the users and the home network head H. When the synchronism between these two entities is lost, it is more prone to the attack and the link between them is lost. To deal with this attack, H does not store any of the verifications information of the user participating in access. Whenever, the authentication process fails due to the corruption of links, still the system is capable of initiating the system. This is performed by the computation of the secret parameters oi,wi without the requirement to re-authenticate to the system.
Proposition 7
The proposed scheme ensures the properties of the session key agreement.
Proof
The session key agreement is the confidential part for the user without any compromise with the adversary. In this, any adversary β indulges in fraudulent activities to acquire the Sess_key for gaining over the access control process. To fight back against this attack, the proposed scheme reveals the key only to every registered ui after the finish of the login, authentication and key agreement process. The Sess_key is issued to the user only after initiating the session with a request message access_request. The SG receives the message and makes the devices ready for future communication with the user.
Proposition 8
MHE-IS-CPMT commits resilience to the Denial - of-Service (DoS) attack.
Proof
Any legitimate user ui pass in inappropriate u_id and pw_user to SG. These details are verified before allowing the user to login to the system. Therefore, the request of the user to get services is proceeded to further stages only when the user details provided are appropriate. In this way the DoS attack by other adversaries is discarded in the system.
Experimental results and analysis
This section presents the efficiency of the proposed approach based on experimental settings, performance metrics, and performance comparison results. These details are described in the following sub-sections.
Experimental settings
The key agreement based device access control in IoT is carried out using the Python tool. The hardware setup required for the implementation is CPU based computer system with 8 GB, 2 GHz Intel Core i7, and 256 GB memory. The simulation software is taken from the available open-source libraries/packages. Library functions like TensorFlow (TF) is an open source software library used for the IoT simulation platform [39, 40]. TF is the second-generation framework of Google Brain. On Feb 11, 2017, edition 1.0.0 was published. TF, unlike the standard version, can run on many Multi-Core CPUs. It is compatible with 64-bit Linux, macOS, Vista, and smart phones devices such as iOS and android. Its adaptable design enables simple computing deployments over a wide diverse array of substrates from PCs to hundreds of computers to smartphones and other devices. TF allows developers to create a dataflow structure that describes how data moves and the mathematically operations should be done on data during its transfer from one point to another in the defined structure. In this, structure data is presented as tensors and the mathematical operations as nodes. In this, the TF is free and is supported on Python versions for high-performance numerical computation using dataflow graphs. The software tool versions are: Python 3.6 TensorFlow 1.4 [41, 42]. Consider that the each user initiates the communication with the device and perform access for every five seconds. In the experimental tests, the effect of simulation time is observed when the data is transmitted between the user and devices as the number of exchanged bits is increased per unit time. Here six users have been considered out of which two users are mobile and four users are static. The simulation parameters used for the implementation of the smart home system are shown in Table 3.Table 3 Parameters for simulation
Parameters Description
Simulation platform Python 3.6
Hardware setup CPU: 8 GB, 2 GHz Intel Core i7, and 256 GB memory
Library function TensorFlow 1.4
Computing deployments 64-bit Linux, macOS, Vista, and smart phones devices such as iOS and android
Area of deployment 500 m × 500 m
Number of SG 4
Total number of users 6
Mobile users 2
Static users 4
Number of devices 20, 40, 60
Communication range of H 250 m
Communication time between user and device access 5 s
Communication range of devices 25 m
Considered simulation time 2000 s
Performance metrics
The parameters considered for the evaluation of the proposed scheme involves the End-to-End Delay (EED), throughput, communication cost, computation cost, encryption time and decryption time.
(i) End to End Delay (EED): It is defined as the amount of time needed for users to access the system devices. In the authentication and the key agreement process, the EED value is vital for the session key establishment between the user and the H. The mathematical expression is denoted as,7 ∑i=1ntrec-tsen/treq
where trec is the time taken to receive the data corresponding to the request sent, tsen is the time taken to send a request to the SG, and treq is the total number of requests sent to SG.
(ii) Throughput: It calculates the amount of data flow rate transmitted successfully from one entity to another within a given time period. Here, it is measured in bits per second (bps). The mathematical expression is repsrented as,8 nd×sp/t
where nd is the total number of data accessed from the devices, sp is the size of the data and t is the total time required to access data from the H.
(iii) Encryption and Decryption Time: The amount of time needed to transform plaintext into ciphertext is called the encryption time. In contrast, decryption time restores the plaintext from the received ciphertext.
(iv) Communication Cost: It is defined as the ratio of total number of exchanged messages to the total number of exchanged bits for each transaction. Here, it is measured in time (ms).
(v) Computation Cost: It is defined as the total amount of validations needed to complete each transaction on the IoT based smart home network. Here, it is measured in milliseconds (ms).
Performance comparison results
This section presents the comprehensive comparative analysis of the proposed MHE-IS-CPMT scheme is compared with existing methods such as Li et al. [43], Li et al. [44], Srinivas et al. [45], Park et al. [46], Mallareddy et al. [47], Rawal et al. [48], Bogos et al. [49], Shahid et al. [35], Yang et al. [50], Tan et al. [51], Cai et al. [52], Gope et al. [53], Cho et al. [54], and Mansoor et al. [34] in terms of end to end delay, throughput, communication cost, computation cost, time complexity, encryption time and decryption time.
End to end delay
As shown in Fig. 7, the proposed method achieves a lower end-to-end delay than the Li et al. [43], Li et al. [44], Srinivas et al. [45], Park et al. [46] approaches. Here, the interactional capability of the users with the smart systems is improved to a great extent by the incorporation of the MHE-IS-CPMT scheme. Following this process, users and devices data are securely transmitted with less delay. Therefore, the delay achieved between the users and the device is much lower. Thus, the system achieves better functionality in a limited time interval.Fig. 7 Comparison results of end to end delay
Throughput
Within the considered simulation time, the throughput values are calculated as the number of packet sizes that are transmitted in the network. Existing methods such as Li et al. [43], Li et al. [44], Srinivas et al. [45], Park et al. [46] have lower throughput when the data is transmitted between the user and devices as the number of exchanged bits is increased per unit time. Using the proposed scheme, the number of exchanged messages is increased with higher data security for different network scenarios. As shown in the Fig. 8, the throughput value is higher than the other existing approaches and hence possesses the ability to provide better results for secure data access in smart home networks.Fig. 8 Comparison results of throughput
Encryption and decryption time
As shown in Fig. 9a, the proposed MHE-IS-CPMT scheme obtains less encryption time than four approaches, Mallareddy et al. [47], Rawal et al. [48], Bogos et al. [49], Shahid et al. [35]. For the existing four techniques, the size of the input data (Kilobytes (Kb)) were similar to the proposed model. Here the time is measured in milliseconds (ms). In the same case of four techniques, the encryption time is increased when the data size is 2 to 10 Kb. This means that the four techniques has the highest encryption time and does not provide data security due to vulnerable attacks. The Fig. 9a observes that the proposed scheme encryption process is done by MHE to encrypt the user and device data. Thus, it can be concluded that the proposed scheme obtains higher security with less encryption time.Fig. 9 a and b Comparison results of encryption and decryption time
In Fig. 9b, the decryption time measures the data confidentiality for the proposed MHE-IS-CPMT scheme and existing four approaches, Mallareddy et al. [47], Rawal et al. [48], Bogos et al. [49], Shahid et al. [35]. In these existing four approaches, the decryption time is increased when the data size large (4 to 8 Kb). Hence the Figure concluded that the proposed approach obtains higher data confidentiality with less decryption time when the data size is large.
Cost complexity analysis
Communication cost
For communication cost analysis, several parameters are considered such as Authentication tag MsgT, smart gateway SG and home network head H. In the proposed model, three main entities are considered: User/ mobile user, SG, H. Msg to SG carrying 455 bits and receives 412 bits from SG. At the same time, SG transmits 757 bits and receives 435 bits from H, when H transmits 455 bits and received 757 bits. In terms of communication cost, the proposed model performs secure data transaction among number of bits exchanged in the network.
As shown in Fig. 10, the communication cost is performed between the proposed and existing methods. The method presented in Tan et al. [51] has higher communication costs when compared to Yang et al. [50], Cai et al. [52], Gope et al. [53], Cho et al. [54], Mansoor et al. [34] models. The figure observes that the proposed MHE-IS-CPMT scheme achieves lower communication cost than other methods. Thus the proposed model only provides robust security.Fig. 10 Comparison results of communication cost
Computation cost
For computation cost analysis, some notations are presented as follows:Cc: Computation cost;
Hf: Security function of Cc;
TE/D: Encryption/Decryption of Cc.
In this experiment, the computation cost is performed on Intel dual-core Pentium processor with specifications of 2 GHz Intel Core i7 processor, 8 GB, and 256 GB memory, respectively. As shown in Fig. 11, the proposed model achieves less computation time of 0.01 ms than existing five methods, Yang et al. [50], Tan et al. [51], Cai et al. [52], Gope et al. [53], Cho et al. [54], Mansoor et al. [34]. For the existing five techniques, the total cost is increased whereas the computation time is also increased as the attackers access the system entities over the communication channel. When compared with these models, the proposed model obtains less computation costs and less running time against different types of attacks. Table 4 shows the analysis of computation cost between the proposed and existing methods in terms of several parameters such as Authentication tag MsgT, smart gateway SG and home network head H. In comparison with five methods, the total computation cost of proposed model obtains less cost which is equal to 7 Hf + 2 TE/D.Fig. 11 Comparison results of computation cost
Table 4 Comparison results of computation time and cost
Cc Yang et al. [50] Tan et al. [51] Cai et al. [52] Gope et al. [53] Cho et al. [54] Mansoor et al. [34] Proposed model
CcT 2 Hf 2 Hf 4 Hf 5 Hf 3 Hf 2 Hf 2 Hf
CcSG 3 Hf 2 Hf 2 Hf 2 Hf 2 Hf 2 Hf 2 Hf
CcH 5 Hf 3 Hf 6 Hf 7 Hf 5 Hf 4 Hf + 2 TE/D 3 Hf + 2 TE/D
CcTotal 10 Hf 7 Hf 12 Hf 14 Hf 10 Hf 8 Hf + 2 TE/D 7 Hf + 2 TE/D
CcTime 0.02 ms 0.02 ms 0.03 ms 0.02 ms 0.03 ms 0.027 ms 0.01 ms
Time complexity analysis
Time complexity refers to the time taken to execute every step at the time of simulation. The execution time for every task must be limited within the time budget of the system so as to achieve better performance. Table 5 describes the approximate time required in the computation of several parameters in security functions.Table 5 Computation time for security parameters
Notation Description (time taken for computation) Approximate time for computation (seconds)
tpwdev_id Password generation 0.00021
tkey Key generation 0.00712
tHE Honey based encryption 0.0921
treg Registration 0.0035
tauth Authentication 0.0234
For various entities, the value of each stage is evaluated to find the time complexity of the system. Consider that the total number of transactions for each security level is represented as n-1. The security level of each entity with the longer bits of 1278 provides more security features for the message length of 2. Thus, its time complexity is signed as O (n). Also, the total number of transactions with a time complexity of O(2n-1). The time complexity of each entity is shown in the Table 6.Table 6 Time complexity
Notation Entities Time complexity
treg+2tpwdev_id User/mobile user 0.00042
5tkey+treg SG 0.0391
2tauth+2treg+2tHE H 0.19588
Total time 0.2354
Security features analysis
The expected security features ensures secure authentication and data access using proposed MHE-IS-CPMT scheme. The list of security features is compared with the existing methods and proposed method are as follows:SF1: Mutual authentication
SF2: Un-traceability
SF3: User anonymity
SF4: Session key agreement
SF5: Eavesdropping attack
SF6: Home gateway impersonation attack
SF7: Replay attack
SF8: Man-in-the-middle attack
SF9: Jamming attacks
SF10: Denial-of-Service (DoS) attack
Table 7 shows the comparison results of security features (SF1 to SF10) between the proposed and existing methods.Table 7 Comparison of security features between the proposed and existing methods (✓: fully covered and mentioned and x: not mentioned)
Security features
(SF) Yang et al. [50] Tan et al. [51] Cai et al. [52] Gope et al. [53] Cho et al. [54] Mansoor et al. [34] Proposed model
SF1 x x ✓ ✓ ✓ ✓ ✓
SF2 x x x ✓ ✓ ✓ ✓
SF3 x x ✓ ✓ x ✓ ✓
SF4 x ✓ x ✓ ✓ x ✓
SF5 x x x ✓ x x ✓
SF6 x x x x ✓ x ✓
SF7 ✓ ✓ ✓ x ✓ ✓ ✓
SF8 ✓ ✓ ✓ ✓ ✓ x ✓
SF9 ✓ ✓ ✓ ✓ ✓ ✓ ✓
SF10 ✓ ✓ ✓ x ✓ ✓ ✓
The security feature comparison of proposed and existing methods is shown in Table. Both the schemes by Yang et al. [50] and Tan et al. [51] does not provide mutual authentication, un-traceability and user anonymity and cannot resist eavesdropping attack and home gateway impersonation attack. The scheme by Cai et al. [52] does not provide session key agreement, eavesdropping attack and un-traceability and the method presented in Gope et al. [53] is vulnerable to home gateway impersonation attack, replay attack and DoS attack. Mansoor et al. [34] obtains more security features but it cannot provide session key agreement, and cannot prevent eavesdropping attack, home gateway impersonation attack and man-in-the-middle attack. From the overall results, the proposed MHE-IS-CPMT scheme achieves all security features than existing methods.
Research limitations
In this research work, there are some limitations of the proposed model, which are mentioned as follows: (1) ensuring the security of smart home systems between the information exchange of IoT devices and the server is robust, but the proposed model does not focus on the computing power of IoT devices, (2) the proposed work primarily focuses on user authentication based on the daily access time to smart home devices. However, most online devices are highly dependent on networks, so offline devices can redirect user access patterns to be incorrect. (3) Unified data access is possible, but our proposed model does not support hardware compatibility on some devices.
Conclusion
In this paper, the MHE-IS-CPMT is proposed for secure authentication and key agreement between the users and devices participating in the smart home system. The initialized users and devices of the network are allowed to register into the system. Then, only the registered users are allowed to access and control the devices of the smart home and gain access to the sensitive data. Further, if any adversaries attack the system, the protocol sends plausible responses to confuse the adversaries present in the system. Also, the system model is designed such that it is more resilient to different type of attacks. Finally, the performance results is evaluated that the capability of the system obtains more security features in comparison with other existing approaches. Also, the proposed MHE-IS-CPMT scheme demonstrates that the comparative analysis results obtains best results in terms of end to end delay, communication cost, throughput, computation cost, time complexity, encryption time and decryption time. From the experimental results, the proposed model achieves a lower computation time of 0.01 ms and more security features than existing methods in the secure data transfer of the IoT smart home system.
Authors' contributions
All the authors have participated in writing the manuscript and have revised the final version. All authors read and approved the final manuscript.
Declarations
Conflict of interest
Authors declares that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants and/or animals performed by any of the authors.
Informed consent
There is no informed consent for this study.
Publisher's Note
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References
1. Chakraborty S Bhatt V Chakravorty T Impact of IoT adoption on agility and flexibility of healthcare organization International Journal of Innovative Technology and Exploring Engineering 2019 8 11 2673 2681 10.35940/ijitee.k2119.0981119
2. Alvi SA Afzal B Shah GA Atzori L Mahmood W Internet of multimedia things: Vision and challenges Ad Hoc Networks 2015 33 87 111 10.1016/j.adhoc.2015.04.006
3. Tweneboah-Koduah S Skouby KE Tadayoni R Cyber security threats to IoT applications and service domains Wireless Personal Communications 2017 95 1 169 185 10.1007/s11277-017-4434-6
4. Gubbi J Buyya R Marusic S Palaniswami M Internet of things (IoT): A vision, architectural elements, and future directions Future Generation Computer Systems 2013 29 7 1645 1660 10.1016/j.future.2013.01.010
5. Alaa M Zaidan AA Zaidan BB Talal M Kiah MLM A review of smart home applications based on Internet of Things Journal of Network and Computer Applications 2017 97 48 65 10.1016/j.jnca.2017.08.017
6. Jaikla, T., Vorakulpipat, C., Rattanalerdnusorn, E., & Hai, H. D. (2019). A secure network architecture for heterogeneous iot devices using role-based access control. In 2019 International conference on software, telecommunications and computer networks (SoftCOM) (pp. 1–5). IEEE. 10.23919/softcom.2019.8903605
7. Togan, M., Chifor, B. C., Florea, I., & Gugulea, G. (2017). A smart-phone based privacy-preserving security framework for IoT devices. In 2017 9th International conference on electronics, computers and artificial intelligence (ECAI) (pp. 1–7). IEEE. 10.1109/ecai.2017.8166453
8. Beitollahi H Deconinck G Analyzing well-known countermeasures against distributed denial of service attacks Computer Communications 2012 35 11 1312 1332 10.1016/j.comcom.2012.04.008
9. Sciancalepore S Piro G Boggia G Bianchi G Public key authentication and key agreement in IoT devices with minimal airtime consumption IEEE Embedded Systems Letters 2016 9 1 1 4 10.1109/les.2016.2630729
10. Atamli, A. W., & Martin, A. (2014). Threat-based security analysis for the internet of things. In 2014 International workshop on secure internet of things (pp. 35–43). IEEE. 10.1109/siot.2014.10
11. Chen, B., Huang, Y. L., & Güneş, M. (2015). S-CBAC: A secure access control model supporting group access for Internet of Things. In 2015 IEEE International symposium on software reliability engineering workshops (ISSREW) (pp. 67–67). IEEE. 10.1109/issrew.2015.7392046
12. Rivera, D., Cruz-Piris, L., Lopez-Civera, G., de la Hoz, E., & Marsa-Maestre, I. (2015). Applying an unified access control for IoT-based intelligent agent systems. In 2015 IEEE 8th international conference on service-oriented computing and applications (SOCA) IEEE, 247–251. 10.1109/soca.2015.40
13. Li, J., Chen, X., Li, J., Jia, C., Ma, J., & Lou, W. (2013). Fine-grained access control system based on outsourced attribute-based encryption. In European symposium on research in computer security (pp. 592–609). Springer. 10.1016/j.jss.2016.12.018
14. Wang H He D Shen J Zheng Z Zhao C Zhao M Verifiable outsourced ciphertext-policy attribute-based encryption in cloud computing Soft Computing 2017 21 24 7325 7335 10.3837/tiis.2017.06.024
15. Gaikwad, P. P., Gabhane, J. P., & Golait, S. S. (2015). 3-level secure Kerberos authentication for smart home systems using IoT. In 2015 1st International conference on next generation computing technologies (NGCT) (pp. 262–268). IEEE. 10.1109/ngct.2015.7375123
16. Mahalle, P. N., Prasad, N. R., & Prasad, R. (2014). Threshold cryptography-based group authentication (TCGA) scheme for the Internet of Things (IoT). In 2014 4th International conference on wireless communications, vehicular technology, information theory and aerospace and electronic systems (VITAE) (pp. 1–5). IEEE. 10.1109/vitae.2014.6934425
17. Forsby, F., Furuhed, M., Papadimitratos, P., & Raza, S. (2017). Lightweight x. 509 digital certificates for the internet of things. In Interoperability, safety and security in IoT (pp. 123–133). Springer. 10.1007/978-3-319-93797-7_14
18. Gyamfi, E., Ansere, J. A., & Xu, L. (2019). ECC based lightweight cybersecurity solution for IoT networks utilising multi-access mobile edge computing. In 2019 Fourth international conference on fog and mobile edge computing (FMEC) (pp. 149–154). IEEE. 10.1109/fmec.2019.8795315
19. Miettinen, M., Marchal, S., Hafeez, I., Asokan, N., Sadeghi, A. R., & Tarkoma, S. (2017). Iot sentinel: Automated device-type identification for security enforcement in iot. In 2017 IEEE 37th international conference on distributed computing systems (ICDCS) (pp. 2177–2184). IEEE. 10.1109/icdcs.2017.283
20. Hao P Wang X Shen W A collaborative PHY-aided technique for end-to-end IoT device authentication IEEE Access 2018 6 42279 42293 10.1109/access.2018.2859781
21. Lee I Lee K The internet of things (IoT): Applications, investments, and challenges for enterprises Business Horizons 2015 58 4 431 440 10.1016/j.bushor.2015.03.008
22. Hossain, M.M., Fotouhi, M., & Hasan, R. (2015). Towards an analysis of security issues, challenges, and open problems in the internet of things. In2015 IEEE world congress on services. IEEE, 21–28. 10.1109/services.2015.12
23. Singh S Sharma PK Moon SY Park JH Advanced lightweight encryption algorithms for IoT devices: Survey, challenges and solutions Journal of Ambient Intelligence and Humanized Computing. 2017 1 8 10.1007/s12652-017-0494-4
24. Alassaf N Gutub A Parah SA Al Ghamdi M Enhancing speed of SIMON: A light-weight-cryptographic algorithm for IoT applications Multimedia Tools and Applications. 2019 78 23 32633 32657 10.1007/s11042-018-6801-z
25. Tewari A Gupta BB Cryptanalysis of a novel ultra-lightweight mutual authentication protocol for IoT devices using RFID tags The Journal of Supercomputing. 2017 73 3 1085 1102 10.1007/s11227-016-1849-x
26. Chifor BC Bica I Patriciu VV Pop F A security authorization scheme for smart home Internet of Things devices Future Generation Computer Systems 2018 86 740 749 10.1016/j.future.2017.05.048
27. Shen J Wang C Li T Chen X Huang X Zhan ZH Secure data uploading scheme for a smart home system Information Sciences 2018 453 186 197 10.1016/j.ins.2018.04.048
28. Anthi E Williams L Słowińska M Theodorakopoulos G Burnap P A supervised intrusion detection system for smart home IoT devices IEEE Internet of Things Journal 2019 6 5 9042 9053 10.1109/jiot.2019.2926365
29. Yan H Wang Y Jia C Li J Xiang Y Pedrycz W IoT-FBAC: Function-based access control scheme using identity-based encryption in IoT Future Generation Computer Systems 2019 95 344 353 10.1016/j.future.2018.12.061
30. Alshahrani M Traore I Secure mutual authentication and automated access control for IoT smart home using cumulative keyed-hash chain Journal of Information Security and Applications 2019 45 156 175 10.1016/j.jisa.2019.02.003
31. Punithavathi P Geetha S Karuppiah M Islam SH Hassan MM Choo KKR A lightweight machine learning-based authentication framework for smart IoT devices Information Sciences 2019 484 255 268 10.1016/j.ins.2019.01.073
32. Naik K Patel S An open source smart home management system based on IOT Wireless Networks 2018 10.1007/s11276-018-1884-z
33. Gochhayat SP Lal C Sharma L Sharma DP Gupta D Saucedo JA Kose U Reliable and secure data transfer in IoT networks Wireless Networks 2020 26 8 5689 5702 10.1007/s11276-019-02036-0
34. Mansoor K Ghani A Chaudhry SA Shamshirband S Ghayyur SA Mosavi A Securing IoT-based RFID systems: A robust authentication protocol using symmetric cryptography Sensors 2019 19 21 4752 10.3390/s19214752 31683885
35. Shahid F Ashraf H Ghani A Ghayyur SA Shamshirband S Salwana E PSDS–proficient security over distributed storage: A method for data transmission in cloud IEEE Access 2020 8 118285 118298 10.1109/access.2020.3004433
36. Samuel O Omojo AB Onuja AM Sunday Y Tiwari P Gupta D Hafeez G Yahaya AS Fatoba OJ Shamshirband S IoMT A COVID-19 healthcare system driven by federated learning and blockchain IEEE Journal of Biomedical and Health Informatics 2022 1 21 10.1109/jbhi.2022.3143576
37. Jaeger, J., Ristenpart, T., & Tang, Q. (2016). Honey encryption beyond message recovery security. In Annual international conference on the theory and applications of cryptographic techniques (pp. 758–788). Springer. 10.1007/978-3-662-49890-3_29
38. Santoso, F. K., & Vun, N. C. (2015). Securing IoT for smart home system. In 2015 international symposium on consumer electronics (ISCE) (pp. 1–2). IEEE. 10.1109/isce.2015.7177843
39. https://www.tensorflow.org/about/bib
40. Sarawale, R., Deshpande, A., & Arora, P. (2021). Implementation pathways of smart home by exploiting internet of things (IoT) and Tensorflow. In Data science and security (pp. 478–489), Springer.
41. Nagpal, A., & Gabrani, G. (2019). Python for data analytics, scientific and technical applications. In 2019 Amity international conference on artificial intelligence (AICAI) (pp. 140–145). IEEE. 10.1109/aicai.2019.8701341
42. https://www.python.org/downloads/release/python-368/
43. Li X Niu J Kumari S Wu F Sangaiah AK Choo KKR A three-factor anonymous authentication scheme for wireless sensor networks in internet of things environments Journal of Network and Computer Applications 2018 103 194 204 10.1016/j.jnca.2017.07.001
44. Li X Niu J Bhuiyan MZA Wu F Karuppiah M Kumari S A robust ECC-based provable secure authentication protocol with privacy preserving for industrial Internet of Things IEEE Transactions on Industrial Informatics 2017 14 8 3599 3609 10.1109/tii.2017.2773666
45. Srinivas J Das AK Wazid M Kumar N Anonymous lightweight chaotic map-based authenticated key agreement protocol for industrial Internet of Things IEEE Transactions on Dependable and Secure Computing 2018 17 6 1133 1146 10.1109/tdsc.2018.2857811
46. Park K Noh S Lee H Das AK Kim M Park Y Wazid M LAKS-NVT: Provably secure and lightweight authentication and key agreement scheme without verification table in medical internet of things IEEE Access 2020 8 119387 119404 10.1109/access.2020.3005592
47. Mallareddy A Bhargavi V Rani KD A single to multi-cloud security based on secret sharing algorithm International Journal of Research 2014 1 7 910 915 10.15373/22501991/mar2013/35
48. Rawal BS Vijayakumar V Manogaran G Varatharajan R Chilamkurti N ‘Secure disintegration protocol for privacy preserving cloud storage’ Wireless Personal Communications 2018 103 2 1161 1177 10.1007/s11277-018-5284-6
49. Bogos S Gaspoz J Vaudenay S Cryptanalysis of a homomorphic encryption scheme Cryptography and Communication 2018 10 1 27 39 10.1109/isit.2012.6283832
50. Yang, J., Park, J., Lee, H., Ren, K., & Kim, K. (2005). Mutual authentication protocol for low-cost RFID. In Workshop on RFID and lightweight crypto WRLC (pp. 17–24). 10.1109/apscc.2010.22
51. Tan CC Sheng B Li Q Secure and serverless RFID authentication and search protocols IEEE Transactions on Wireless Communications 2008 10.1109/twc.2008.061012
52. Cai S Li Y Li T Deng RH Attacks and improvements to an RIFD mutual authentication protocol and its extensions Proceedings of the Second ACM Conference on Wireless Network Security, Zurich, Switzerland 2009 16–19 51 58 10.1145/1514274.1514282
53. Gope P Hwang T A realistic lightweight authentication protocol preserving strong anonymity for securing RFID system Computers and Security 2015 55 271 280 10.1016/j.cose.2015.05.004
54. Cho JS Jeong YS Park SO Consideration on the brute-force attack cost and retrieval cost: A hash-based radio-frequency identification (RFID) tag mutual authentication protocol Computers and Mathematics with Applications 2015 69 58 65 10.1016/j.camwa.2012.02.025
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==== Front
Rev Ind Organ
Rev Ind Organ
Review of Industrial Organization
0889-938X
1573-7160
Springer US New York
9891
10.1007/s11151-022-09891-w
Article
Research Diversity and Invention
Scott John T. [email protected]
grid.254880.3 0000 0001 2179 2404 Department of Economics, Dartmouth College, Hanover, NH 03755 USA
7 12 2022
119
14 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
This paper explains that when there is great uncertainty about which elements of knowledge must be combined to make an invention, the likelihood of invention increases markedly—by many orders of magnitude—when there are numerous diverse research organizations, rather than just a few. The paper examines the possibility that competition (antitrust) policy toward mergers would be improved if enforcement efforts placed more emphasis on protecting the diversity that is provided by numerous research rivals in a market.
Keywords
Antitrust
Competition policy
Diversity
Innovation policy
Invention
JEL Classification
O31
O32
O33
O34
O38
K21
L40
L41
==== Body
pmcIntroduction
This paper explains why having numerous diverse research organizations greatly increases the likelihood of invention. An open question is discussed: Does the invention-increasing effect of research diversity justify adjusting competition (antitrust) merger policy by encouraging greater stringency in merger approvals so as to protect the diversity that numerous research rivals in a market would provide?
The importance of diversity for successful research is a theme that is found in the literature about invention and innovation. That literature defines an invention as a new combination of essential elements of knowledge—envisaged together in their working configuration for a new product or service—and defines an innovation as the commercialization of an invention.
The key reason for the beneficial effects of diversity on invention is that an invention combines existing ideas in new ways, and the ideas that are combined in a successful invention are often diverse, coming from very different sources of knowledge and experience. Because diversity within an organization expands the set of ideas that the organization has available for invention, diversity fosters the inventions that become innovations.1 This paper adds an explanation for why a diverse collection of research organizations further stimulates invention.
In terms of the set of knowledge elements from which elements combined in an invention are chosen, Sect. 2 defines uncertainty for an invention and establishes that, given such uncertainty, numerous diverse research organizations make invention more likely.2 Section 3 discusses the possibility that the pace of invention could be increased if competition (antitrust) merger policy placed more emphasis on preserving numerous diverse research organizations.
Section 4 concludes by emphasizing that the proposed change in merger policy is efficiency-based and is important because of its potential for increasing the pace of discovery of new ideas and increasing socially beneficial economic growth.
Uncertainty and Invention with Diverse Research Organizations
Inventions combine existing elements of knowledge in new ways, and the process of discovering an invention is uncertain because of the large number of different elements of knowledge in the set from which must be chosen those that are needed for the right combination of elements for the invention.3 A research organization—wherever situated in the range from large to as small as an individual researcher—confronts the uncertainty of finding the requisite combination of elements from the set of knowledge elements.
A research organization as a practical matter can work with just a subset of the complete set of knowledge elements.4 Successful invention requires that the diversity of ideas in a research organization’s knowledge set must be limited in practice so that the organization can be effectively managed.5 Consequently, there is the possibility that the subset with which it works will not include one or more of the knowledge elements that are needed for the invention.
The type of uncertainty that is the focus of this paper implies that the organization does not know whether the knowledge set with which it works lacks the needed elements. As will be detailed subsequently, the organization can add knowledge elements—for example, additional knowledge elements could be acquired in the market—but although with the larger collection of knowledge elements there is an increased chance that the requisite knowledge elements for the invention are included, whether they are included is unknown.
The uncertainty in the process of invention—the possibility that a research organization is working with a set of knowledge elements that does not include the full set of requisite elements for the invention that is sought—implies that when the uncertainty is great, numerous diverse research organizations will increase the likelihood that some of them will be working with a set of knowledge elements from which the right combination for the invention could be found. To develop that point, we formulate the uncertainty about whether a research organization is working with a set of knowledge elements containing the requisite ones.
An invention combines t elements of knowledge from among the s knowledge elements that a research team has acquired with study and experience from the universe of n knowledge elements. The number n is much larger than s, which in turn is much larger than t.6
Let pf denote the proportion of all possible combinations of s elements chosen from the universe of elements that is taken by cases for which f of the s elements that are available to the research team coincide with f elements in the set of t elements that together define the invention.7 For a research team to be able to discover the essential combination of knowledge elements necessary for an invention, the t essential elements for the invention must be among the s elements that are available to the research team. In that case, f=t; and as was shown in Scott (2016, p. 420):1 Pt≡pf=t=∏i=0t-1s-in-i.
If we think of a research organization abstractly as the set of s knowledge elements with which it works, successful invention requires that the organization has the requisite t elements of knowledge among the s elements; yet the ways that the organization could have the essential t elements among its set of s constitute a minuscule proportion of the potential knowledge sets of s elements with which the research organization could have chosen to work.8
For an example, suppose that there is a universe of a million knowledge elements (n = 1,000,000), an invention that combines three elements (t = 3), and a research organization’s knowledge set with a thousand elements (s = 1,000): Then the proportion of all possible combinations of knowledge elements that include the cases where the organization’s set of knowledge elements include the necessary t elements for the invention is 0.9970 × 10− 9 or about one billionth.
Since a research organization is restricted in the size of the knowledge set that can be managed effectively within an organization, in practice the number of knowledge elements with which its researchers work (s elements for the organization) will be far less than the number of elements n in the universe of knowledge elements. The implication is that a given organization may not have within its knowledge set the requisite t elements for an invention. Pt is extraordinarily small—close to zero—in the case of great uncertainty, defined as the case when n is much larger than s.
For a given research organization, we expect Pt to be small because adding to an organization’s knowledge set is costly, whether for the reasons in the management literature that focus on the difficulty of managing a large number of diverse points of view, or whether because of the direct costs of the knowledge acquisition itself. The knowledge set would not be expected to be increased beyond the point where the marginal benefits equal the marginal costs: where the value of increasing Pt has fallen to the additional cost for the increase in Pt.
The increasing costs that are faced by the research organization as it adds new elements of knowledge to the knowledge set with which it works are necessary for understanding the practical limitation on an organization’s knowledge set because as a research organization expands the number of elements of knowledge in its knowledge set, Pt increases at an increasing rate, as will be shown in the following paragraphs. Each knowledge element that is added to the set essentially doubles the number of possible combinations that could be considered and evaluated.9
If a research organization expands its knowledge set—the organization increases the number of knowledge elements in the organization’s set by v elements, so as to have s + v elements—then the proportion Pt,v of the sample space for which the research organization’s now expanded set of knowledge elements will overlap completely with the t elements of the essential idea is:2 Pt,v=∏i=0v-1s+1+is-t+1+iPt.
Thus, the change in the proportion for each unit increase in the number of elements in the research organization’s knowledge set is:3 Pt,v-Pt,v-1=ts-t+vPt,v-1>0.
Equation (3) shows that the proportion—of all possible combinations of knowledge elements that are taken by the cases where the organization’s set of knowledge elements include the necessary t elements for the invention—is increasing as the number of elements in the organization’s knowledge set increases.
For successive unit increases in the number of elements that are in the organization’s knowledge set, the Appendix derives Eq. (4), which shows that the successive changes in the proportion are increasing:104 (Pt,v+1-Pt,v)-(Pt,v-Pt,v-1)=Pt∏i=0v-2s+1+is-t+1+it(t-1)s-t+v(s-t+v+1)>0.
Because the expansion of a research organization’s knowledge set increases Pt at an increasing rate, increasing cost with knowledge acquisition (as was discussed in note 5) is key to understanding why we expect Pt to be a very small proportion for a research organization.
Many diverse research organizations—with their diversity defined by the differences in their knowledge sets—will make it more likely that there will be research organizations with knowledge sets that include the requisite knowledge elements. If there were z independent research organizations and for each organization α was the probability of not having the requisite t elements within its knowledge set of s elements, the probability that at least one organization has the requisite t elements is 1-αz, which approaches 1.0 as z becomes larger.11
Observe that great uncertainty—n is much larger than s—is necessary for the efficacy of numerous diverse research organizations. Suppose that the set of knowledge elements from which the research organization selects s elements to study (in the hope that within those s elements the requisite t elements can be found) has been successfully reduced. And suppose the reduction is sufficiently great, from n to a number n^, so that s, although less than n^, is large relative to n^. In that case, having numerous diverse research organizations is of little value and can even reduce (as will be argued below) the chance that organizations are working with knowledge sets with the requisite elements for the invention sought:
Define the proportion Pt^ as in Eq. (1) but with n replaced with n^, and assuming the set of knowledge elements (from which the research organization selects s with which to work) is successfully reduced to n^ (i.e., the essential t elements of knowledge are among the n^ elements). Pt^ is the proportion—of the potential knowledge sets of s elements chosen from among the n^ and with which the research organization could have chosen to work—that include all t essential elements. With s close to n^, Pt^ has become close to 1 for an individual research organization, and the gain from having multiple research organizations is small at best.
Consider the extreme case where n has been successfully reduced to n^ and a research organization can study those elements: s = n^. Pt^ = 1, and for this special case there is no uncertainty of the type that was addressed with numerous diverse organizations in the foregoing discussion—although having intra-organizational diversity for the organization pursuing the n^ ideas can be the essence of considering all those ideas.
However, if there were any significant uncertainty as to whether an organization would recognize among the n^ elements the right combination of t elements for the invention, numerous organizations could serve usefully (if the cost for additional search were outweighed by the expected gain) for a parallel path strategy to increase the probability of invention. But these would not be diverse organizations but would be identical in the sense that for each its s set would coincide with n^.
In that foregoing extreme case, if one insisted that all organizations be diverse, then for all but at most one organization, the s set would not exactly overlap with n^, and so the diversity across organizations could reduce the likelihood that organizations were working with knowledge sets within which the requisite elements to be combined in the invention could be found. In the extreme case, introducing diversity across the organizations in the s elements can reduce the chance that the t elements are included in an organization’s s set, especially so if s is small. Such extreme cases are not the cases of great uncertainty of interest here.
In sum, the case of interest to us is t < < s << n, and Pt is vanishingly small, many orders of magnitude removed from the Pt = 1 case—nine orders of magnitude in our 1 in a billion example. Numerous diverse firms are helpful for the case of interest.12
What kind of inventions would be examples of the case of interest? Those that come readily to mind are the more dramatic inventions. A recent example is the massive effort by many diverse organizations to develop a vaccine to mitigate the Covid-19 pandemic (Mullard, 2020). Archetypal examples of inventions that each played out over many decades of research by numerous diverse research organizations, including individual researchers, are the invention of the electric lightbulb (Johnson, 2014, pp. 205–215) and the invention of the airplane (Meyer, 2015).13
Less dramatic and prominent inventions may not entail the case of great uncertainty for which numerous diverse research organizations make the invention more likely. Yet because we are often first cognizant of inventions during the later stages of their discovery, the number of knowledge elements from which research organizations choose s for study may well have been considerably reduced (from n to n^) by the time that the discovery process is observed. If so, we might not realize that initially the problem of finding the invention was uncertain in our sense that Pt was vanishingly small and having numerous diverse research organizations would have been helpful.14
Implication for Competition Policy Toward Mergers
Greater Diversity Coincides with a Larger Number of Research Organizations
As discussed in Sect. 3.2 below, competition policy toward mergers has not placed an emphasis on maintaining numerous research organizations in markets. Yet if merger policy did serve to maintain numerous research organizations in markets, the industrial organization literature suggests that the policy would also serve to maintain numerous diverse organizations. The papers typically discuss a combination of invention and innovation activities—industrial R&D expenditures cover a range of activities from research for invention to the development of inventions in pursuit of innovations—and support the view that having more organizations increases the diversity of their research.
Scherer (1970, p. 357) emphasizes the diversity across firms of different sizes, with smaller firms disproportionately active in invention—which is consistent with Sect. 2’s description of increasing costs for the expansion of a research organization’s knowledge set—and then with larger firms’ playing important roles in innovation. Cohen and Klepper (1991) emphasize the many possible different productive approaches to innovation that can result from having a larger number of firms in an industry.
Scott (1991, pp. 136–139) emphasizes that each firm among a rivalrous group may have an incentive to bring different knowledge to its research to find a unique invention that when developed will dominate post-innovation competition among competing substitute innovations. The rivals strive to be different.
Describing the contrasting situation in which rivals do not strive to be different, Nelson (1981, p. 107) discusses “a syndrome regarding R&D allocation similar to that described by Hotelling in the case of location decisions” and observes that competitive R&D rivals will not necessarily pursue different opportunities. The rivals strive to take different approaches in Scott (1991) because the dominant version of the innovation is unknown in advance of development and commercialization of the underlying invention, and so the conditions that would cause R&D rivals to cluster their efforts around similar development efforts and a similar version of the innovation are not present.15
Thus, given uncertainty, we expect that independent research entities provide unique perspectives. The evidence that firms in the same industry pursue different R&D strategies is strong. Regarding company-specific research policies, interpreting the results in Scott (1984), Griliches (1984, p. 7) observed, “… there appear to be significant differences in company R&D policy above and beyond what would have been predicted just from their differential location within the industrial spectrum.”
There is also evidence (Scott, 1991, pp. 139–145) that research rivalry and the diversity of the rivals are synonymous. Given the competitors in an area of research, distinct R&D strategies are observed for firms in the systems orientation of their portfolios of patents, in the purposive diversification of their R&D across industries, and in the intensity of their R&D. Moreover, the firm effects in R&D intensity are more significant in markets with more competitive structure—which is consistent with the hypothesis that with more firms competing, firms have more incentive to strive for a distinct innovation so as to avoid the erosion of rents in the post-innovation market.
Taken together, the several types of evidence that different firms in the same industries pursue different research strategies support the inferences that firms’ capabilities differ fundamentally and that firms would choose different strategies even if their capabilities were the same.16
The Need for New Competition (Antitrust) Policy Regarding Diversity
Has competition policy been adequate to protect the desirable diversity that numerous research organizations provide to the process of invention in an area of research? The discussion to follow focuses on the antitrust law of the United States; but although the institutional details differ, the essential problem discussed is present in competition policy throughout the world, and it results from the nexus of statute law, enforcement, and interpretation.17
The statute law that protects competition uses language that is broad enough to protect the desirable diversity that is provided by large numbers of firms competing in a given market; and any inadequacy would result because of the historical evolution of enforcement and interpretation of the statutes.18 When considering mergers, coordinated behavior among firms, or dominant firm behavior that would lessen the number of independent research entities in an area of research, both dynamic efficiency—which relates to new products and processes from innovation—and static allocative efficiency—which is a nexus of price, cost, and output given existing products and processes—are considered desirable attributes of performance.
In an insightful analysis based on well-informed understanding of both the law and the economics, Baker (2007) addresses the question of whether competition policy can be used successfully to promote innovation. His analysis develops and supports well the view that “[o]n the whole, … antitrust rules and enforcement today are appropriately focused to promote innovation” (Baker, 2007, p. 576).
Baker’s view is supported with his careful review of the law and the economics to show that “… the modern economic learning about the connection between competition and innovation helps clarify the types of firm conduct and industry settings where antitrust interventions are most likely to foster innovation. Measured against this standard, contemporary competition policy holds up well” (Baker, 2007, p. 576).19
Baker’s reasoning and his conclusion are compelling. Just one amendment is suggested here because of the importance of diversity for invention: Competition policy toward mergers could potentially be improved by addressing the need for large numbers of diverse research organizations in an area of research to increase the probability that research organizations will have the requisite elements of knowledge for a sought-after invention.20
Baker (2007, p. 592) observes “. . antitrust promotes innovation by challenging horizontal mergers that reduce the number of likely innovators when there are few, absent countervailing innovation efficiencies.” Thus, the enforcement agencies’ challenges to horizontal mergers occur when the relevant markets have only a few likely innovators. Consolidation of likely innovators prior to leaving only a few occurs without a challenge from competition policy. The industrial R&D of the firms that are consolidated to leave a few likely innovators entails a mixture of research and invention and development and innovation; the benefit of numerous firms investing in R&D can be lost.
There are arguably two reasons why competition policy toward mergers does not protect the diversity that would be provided by numerous innovative competitors in a market: One is the consensus view that for good innovation performance a moderate amount of seller concentration is ideal—not so much structural competition that investment in research is discouraged because firms expect insufficient returns in post-innovation markets, and not so much concentration that the profitable firms that are shielded from preemption by innovative rivals lack the incentive to invest in research.21
A second reason is that at least a moderate amount of seller concentration may be needed to achieve scale economies that promote efficiency and may do so to a sufficient extent that the efficiency gains increase total economic surplus by more than what is lost by any increase in market power.22
Thus, performance gains from economies of scale in markets with fewer sellers or from economies of scope across the markets of diversified and vertically integrated firms are recognized, while harm to innovative performance from a loss of independent research units is not anticipated given the consensus that a moderate amount of competition—equivalent in practice to a moderate amount of concentration of resources among sellers—is ideal for innovation.23
The consensus about innovation performance’s being best in moderately concentrated markets is strong, yet it is open to question even without the importance of diversity in research efforts.
In the consensus view, the problem with too much competition is that investors might expect too little return from research given the probability that competitors would market competing substitute innovations—perhaps imitations that use the results of the investments of others, or that a competitor would have a dominant innovation. Yet government subsidies can make research investments profitable even in highly competitive markets (Link and Scott, 2001).
The consensus-view problem with too little competition is that there will be insufficient incentive for research investment by firms that are not anticipating preemption by the innovations of rivals. Yet, theory (Scott and Scott, 2014, Appendix Remark 3 and Remark 4, pp. 52–53) predicts and evidence (Scott and Scott, 2014) finds higher R&D investments in more highly concentrated markets when the research expenditures of the oligopolists are sufficiently strong strategic substitutes.
If an increased number of research organizations is associated with an increased diversity of knowledge sets, and consequently it is more likely that there will be research organizations with the requisite knowledge elements for a sought-after invention and that the invention will be found, then at least one aspect of innovation performance—invention—would not be subject to an inverted-U relationship. Thus, the inverted-U relationship, if it exists, would derive from other aspects of the innovation process—presumably ones that are related to commercialization rather than to invention.24
Conclusion
In practice, competition policy toward mergers does not pay attention to maintaining large numbers of independent research entities that provide diversity for inventive efforts that support innovation in a market. The inattention occurs even though the goal of competition policy is to promote competition—in part because “[c]ompetition often spurs firms to innovate” (U.S. Department of Justice and Federal Trade Commission, 2010, p. 23).
The consensus view that a moderate amount of concentration of research resources promotes innovation has aligned in the application of competition policy with the view that economic performance given existing technologies is improved when markets are sufficiently concentrated to achieve significant economies of scale and when firms’ operations across markets capture available efficiency gains from vertical integration and from economies of scope.25 Attention to the improvement in innovation performance that results from the diversity that is provided by numerous research competitors is simply not a focus of competition policy.26
The focus in this paper on the benefits of diversity in research efforts is a narrow economics argument about the efficiency of the research process; thus, the focus is different than the one that has been emphasized by the Biden administration’s FTC.
The FTC has proposed new approaches to competition policy that include, among other things, actions “to ensure that all members of the public reap the benefits of competition, particularly members of underserved, marginalized and diverse groups … [and] to identify and redress the potentially disparate impact anticompetitive transactions or business practices have on traditionally underserved and marginalized communities, particularly when conduct may seek to deliberately exploit or prey upon the disadvantages of these diverse communities.” (Federal Trade Commission, October 2021, p. 21).27
The FTC’s initiatives are controversial because competition policy—as it has evolved with the enforcement and interpretation of the statute law—has had the narrow goal of promoting competition in markets to increase efficiency and innovation for the benefit of consumers.28 The FTC proposes to use competition policy to address equity among diverse groups—an approach that is distinct from but complementary with the use of competition policy to ensure diverse research efforts.29
Changing competition policy to address a goal of preserving the diversity that is provided by large numbers of competitors in a market has a narrowly economic, efficiency-based justification: improving innovative performance.30 An economy’s dynamic performance is important; when good, it can create productivity gains and growth that allow better living standards for households throughout the distributions of income and wealth.
Thus, an implication of this paper’s findings about how numerous diverse research organizations can increase the likelihood of invention would be that in the calculus of antitrust enforcement decisions about mergers, additional weight should be assigned to the benefits for invention from avoiding the loss of independent research organizations because of mergers. Translating the implication into policy is difficult, and several key issues must be addressed:It is important to keep conceptually separate—at least in principle—the size and structure for the inventing (or R&D) organization from the size and structure of the production organization in which the inventing organization may or may not be housed. As was discussed in note 5, there are economies of scale in inventing; yet the metric for the scale of research output differs from the metric for the scale of the production of goods and services to which an invention may apply, and the differences in the metrics are important when examining tradeoffs: Mergers decrease the number of independent research centers but increase the scale of production and possibly of invention and R&D activities.
Seller concentration in the relevant goods/services market need not be the same as—or have the same effects as—the concentration in the underlying research “market” that is especially important for evaluating a merger’s impact on the number of diverse research organizations.
The tradeoffs must be enumerated. The key tradeoff to confront would be to weigh gains from a larger number of diverse research organizations with the advantages that are provided by fewer firms that may not only realize scale economies in research and production but also appropriate more of the social returns when an invention is developed and commercialized (Cohen and Klepper, 1991).31 The tradeoff also entails the different roles that are played by small and large firms in the process of invention and innovation (Scherer, 1970, p. 357), with the need to maintain a sufficient presence of larger firms so as to ensure the successful innovations that build on the inventions that are generated by smaller firms.32
The point here is that competition policy should increase the weight that is placed on the diversity that is provided by a larger number of innovative rivals because of the increased likelihood that there will be research organizations with the requisite knowledge elements for the invention that precedes further development work and commercialization of an innovation.33 Without the invention, there will be no innovation. But clearly there are the foregoing issues to address if merger policy is to implement an increase in the weight that is placed on the value of numerous diverse research centers.
Moreover, although the statute law that governs competition policy is stated broadly enough to encompass enforcement to protect desirable diversity of numerous research rivals in a market, new legislation would probably be needed to implement the proposed change in merger policy. Using competition policy toward mergers to ensure the diversity of research that is important for invention would probably require new legislation, given the current interpretation of the current statutes and because interpretation of the statute law develops slowly through case law.34
Such new legislation would state that protecting the diversity of research efforts is important for effective competition and thus is an important goal of competition policy. The legislation would add information about the intent of the broadly-worded statute laws—adding language to state explicitly that maintaining the diversity that is provided by numerous competitors in a market is an important part of what is meant by maintaining competition.
The proposed change in antitrust policy toward mergers—to emphasize the importance of maintaining numerous diverse research organizations in markets—could have a significant impact on the pace of invention; this is an impact that would be especially helpful in the context of evidence that ideas are becoming harder to find (Bloom et al., 2020).35
We described above the increasing costs that are faced by a research organization when expanding its own knowledge set, but also showed that a collection of diverse research organizations could increase the likelihood that some of the organizations would have within their knowledge sets the requisite knowledge for invention. Policy that promotes numerous diverse research organizations may therefore unleash the possibilities of combinatorial growth that is described by Weitzman (1998).
Appendix
From Eq. (3),(Pt,v+1-Pt,v)-(Pt,v-Pt,v-1)=Pt,vts-t+v+1-Pt,v-1ts-t+v
From Eq. (2), the right-hand side equals∏i=0v-1s+1+is-t+1+its-t+v+1Pt-∏i=0v-2s+1+is-t+1+its-t+vPt
=Pt∏i=0v-2s+1+is-t+1+is+vs-t+vts-t+v+1-ts-t+v
=Pt∏i=0v-2s+1+is-t+1+it(s+v)(s-t+v)2+(s-t+v)-ts-t+v
=Pt∏i=0v-2s+1+is-t+1+its+vs-t+v-t[s-t+v2+s-t+v][s-t+v2+s-t+v](s-t+v)
=Pt∏i=0v-2s+1+is-t+1+its-t+v[s+v-(s-t+v+1[s-t+v2+s-t+v](s-t+v)
=Pt∏i=0v-2s+1+is-t+1+it(s-t+v)(t-1)[s-t+v2+s-t+v](s-t+v)
=Pt∏i=0v-2s+1+is-t+1+it(t-1)s-t+v(s-t+v+1)>0
Acknowledgements
I am indebted to Lawrence J. White and two anonymous referees for exceptionally thoughtful and constructive criticism that resulted in many substantive improvements in the paper.
Declarations
Conflict of interest
Not Applicable
1 In the context of their own original research about the challenges in effectively using knowledge diversity within research teams to create new products, Pollok et al. (2021) provide an integrative discussion of key contributions in the large, well-developed management science literature that finds that diversity benefits innovation because it allows taking advantage of more combinatorial possibilities to discover the right combination for an invention.
2 Sect. 2 develops the definition of uncertainty and establishes the result that numerous diverse research organizations increase the likelihood of invention by using the description in Scott (2016) of the invention sample space—the set of possibilities for the combinations of essential elements of knowledge in the creative process of finding the right combination for an invention. Scott (2016) used the description to set out the steps in creative individuals’ process of discovering an invention, as individual inventors or within research organizations, and to describe various corporate strategies for sharing information. In this paper, the description is used to define a particular type of uncertainty and then to show how the uncertainty can be resolved by having numerous diverse research organizations. Additionally, this paper develops the potential implication for merger policy of the new ideas that are developed in Sect. 2.
3 As described by Usher (1929, p. 11), “Invention finds its distinctive feature in the constructive assimilation of preexisting elements into new syntheses, new patterns, or new configurations of behavior.” Invention combines diverse ideas. Weitzman (1998, pp. 334–336) has several noteworthy statements—including Usher’s classic statement—from writers who have explained that the creative process of invention is a process of combining ideas and, moreover, combining quite diverse ideas. The mathematician Poincaré observed in 1908, as quoted by Weitzman (1998, p. 335): “To create consists precisely in not making useless combinations and in making those which are useful and which are only a small minority. Invention is discernment, choices…. Among chosen combinations the most fertile will often be those formed of elements drawn from domains which are far apart.”
4 Pollok et al. (2021) review the management literature that develops the insight that too much diversity in the points of view that inform an organization’s research process is counterproductive because the research will lose focus and be difficult to manage. They study knowledge diversity’s positive and negative effects on team creativity and “… argue that while diversity creates combinatorial opportunities that increase the likelihood of novel creative output, it also impedes team coordination making convergent refinement towards useful solutions less effective” (Pollok et al., 2021, p. 2).
5 The increasing costs for working with a larger set of knowledge elements is an example, in the context of a research organization, of the U-shaped cost curves shown in microeconomics textbooks. The organization’s desire to encompass more knowledge elements to increase its likelihood of discovering an invention reflects an “economy of scale” in invention (along with other sources of economies of scale such as the large, expensive equipment that may be needed for some kinds of research). In the textbook case, the U-shaped unit cost curves turn upward in the short run as more variable factors of production are used with the fixed factors of plant and equipment; and even in the long run when all factors of production are variable and plant and equipment can be expanded, the long-run unit cost curves will be U-shaped if there are diseconomies of scale. The classical reason for diseconomies of scale is managerial diseconomies, and that is what the organizational science literature is observing for research organizations that face limitations on the amount of diversity in their knowledge sets that is manageable. One could think of the research organization’s knowledge set as an asset, just as the specialized equipment that its researchers use, and in the long run the research organization’s knowledge set can be expanded, adding more elements of knowledge to the knowledge set that is used with its human and physical capital. However, the difficulties of managing the organization increase, the organization incurs costs of dealing with those difficulties; and eventually the cost of a unit of research output increases with further expansion of the knowledge set.
6 For examples of the requisite t elements of knowledge for each of several prominent inventions, see Scott (2016, Table 1, pp. 413–414).
7 The summation of p(f) from f = 0 to t equals 1. The proportions are not probabilities: The set of possible outcomes has been described; but a numerical value for probability has not been associated with each potential outcome. If for example all potential outcomes were equally likely, then the proportions would be probabilities; but that is not the case.
8 Restricting the portion of the universe of knowledge from which a research team chooses its s elements of knowledge for study can—if the portion’s set of knowledge elements includes the requisite t elements—increase the proportion, of all the ways that the s elements could be chosen, for which the chosen set of s elements includes the necessary t elements. See the discussion of the “exclusion step” in Scott (2016, pp. 421–425).
9 If a research team works with s elements of knowledge from which could be chosen a combination to create an invention, the total number of possible combinations in distinct groups with one or more of the elements is 2s-1. See the explanation and discussion in Scott (2016, n. 8, p. 427) and the references there. Adding one element of knowledge to the set that is used by the researchers essentially doubles the number of possible combinations. The ratio of the combinations of s + 1 to combinations of s is (2s+1-1)/2s-1=(2-1/2s)/(1-(1/2s)), which approaches 2 as s becomes large.
10 For our example with n = 1,000,000, s = 1,000, and t = 3, if—to provide an illustrative example—v = 61, then computing the change in the change using the formula given by Eq. (4) yields the answer 53/(8,333,308,333,350,000) = 6.36001908004452… x 10− 15. Although we need Eq. (4) to prove that the proportion Pt increases at an increasing rate as s is increased, we can compute the change in the changes more directly. One gets the same answer if Eq. (1) is used to compute the values for Pt for the cases when s = 1060, s = 1061, and s = 1062 (with n = 1,000,000 and t = 3) and then computes directly, from those values for Pt, the change in the two successive changes as s is increased by 1 from 1060 to 1061 and then again from 1061 to 1062. Also, the same answer is found using Eq. (2) to compute the two successive values for Pt and then computing the changes and the change in the changes. Further, the same answer is found if Eq. (3) is used to compute each successive change and then the change in the changes is computed.
11 The assumption here is independence across research organizations with regard to whether a research organization has in its knowledge set the t elements of knowledge essential for the invention pursued. However, even if there were some positive correlation across organizations in the presence of the t elements, the result here remains: A larger number of organizations implies a larger probability that at least one organization has the essential t elements in its knowledge set. Moreover, a larger number of organizations implies a larger probability that somewhat similar (differentiated) inventions can emerge as the successful invention that results when the numerous diverse organizations are pursuing “the invention” and several find the successful combination of knowledge elements, differentiating their versions sufficiently to allow obtaining intellectual property or at least avoid rival organizations blocking the marketing of their versions. For example, as documented in Danziger and Scott (2022), there have been many competing versions of drug-eluting coronary stents, with the variations in them sufficient to allow the differentiated and patented products to be marketed. Danziger and Scott also explain why theoretically the competition that involves similar products might not have a detrimental effect on R&D investment.
12 Thinking in terms of the “demand” for and the “supply” of inventions is helpful for understanding where the findings here fit within the industrial organization literature. For a cost-reduction invention, the demand comes from an enterprise (or from an entrepreneur) that seeks a lower-cost way of producing some product or service. The strength of that demand will depend on the market structure of that product or service—as has been developed in the large literature that was spawned by Arrow’s (1962) seminal article. The supply will be a function of the elements/diversity argument that is developed in this paper, economies of scale, and the difficulties of managing a large research organization. There is also the “vertical integration” issue of in-house versus stand-alone research, which then raises the familiar issues of appropriability, asymmetric information, and financing, among others. A similar demand and supply framework could apply to an invention that creates a differentiated substitute for an existing product.
13 With these iconic examples, individual researchers and research organizations shared information, “borrowing” ideas from others. In addition to the discussion in Pollok et al. (2021) about the open sharing of information among researchers, see Meyer (2015, pp. 214–215) who provides, with citations of numerous important contributions, an excellent window on the very large literature about the benefits, for invention and innovation, of freely sharing information. Meyer provides references to the works of many scholars (for example, von Hippel (2005) with his focus on user (consumer) led innovation) who have made contributions to the concept and understanding of open innovation that occurs when individuals, firms, and organizations more generally find sharing ideas to be advantageous. In the context of the sample space for invention, Scott (2016) discusses the sharing of information as a corporate strategy.
14 For example, the inventors of the drug-eluting coronary stent benefited from a vast amount of research from diverse research organizations about the causes of narrowing of coronary arteries, about the methods of treatment, and about anticancer drugs that prevent unwanted proliferation of tissue cells. Observing the two NIH inventors brainstorming the idea for the drug-eluting coronary stent, demonstrating proof of concept, and obtaining a patent, we need to remember the numerous diverse research organizations that preceded and made possible the invention and effectively reduced n to a much more manageable n^ by the time that we observe the invention’s discovery. See Nijhara et al. (2005) and Danziger and Scott (2022).
15 Monopoly is unlikely to replicate the diversity that free entry of diverse research organizations would provide because of the difficulty of managing a large knowledge set (large s). Moreover, the monopolist would not have an incentive to incur the costs of ensuring diverse outcomes for research trials to increase the likelihood of a dominant innovation, because the monopolist gains the same expected benefit regardless of the number of successful trials yielding substitutable innovations. Substitutable products that are commercialized because of the monopolist’s research trials will not create rent-eroding price competition in the post-innovation market (Scott, 1991, p. 139).
16 The theoretical and empirical evidence that supports the idea that diversity across research organizations increases with their number is now three decades old, and it would be useful to have new research on the subject. The research from three to four decades ago was able to make use of the data that were provided by the now discontinued Federal Trade Commission’s Line of Business Program. Appropriate new data are now available: Three decades after the FTC stopped gathering line of business data, the U.S. National Science Foundation introduced the Business R&D and Innovation Survey (the successor to the Survey of Industrial Research and Development), which provides a source of high-quality R&D data that are segmented by type of business that can be combined with the Census Bureau’s Longitudinal Establishment Data file (see Scott, 2014).
17 Gilbert (2020), which will be discussed subsequently, reviews U.S. and European Commission (EC) merger cases that address innovation competition; and Martin (2008) provides an insightful and authoritative overview, comparison, and contrast of U.S. competition policy with policies in the European Union.
18 In the United States, the key federal laws that could be used to protect diversity in the innovation process are the Sherman Antitrust Act (26 Stat. 209, 15 U.S.C. 1 and following), the Clayton Antitrust Act (Public Law 63–212, 38 Stat. 730, 15 U.S.C. 12 and following), and the Federal Trade Commission Act (Public Law 63–203, 38 Stat. 717, 15 U.S.C. 41 and following). The key U.S. federal enforcement agencies are the Antitrust Division of the U.S. Department of Justice (DOJ) and the Federal Trade Commission (FTC). The U.S. federal courts interpret the law in the context of the cases that are filed by the DOJ and the FTC, as well as by private parties and by state Attorneys General.
19 A reader of the earlier version of this paper observed the tension between my endorsement of Baker’s article and my subsequent explanation of how antitrust policy has ignored, or had inadequate tools to address, the need to consider the importance of numerous diverse research competitors in a market. The resolution of the tension is that Baker’s view is based on an understanding of the literature as it was, while in this article I advance a new dynamic-efficiency-based reason for change in both the economics and the law.
20 Such a change in policy would be consistent with the competition and innovation policies that are advocated by Aghion et al., (2021) to promote what they term “inclusive growth,” although the policy change proposed here is a narrow, focused one that is based on the idea that was developed above. Aghion et al. (2021) consider a much broader range of policies, including some akin to those in Federal Trade Commission (October 2021, p. 21) as will be discussed below. They also explicitly place their analysis in the worldwide context of emerging markets and developing economies as well as advanced economies.
21 Providing an overview of the literature about competition and innovation that is used in competition policy, Hovenkamp (2016, p. 1) observes, “A broad consensus today is that the market structure/innovation curve is a lopsided, inverted “U.”. . . Neither monopoly nor atomistic competition is especially conducive to innovation. Rather, most innovation occurs in moderately competitive, product differentiated markets.” The broad consensus has a firm foundation in the literature. As Scherer (1970, p. 378) surmised early in the development of the literature: “What is needed for rapid technical progress is a subtle blend of competition and monopoly, with more emphasis in general on the former than the latter, and with the role of monopolistic elements diminishing when rich technological opportunities exist.” The rich technological opportunities allow sufficient appropriation of returns to support the investments of firms in more competitive markets. For an important review and perspective about the early theory and evidence of the inverted-U relation between market structure and innovation, see Scherer & Ross (1990, pp. 630–651). Baker (2007, p. 584) discusses papers subsequent to the Scherer and Ross review that “appear to have resurrected the “inverted U” result” but “do not control satisfactorily for differences across industries in the extent and rate of growth of technological opportunity and in the conditions of appropriability.”
22 Williamson (1968) provides the landmark examination of the increased economic performance from efficiency-enhancing concentration of a market’s sellers despite an increase in their market power: the ability to control price.
23 The enforcement agencies consider a moderately concentrated market to have a Herfindahl-Hirschman Index (HHI) between 1500 and 2500 (U.S. Department of Justice and Federal Trade Commission, 2010, p. 19), which corresponds to a market with between 6.67 and 4 equal-sized firms. Some substantial mergers in moderately concentrated markets could in theory be challenged, but the mergers that are challenged by the agencies typically are in markets that are highly concentrated, with HHI greater than 2500—often considerably so.
24 The evidence in Scott (1984) and the theory and evidence in Scott and Scott (2014) suggest that the sightings of the inverted-U have been the result of insufficient controls for the many forces that affect R&D investment.
25 Kwoka (2017), who examines U.S. policies, and Affeldt et al., (2021), who examine European Union policies, conclude that antitrust enforcement has been too lenient because too much weight has been placed on the possibilities for efficiency gains as compared to the effects on market power from lost competition.
26 Gilbert’s (2020) careful review of U.S. and EC merger cases that have addressed concern about innovation competition supports the view that protecting large numbers of diverse research rivals is not a focus of merger policy. As was discussed above, Baker (2007, p. 592) observed that the merger challenges that entail a concern about innovation occur when there are just a few likely innovators—and even then, only when offsetting innovative efficiencies are not anticipated. The enforcement actions—whether to block a merger, require divestiture of assets, or require licensing of technology—occur when few research rivals remain in the market. Gilbert (2020, pp. 163–165) does provide what might appear to be an exception—the EC’s challenge to a merger of the agrochemical businesses of Dow and DuPont. Conforming with the norm of addressing loss of innovation competition only when a few innovation rivals remain, when it challenged the merger, the U.S. DOJ did not require the divestiture of any R&D assets. However, the EC did require DuPont to divest R&D assets for agricultural pesticides, applying “… unilateral effects theory for early-stage R&D incentives in an industry with more than a few potential innovators” (Gilbert, 2020, p. 164). Although the case is novel, Gilbert’s detailed discussion explains that although there are many research organizations doing R&D for agricultural pesticides, the EC specifically restricted the set of potential innovators in various ways that left just a few in the relevant “innovation spaces.” Thus, even this one novel case conforms to the enforcement agencies’ concerns (about a merger lessening innovation competition) only when a few research competitors remain.
27 The FTC even voted to withdraw its 2015 statement about its enforcement principles as a part of its decision to take a more expansive approach to its enforcement efforts under Sect. 5 of the FTC Act (Federal Trade Commission, July 1, 2021). The withdrawn 2015 statement enumerated “the Commission will be guided by the public policy underlying the antitrust laws, namely, the promotion of consumer welfare; the act or practice will be evaluated under a framework similar to the rule of reason, that is, an act or practice challenged by the Commission must cause, or be likely to cause, harm to competition or the competitive process, taking into account any associated cognizable efficiencies and business justifications; and the Commission is less likely to challenge an act or practice as an unfair method of competition on a standalone basis if enforcement of the Sherman or Clayton Act is sufficient to address the competitive harm arising from the act or practice.” (Federal Trade Commission, 2015). For the meaning of the goal of promoting “consumer welfare,” see Martin (2008, pp. 46–49).
28 Thinking about the entire spectrum of proposals to use antitrust policy to address more than maintaining competition in markets, White (2021, p. 14) observes, “The focus of antitrust is narrow: maintaining competition, with the goal of enhancing the efficiency and innovativeness of markets in ways that ultimately benefit consumers. To widen the goals of antitrust—as has been advocated by some critics of current antitrust policies …—so as to encompass goals such as expanded employment, a cleaner environment, improved income distribution, community development, etc., would be a mistake. It would dilute and distract antitrust enforcement, since additional tradeoffs between efficiencies and these other goals would need to be considered—and additional data and modeling would be needed so as to measure/quantify these tradeoffs. The current tasks of antitrust enforcers are already difficult; to add dimensions that they would have to evaluate and for which they would have to acquire expertise and determine tradeoffs could make their tasks near-impossible. Instead, if antitrust enforcement is perceived as contravening other goals … then there should be other policies that are brought to bear to provide appropriate remedies.”
29 The FTC’s intention to address equity is made explicit in the title to the section quoted: “Objective 2.4: Advance racial equity, and all forms of equity, and support underserved and marginalized communities through the FTC’s competitive mission.” (Federal Trade Commission, October 2021, p. 21).
30 The new policy proposed would be consistent with Gilbert’s (2020, p. 235) call for competition policy to become more “innovation-centric” while not abandoning its traditional “price-centric” orientation.
31 Scale economies in R&D could arise not only from the “traditional” reasons—research labs are expensive, so are experimental nuclear reactors, etc.—but also (building on the “elements” structure of inventions) from the reason that some companies may be better at managing larger numbers of the elements that need to be combined into an invention. This is wholly parallel to the idea that some senior executives are better at managing larger production processes, larger (deeper) vertical processes, and/or larger (wider) scope processes.
32 Note that the implementation of the change in policy would not necessarily require antitrust enforcers to evaluate the diversity in individual cases: Perhaps enforcers could favor a merger if the scientists and engineers in the two firms came from different disciplines or different graduate programs, work in different cities, or attend different research conferences, or favor the union of the research organizations if they each pursued different theoretical approaches in their research programs. The reason is that because of the increasing costs that limit the number of elements of knowledge that can be effectively managed within a research organization, the merger of such diverse firms would be likely to eliminate their diversity. Arguably a good approach would be for the enforcers to use our understanding that the diversity of knowledge sets is positively related to the number of research organizations and, on the diversity dimension, consider just whether the merger reduces the number of diverse competitors—although, as was noted above, more research is needed on that subject. Merging firms might argue that they planned after the merger to continue their individual research streams and work with the elements in their individual knowledge sets; but the argument that has been developed in this paper is that the increasing costs associated with expanding an organization’s knowledge set would be likely to cause the merging firms to abandon the plans to maintain the pre-merger diversity of their research.
33 With reference to note 11, observe that whether multiple firms that invest in research discover “the invention,” or instead just one firm finds it, many firms may be able to commercialize it by finding ways to differentiate their version of the invention. Alternatively it is possible that product market competition will instead require multiple inventions, with each distinguished as a different combination of elements of knowledge but with each of the differentiated products interchangeable in use. Whatever the case, the central finding remains that blocking mergers to preserve independent centers of research will increase the likelihood of successful invention because it will increase the chances that one or more research organizations will be working with knowledge sets that include the requisite elements for invention.
34 The history of the antitrust law regarding resale price maintenance challenged under the Sherman Act illustrates the slowness of the evolution of antitrust law in response to new understanding about the economics of the behavior involved. Close to a century passed from the U.S. Supreme Court’s precedent-setting opinion in the 1911 Dr. Miles case (220 U.S. 373) until it was overturned in the Supreme Court’s 2007 decision in the Leegin case (127 S. Ct. 2705).
35 The findings of Bloom et al. (2020) about a decline in the productivity of scientific research are consistent with Gordon’s (2016) historical analysis of the slowdown in economic growth for the U.S. economy and with Jones’s (2009) observations about inventors’ difficulties of reaching the frontiers of knowledge as knowledge accumulates. See also the evidence and discussion in Link and Scott (2021) about the increase in the resources needed to achieve gains in knowledge.
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References
Affeldt, P., Duso, T., Gugler, K., & Piechucka, J. (2021). Assessing EU merger control through compensating efficiencies. DIW Berlin, German Institute for Economic Research Discussion Paper No. 1979, available at https://ssrn.com/abstract=3959849.
Aghion, P., Cherif, R., & Hasanov, F. (2021). Competition, innovation, and inclusive growth. International Monetary Fund Working Paper 21/80, available at https://ssrn.com/abstract=4026257.
Arrow KJ Universities-National Bureau Committee for Economic Research Economic welfare and the allocation of resources for invention The rate and direction of inventive activity 1962 Princeton University Press 609 625
Baker JB Beyond Schumpeter vs. Arrow: How antitrust fosters innovation Antitrust Law Journal 2007 74 3 575 602
Bloom N Jones CI Van Reenen J Webb M Are ideas getting harder to find? American Economic Review 2020 110 4 1104 1144 10.1257/aer.20180338
Cohen WM Klepper S Acs ZJ Audretsch DB Firm size versus diversity in the achievement of technological advance Innovation and technological change 1991 Harvester-Wheatsheaf and University of Michigan Press 183 203
Danziger RS Scott JT Government royalties on sales of pharmaceutical and other biomedical products developed with substantial public funding: Illustrated with the technology transfer of the drug-eluting coronary stent Annals of Science and Technology Policy 2022 6 1 1 104 10.1561/110.00000020
Federal Trade Commission (2021, July 1). FTC rescinds 2015 policy that limited its enforcement ability under the FTC Act. https://www.ftc.gov/news-events/press-releases/2021/07/ftc-rescinds-2015-policy-limited-its-enforcement-ability-under. Accessed March 21, 2022.
Federal Trade Commission (2015). Statement of enforcement principles regarding “Unfair Methods of Competition” under Sect. 5 of the FTC Act. https://www.ftc.gov/system/files/documents/public_statements/735201/150813section5enforcement.pdf. Accessed March 21, 2022.
Federal Trade Commission (2021, October). Strategic plan for fiscal years 2022–2026: Draft for public comment. https://www.regulations.gov/document/FTC-2021-0061-0001. Accessed March 21, 2022.
Gilbert RJ Innovation matters: Competition policy for the high-technology economy 2020 MIT Press
Gordon RJ The rise and fall of American growth: The U.S. standard of living since the Civil War 2016 Princeton University Press
Griliches Z Griliches Z Introduction R&D, patents, and productivity 1984 University of Chicago Press for the National Bureau of Economic Research 1 19
Hovenkamp, H. J. (2016). Intellectual property and competition. University of Pennsylvania Law School Institute for Law and Economics Research Paper No. 17–36, available at https://ssrn.com/abstract=2569129.
Johnson S How we got to now: Six innovations that made the modern world 2014 Penguin Group
Jones BF The burden of knowledge and the “death of the renaissance man”: Is innovation getting harder? Review of Economic Studies 2009 76 1 283 317 10.1111/j.1467-937X.2008.00531.x
Kwoka J The structural presumption and the safe harbor in merger review: False positives or unwarranted concerns? Antitrust Law Journal 2017 81 3 837 872
Link AN Scott JT Public/private partnerships: Stimulating competition in a dynamic market International Journal of Industrial Organization 2001 19 5 763 794 10.1016/S0167-7187(00)00093-X
Link AN Scott JT Technological change in the production of new scientific knowledge: A second look Economics of Innovation and New Technology 2021 30 4 371 381 10.1080/10438599.2019.1705004
Martin S Collins WD The goals of antitrust and competition policy Issues in competition law and policy 2008 I American Bar Association Section of Antitrust Law 19 84
Meyer PB Greif A Kiesling L Nye JVC The catapult of riches: The airplane as a creative macroinvention Institutions, innovation, and industrialization: Essays in economic history and development 2015 Princeton University Press 201 224
Mullard A COVID-19 vaccine development pipeline gears up The Lancet 2020 395 10239 1751 1752 10.1016/S0140-6736(20)31252-6
Nelson RR Assessing private enterprise: An exegesis of tangled doctrine The Bell Journal of Economics 1981 12 1 93 111 10.2307/3003510
Nijhara R Tidwell JL Ferguson S Balakrishnan K Bypassing bypass surgery and other success stories from the National Institutes of Health Journal of the Association of University Technology Managers 2005 17 2 1 16 23730679
Pollok P Amft A Diener K Lüttgens D Piller FT Knowledge diversity and team creativity: How hobbyists beat professional designers in creating novel board games Research Policy 2021 50 8 1 15 10.1016/j.respol.2020.104174
Scherer FM Industrial market structure and economic performance 1970 Rand McNally
Scherer, F. M., & Ross, D. (1990). Industrial market structure and economic performance, Third Edition. Houghton Mifflin Company.
Scott JT Griliches Z Firm versus industry variability in R&D intensity R&D, patents, and productivity 1984 University of Chicago Press for the National Bureau of Economic Research 233 245
Scott JT Acs ZJ Audretsch DB Research diversity induced by rivalry Innovation and technological change 1991 Harvester-Wheatsheaf and University of Michigan Press 132 151
Scott JT The U.S. Federal Trade Commission’s Line of Business Program and innovation research Science and Public Policy 2014 41 4 438 448 10.1093/scipol/sct058
Scott JT Creativity for invention insights: Corporate strategies and opportunities for public entrepreneurship Economia e Politica Industriale-Journal of Industrial and Business Economics 2016 43 4 409 448 10.1007/s40812-016-0039-4
Scott JT Scott TJ Innovation rivalry: Theory and empirics Economia e Politica Industriale-Journal of Industrial and Business Economics 2014 41 1 25 53 10.3280/POLI2014-001003
U.S. Department of Justice and the Federal Trade Commission (2010). Horizontal Merger Guidelines, available at https://www.justice.gov/atr/file/810276/download.
Usher, A. P. (1929). A history of mechanical inventions, First Edition. McGraw-Hill Book Company.
von Hippel E Democratizing innovation 2005 MIT Press
Weitzman ML Recombinant growth Quarterly Journal of Economics 1998 113 2 331 360 10.1162/003355398555595
White, L. J. (2021). Antitrust policy for the 2020s: Some sensible ways forward. NYU Stern School of Business, available at https://ssrn.com/abstract=3775943 or 10.2139/ssrn.3775943.
Williamson OE Economies as an antitrust defense: The welfare tradeoffs American Economic Review 1968 58 1 18 36
| 0 | PMC9734633 | NO-CC CODE | 2022-12-14 23:28:30 | no | Rev Ind Organ. 2022 Dec 7;:1-19 | utf-8 | Rev Ind Organ | 2,022 | 10.1007/s11151-022-09891-w | oa_other |
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J Mol Evol
J Mol Evol
Journal of Molecular Evolution
0022-2844
1432-1432
Springer US New York
36482210
10079
10.1007/s00239-022-10079-9
Original Article
Long-Term Adaptation to Galactose as a Sole Carbon Source Selects for Mutations Outside the Canonical GAL Pathway
Martínez Artemiza A. 1
Conboy Andrew 1
Buskirk Sean W. 2
Marad Daniel A. 1
http://orcid.org/0000-0002-7931-0428
Lang Gregory I. [email protected]
1
1 grid.259029.5 0000 0004 1936 746X Department of Biological Sciences, Lehigh University, Bethlehem, PA USA
2 grid.268132.c 0000 0001 0701 2416 Department of Biology, West Chester University, West Chester, PA USA
Handling editor: Kerry Geiler-Samerotte.
8 12 2022
114
19 5 2022
23 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Galactose is a secondary fermentable sugar that requires specific regulatory and structural genes for its assimilation, which are under catabolite repression by glucose. When glucose is absent, the catabolic repression is attenuated, and the structural GAL genes are fully activated. In Saccharomyces cerevisiae, the GAL pathway is under selection in environments where galactose is present. However, it is unclear the adaptive strategies in response to long-term propagation in galactose as a sole carbon source in laboratory evolution experiments. Here, we performed a 4,000-generation evolution experiment using 48 diploid Saccharomyces cerevisiae populations to study adaptation in galactose. We show that fitness gains were greater in the galactose-evolved population than in identically evolved populations with glucose as a sole carbon source. Whole-genome sequencing of 96 evolved clones revealed recurrent de novo single nucleotide mutations in candidate targets of selection, copy number variations, and ploidy changes. We find that most mutations that improve fitness in galactose lie outside of the canonical GAL pathway. Reconstruction of specific evolved alleles in candidate target of selection, SEC23 and IRA1, showed a significant increase in fitness in galactose compared to glucose. In addition, most of our evolved populations (28/46; 61%) fixed aneuploidies on Chromosome VIII, suggesting a parallel adaptive amplification. Finally, we show greater loss of extrachromosomal elements in our glucose-evolved lineages compared with previous glucose evolution. Broadly, these data further our understanding of the evolutionary pressures that drive adaptation to less-preferred carbon sources.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00239-022-10079-9.
Keywords
Experimental evolution
Galactose
Saccharomyces cerevisiae
http://dx.doi.org/10.13039/100000057 National Institute of General Medical Sciences R01GM127420 Lang Gregory I.
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pmcIntroduction
Catabolic repression–the inability to utilize a less-preferred carbon source when a more favorable one is present–is a core principle of metabolic gene regulation. The standard example is the lac operon in E. coli where expression of the structural genes needed to assimilate alternative carbon sources require that two conditions be met: the absence of the preferred carbon source and the presence of the alternative carbon source (Jacob and Monod 1961). This logic is used to regulate the assimilation of a variety of secondary fermentable (e.g., sucrose, maltose, and galactose) and non-fermentable (e.g., acetate, glycerol, and ethanol) carbon sources (Zaman et al. 2008; Fendt and Sauer 2010).
In the yeast, Saccharomyces cerevisiae, galactose is a widely used secondary carbon source. Galactose is a common sugar found in dairy products, fruits, grains, and vegetables (Acosta and Gross 1995; Lee et al. 2011). Galactose assimilation requires three regulatory genes and four structural genes, which are expressed only when glucose is absent and galactose is present. In the absence of glucose, the Snf1 complex attenuates catabolite repression by phosphorylating the Mig1 transcriptional repressor, leading to its inactivation (Conrad et al. 2014; Nair and Sarma 2021). Full activation of galactose structural genes is mediated by a transcription factor (Gal4p), a repressor (Gal80p), and a co-inducer (Gal3p). In the absence of galactose, Gal80p sequesters Gal4p in the cytoplasm. When present, galactose binds to Gal3p, which in turn binds to Gal80p, releasing Gal4p. Once released, Gal4p relocalizes to the nucleus and increases up to ~ 1000-fold the transcription of the GAL structural genes, which are clustered in a 7 kb region on Chromosome II (Sellick et al. 2008).
Galactose initially enters the cell through low-affinity hexose transporters (Escalante-Chong et al. 2015). However, once the switch occurs, galactose enters the cell predominantly through the high-affinity galactose transporter Gal2 (Conrad et al. 2014). Once in the cell, three main enzymes are necessary to catalyze four sequential steps in galactose assimilation. Gal1p is the galactokinase. Gal10p contains two catalytic domains: a mutarotase that interconverts galactose enantiomers and an epimerase that converts UDP-galactose to UDP-glucose. Gal7p is the galactose-1-phosphate uridylyltransferase. These enzymes are tightly regulated to reduce their costly expression and avoid accumulation of the toxic intermediate galactose-1-phosphate (Slepak et al. 2005; Wang et al. 2015).
The genetic switch from glucose to galactose utilization has been extensively studied as a model system to understand the evolution of gene clustering (Hittinger and Carroll 2007, Lang and Botstein 2011, Harrison et al. 2021), transcriptional regulation (van denBrink et al. 2009; New et al. 2014; Peng et al. 2015), nutrient-sensing metabolism (Escalante-Chong et al. 2015; Lee et al. 2017), and cellular memory (Acar et al. 2005; Sood and Brickner 2017). The clustering and regulation of the GAL pathway has evolved independently multiple times in fungi. Relative to other yeast, S. cerevisiae evolved strong repression and slow induction of the GAL genes, which confers a fitness advantage in environments where glucose is in excess (Harrison et al. 2021). However, studies on natural environments identified novel strategies in S. cerevisiae isolates that are associated with improved growth on galactose. For example, natural variation in catabolite repression varies with the length of diauxic lag such that galactose is only assimilated once glucose drops below a certain threshold (Wang et al. 2015). Lineages isolated from dairy products harbor GAL variation, such as GAL3 polymorphisms, GAL2 amplification, and GAL cluster introgressions from S. paradoxus reflecting adaptation to a galactose-rich environment (Duan et al. 2018; Legras et al. 2018; Boocock et al. 2021). These suggest that the structural and regulatory genes in the GAL pathway are under selection in environments where galactose is present. However, natural environments are complex and variable environments; therefore, it is unclear how selection acts to improve the growth in a simple environment containing galactose as the sole carbon source.
Experimental evolution of microbes is a powerful tool to identify genomic changes during adaptation in different environments (Voordeckers et al. 2015; Swamy and Zhou 2019). The molecular targets of selection can be informative on the pressure that drive adaptation in each system. For example, in glucose-limitation laboratory evolution, recurrent mutations arise in nutrient signaling pathways, such as the Ras/PKA pathway and TOR pathway (Venkataram et al. 2016). In chemostat, amplification of glucose transporters is another recurrent adaptive mechanism (Kao and Sherlock 2008; Wenger et al. 2011). In glucose-rich laboratory evolution, genetic targets of selection are involved in cell wall biogenesis, assembly, and cytokinesis, as well as nutrient sensing and signaling (Lang et al. 2013; Fisher et al. 2018; Marad et al. 2018; Johnson et al. 2021). Previous laboratory evolution experiments in galactose have identified mutations in genes encoding the transcriptional repressor GAL80 (Quarterman et al. 2016), proteins involved in polarized growth (Jerison et al. 2020), and regulators of the Ras/PKA pathway (Hong et al. 2011; Hong and Nielsen 2013). In contrast to variation found in galactose-rich natural environments, mutations identified in laboratory evolution are predominantly outside the canonical GAL genes.
Previously, we evolved 48 diploid populations in glucose over 4,000 generations (Marad et al. 2018). Here, we perform an identical 4,000-generation diploid evolution experiment using galactose as the sole carbon source. We directly compare the rates of adaptation and genetic targets of selection between glucose and galactose evolution. Consistent with previous work, we find that most mutations that improve fitness in galactose lie outside of the canonical GAL pathway. In addition, we identify recurrent copy number variants, including aneuploidies on Chromosome VIII. Reconstruction of specific evolved alleles in SEC23 and IRA1 showed significant increases in fitness under galactose conditions. Finally, we show multiple losses of extrachromosomal elements, two of which (2-micron plasmid and Killer phenotypes) were also observed in galactose-evolved populations, and one of which (mitochondrial genome) was not.
Results
Higher Rate of Adaptation in Rich Galactose Medium Compared to Rich Glucose Medium
To determine the evolutionary response to constant growth in an alternative carbon source, we evolved 48 replicate populations of the same diploid ancestor in a rich medium with galactose as the sole carbon source (YPGal). After 2,000 generations, all populations increased in fitness compared to the ancestor (Fig. 1A) with a mean fitness gain of 8.2 ± 0.1% (α = 0.05). This is significantly greater than the fitness gains for the identically evolved populations using glucose as a sole carbon source (p < 0.0001, Wilcoxon rank-sum test; Fig. 1B), which showed mean fitness gains of 3.7 ± 0.06% (α = 0.05) in the first 2,000 generations of evolution.Fig. 1 Galactose-evolved populations have a higher fitness advantage after 2,000 generations of laboratory evolution. A Relative fitness advantage of 48 evolved populations on galactose. Vertical error bars reflect ± standard error of the regression. B Adaptation in galactose has a significantly higher fitness advantage compared with glucose-evolved populations (p < 0.0001, Wilcoxon rank-sum test). Box plot reflects the mean fitness of 48 populations in both conditions. Galactose populations have a mean fitness advantage of 8.2%, whereas glucose populations have a mean of 3.7%. Glucose fitness data are from Marad et al. 2018
To identify mutations that arose in the galactose-evolved populations, we sequenced two clones from each of the 48 populations at Generation 4,000. We found 2,406 de novo mutations across 96 evolved clones distributed across all 16 chromosomes with a mean of 25 ± 6 mutations per clone. Of these mutations, 794 are present in both clones from the same population, and 735 mutations are only found in one clone.
Of the 1,529 unique mutations, 91% are single nucleotide polymorphisms, most of which are in coding genes (1092 out of 1529; 71.4%). 712 of these mutations are mostly missense (46.6%), 225 are synonymous (14.7%), 76 are nonsense (5%), 59 are frameshift (3.9%), and 20 are complex mutations (1.3%) (Fig. 2 and Supplementary Data). Consistent with our previous work (Fisher et al. 2018; Marad et al. 2018), we find that heterozygous mutations outnumber homozygous mutations ~ 19:1 (Supplementary Fig. 1A), and that homozygous mutations are clustered on the right arm of Chromosome XII (Supplementary Fig. 1B). This region is a hotspot for loss of heterozygosity (LOH) due to the rDNA locus: approximately one third of the homozygous mutations are located on this chromosome.Fig. 2 The spectrum of mutations in 96 evolved clones under galactose evolution. Distribution of 1,529 unique evolved mutations across 16 Chromosomes. The vertical bars represent each Chromosome labeled by Roman numeral. The horizontal lines reflect each mutation colored based upon their protein-coding effect (top box). Other mutations group conservative inframes, disruptive inframes, and complex mutations. Centromers are represented with a black horizontal line
Beneficial Mutations are Commonly Found Outside the Canonical GAL Pathway
To identify the pathways under selection in galactose medium we performed Gene Ontology (GO) enrichment using all 860 coding genes that were mutated across all populations. This analysis showed, at a broad level, an enrichment for genes involved in: positive regulation of the metabolic process, cellular response to stimulus, intracellular signal transduction, and cellular component organization (biological process enrichment, p < 0.001). We next restricted our GO-term enrichment analysis to the 24 genes that acquired mutations in three or more populations. This showed enrichment for genes involved in the negative regulation of Ras signal transduction including IRA1, IRA2, and BEM2 (p < 0.005). In addition, we found mutations in GPB1, PDE2, and CDC25 in one or two populations. All the mutations found in Ras pathway genes are nonsynonymous.
We identified individual genes that are targets of selection by determining which genes are mutated more often than expected by chance across replicate populations. Using this approach, we identified five targets of selection with a p < 0.001 (Fig. 3A). These five genes are involved in the Ras/PKA pathway (IRA1), histone deacetylation (SNT1), endosome organization/vacuolar biogenesis (PEP5), secretory pathway (SEC23), and actin filament (BNI1). Notably, we did not find a GO enrichment or a significant number of mutations in genes with an obvious connection to galactose metabolism. We found two missense and one conservative inframe in GAL10, two missense mutations in GAL2, one missense mutation in GAL4, one missense mutation in GAL7, one nonsense and one synonymous in GAL1. None of these genes, however, were acquired more mutations than expected by chance at p < 0.001. None of the candidate targets of selection in galactose are significantly overrepresented in glucose evolution experiment and vice versa (Fig. 3B). The most common targets of selection in glucose-evolved populations are cell wall-associated genes, CTS1, ACE2, and RPL33A (p < 0.001, Poisson distribution; Fig. 3B). Of these, only one mutation in ACE2 was observed in one galactose-evolved population.Fig. 3 Common targets of selection in galactose-evolved populations. A Plotted on the x-axis is the observed number of coding sequence (CDS) mutations in each of the 5800 genes. The y-axis is the probability that the observed number of CDS mutations in each gene (without mutation type distinction) occurred by chance. We used a Poisson distribution weighted for the length of each gene (Fisher et al. 2018). The gray dotted line indicates the cut-off of genes with 3 or more CDS mutations with corresponding p-value < 0.001 (solid dark cyan). Genes in this area are common targets of selection. We also denoted gal10 with p-value = 0.002 (solid light green). B Common targets of selection in galactose-evolved populations differ from glucose-evolved populations. Plotted is the ratio of the probability that the observed number of CDS mutations in a gene occurred by chance in galactose populations (cyan circles) versus glucose populations (gold circles). The gray dotted line indicates the cut-off genes with a p-value < 0.001. Targets of selection were labeled with the gene name and bigger solid dark cyan circles. Open purple circles indicate CDS mutated in both conditions. Gray circles indicate CDS that were not mutated under any conditions. Glucose data are from Marad et al. 2018
Based on the types of mutations observed, we can determine how selection is acting on the candidate targets of selection (Table 1). We observed enrichment for nonsense and frameshift mutations (high impact mutations) in SEC23, PEP5, and IRA1, suggesting selection for loss-of-function. In contrast, we only observe missense mutations in SNT1. Out of the five mutations found in BNI1, three are synonymous and conservative inframe mutations, suggesting that this locus may not have a strong effect in the adaptation of galactose. Though there are a few notable exceptions of beneficial synonymous mutations in other systems (Bailey et al. 2014; Kristofich et al. 2018), most synonymous mutations in our system are neutral (Buskirk et al. 2017) and reach high frequency by genetic hitchhiking (Lang et al. 2013). Ignoring synonymous mutations removes a large background of hitchhiker mutations and produces more robust predictions of true targets of selection. If we restrict our analysis to nonsynonymous mutations, PEP5 and BNI1 are no longer significant at p < 0.001 (Supplementary Data).Table 1 Common targets of selection in galactose-evolved populations
Gene p-valuea Amino acid change Zygosity Cloneb Biological process (SGD)
SNT1
(Chr III)
4.55–04 Ala168Serd
Val237Ile
Val374Leu
Arg1009Lysd
Heterozygous
Heterozygous
Heterozygous
Heterozygous
F51, F52
B42
E81, E82
A91, A92
Subunit of the Set3C deacetylase complex
SEC23
(Chr XVI)
8.01–05 Gln167c
Gln494c
Arg592Iled
Leu701fs
Heterozygous
Heterozygous
Heterozygous
Heterozygous
F41, F42
A91, A92
G61, G62
H61, H62
COPII vesicle coating
IRA1
(Chr II)
2.84–04 Ser700Prod
Gln933c
Pro1013fs Leu1402c
Gln2083c
Ala2292Ser
Homozygous
Homozygous
Heterozygous
Heterozygous
Heterozygous
Heterozygous
C41, C42
H81, H82
A91, A92
G91, G92
A61, A62
B51, B52
Inhibitory
Regulator of the
RAS-cAMP pathway
Bolded clones indicate the SNP was found in all clones of the population
aStatistical analysis focus on nonsynonymous mutations
bClones indicate the well ID followed by the clone number
cNonsense
dReconstructed mutations
fs Frameshift
Galactose-Evolved Alleles Show Carbon Source Dependence Effect
To quantify the fitness effect of individual mutations, we reconstructed evolved mutations in putative targets of selection (snt1-A168S, snt1-R1009K, sec23-R592I, ira1-S700P, Table 1) as well as evolved mutations in the galactose pathway (gal10-D302N, gal10-R433P, gal7-Q265E, and gal1-G347*, Supplementary Fig. 3B) even though our statistical analysis did not identify them as candidate targets of selection. Each mutation was reconstructed in the ancestral background as haploids, heterozygous diploids, and homozygous diploids. As a control, we constructed two previously identified adaptive mutations, hsl1-A262P (Buskirk et al. 2017; Vignogna et al. 2021), and ace2-R669* (Marad et al. 2018) from haploid-glucose evolution and diploid-glucose evolution, respectively.
We performed competitive fitness assays of the reconstructed strains against a fluorescently labeled ancestral reference in both galactose and glucose. Reconstruction of heterozygous evolved mutations in the GAL pathway does not show fitness advantage in galactose (Supplementary Fig. 3B). We observed the same pattern for the homozygous reconstruction. In contrast, for all evolved mutations identified in our candidate targets of selection, we find that the fitness effects in glucose and galactose are highly correlated (r = 0.69, p = 0.0122, Pearson correlation coefficient; Supplementary Fig. 2). Nevertheless, the magnitude of the fitness effect was greater in the condition in which the specific mutation arose, and this difference is more exaggerated for homozygous mutations. We found a fitness advantage of the heterozygous sec23-R592I mutation of 3.9 ± 0.4% (α = 0.05; p < 10−6 one-way ANOVA, Tukey's HSD test) in galactose than glucose and a larger fitness advantage of 6.2 ± 0.5% (α = 0.05; p < 10−8, one-way ANOVA, Tukey's HSD test) as homozygous in galactose compared to glucose. We observed similar fitness advantage for ira1-S700P mutation; 3.3 ± 0.3% (α = 0.05; p < 10−3, one-way ANOVA, Tukey’s HSD test) as heterozygous and 5.3 ± 0.3% (α = 0.05; p < 10−8, one-way ANOVA, Tukey's HSD test) as homozygous (Fig. 4B). Despite the greater fitness benefit of the homozygote mutations, only ira1-S700P lost heterozygosity in the evolution experiment. Surprisingly, neither of the two SNT1 alleles provided a selective benefit in galactose or glucose. The heterozygous snt1-R1009K mutation is strongly deleterious, but it is neutral as a homozygote. The snt1-A592S shows the opposite pattern: the heterozygous mutation is neutral but homozygous mutation is deleterious (Fig. 4). As expected, the ploidy, glucose-evolved alleles of hsl1-A262P and ace2-R669* are more beneficial in glucose although both alleles also improved fitness in galactose (Fig. 4 and Supplementary Fig. 3). Our results show that evolved mutations on SEC23 and IRA1 are beneficial only in the condition in which they arose.Fig. 4 Galactose-evolved mutations show variation in fitness effect and carbon source dependence. Average fitness effects of the reconstructed mutations in snt1 (n = 4), sec23 (n = 6), and ira1 (n = 4) in both zygosities; A heterozygous and B homozygous mutations. Fitness effect were compared with wild-type version (n = 6), hsl1 mutation (n = 4) from glucose, haploid evolution (Fisher et al. 2018), and ace2 mutation (n = 4) from glucose, diploid-evolution (Marad et al. 2018). We were not able to generate hsl1 homozygous mutation. The sec23-R592I has a significant fitness gain in galactose compare to glucose. Asterisk (****) indicate p < 10–8, (***) p < 10–5, (**) p < 10–4, (*) p < 10–3, and NS: not significant; one-way ANOVA, tukey's HSD test. Error bars are the s.e.m
Aneuploidies and CNVs are Common in Galactose-Evolved Populations
In addition to point mutations, copy number variants (CNVs) and aneuploidies can contribute to adaptation (Gresham et al. 2008; Yona et al. 2012; Sunshine et al. 2015). To identify CNVs and aneuploidies in our galactose-evolved populations, we calculated the relative coverage across all 16 chromosomes. We find that most of our evolved clones (28/46; 61%) have one or two extra copies of Chromosome VIII. In addition, we find one population with monosomy for Chromosome I (Fig. 5). We validated these findings by sequencing eight random clones by long-read sequencing (Supplementary Fig. 4A). Although the high occurrence of additional copies for Chromosome VIII strongly suggests an adaptive strategy under galactose, populations with extra copies do not correlate with higher fitness than euploid populations (p = 0.56, Wilcoxon rank-sum test; Supplementary Fig. 4B).Fig. 5 Aneuploidy on Chromosome VIII appears to be a parallel evolutionary adaptation in the galactose condition. To estimate the ploidy of 96 clones, we calculated the median coverage across each chromosome compared to genome-wide coverage. Baseline ploidy is 2 N. Aneuploidies are shown as filled red circles and labeled by name population. Empty circles indicate euploidy. Notably, duplication of Chromosome VIII occurred in 28 populations out of 46 populations
In addition to loss or gain of entire chromosomes, we also detect large (> 40 kb) CNVs in our evolved clones, including eight unique amplifications and two deletions (Table 2 and Supplementary Fig. 5). We identified several populations with CNVs in the right arm of Chromosome II; however, in only population does the amplification include the GAL1-GAL10-GAL7 gene cluster (Population A4, Chromosome II: 268,984–275,164). No other recurrent CNVs were identified that overlap with GAL genes (Table 2 and Supplementary Fig. 5). In Populations A4 and B9, we identified duplication of genes associated with Ras/PKA signaling pathway; IRA1 (Chromosome II: 534,751–544,029) and RAS2 (Chromosome XIV: 440,898–441,866), respectively. Additionally, we found amplifications of regions containing hexose transporters genes; HXT14 (Population B9), HXT9, HTX8, HXT16 (Population G4), HXT4, HXT1, and HXT5 (populations with aneuploidies for Chromosome VIII). These data demonstrate recurrent amplifications of regions that contain genes encoding hexose transporters, suggesting a potential adaptive mechanism in our galactose evolution. We do not, however, find a significant correlation between higher fitness and CNVs (p = 0.89, Wilcoxon rank-sum test; Supplementary Fig. 4B).Table 2 Structural variants in galactose-evolved populations
Chr Start (kb) Stop (kb) Length (kb) Copy number Class Cloneb
I 0 161,000 161 1 N Aneuploidy C61, C71c
II1,3 226,000 844,051 618 3 N CNV A41, A42c
II 666,000 836,000 170 3 N CNV B61, B62
II3 354,000 836,000 482 3 N CNV H71, H72
II 737,000 844,051 107 1 N CNV G71, G72
VII 749,000 1,092,105 343 3 N CNV D51, D52
VIII2 0 844,051 844 3 N & 4 N Aneuploidy G71, G72, G61, G62, D81, D82, F41, F42, F91, F92, B81, B82, A51, A52, G41, G42, G51, G52, C71c, C61c, F61c, F62c, F71c, C51, C52, H41, H42, F81, F82, E81, E82, B41, B42, C81, C82, D71, D72, B51, B52, G91, G92, D61, D62, A41c, A42c, E71c, E72c, A61, A62, C91, C92, E41, E42, C61c, C721c, D91, D92
X2 502,000 762,303 260 4 N CNV G41,G42
XI 0 297,000 297 3 N & 4 N CNV H91, H92, H82
XIII 379,000 750,000 371 3 N CNV F52
XIII 0 44,000 44 3 N CNV D41, D42
XIV2,3 0 479,001 479 3 N CNV B91, B92
Bolded population indicates that the CNV was found in all clones of the population
bClones indicate the well ID followed by the clone number
cPopulations with cross-contamination (See Supplementary Data)
1Duplication of the GAL cluster. Coordinates: chrII. 268,984–275,164, W303 ref
2Duplication of hexose transporters
3Duplication of components of the Ras/PKA pathway
Changes in Copy Number of Extrachromosomal Elements and Reduction of the Killer Phenotype in Galactose-Evolved Populations
In addition to evolution in the nuclear genome, we determined the extent to which cytoplasmic elements (the mitochondrial genome, the 2-micron plasmid, and the yeast dsRNA Killer virus) changed during evolution in galactose. Using read depth as a proxy, we estimated the copy number of mitochondrial DNA for each clone according to Chiara et al. 2020. Estimates of mitochondrial copy number is highly correlated between clones from the same population (r = 0.928, p < 0.0001, Pearson correlation; Supplementary Fig. 7A). Most of the populations show a significant decrease in the mitochondrial copy number (p < 0.0001, Wilcoxon rank-sum test), with a global mean of ~ 8:1 mitochondrial to nuclear genomes (Supplementary Fig. 6A) and with only six galactose-evolved populations maintaining or increasing mitochondrial copy number (19:1 ratio between mitochondrial and nuclear genomes). In contrast mitochondrial copy number is maintained throughout evolution in glucose-evolved populations (Supplementary Fig. 7C).
Like mitochondrial copy number, our estimates of the 2-micron plasmid copy number are highly correlated between clones from the same population (r = 0.66, p < 0.0001, Pearson correlation; Supplementary Fig. 7B). Our galactose-evolved populations show a drastic loss of 2-micron copy number (from 133 initial copies to an average of 57 copies per every copy of the nuclear genome). Only three populations showed a higher 2-micron copy number than the ancestor (Supplementary Fig. 6B). We did not observe differences in reduction of 2-micron copy number between galactose and glucose-evolved populations (p = 0.43, Wilcoxon rank-sum test; Supplementary Fig. 7D). We also did not find correlation between reduction of mitochondrial DNA and 2-micron (r = -0.07, p = 0.48, Pearson correlation).
As a proxy for the loss of the killer toxin, we quantified killing ability in our populations (Buskirk et al. 2020). Similar with glucose evolution, we find that the majority of the populations (42/48) lost totally or partially the killer-associated phenotype (Supplementary Fig. 6C, Supplementary Fig. 8). We did not observe a significant difference of the loss of the killer phenotype between both conditions (p = 0.17, Wilcoxon rank-sum test). Consistent with previous glucose evolution, reduction of the 2-micron and killing ability is also a common mechanism in our galactose evolution adaptation. In contract, mitochondrial DNA has recurrent losses only in galactose evolution.
Discussion
The genetic switch from glucose to galactose utilization in S. cerevisiae has been extensively studied (Acar et al. 2005, Ronen and Botstein 2006, van den Brink et al. 2009, Escalante-Chong et al. 2015). However, the strategies for long-term adaptation to galactose as a sole carbon source are not well understood. To determine how galactose affects adaptation in budding yeast, we evolved 48 diploid populations in rich galactose medium under identical conditions to our previous glucose evolution experiment (Marad et al. 2018). We show that fitness gains over the first 2,000 generations were greater in the galactose medium compared to glucose. We find that beneficial mutations in the galactose-evolved populations are beneficial in glucose medium but that the magnitude of the benefit is smaller. Similarly, glucose-evolved mutations are strongly beneficial in glucose, but beneficial in galactose, suggesting that environment-specific selective pressures drive the fixation of specific mutations in each environment. These results are consistent with findings of others showing a positive correlation between fitness in glucose and fitness in galactose (Chen and Zhang 2020; Jerison et al. 2020).
To identify the targets of selection during long-term growth on galactose, we sequenced two clones from each population after 4,000 generations. Several studies have identified functional variants in the GAL pathway that tune the response of the galactose pathway in natural populations (Roop et al. 2016; Lee et al. 2017; Boocock et al. 2021). It is, therefore, reasonable to expect laboratory adaptation to constitutive galactose to select for mutations in these same genes. While we did observe several mutations in the GAL pathway genes, we do not observe more mutations than expected by chance, and reconstruction experiments failed to identify a fitness advantage (Supplementary Fig. 3B).
We identify candidate targets of selection outside of the canonical galactose pathways, with SNT1, SEC23, and IRA1 as the most significant hits. IRA1 is repeatedly observed as a target of selection across evolution experiments (Lang et al. 2013; Fisher et al. 2018; Li et al. 2018; Johnson et al. 2021), whereas SNT1 is rarely observed (Fisher et al. 2018). SEC23 has not been previously identified as recurrent mutated gene in glucose. These three genes show enrichment of missense and nonsense mutations consistent with being under selection in galactose. In diploid evolution experiments, beneficial mutations are partially dominant or overdominant (Aggeli et al. 2022). Reconstruction of evolved alleles shows that ira1-S700P and sec23-R592I are partially dominant. Consistent with being partially dominant, we find that the allele ira1-S700P fixed as a homozygote. It is not surprising that sec23-R592I did not undergo loss of heterozygosity since the majority of mutations in the evolved clones are heterozygous (1,444 of 1,529 mutations).
IRA1 is a negative regulator of the Ras/PKA signaling pathway, one of the best-known glucose-triggered signaling cascades (Tamanoi 2011; Broach 2012). The Ras pathway is a hotspot for functional variation owing to its role in regulating metabolic, transcriptional, and physiological responses to nutrient availability. Because of this, genes in the Ras pathway are common targets of selection in nearly all yeast evolution experiments including rich glucose medium (Lang et al. 2013), defined low glucose medium (Venkataram et al. 2016), as well as glucose-limited (Kvitek and Sherlock 2013) and nitrogen-limited (Hong and Gresham 2014) chemostats.
Mutations identified in experimental evolution are often pleiotropic, affecting fitness (either positively or negatively) in other environments (Ostrowski et al. 2005; Jerison et al. 2020; Bakerlee et al. 2021). Mutations in the Ras pathway have been shown to result in fitness tradeoffs under alternative carbon sources (Hong et al. 2011; Hong and Nielsen 2013) or prolonged starvation (Li et al. 2018). Here, we find that the galactose-evolved mutation, ira1-S700P, has a greater fitness benefit in galactose compared in glucose. These results suggest that though the Ras/PKA pathway is a general hub for adaptive mutations in all laboratory evolution experiments, individual mutations are condition specific, adjusting cell physiology match the environment.
Outside of the Ras/PKA pathway, the secretory pathway is another common target of selection in galactose. Apart from recurrent mutations in SEC23, we observe independent moderate-impact mutations in six more genes that encode secretory proteins. The endoplasmic reticulum has a role in maintaining metabolic homeostasis by sensing nutrient availability (Fu et al. 2012). Another common target of selection is SNT1, which encodes a histone deacetylase. However, despite SNT1 being a common target of selection, neither of our reconstructed SNT1 mutations are beneficial on their own (Fig. 4). It is possible the presence of epistasis interactions between SNT1 mutations and the genetic background. The snt1-A1009S and snt1-V237I mutations arose in populations with mutations in ira1 and ira2, respectively. Genetic interaction among co-evolved mutations is common in experimental evolution (Fisher et al. 2019; Vignogna et al. 2021).
Increasing the copy number of specific genes whose expression level is limiting is another common mode of adaptive evolution. For example, the amplification of transporter and specific permeases are a recurrent adaptive mechanism to selection in medium limited for glucose (Gresham et al. 2008; Kao and Sherlock 2008), nitrogen (Hong and Gresham 2014), sulfur (Sunshine et al. 2015), or raffinose (Scott et al. 2017). An essential step in utilizing galactose is its transport achieved by Gal2p, a closely related hexose transporter (Boles and Hollenberg 1997). Notably, we did not detect any duplications of the transporter GAL2 located on Chromosome XII. Of the four CNVs on Chromosome II, only the largest one encompasses the GAL1-GAL10-GAL7 gene cluster (Supplementary Fig. 5). We do, however, find that 61% of our populations have fixed aneuploidies on Chromosome VIII. We suggest that a strong adaptive advantage in our populations can be explained by the amplification of hexose transporters on Chromosome VIII: HXT4, HXT1, and HXT5. Under galactose conditions, selection for spontaneous duplication of Chromosome VIII may favor nutrient transporters, leading to more efficient nutrient uptake into central metabolism (Torres et al. 2007). We only detected one point mutation in any of the HXT genes (a single missense mutation in HXT3).
Most of the observed adaptive processes have focused on the nuclear genome. Little is known about the evolution of extrachromosomal elements in different environments. Changes in copy number can give us a first light of whether these elements are under selection or not. Recently, Johnson et al. 2021 showed the recurrent loss of 2-micron plasmids and reduction of the killer phenotype of the Killer virus under rich glucose and synthetic complete media. Here we find a similar pattern in 2-micron plasmids and Killer-associated phenotypes in galactose-evolved populations (Supplementary Fig. 6). The selective benefit decreasing 2-micron copy number are unclear; however, we previously showed that the loss of Killer virus occurs due to an intracellular fitness advantage of viruses that do not produce toxin (Buskirk et al. 2020).
We observe multiple losses of mitochondrial DNA (Supplementary Fig. 6). When growing on galactose, S. cerevisiae does not exhibit a Kluyver effect (inability to grow on and ferment sugars under anaerobic conditions). Therefore, it can consume galactose under respiration and fermentation (van den Brink et al. 2009). The existence of this respiration-dependent assimilation of sugars is an essential link between mitochondria and sugar utilization (Quarterman et al. 2016). The reduction of mitochondrial genome copy number may indicate that the evolved populations are increasing fermentation relative to respiration. Mitochondrial genome copy number, however, is dynamic with considerable strain-to-strain variation (Galeota-Sprung et al. 2022). We, therefore, cannot determine if the changes we observe are adaptive or are a secondary response to changes in growth.
Overall, we find that long-term adaptation to growth on galactose is driven mainly by mutations outside of the canonical GAL pathway. Specifically, we identify Ras/PKA signaling as a major target of selection, as it is in nearly all environments. We find that glucose and galactose-evolved alleles are more beneficial in the condition in which they arose. Unlike in glucose-evolved populations, we find recurrent aneuploidy for Chromosome VIII suggestion a potential role in galactose adaptation by increasing the copy number of HXT genes. We observe a reduction in 2-micron copy number, mitochondrial copy number, and killing ability across our evolved populations.
Methods
Strains Construction
All strains used in this study are derived from the W303 background (ade2-1, CAN1, his3-11, leu2-3,112, trp1-1, URA3, bar1Δ::ADE2, hmlαΔ::LEU2, GPA1::NatMX, ura3Δ::pFUS1-yEVenus). All the derivative strains are identified by their yGIL prefix and the number in the Lang Lab yeast collection. Mutant strains were constructed using CRISPR-Cas9 as described previously (Fisher et al. 2019). Repair oligonucleotide templates were generated by amplifying 500 bp gBlocks (IDT) that contained the point mutation and a synonymous PAM site substitution. We co-transformed a high-copy plasmid that contains the Cas9 gene and the guide RNA expression cassette (pML104; Addgene #67,638) (Laughery et al. 2015) and the linear repair template into yGIL432 (MATa) and yGIL646 (MATα) strains. We designed the following sgRNA; snt1-A168S (5ʹ-TGGAGCGTTT GATAATGCCG AGG-3ʹ), snt1-R1009K (5ʹ-ATGGCTCTAT AAGACCATTT GGG-3ʹ), sec23-R592I (5ʹ-TTGGGATCTT CTTAAATAAT AGG-3ʹ), and ira1-S700P (5ʹ-GAAGAGATTC TACAACTTGT TGG-3ʹ). After editing, we removed the plasmid on media containing 5-FOA. Diploid mutants were generated by crossing each mutant strain with the opposite mating type mutant strain or wild-type strain to produce homozygotes and heterozygotes, respectively. Crosses were sporulated to confirm diploid strains. All plasmids and strain construction were confirmed by Sanger sequencing (Genscript).
Evolution Experiment
Long-term evolution was performed as described previously (Marad et al. 2018). Briefly, the ancestral diploid strain, yGIL672, was grown to saturation in YPD (yeast extract, peptone, dextrose) medium. A dilution of 1:210 was used to seed 48 replicate populations in a single round bottom 96-well plate. The cultures were propagated for 4,000 generations in YPGal medium (yeast extract, peptone, 2% galactose) containing ampicillin (100 mg/mL) and tetracycline (25 mg/mL) to prevent bacterial contamination. The cultures were incubated at 30 °C in an unshaken 96-well plate. Every 24 h, the populations were diluted 1:1,024 by serial dilution 1:32 (4 μl into 125 μl) × 1:32 (4 μl into 125 μl) into a new YPGal 96-well plate. This regime corresponds to 10 generations of growth per day at an effective population size of ~ 105. The long-term experimental evolution was performed using the Biomek Liquid Handler. Approximately every 50 generations, populations were cryo-archived in 15% glycerol at − 80 °C.
Competitive Fitness Assays
To measure the effect of evolved mutations we used flow-cytometry-based competitive fitness assay as described previously (Buskirk et al. 2017). We used for the competition the reference strains; yGIL519 (MATa), yGIL699 (MATα), and yGIL702 (MATa/α). These strains have the ancestral background with constitutive ymCitrine integrated at the URA3 locus. For all the evolved alleles, we performed the competition in YPD and YPGal under identical conditions. Diploid and haploid strains were competed in independent 96-well plates in an identical fashion to the evolution experiment. The reference and the experimental strains were mixed 1:1 at Generation 0 using a Biomek Liquid handler. The assays were performed for 50 generations and sampled every 10 generations. To measure density using flow-cytometry (BD FACSCanto II), we transferred 4 µL of each sample into 60µL of PBS and stored at 4 °C for 1 day. Data were analyzed in FlowJo 10.3. The selective coefficient was calculated as the slope of the change in the natural log ratio between query and reference strains. For each fitness measurement, we performed between 4–6 independent biological replicates and one technical replicate.
Whole-Genome Sequencing
Each population, from generation 4,000, was struck to singles colonies on YPGal and two clones were isolated for sequencing. Clones were grown to saturation in YPGal and total genomic DNA was isolated for each sample using phenol–chloroform extraction and ethanol precipitation. We used the Nextera sequencing library preparation kit as described previously (Buskirk et al. 2017). Sequencing was performed on an Illumina HiSeq 2500 sequencer with 150-nucleotide paired-end reads by the Sequencing Core Facility within the Lewis-Sigler Institute for Integrative Genomics at Princeton University.
The Oxford Nanopore MinION Genomic DNA Sequencing Kit (SQK-LSK109) was used to prepare the DNA libraries of 8 evolved clones. Briefly, we performed DNA extraction using a QIAGEN 100/G. One microgram of DNA per sample was diluted in 48µL of water. End-repair was performed using NEBNext FFPE Repair Mix and the product was purified using 60 μl of Agencourt AMPure XP beads. End-prepped gDNA was quantified using the Qubit High Sensitivity assay. dA-tailing was performed using NEBNext dA-tailing module. A ligation reaction was then performed by adding 2.5µL of the Native Barcode (EXP-PBC001 and EXP-PBC096) and 25µL of Blunt/TA Ligase Master Mix. The adapter-ligated DNA was purified using Agencourt AMPure XP beads and washed with long fragment buffer. DNA was quantified using a Qubit and then loaded on to Minion R9.4.1 (product code FLO-MIN106D R9) flow cells.
Sequencing Analysis Pipeline
Raw Illumina sequencing data were concatenated and demultiplexed using barcode_splitter 0.18.6 from L. Parsons (Princeton University). Adapter sequences were trimmed using trimmomatic/0.36 (Bolger et al. 2014) using PE -phred33 parameter. Each sample was aligned to the complete and annotated W303 genome (Matheson et al. 2017) using BWA-MEM, v.0.7.15 (Li and Durbin 2009). Each clone was sequenced to an average depth of approximately 50X coverage (Supplementary Fig. 1). Common variants were called using FreeBayes/1.1.0 (Garrison and Marth 2012), using default parameters. Variants common were filtered using the VCFtools/0.1.15 vcf-isec function (v.0.1.12b). Individual VCF files were annotated using SnpEff/5.0 using -formatEff flag (Cingolani et al. 2012). Manually we did a more punctual filtering of common variants by viewing BAM files using Integrated Genome Viewer (Broad Institute). We removed the variant calls found in low complexity regions (TY elements, centromeres, and telomeric regions) and with less than 5X coverage. Only nuclear mutations were analyzed. We used R package idiogramFISH to plot the distribution of our evolved mutations. Zygosity was determined by establishing a cut-off of mutation frequency values above 0.9 and p-values < 0.001. If both parameters were satisfied, we called those mutations homozygous. Copy Number Variants (CNVs) were identified using ControlFREEC version 11.5 (Boeva et al. 2012). All the.txt outputs were merged into one data frame to remove all the common calls. We applied the following criteria to filtered CNVs: the variant is calling more than 10 times, had length less than 5 kb, and variants that were located close to telomeres and centromeres (5 kb of distance) regions. CNVs and aneuploidies were corroborated by visual inspection of chromosome coverage plots created in R. Briefly, we used samtools-depth to calculate per-site depth from the sorted-bam files. We divided the median chromosome coverage by the median genome-wide coverage using non-overlapping 1000 bp window size and 500 nt step size. The total coverage of the genome was normalized to 2 (diploid population). The same analysis was used to estimate copy number of the 2-micron plasmid. Copy number of mitochondrial DNA was estimated using the same sliding window approach but only from the ATP6, COX2, and COX3 regions (De Chiara et al. 2020) to avoid overcounting the highly repetitive sequences in the mitochondrial genome. For Nanopore sequencing, we performed basecalling and demultiplex barcode using guppy/3.1.5. We aligned reads to the S288C reference using the long-read mapper ngmlr/0.2.7 and identified structural variants using Sniffles (Sedlazeck et al. 2018). To visualize chromosome coverage, we used the same methodology described for Illumina data. For glucose-evolved populations, we performed the same analysis as galactose. However, the whole-genome sequencing was performed at Generation 2,000.
Gene Ontology analysis was conducted using Gene Ontology Term Finder (https://www.yeastgenome.org/) and PANTHER (http://pantherdb.org/), both analysis were conducted on Sep, 2022.
Identification of Common Targets
The p-values of coding genes hit by a mutation just by chance were calculated using the Poisson distribution (Fisher et al. 2018). We determined the probability that chance alone explains the observed number of mutations across all 5,800 genes by assuming a random Poisson distribution of CDS mutations weighted by the length of the gene across the 8,453,525 bp genome-wide CDS. First, we determined p-values of the 1,040 CDS mutations without mutation type distinction. However, to increase the statistical power, we also performed the same statistical analysis but focus on nonsynonymous CDS mutation. Final common targets of selection were defined as genes with three or more nonsynonymous CDS mutations and a corresponding probability of less than 0.1%. To determine if the targets of selection are unique to galactose, we compare the p-values with prior glucose evolution experiments (Marad et al. 2018). To determine the targets of selection for each condition, we calculated the ratio between probabilities (Supplementary Data).
Halo Assay
Killer phenotype was performed using the protocol described previously (Buskirk et al. 2020). Assay was performed using YPD agar that had been buffered to pH 4.5 (citrate–phosphate buffer), dyed with methylene blue (0.003%), and poured into a 1-well rectangular cell culture plate. Killing ability was assayed against a hypersensitive tester strain (yGIL1097). The hypersensitive tester was grown to saturation, diluted 1:10, and spread (150 ml) evenly on the buffered agar. Glucose and galactose-evolved populations were grown to saturation, concentrated five-fold, and spotted (2 µL) using liquid handler (Biomek FX). Plates were incubated at room temperature for 3 days before assessment. Killer phenotype was scored according to the scale as shown in Buskirk et al. 2020.
Statistical Analyses
All statistical analyses reported were performed using tools in the R Stats package in R v.4.0.2. All plots were produced in R using the ggplot2 package (Wickham et al. 2016).
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (XLSX 1106 kb)
Supplementary file2 (PDF 2139 kb)
Supplementary file3 (PDF 515 kb)
Supplementary file4 (PDF 926 kb)
Supplementary file5 (PDF 748 kb)
Supplementary file6 (PDF 9432 kb)
Supplementary file7 (PDF 8071 kb)
Supplementary file8 (PDF 538 kb)
Supplementary file9 (PDF 6373 kb)
Acknowledgements
We thank the members of the Lang Lab for comments on the manuscript. This study was supported by a grant from the National Institutes of Health (R01GM127420). Portions of this research were conducted on Lehigh University’s Research Computing infrastructure partially supported by the National Science Foundation (Award 2019035).
Author Contributions
GIL contributed to conceptualization, supervision, and funding acquisition. AAM and, GIL contributed to formal analysis, writing–original draft preparation, writing–review & editing, and visualization. AAM, AC, DM, and SWB contributed to investigation.
Data Availability
The short-read sequencing data reported in this study have been deposited to the NCBI BioProject database, accession number PRJNA835840. The previously published dataset from Marad et al. 2018 is available under NCBI BioProject PRJNA418180.
Declarations
Conflict of interest
The authors declare no competing interests.
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References
Acar M Becskei A Van Oudenaarden A Enhancement of cellular memory by reducing stochastic transitions Nature 2005 435 7039 228 232 10.1038/nature03524 15889097
Acosta PB Gross KC Hidden sources of galactose in the environment Eur J Pediatr 1995 154 2 S87 S92 10.1007/BF02143811 7671974
Aggeli D Marad DA Liu X Buskirk SW Levy SF Lang GI "Overdominant and partially dominant mutations drive clonal adaptation in diploid Saccharomyces cerevisiae" Genetics 2022 221 2 iyac061 10.1093/genetics/iyac061 35435209
Bailey SF Hinz A Kassen R Adaptive synonymous mutations in an experimentally evolved Pseudomonas fluorescens population Nat Commun 2014 5 1 1 7 10.1038/ncomms5076
Bakerlee CW Phillips AM Ba ANN Desai MM Dynamics and variability in the pleiotropic effects of adaptation in laboratory budding yeast populations Elife 2021 10 e70918 10.7554/eLife.70918 34596043
Boeva V Popova T Bleakley K Chiche P Cappo J Schleiermacher G Janoueix-Lerosey I Delattre O Barillot E Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data Bioinformatics 2012 28 3 423 425 10.1093/bioinformatics/btr670 22155870
Boles E Hollenberg CP The molecular genetics of hexose transport in yeasts FEMS Microbiol Rev 1997 21 1 85 111 10.1111/j.1574-6976.1997.tb00346.x 9299703
Bolger AM Lohse M Usadel B Trimmomatic: a flexible trimmer for Illumina sequence data Bioinformatics 2014 30 15 2114 2120 10.1093/bioinformatics/btu170 24695404
Boocock J Sadhu MJ Durvasula A Bloom JS Kruglyak L Ancient balancing selection maintains incompatible versions of the galactose pathway in yeast Science 2021 371 6527 415 419 10.1126/science.aba0542 33479156
Broach JR Nutritional control of growth and development in yeast Genetics 2012 192 1 73 105 10.1534/genetics.111.135731 22964838
Buskirk SW Peace RE Lang GI Hitchhiking and epistasis give rise to cohort dynamics in adapting populations Proc Natl Acad Sci U S A 2017 114 31 8330 8335 10.1073/pnas.1702314114 28720700
Buskirk SW Rokes AB Lang GI Adaptive evolution of nontransitive fitness in yeast Elife 2020 9 e62238 10.7554/eLife.62238 33372653
Chen P Zhang J Antagonistic pleiotropy conceals molecular adaptations in changing environments Nat Ecol Evol 2020 4 3 461 469 10.1038/s41559-020-1107-8 32042119
Cingolani P Platts A Wang LL Coon M Nguyen T Wang L Land SJ Lu X Ruden DM A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3 Fly 2012 6 2 80 92 10.4161/fly.19695 22728672
Conrad M Schothorst J Kankipati HN Van Zeebroeck G Rubio-Texeira M Thevelein JM Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae FEMS Microbiol Rev 2014 38 2 254 299 10.1111/1574-6976.12065 24483210
De Chiara M Friedrich A Barré B Breitenbach M Schacherer J Liti G Discordant evolution of mitochondrial and nuclear yeast genomes at population level BMC Biol 2020 18 1 1 15 10.1186/s12915-020-00786-4 31898513
Duan S-F Han P-J Wang Q-M Liu W-Q Shi J-Y Li K Zhang X-L Bai F-Y The origin and adaptive evolution of domesticated populations of yeast from Far East Asia Nat Commun 2018 9 1 1 13 10.1038/s41467-018-05106-7 29317637
Escalante-Chong R Savir Y Carroll SM Ingraham JB Wang J Marx CJ Springer M Galactose metabolic genes in yeast respond to a ratio of galactose and glucose Proc Natl Acad Sci 2015 112 5 1636 1641 10.1073/pnas.1418058112 25605920
Fendt S-M Sauer U Transcriptional regulation of respiration in yeast metabolizing differently repressive carbon substrates BMC Syst Biol 2010 4 1 1 11 10.1186/1752-0509-4-12 20056001
Fisher KJ Buskirk SW Vignogna RC Marad DA Lang GI Adaptive genome duplication affects patterns of molecular evolution in Saccharomyces cerevisiae PLoS Genet 2018 14 5 e1007396 10.1371/journal.pgen.1007396 29799840
Fisher KJ Kryazhimskiy S Lang GI Detecting genetic interactions using parallel evolution in experimental populations Philos Trans R Soc Lond B Biol Sci 2019 374 1777 20180237 10.1098/rstb.2018.0237 31154981
Fu S Watkins SM Hotamisligil GS The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling Cell Metab 2012 15 5 623 634 10.1016/j.cmet.2012.03.007 22560215
Galeota-Sprung B Fernandez A Sniegowski P Changes to the mtDNA copy number during yeast culture growth Royal Soc Open Sci 2022 9 7 211842 10.1098/rsos.211842
Garrison, E. and G. Marth (2012). "Haplotype-based variant detection from short-read sequencing." arXiv preprint arXiv:1207.3907.
Gresham D Desai MM Tucker CM Jenq HT Pai DA Ward A DeSevo CG Botstein D Dunham MJ The repertoire and dynamics of evolutionary adaptations to controlled nutrient-limited environments in yeast PLoS Genet 2008 4 12 e1000303 10.1371/journal.pgen.1000303 19079573
Harrison M-C LaBella AL Hittinger CT Rokas A The evolution of the GALactose utilization pathway in budding yeasts Trends Genet 2021 38 97 106 10.1016/j.tig.2021.08.013 34538504
Hittinger CT Carroll SB Gene duplication and the adaptive evolution of a classic genetic switch Nature 2007 449 7163 677 681 10.1038/nature06151 17928853
Hong J Gresham D Molecular specificity, convergence and constraint shape adaptive evolution in nutrient-poor environments PLoS Genet 2014 10 1 e1004041 10.1371/journal.pgen.1004041 24415948
Hong K-K Nielsen J Adaptively evolved yeast mutants on galactose show trade-offs in carbon utilization on glucose Metab Eng 2013 16 78 86 10.1016/j.ymben.2013.01.007 23376593
Hong K-K Vongsangnak W Vemuri GN Nielsen J Unravelling evolutionary strategies of yeast for improving galactose utilization through integrated systems level analysis Proc Natl Acad Sci 2011 108 29 12179 12184 10.1073/pnas.1103219108 21715660
Jacob F Monod J Genetic regulatory mechanisms in the synthesis of proteins J Mol Biol 1961 3 3 318 356 10.1016/S0022-2836(61)80072-7 13718526
Jerison ER Nguyen Ba AN Desai MM Kryazhimskiy S Chance and necessity in the pleiotropic consequences of adaptation for budding yeast Nature Ecol Evol 2020 4 4 601 611 10.1038/s41559-020-1128-3 32152531
Johnson MS Gopalakrishnan S Goyal J Dillingham ME Bakerlee CW Humphrey PT Jagdish T Jerison ER Kosheleva K Lawrence KR Min J Moulana A Phillips AM Piper JC Purkanti R Rego-Costa A McDonald MJ Nguyen Ba AN Desai MM Phenotypic and molecular evolution across 10,000 generations in laboratory budding yeast populations Elife 2021 10.7554/eLife.63910
Kao KC Sherlock G Molecular characterization of clonal interference during adaptive evolution in asexual populations of Saccharomyces cerevisiae Nat Genet 2008 40 12 1499 1504 10.1038/ng.280 19029899
Kristofich J Morgenthaler AB Kinney WR Ebmeier CC Snyder DJ Old WM Cooper VS Copley SD Synonymous mutations make dramatic contributions to fitness when growth is limited by a weak-link enzyme PLoS Genet 2018 14 8 e1007615 10.1371/journal.pgen.1007615 30148850
Kvitek DJ Sherlock G Whole genome, whole population sequencing reveals that loss of signaling networks is the major adaptive strategy in a constant environment PLoS Genet 2013 9 11 e1003972 10.1371/journal.pgen.1003972 24278038
Lang GI Botstein D A test of the coordinated expression hypothesis for the origin and maintenance of the GAL cluster in yeast PLoS ONE 2011 6 9 e25290 10.1371/journal.pone.0025290 21966486
Lang GI Rice DP Hickman MJ Sodergren E Weinstock GM Botstein D Desai MM Pervasive genetic hitchhiking and clonal interference in forty evolving yeast populations Nature 2013 500 7464 571 574 10.1038/nature12344 23873039
Laughery MF Hunter T Brown A Hoopes J Ostbye T Shumaker T Wyrick JJ New vectors for simple and streamlined CRISPR–Cas9 genome editing in Saccharomyces cerevisiae Yeast 2015 32 12 711 720 10.1002/yea.3098 26305040
Lee KS Hong ME Jung SC Ha SJ Yu BJ Koo HM Park SM Seo JH Kweon DH Park JC Improved galactose fermentation of Saccharomyces cerevisiae through inverse metabolic engineering Biotechnol Bioeng 2011 108 3 621 631 10.1002/bit.22988 21246509
Lee KB Wang J Palme J Escalante-Chong R Hua B Springer M Polymorphisms in the yeast galactose sensor underlie a natural continuum of nutrient-decision phenotypes PLoS Genet 2017 13 5 e1006766 10.1371/journal.pgen.1006766 28542190
Legras J-L Galeote V Bigey F Camarasa C Marsit S Nidelet T Sanchez I Couloux A Guy J Franco-Duarte R Adaptation of S. cerevisiae to fermented food environments reveals remarkable genome plasticity and the footprints of domestication Mol Biol Evol 2018 35 7 1712 1727 10.1093/molbev/msy066 29746697
Li H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 2009 25 14 1754 1760 10.1093/bioinformatics/btp324 19451168
Li Y Venkataram S Agarwala A Dunn B Petrov DA Sherlock G Fisher DS Hidden complexity of yeast adaptation under simple evolutionary conditions Curr Biol 2018 28 4 515 525.e516 10.1016/j.cub.2018.01.009 29429618
Marad DA Buskirk SW Lang GI Altered access to beneficial mutations slows adaptation and biases fixed mutations in diploids Nat Ecol Evol 2018 2 5 882 889 10.1038/s41559-018-0503-9 29581586
Matheson K Parsons L Gammie A "Whole-genome sequence and variant analysis of w303, a widely-used strain of saccharomyces cerevisiae" G3 (bethesda) 2017 7 7 2219 2226 10.1534/g3.117.040022 28584079
Nair A Sarma SJ The impact of carbon and nitrogen catabolite repression in microorganisms Microbiol Res 2021 251 126831 10.1016/j.micres.2021.126831 34325194
New AM Cerulus B Govers SK Perez-Samper G Zhu B Boogmans S Xavier JB Verstrepen KJ Different levels of catabolite repression optimize growth in stable and variable environments PLoS Biol 2014 12 1 e1001764 10.1371/journal.pbio.1001764 24453942
Ostrowski EA Rozen DE Lenski RE Pleiotropic effects of beneficial mutations in Escherichia coli Evolution 2005 59 11 2343 2352 16396175
Peng W Liu P Xue Y Acar M Evolution of gene network activity by tuning the strength of negative-feedback regulation Nat Commun 2015 6 1 1 9 10.1038/ncomms7226
Quarterman J Skerker JM Feng X Liu IY Zhao H Arkin AP Jin Y-S Rapid and efficient galactose fermentation by engineered Saccharomyces cerevisiae J Biotechnol 2016 229 13 21 10.1016/j.jbiotec.2016.04.041 27140870
Ronen M Botstein D Transcriptional response of steady-state yeast cultures to transient perturbations in carbon source Proc Natl Acad Sci 2006 103 2 389 394 10.1073/pnas.0509978103 16381818
Roop JI Chang KC Brem RB Polygenic evolution of a sugar specialization trade-off in yeast Nature 2016 530 7590 336 339 10.1038/nature16938 26863195
Scott AL Richmond PA Dowell RD Selmecki AM The influence of polyploidy on the evolution of yeast grown in a sub-optimal carbon source Mol Biol Evol 2017 34 10 2690 2703 10.1093/molbev/msx205 28957510
Sedlazeck FJ Rescheneder P Smolka M Fang H Nattestad M Von Haeseler A Schatz MC Accurate detection of complex structural variations using single-molecule sequencing Nat Methods 2018 15 6 461 468 10.1038/s41592-018-0001-7 29713083
Sellick CA Campbell RN Reece RJ Galactose metabolism in yeast—structure and regulation of the Leloir pathway enzymes and the genes encoding them Int Rev Cell Mol Biol 2008 269 111 150 10.1016/S1937-6448(08)01003-4 18779058
Slepak T Tang M Addo F Lai K Intracellular galactose-1-phosphate accumulation leads to environmental stress response in yeast model Mol Genet Metab 2005 86 3 360 371 10.1016/j.ymgme.2005.08.002 16169270
Sood V Brickner JH Genetic and epigenetic strategies potentiate Gal4 activation to enhance fitness in recently diverged yeast species Curr Biol 2017 27 23 3591 3602.e3593 10.1016/j.cub.2017.10.035 29153325
Sunshine AB Payen C Ong GT Liachko I Tan KM Dunham MJ The fitness consequences of aneuploidy are driven by condition-dependent gene effects PLoS Biol 2015 13 5 e1002155 10.1371/journal.pbio.1002155 26011532
Swamy K Zhou N Experimental evolution: its principles and applications in developing stress-tolerant yeasts Appl Microbiol Biotechnol 2019 103 5 2067 2077 10.1007/s00253-019-09616-2 30659332
Tamanoi F Ras signaling in yeast. Genes Cancer 2011 2 210 215
Torres EM Sokolsky T Tucker CM Chan LY Boselli M Dunham MJ Amon A Effects of aneuploidy on cellular physiology and cell division in haploid yeast Science 2007 317 5840 916 924 10.1126/science.1142210 17702937
van den Brink J Akeroyd M van der Hoeven R Pronk J De Winde J Daran-Lapujade P Energetic limits to metabolic flexibility: responses of Saccharomyces cerevisiae to glucose–galactose transitions Microbiology 2009 155 4 1340 1350 10.1099/mic.0.025775-0 19332835
Venkataram S Dunn B Li Y Agarwala A Chang J Ebel ER Geiler-Samerotte K Herissant L Blundell JR Levy SF Fisher DS Sherlock G Petrov DA Development of a comprehensive genotype-to-fitness map of adaptation-driving mutations in yeast Cell 2016 166 6 1585 1596.e1522 10.1016/j.cell.2016.08.002 27594428
Vignogna RC Buskirk SW Lang GI Exploring a local genetic interaction network using evolutionary replay experiments Mol Biol Evol 2021 38 8 3144 3152 10.1093/molbev/msab087 33749796
Voordeckers K Kominek J Das A Espinosa-Cantu A De Maeyer D Arslan A Van Pee M van der Zande E Meert W Yang Y Adaptation to high ethanol reveals complex evolutionary pathways PLoS Genet 2015 11 11 e1005635 10.1371/journal.pgen.1005635 26545090
Wang J Atolia E Hua B Savir Y Escalante-Chong R Springer M Natural variation in preparation for nutrient depletion reveals a cost–benefit tradeoff PLoS Biol 2015 13 1 e1002041 10.1371/journal.pbio.1002041 25626068
Wenger JW Piotrowski J Nagarajan S Chiotti K Sherlock G Rosenzweig F Hunger artists: yeast adapted to carbon limitation show trade-offs under carbon sufficiency PLoS Genet 2011 7 8 e1002202 10.1371/journal.pgen.1002202 21829391
Wickham H Chang W Wickham MH "Package ‘ggplot2’". Create elegant data visualisations using the grammar of graphics Version 2016 2 1 1 189
Yona AH Manor YS Herbst RH Romano GH Mitchell A Kupiec M Pilpel Y Dahan O Chromosomal duplication is a transient evolutionary solution to stress Proc Natl Acad Sci 2012 109 51 21010 21015 10.1073/pnas.1211150109 23197825
Zaman S Im Lippman S Zhao X Broach JR How saccharomyces responds to nutrients Annu Rev Genet 2008 42 27 81 10.1146/annurev.genet.41.110306.130206 18303986
| 36482210 | PMC9734637 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Mol Evol. 2022 Dec 8;:1-14 | utf-8 | J Mol Evol | 2,022 | 10.1007/s00239-022-10079-9 | oa_other |
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J Biol Inorg Chem
J Biol Inorg Chem
Journal of Biological Inorganic Chemistry
0949-8257
1432-1327
Springer International Publishing Cham
36484826
1979
10.1007/s00775-022-01979-8
Original Paper
Antibacterial activity of metal–phenanthroline complexes against multidrug-resistant Irish clinical isolates: a whole genome sequencing approach
http://orcid.org/0000-0001-5888-2382
O’Shaughnessy Megan 12
Hurley Jasmine 1
Dillon Shane C. 1
Herra Celine 1
http://orcid.org/0000-0002-6398-6036
McCarron Pauraic 2
McCann Malachy 3
http://orcid.org/0000-0002-5378-0536
Devereux Michael 2
http://orcid.org/0000-0002-5150-022X
Howe Orla [email protected]
12
1 grid.497880.a School of Biological, Health and Sport Sciences, Technological University Dublin, City Campus, Dublin, Ireland
2 grid.497880.a Centre for Biomimetic and Therapeutic Research, FOCAS Research Institute, Technological University Dublin, City Campus, Dublin, Ireland
3 grid.95004.38 0000 0000 9331 9029 Chemistry Department, Maynooth University, Co., Kildare, Ireland
9 12 2022
119
21 7 2022
8 11 2022
© The Author(s), under exclusive licence to Society for Biological Inorganic Chemistry (SBIC) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is now an urgent need to develop novel therapeutic agents that can overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. The antibacterial activity of metal complexes (metal = Cu(II), Mn(II), and Ag(I)) incorporating 1,10-phenanthroline (phen) and various dianionic dicarboxylate ligands, along with their simple metal salt and dicarboxylic acid precursors, against common AMR pathogens were investigated. Overall, the highest level of antibacterial activity was evident in compounds that incorporate the phen ligand compared to the activities of their simple salt and dicarboxylic acid precursors. The chelates incorporating both phen and the dianion of 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the activity varied depending on the metal centre. Whole-genome sequencing (WGS) was carried out on the reference Pseudomonas aeruginosa strain, PAO1. This strain was exposed to sub-lethal doses of lead metal-tdda-phen complexes to form mutants with induced resistance properties with the aim of elucidating their mechanism of action. Various mutations were detected in the mutant P. aeruginosa genome, causing amino acid changes to proteins involved in cellular respiration, the polyamine biosynthetic pathway, and virulence mechanisms. This study provides insights into acquired resistance mechanisms of pathogenic organisms exposed to Cu(II), Mn(II), and Ag(I) complexes incorporating phen with tdda and warrants further development of these potential complexes as alternative clinical therapeutic drugs to treat AMR infections.
Graphical abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s00775-022-01979-8.
Keywords
Metal complexes
Antimicrobial resistance
Pseudomonas aeruginosa
1,10-Phenanthroline
Whole genome sequencing
http://dx.doi.org/10.13039/501100009246 Technological University Dublin
==== Body
pmcIntroduction
Over the past few decades, the emergence of antimicrobial resistance (AMR) has outpaced the development and market entry of new antimicrobial agents [1–5]. Drug-resistant infections are associated with higher morbidity, mortality, and health expenditures. Consequently, AMR is now one of the biggest challenges facing modern medicine. The European Antimicrobial Resistance Surveillance Network (EARS-Net) reports that approximately 670,000 infections occur in the EU each year due to resistant bacteria, with 33,000 directly attributable deaths, costing €1.1 billion in healthcare costs [6]. While on a worldwide scale, the resistance of microorganisms to antimicrobial agents is reported to account for 700,000 deaths annually, and this is set to increase to 10 million by the year 2050 [7]. Although a recent systemic analysis estimated there were 4.95 million deaths associated with bacterial AMR in 2019, including 1.27 million deaths directly attributable to bacterial AMR alone [8]. As seen with the Coronavirus Disease 2019 (COVID‑19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the global monitoring of infectious agents in addition to the research and development of new therapeutics to deal with them is paramount. Moreover, the pandemic has exacerbated the existing AMR crisis due to incorrect prophylactic treatment [9]. The World Health Organization (WHO) established the Global Antimicrobial Resistance Surveillance System (GLASS), an operational framework for surveillance of resistance, and in conjunction published a list of antibiotic-resistant priority pathogens in a bid to guide and promote investigation and production of new agents for these highly resistant microorganisms [10]. The priority pathogen list is divided into three categories according to the urgency for new therapeutics and includes Gram-negative bacteria Pseudomonas aeruginosa and Enterobacterales (critical status), and the Gram-positive bacteria Enterococcus faecium and Staphylococcus aureus (high status). Infections caused by these microorganisms pose a severe worldwide hazard, and the 2020 WHO clinical antibacterial pipeline analysis report stated that the demand for new antimicrobial agents to treat these bacterial infections had not been met [11]. The WHO also included for the first time a comprehensive overview of non-traditional antibacterial medicines in the pipeline, with the aim of encouraging more research in this area. As the post-antibiotic era looms, the crucial need to develop entirely novel therapeutic agents to the current clinical drugs that can overcome antibiotic resistance, preferably through different and multiple biological targets or pathways, is now widely recognised [12].
Interdisciplinary research in inorganic medicinal chemistry with biology is advancing the knowledge and implementation of transition metal complexes into therapy and is offering a realistic alternative to traditional organic antibiotics [13–17]. Several metal-based therapies are progressing through clinical trials and some have already been approved for clinical use [18, 19]. 1,10-Phenanthroline (phen) is a classic chelating bidentate ligand known to exert antimicrobial activity against a broad spectrum of bacteria [20]. The coordination of metal ions with the bioactive hydrophobic N,N’-donor phen can increase their bioavailability through improved cell membrane permeability, yielding significant improvements in activity compared to the free (uncoordinated) metal ions. The development of novel inorganic complexes with phen or phen-like ligands have demonstrated therapeutic promise for treatment of bacteria [21, 22], fungi [23–25], parasites [26, 27] and viruses [28, 29]. Our research group has investigated the antimicrobial potential of metal-based complexes incorporating phen and its derivatives. 1,10-Phenanthroline-5,6-dione (phendione) and its metal complexes, [Cu(phendione)3](ClO4)2·4H2O (Cu-phendione) and [Ag(phendione)2]ClO4 (Ag-phendione), were tested against Brazilian clinical isolates of P. aeruginosa [30], Acinetobacter baumannii [31] and Klebsiella pneumoniae [32] that had demonstrated multidrug-resistant (MDR) patterns. The metal–phendione complexes were potent against both planktonic- and biofilm-growing cells while having low toxicity in Galleria mellonella larvae [25, 33] and in mice [34]. They were effective inhibitors of the metalloenzyme Elastase B (lasB), which is secreted by P. aeruginosa, suggesting this as a novel potential chemotherapeutic target [35]. Moreover, they were able to interact with double-stranded DNA and promote oxidative damage, suggesting multiple mechanisms of action in P. aeruginosa [36].
Herein, we present the antibacterial activity of copper(II), manganese(II) and silver(I) complexes incorporating phen and dicarboxylate ligands against WHO priority pathogens that are also problematic within Irish clinical settings. The microbial panel comprised the Gram-positive bacteria methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), and the Gram-negative bacteria carbapenem-resistant and ESBL-producing Enterobacterales and Pseudomonas aeruginosa, derived from patients in Irish hospitals. For the microbiological screening of the complexes, European Committee on Antimicrobial Susceptibility Testing (EUCAST) standardised susceptibility testing methods were utilised as currently these guidelines are used in all diagnostic laboratories throughout Europe. The well-characterised susceptible P. aeruginosa PAO1 strain was selected for subsequent acquired resistance studies to selected lead metal complexes with the aim of deciphering the complexes mechanism of action. This strain was dosed with sub-lethal concentrations of the selected complexes and whole-genome sequencing (WGS) was then performed to unveil any genome changes implicated in acquired resistance mechanisms.
Materials and methods
Test complexes
A range of previously published Cu(II), Mn(II) and Ag(I) complexes incorporating dicarboxylate and 1,10-phenanthroline (phen) ligands, along with their relevant non-phen metal-dicarboxylate precursor complexes were selected for the study. The 22 complexes were generated, purified and characterised as previously published using a similar facile two-step approach involving; (i) reaction of the dicarboxylic acid with the respective metal acetate salt to yield the metal–dicarboxylate complex; and (ii) reaction of the metal–dicarboxylate with excess 1,10-phenathroline to generate the metal–dicarboxylate–phenanthroline complex. The dicarboxylic acids included butanedioic acid (bdaH2), pentanedioic acid (pdaH2), hexanedioic acid (hxdaH2), heptanedioic acid (hpdaH2), octanedioic acid (odaH2), undecanoic acid (uddaH2), phthalic acid (phH2) and 3,6,9-trioxaundecanedioic acid (tddaH2). The codes, chemical formulae, solubility and references to the original synthetic routes and characterisation for all the 22 complexes are presented in Table 1.Table 1 Metal complexes assessed in this study
Code Complex formula Solubility References
Cu(II) complexes
Cu-ph-phen [Cu(ph)(phen)(H2O)2] DMSO [38]
Cu-oda [Cu(oda)]H2O DMSO [39]
Cu-oda-phen [Cu(oda)(phen)2]8H2O DMSO [39]
Cu2-oda-phen [Cu2(oda)(phen)4](ClO4)22.76H2O.EtOH H2O [40]
Cu-tdda [Cu(3,6,9-tdda)]H2O H2O [23]
Cu-tdda-phen [Cu(3,6,9-tdda)(phen)2]3H2O.EtOH H2O [23]
Mn(II) complexes
Mn-bda [Mn(bda)]0.2H2O H2O [41]
Mn-bda-phen [Mn2(bda)2(phen)2(H2O)4]0.4H2O H2O [41]
Mn-pda [Mn(pda)].H2O H2O [42]
Mn-pda-phen [Mn(pda)(phen)] H2O [42]
Mn-hxda [Mn(hxda)].H2O H2O [43]
Mn-hxda-phen [Mn(hxda)(phen)2(H2O)]0.7H20 H2O [43]
Mn-hpda [Mn(hpda)] H2O [43]
Mn-hpda-phen [Mn(phen)2(H2O)2][Mn(hpda)(phen)2(H2O)]pda.12.5H2O H2O [43]
Mn-oda [Mn(oda)]H2O H2O [43]
Mn-oda-phen [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2]0.4H2O H2O [43]
Mn-tdda [Mn(3,6,9-tdda)]H2O H2O [37]
Mn-tdda-phen {[Mn(3,6,9-tdda)(phen)2]3H2O.EtOH}n H2O [37]
Ag(I) complexes
Ag-udda [Ag2(udda)] H2O [44]
Ag-udda-phen [Ag2(phen)3(udda)]0.3H2O H2O [44]
Ag-tdda [Ag2(3,6,9-tdda)]2H2O H2O [23]
Ag-tdda-phen [Ag2(3,6,9-tdda)(phen)4]EtOH H2O [23]
Controls
Copper chloride H2O
Manganese chloride H2O
Silver nitrate H2O
1,10-phenanthroline MeOH
Figure S 1 shows the core structures of the three key lead complexes that have emerged from this study, {[Cu(3,6,9-tdda)(phen)2]3H2O.EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2]3H2O.EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4]EtOH (Ag-tdda-phen). X-ray crystallography has established that the Mn-tdda-phen complex is polymeric in nature. Figure S 1(a) shows the repeating unit for Mn-tdda-phen which comprises a six coordinate Mn(II) centre in a slightly distorted octahedral coordination environment, with the nitrogen atoms from two bidentate phenanthroline ligands and the oxygen atoms from two mono-dentate carboxylates from two symmetry-related diacids (which are coordinated in a cis fashion) occupying the coordination sphere [37]. The Cu-tdda-phen complex is believed to have an analogous polymeric structure with its repeating unit (postulated on the basis of very similar analytical and spectral data to those of Mn-tdda-phen) is shown in Fig. S 1(b). The silver complex Ag-tdda-phen, which has been characterized using spectroscopic methods, on the other hand is a binuclear complex comprising two Ag(I)(phen)2 moieties connected via a tdda2− bridge, with each carboxylate function binding to the Ag(I) centres in a monodentate fashion to yield a square pyramidal geometry [Fig. S 1(c)]. All three of these lead complexes are stable and the presence of the tdda2− ligand renders them highly water soluble.
To illustrate that any observed effects were in fact due to the complexes rather than the attached ligands or free metal ions that may be produced within the cellular environment, the activity of the simple metal salts and the metal-free dicarboxylic acids were also included in the study as direct comparators. These included the following: copper(II) chloride (CuCl2), manganese(II) chloride (MnCl2) and silver(I) nitrate (AgNO3), and the free 1,10-phenanthroline (phen) ligand. The metal-free dicarboxylic acids were also included in the study All of the complexes were dissolved in their corresponding diluent (see Table 1) at a concentration of 10 mg/mL. Complexes which were only soluble in dimethyl sulfoxide (DMSO) were made in a 0.1% (DMSO/H2O) solution, while phen and the dicarboxylate ligands were dissolved in methanol (MeOH) and diluted down to a 1% (MeOH/H2O) solution. The remaining complexes were fully water-soluble. Working solutions (512 µg/mL) for the bacterial screen were made up in Mueller Hinton Broth (MHB; Cruinn).
Phen 1,10-phenanthroline, bdaH2 butanedioic acid, pdaH2 pentanedioic acid, hxdaH2 hexanedioic acid, hpdaH2 heptanedioic acid, odaH2 octanedioic acid, uddaH2 undecanoic acid, phH2 phthalic acid, 3,6,9-tddaH2 3,6,9-trioxaundecanedioic acid
Clinical isolates and control strains
The clinical isolates obtained for this study were: Gram-positive methicillin-resistant Staphylococcus aureus (n = 5; MRSA1-MRSA5) and vancomycin-resistant Enterococci (n = 6; VRE1-VRE6), and Gram-negative Enterobacterales, included an extended-spectrum β-lactamase-producer (n = 1; ESBL1), metallo-β-lactamase-producer (n = 1; MBL1) and Klebsiella pneumoniae carbapenemase-producer isolates (n = 1; KPC1), and Pseudomonas aeruginosa (n = 4; PA1–PA4) isolates collected from a range of hospitals throughout Ireland. In addition to the clinical isolates, reference American Type Culture Collection (ATCC) control strains were included in the study. Gram-positive controls included S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, and Gram-negative controls included Escherichia coli ATCC 25922, K. pneumoniae ATCC 10031, and P. aeruginosa ATCC 27853 and PAO1. K. pneumoniae (ATCC 700603 and ATCC BAA-1705) were also included in the Gram-negative panel as ESBL-, KPC-positive resistant control stains, respectively.
Antimicrobial susceptibility testing by disc diffusion
Antimicrobial susceptibility profiles of clinical isolates were established through the qualitative Kirby–Bauer disc-diffusion method, performed according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines [45]. Selections of antimicrobial agents were chosen according to EUCAST recommendations for quality control and are displayed in Table 2. All antimicrobial discs were obtained from Oxoid™ Ltd (Thermo Fisher Scientific). Bacteria were stored on beads in cryogenic vials (Microbank™Cryovials) at – 80 °C and resuscitated on 5% blood agar 24 h before experiments. Three to five colonies were transferred from the agar plate to 5 mL of sterile saline (NaCl) solution, and adjusted until the turbidity matched that of a 0.5 McFarland standard (equivalent to a 1.5 × 108 CFU/mL). This was carried out for each individual strain. When the inoculum matched the 0.5 McFarland standard, a cotton swab was used to spread it on a Mueller–Hinton agar (MHA) plate. The plate was allowed to dry for 3–5 min before the corresponding antimicrobial disc (Table 2) was added to the plate with a sterile forceps. After incubation for 16–18 h at 37 °C, the zone of inhibition was determined by measuring the inhibition of growth around the disc at 3 points using a digital calliper. Studies were performed in triplicate, three independent times, and results are expressed as the mean measurement.Table 2 Disc-diffusion antimicrobial susceptibility testing using common antibacterial agents
Strains Antibiotic (Antibiotic class) Disc content (µg)
Gram-positive panel
S. aureus (ATCC 29213)
Clinical isolates MRSA1–MRSA5
Cefoxitin (Cephalosporin)
Ciprofloxacin (Fluoroquinolone)
Gentamicin (Aminoglycosidase)
Linezolid (Oxazolidinones)
Rifampicin (Ansamycin)
30
5
10
10
5
E. faecalis (ATCC 29212)
Clinical isolates VRE1–VRE6
Ampicillin (Penicillin)
Ciprofloxacin (Fluoroquinolone)
Gentamicin (Aminoglycosidase)
Vancomycin (Glycopeptide)
Linezolid (Oxazolidinone)
2
5
30
5
10
Gram-negative panel
E. coli (ATCC 25992)
K. pneumoniae (ATCC 10031)
K. pneumoniae (ATCC 700603—ESBL, ATCC BAA1705—KPC)
Clinical isolates ESBL1, MBL1 and KPC1
Ampicillin (Penicillin)
Cefotaxime (Cephalosporin)
Ceftazidime (Cephalosporin)
Erthapenem (Carbapenem)
Gentamicin (Aminoglycosidase)
10
5
10
10
10
P. aeruginosa (ATCC 27853, PAO1)
Clinical isolates PA1–PA4
Piperacillin–tazobactam (Penicillin–β-lactamase inhibitor)
Ceftazidime (Cephalosporin)
Meropenem (Carbapenem)
Ciprofloxacin (Fluoroquinolone)
Gentamicin (Aminoglycoside)
36 (30–6)
10
10
5
10
Minimum inhibitory concentration (MIC)
The antibacterial activity of the test complexes and the common antibiotics was also investigated using minimum inhibitory concentration (MIC) antimicrobial susceptibility testing. The MIC of the complexes determined against clinical isolates and reference strains using the 96-well broth micro-dilution method outlined by EUCAST (2017b). A twofold dilution series of the test complexes was prepared in cation-adjusted Mueller–Hinton broth (CAMHB) and mixed with equal volumes (50 µL) of diluted bacteria in 96-well plates (Cruinn), generating a final test complex concentration range of 0.25–256 µg/mL. Each plate included a positive growth control (bacteria and broth) and a broth only no growth control. In addition to the metal complexes and the common antibiotic agents (Table 2), the MIC of the vehicle control (0.1% DMSO, 1% MeOH), starting materials (simple metal salts, phen and bridging ligands) was also determined (Table 1). The MIC was recorded as the lowest concentration to inhibit the visible growth (no turbidity observed) of the test strains following 16–18 h incubation at 37 °C. Studies were performed in triplicate, three independent times, and results are expressed as the mean MIC value.
Minimum bactericidal concentration (MBC)
The minimum bactericidal concentration (MBC) of the metal complexes against test isolates was determined by sub-culturing 5 μL of test dilution from each well in the MIC assay, which failed to show turbidity growth, onto antibiotic free MHA plates. Plates were incubated for a further 16–18 h at 37 °C. The MBCs was recorded as the lowest concentration of agent that prevented the growth (no growth observed) of an organism after subculture. Studies were performed in triplicate, three independent times, and results are expressed as the mean MBC value.
Fractional inhibitory concentration (FIC)
The antibacterial activity of individual metal–phen complexes in combination with the conventional common antibiotics was evaluated using the broth micro-dilution checkerboard assay [46]. Plates were prepared as described in Sect. 2.4. After incubation at 37 °C for 16–18 h, the fractional inhibitory concentration (FIC) index (FICI) for combinations of metal complexes with antibiotics was calculated according to the equation: FICI = FIC(metal complex) + FIC(antibiotic). Where, FIC(metal complex) = (MIC of metal complex in combination with antibiotic)/(MIC of metal complex alone) and FIC(antibiotic) = (MIC of antibiotics in combination with metal complex)/(MIC of antibiotic alone). With this method, FICI values were interpreted as synergy at a FIC index ≤ 0.5; additive at a FIC index > 0.5 to 1; indifference at a FIC index > 1– < 2; and antagonism at a FIC index ≥ 2 [47]. Studies were performed in triplicate, three independent times, and the results were expressed as mean FIC value.
Mutant selection
Mutants with decreased susceptibility to selected metal-tdda-phen complexes (metal = Mn(II), Cu(II) and Ag(I)) were generated by serial passage of P. aeruginosa PAO1 to increasing concentrations of the test complex, see Fig. 1 for a schematic overview of mutants. Briefly, conical flasks containing 10 mL of MHB with twofold increasing concentrations of either Mn-tdda-phen, Cu-tdda-phen, or Ag-tdda-phen were inoculated with an inoculum density equivalent to 1 × 107 CFU/mL of PAO1. Following overnight incubation at 37 °C aerated at 200 rpm, the MIC of the twofold dilution series was determined by the micro-dilution method. The conical flasks with the highest drug concentration that permitted growth (turbidity observed) were used to inoculate a series of tubes containing fresh MHB with twofold increasing concentrations of Mn-tdda-phen, Cu-tdda-phen, or Ag-tdda-phen adjusted to a starting concentration equivalent to 1 × 107 CFU/mL. The inoculated tubes were incubated overnight at 37 °C aerated at 200 rpm. Again, the MIC was recorded as the lowest concentration to inhibit the visible growth of the test strains, and the tube with growth at the highest drug concentration was used to prepare the inoculum for the following passage.Fig. 1 Schematic overview of reducing drug susceptibility of lead metal-tdda-phen complexes, Mn-tdda-phen, Cu-tdda-phen, and Ag-tdda-phen in reference strain P. aeruginosa PAO1 (PAO1_Mn, PAO1_Cu, PAO1_Ag, respectively). PAO1_NT refers to the control strain that did not receive any treatment
Whole-genome sequencing and analysis
The whole-genome sequencing (WGS) of mutant P. aeruginosa PAO1 strain (PAO1_NT, PAO1_Mn, PAO1_Cu, PAO1_Ag, respectively) were performed by MicrobesNG (http://www.microbesng.com). FASTQ files received from MicrobesNG were imported into Geneious Prime and mapped against reference genomes from the NCBI Nucleotide database. ‘PAO1, complete genome’ (Accession no. NC_002516) was used as the reference genome for the P. aeruginosa files. Variants were detected within Geneious Prime and exported as csv files. Settings used were taken from the WGS guide created by Gautam et al. [48], including the following; mapper—Bowtie 2, trim before mapping—do not trim, threshold: highest quality, threshold for sequences without quality: 95%, no coverage call.
The csv files were saved as xlsx files and opened with Microsoft Excel. Variants present in resistant strains of P. aeruginosa were compared to each other, and to the P. aeruginosa control using Ablebits add-in in Microsoft Excel. Any variants that were shared between at least two of the resistant strains and were not present in the control were noted. Any variants within the data that caused an amino acid (aa) change were investigated. BLAST searches were carried out to identify the possible function of any variant-containing hypothetical proteins. The data for this study have been deposited in the European Nucleotide Archive (ENA) at EMBL–EBI under accession number PRJEB52838.
Statistics
All experiments were performed in triplicate, in three independent experimental sets. All data were statistically analysed using one-way analysis variance (ANOVA). The data were expressed as mean values. Data with P values smaller than 0.05 were considered statistically significant. All statistical analyses were performed using GraphPad Prism (GraphPad Software Inc., USA).
Results
Susceptibility profile of all clinical isolates
Clinical isolates were first assessed against a range of commercial antibacterial agents commonly used within the clinic. The susceptibility profile of Gram-positive bacteria represented by S. aureus and Enterococcus species (E. faecium and E. faecalis) and Gram-negative bacteria, Enterobacterales (E. coli and K. pneumoniae) and P. aeruginosa are presented in Table 3. Each representative bacterial group consists of an ATCC control strain and clinical strains isolated from patients with bloodstream infections in Irish hospitals. The susceptibility profiles of these microorganisms were assessed in accordance to the EUCAST guidelines [45, 49]. The zones of inhibition for the ATCC control strains fell within the accepted ranges [50].Table 3 Susceptibility profile of control strains and clinical isolates against clinically used antibiotics, as determined by disc diffusion and classified according to EUCAST guidelines
Species Strain Antibiotic (zone of inhibition as mm)
Gram-positive panel
Cefoxitin Ciprofloxacin Gentamicin Linezolid Rifampicin
Staphylococcus aureus ATCC 29213 27 (S) 24 (S) 21 (S) 24 (S) 33 (S)
MRSA1 10 (R) 0 (R) 8 (R) 23 (S) 27 (S)
MRSA2 13 (R) 0 (R) 8 (R) 22 (S) 28 (S)
MRSA3 11 (R) 0 (R) 19 (S) 24 (S) 27 (S)
MRSA4 15 (R) 0 (R) 21 (S) 24 (S) 27 (S)
MRSA5 13 (R) 0 (R) 20 (S) 24 (S) 28 (S)
Vancomycin Ciprofloxacin Gentamicin Linezolid Ampicillin
Enterococcus faecalis, Enterococcus faecium ATCC 29212 24 (S) 25 (S) 20 (S) 23 (S) 24 (S)
VRE1 0 (R) 0 (R) 0 (R) 0 (R) 0 (R)
VRE2 0 (R) 0 (R) 0 (R) 13 (R) 0 (R)
VRE3 0 (R) 0 (R) 0 (R) 11 (R) 0 (R)
VRE4 0 (R) 0 (R) 0 (R) 13 (R) 0 (R)
VRE5 0 (R) 0 (R) 0 (R) 11 (R) 0 (R)
VRE6 0 (R) 0 (R) 0 (R) 10 (R) 0 (R)
Gram-negative panel
Ertapenem Ceftazidime Cefotaxime Gentamicin Ampicillin
Escherichia coli, Klebsiella pneumoniae ATCC 25922 32 (S) 26 (S) 27 (S) 21 (S) 20 (S)
ATCC 10031 27 (S) 13 (R) 14 (R) 13 (R) 10 (R)
ATCC 700603 26 (S) 8 (R) 15 (R) 12 (R) 0 (R)
ESBL1 25 (S) 0 (R) 0 (R) 0 (R) 0 (R)
MBL1 0 (R) 0 (R) 0 (R) 0 (R) 0 (R)
ATCC BAA1705 0 (R) 0 (R) 0 (R) 17 (S) 0 (R)
KPC1 0 (R) 0 (R) 0 (R) 0 (R) 0 (R)
Ceftazidime Ciprofloxacin Gentamicin Meropenem Piperacillin–Tazobactam
Pseudomonas aeruginosa ATCC 27853 25 (S) 29 (S) 20 (S) 27 (S) 25 (S)
PAO1 15 (S) 25 (S) 18 (S) 18 (S) 25 (S)
PA1 20 (S) 24 (S) 13 (R) 25 (S) 21 (S)
PA2 16 (R) 0 (R) 0 (R) 0 (R) 0 (R)
PA3 0 (R) 0 (R) 0 (R) 17 (R) 0 (R)
PA4 0 (R) 0 (R) 0 (R) 9 (R) 11 (R)
Zones of inhibition are presented in mm. Resistant (R; Red); Susceptible (S; Green)
All five clinical MRSA strains (MRSA1–MRSA5) were resistant to cefoxitin and ciprofloxacin, while two (MRSA1 and MRSA2) isolates were also resistant to gentamicin (Table 2). The clinical, vancomycin-resistant Enterococci strains (VRE1–VRE6) demonstrated resistance to all of the standard antibacterial agents. Representative Gram-negative sub-panels included the Enterobacterales panel encompassed by extended-spectrum β-lactamase (ESBL)-producing strains, ATCC 700603 (K. pneumoniae) and clinical isolate ESBL1, metallo-β-lactamase (MBL)-producing clinical isolate MBL1, and K. pneumoniae carbapenemase (KPC)-producing strain ATCC BAA1705 and clinical isolate KPC1. As expected, the ESBL + strain demonstrated resistance to all β-lactams tested but remained susceptible to the carbapenem. Similarly, both MBL + and KPC + CRE test strains also demonstrated the expected antimicrobial susceptibility testing (AST) profiles with resistance expressed to all β-lactams including the carbapenem, a last resort drug. The P. aeruginosa group incorporated four clinical isolates (PA1–PA4). PA1 was susceptible to all test antibiotics except gentamicin, while PA2, PA3 and PA4 were resistant to all examined agents.
Based on the criteria released by the European Centre for Disease Prevention and Control (ECDC) and the Centres for Disease Control and Prevention (CDC), the bacterial panel is comprised of several multidrug-resistant (MDR) isolates [51].
Antibacterial testing of metal complexes
Once the susceptibility profiles of the clinical isolates were established, in vitro studies were carried out to determine the antibacterial activity of the metal–dicarboxylate–phen complexes against the Gram-positive and Gram-negative panels (Figs. 2 and 3, respectively). Quantitative serial broth dilutions of each complex were performed so as to establish the MIC and MBC values. In addition, the simple metal salts, metal-free ligands and antibiotics were included, along with all of the respective metal-free dicarboxylic acids, butanedioic acid (bdaH2), pentanedioic acid (pdaH2), hexanedioic acid (hxdaH2), heptanedioic acid (hpdaH2), octanedioic acid (odaH2), undecanoic acid (uddaH2), phthalic acid (phH2) and 3,6,9-trioxaundecanedioic acid (tddaH2). Ciprofloxacin and gentamicin were used as controls for the Gram-positive panel as they are well-known broad-spectrum antibiotics that have different mechanisms of activity, inhibition of DNA synthesis (ciprofloxacin) and protein synthesis (gentamicin). Gentamicin and meropenem (inhibition of cell wall synthesis) were utilised for the Gram-negative panel.Fig. 2 Gram-positive panel. Heat map displaying the mean MIC of metal complexes, grouped according to their metal centre and antibiotic controls (ciprofloxacin and gentamicin) for (A) S. aureus, control strain ATCC 29213, and clinical isolates, MRSA1–MRSA5, and (B) Enterococcus spp, control strain ATCC 29212 (E. faecalis) and clinical isolates, VRE1–VRE6. Graph tiles that are white without a value, did not have a MIC that fell within the tested range (> 256 µg/mL). Detail of the concentration range, and its relation to colour, is displayed in the figure legend
Fig. 3 Gram-negative panel. Heat map displaying the mean MIC values of metal complexes, grouped according to their metal centre and also antibiotic controls (meropenem and gentamicin) for (A) Enterobacterales control strain ATCC 29213 (E. coli), ATCC 10031 (K. pneumoniae), ATCC 700603 (ESBL +), ATCC BAA1705 (KPC +) and clinical isolates ESBL1, MBL1 and KPC1, and (B) Pseudomonas aeruginosa, control strain ATCC 27853 and PAO1, and clinical isolates PA1–PA4. Graph tiles that are white without a value, did not have a MIC value that fell within the test range (> 256 µg/mL). Details of the concentration range, and its relation to colour, is displayed in the figure legend
Gram-positive panel
Staphylococcus aureus
The MIC values (µg/mL) of the metal complexes and commonly used antibiotics against S. aureus strains are displayed in Fig. 2A. With the exception of Mn-hpda-phen, metal complexes containing the phen ligand demonstrated a higher level of antibacterial activity against both the control strain (ATCC 29213) and the clinical isolates (MRSA1–MRSA5) in comparison with their non-phen precursors. The MIC value for gentamicin was 1 µg/mL (1.74 µM) for ATCC 29,213 (S. aureus) and MRSA3–MRSA5 isolates which interprets them as being susceptible to the antibiotic according to EUCAST breakpoints. Ciprofloxacin also had an MIC value of 1 µg/mL (3.02 µM) against ATCC 29213, while all of the clinical isolates were resistant to the antibiotic (> 256 µg/mL) (> 772 µM). The Cu(II)-phen complexes, Cu-ph-phen (2.25 µM), Cu-oda-phen (1.35 µM), Cu2-oda-phen (0.76 µM) and Cu-tdda-phen (1.34 µM), and Mn(II) complex Mn-tdda-phen (1.36 µM) also produced a MIC of 1 µg/mL against ATCC 29,213. The simple salts, CuCl2 and MnCl2, had no appreciable effects against the strain (Table S 1), and although phen alone was able to inhibit growth, it was not as effective as the Cu(II) and Mn(I)-phen complexes. Moreover, none of the metal-free dicarboxylic acids demonstrated any inhibitory effects below a concentration of 256 µg/mL (data not shown), and this is in agreement with previously reported data [52]. This suggests that the activity of metal-phen complexes are a consequence of the whole complex rather than its separate constituent parts. However, activity is not necessarily dependent on the number of coordinated phen ligands present per complex. For instance, Cu-oda-phen, Cu-tdda-phen and Mn-tdda-phen contain two phen ligands, and Cu2-oda-phen contains four ligands. Mn-oda-phen has the greatest amount of phen ligands attached (eight) but had an MIC value of 32 µg/mL (104 µM) against ATCC 29213. A sub-set of these complexes (Mn-oda-phen, Mn-tdda-phen and Cu2-oda-phen) were previously examined against Mycobacterium tuberculosis and a similar observation was made [53].
Cu-tdda-phen had an MBC value of 4 µg/mL (5.38 µM) which matched the MBC of gentamicin (6.95 µM). Antibiotics are usually regarded as bactericidal if the MBC is no more than four times the MIC value [54], so in this regard the majority of Cu-tdda-phen MBCs are four times the established MIC value (Table S 1). Strains resistant to gentamicin had an MIC value of 64 µg/mL (100 µM) (MRSA1) and 128 µg/mL (500 µM) (MRSA2), while Mn-tdda-phen (MIC of 1 µg/mL/1.36 µM and 8 µg/mL/10.9 µM against MRSA1 and MRSA2, respectively) and Cu-tdda-phen required a lower concentration to inhibit growth of the isolates (MIC of 8 µg/mL/10.8 µM against both). The similar activities of Cu-tdda-phen and Mn-tdda-phen suggests that, in these particular cases, antimicrobial activity is independent of the nature of the central transition metal dication. This supports previous observations that, in certain instances, activity can be independent of the metal present [14]. However, the metal complexes that contain an Ag(I) nucleus behaved differently to their Cu(II) and Mn(II) counterparts. Ag-tdda-phen (6.65–13.3 µM) and Ag-udda-phen (7.81–15.6 µM) had a MIC range of 8–16 µg/mL across all of the test isolates. Their non-phen precursors, Ag-tdda (67 µM) and Ag-udda (74 µM), maintained activity across all strains at the administered concentration of 32 µg/mL. From previous studies we know that the silver(I)-dicarboxylate precursors are far less stable in aqueous solution than their silver(I)-dicarboxylate-phen derivatives, whereby they rapidly decompose over several days when left standing in direct sunlight [40]. The silver(I)-dicarboxylate-phen derivatives studied were found to be completely photo-stable up to 8 months of exposure to direct sunlight in aqueous solution (confirmed by clarity of colour, lack of any precipitation and UV–Vis spectrophotometry) [40]. In that study cyclic voltammetric (CV) analysis demonstrated that the silver(I)-dicarboxylate precursors studied behaved in a similar fashion to the redox inactive silver acetate resulting in a large silver-stripping peak in the CV profile. The silver(I)-dicarboxylate-phen derivatives on the other hand were found to be redox active and producing only a slight silver stripping peak. Furthermore, the silver(I)-dicarboxylate-phen derivatives were found to have avid DNA binding capability and DNA viscosity studies demonstrated that they exhibit far greater DNA-intercalating ability than ethidium bromide which is the benchmark for comparison of DNA intercalation.
Therefore, based on their relative instability in aqueous solution and the electrochemical analysis, it is postulated that the Ag-udda and the Ag-tdda complexes exerted their toxicity through the release of Ag(I) ions from the complex into the growth medium. This is substantiated by the observation that the simple metal salt, AgNO3, exerted similar activity (MIC value 4–64 µg/mL) (Table S 1). This is not surprising as silver is widely reported to have strong antibacterial properties, particularly against S. aureus with a multi-target mode of action and the ability to overcome antibiotic resistance [51]. The Ag-udda-phen and the Ag-tdda-phen derivatives on the other hand are stable in aqueous solution, redox active and their antibacterial activities are superior to those observed for their non-phen precursors, suggesting that their mechanism of antibacterial activity is significantly different to that of their non-phen precursors, although slow release of silver ions may be part of their multimodal mechanism of action. The DNA binding and intercalating studies previously reported provide further evidence for this differential in their potential modes of action.
Enterococcus faecium and Enterococcus faecalis
The MIC values of the metal complexes and commonly used antibiotics against Enteroccous spp are displayed in Fig. 2B. The control antibiotics ciprofloxacin and gentamicin had an MIC of 1 µg/mL (3.02 µM) and 8 µg/mL (18.3 µM), respectively, against the control strain ATCC 29212, which fell within the recommended values provided by EUCAST. In contrast, all of the clinical isolates had MICs greater than the highest concentration of antibiotic used (256 µg/mL), thus classifying them as being resistant to the antibacterial agents. Fewer metal complexes exercised antibacterial action against the Enterococci group of isolates. Although the Cu(II)-phen complexes inhibited the growth of all strains considerably higher concentrations were required (16–256 µg/mL) (12.2–443 µM). Of the Cu(II) and Mn(II) panel, Cu-tdda-phen and Mn-tdda-phen were the most active. Both complexes established MICs of 16–64 µg/mL (21.5–87 µM) across the bacterial strains and were superior to the control antibiotics, ciprofloxacin and gentamicin (> 256 µg/mL). Moreover, the MBCs for Cu-tdda-phen ranged from 32 µg/mL (43 µM) to 128 µg/mL (172 µM) (Table S 2), demonstrating that not only was the complex able to inhibit the growth of highly resistant microorganisms at lower concentrations than the control antibiotics, but was also able kill them at concentrations below the MICs of the antibiotics. As with the MRSA isolates, the Ag(I) complexes behaved differently to the other metal complexes. Ag-tdda-phen (6.65–13.3 µM) and Ag-udda-phen (7.81–15.6 µM) had a MIC range of 8–16 µg/mL across all strains, while their non-phen precursors, Ag-tdda (67 µM) and Ag-udda (74 µM), respectively, required 32 µg/mL to inhibit growth of the bacterial isolates. The MBCs of the phen-containing complexes, Ag-tdda-phen (26.6–53.2 µM) and Ag-udda-phen (31.2–62.5 µM), were 32–64 µg/mL and their non-phen complexes had an MBC value of 128 µg/mL (271–297 µM). The simple metal salt, AgNO3, inhibited all of the bacterial isolates at a concentration of 4 µg/mL, outperforming the Ag(I) complexes. However, the Ag(I) complexes were able to kill the same bacteria at lower concentrations. Metal-free phen and the dicarboxylic acids did not have MBC values within the test concentration range, and therefore, it is postulated that coordination of the ligands to the metal enhances the bactericidal effect.
Gram-negative panel
Escherichia coli and Klebsiella pneumoniae
The Enterobacterales panel are represented by susceptible control strains ATCC 25922 (E. coli) and ATCC 10031 (K. pneumoniae), resistant control strains ATCC 700603 (K. pneumoniae extended-spectrum β-lactamase (ESBL)-producer) and ATCC BAA1705 (K. pneumoniae carbapenemase (KPC)-producer), and clinical isolates ESBL producer (ESBL1) a metallo-β-lactamase (MBL)-producer (MBL1) and a KPC producer (KPC1). Figure 3A highlights that a reduced selection of complexes retained activity when screened against Gram-negative bacteria and, overall, complexes containing a phen ligand had heightened activity. Of the Cu(II) complexes, Cu2-oda-phen (48.7–194 µM) and Cu-oda-phen (80.5–345 µM) had an MIC value in the range 64–256 µg/mL, while Cu-ph-phen was essentially inactive against the Gram-negative panel. Gram-negative bacteria, unlike Gram-positive bacteria, possess a protective outer membrane (OM) which can impede access of some antibacterial agents and this can be a limiting factor in a chemotherapeutic treatment protocol [55]. Cu-tdda-phen (MICs = 16–64 µg/mL) (21.5–86 µM), Mn-tdda-phen (MIC = 16–128 µg/mL) (21.8–174 µM) and Ag-tdda-phen (MIC = 8–64 µg/mL) (6.7–53.2 µM) were the most active agents from within each representative group. The Ag(I) complexes, Ag-udda, Ag-udda-phen and Ag-tdda, produced a similar toxicity profile as the silver salt, AgNO3 (Table S 3), across all strains, again suggesting that the binuclear silver complexes may be exerting activity by releasing Ag(I) ions into solution. Ag-tdda-phen generated an MBC value (64–128 µg/mL) twice that of its MIC value (32–64 µg/mL) across the clinical isolates apart from ESBL1 that required 4 times the MIC value (16 µg/mL) to eliminate the isolate. Transmission election microscopy observation of AgNO3 treated E. coli identified morphological and structural changes as well as enhanced permeability in the bacterial cell envelope [56] suggesting that the Ag(I) complexes are exerting their antibacterial activity in this manner.
Pseudomonas aeruginosa
When investigating the MIC of the metal complexes (Fig. 3B), Cu-tdda-phen (21.5–86 µM) and Mn-tdda-phen (21.8–87 µM) were decidedly the most active complexes from those that harbour a Cu(II) or Mn(II) nucleus. A related activity pattern was observed through the test strains, with ATCC 27,853 having an MIC value of 16 µg/mL (21.5 µM and 21.8 µM, respectively) for both chelates and an MBC value of 32 µg/mL (43 µM and 43.5 µM, respectively). For the Cu(II) and Mn(II) tdda-phen complexes to inhibit growth of the clinical isolates PA2 and PA4, an MIC value of 16 µg/mL was necessary, whereas both of these bacterial strains were resistant to the control antibiotics, meropenem (MIC = > 256 µg/mL, > 585 µM) and gentamicin (MIC = > 256 µg/mL, 444 µM). Ag-tdda-phen presented with an MIC value of 8 µg/mL (6.6 µM) for ATCC 27,853 and PA1, and 32–64 µg/mL (26.6–53.2 µM) across the remaining strains. The non-phen derivative, Ag-tdda, had an MIC value of 128–256 µg/mL (106–213 µM) for all of the clinical strains, indicating that the inclusion of the phen ligand caused a more potent effect.
Combination effects of selected clinical isolates with lead metal-tdda-phen complexes and antibiotics
Combination therapy is a method for restoring the clinical efficacy of antibiotics and avoiding the development of drug resistance in the clinic. Therefore, combinatorial testing of elected metal-tdda-phen complexes and control antibiotics was used to determine the interaction and potency of the combined treatments compared to their individual activities against the selected clinical isolates. Representative isolates were chosen from each genera, particularly strains that had a more extensive resistance profile (Table 3). They were as follows: S. aureus clinical isolates, MRSA1 and MRSA2, Enterococci isolates, VRE1 and VRE6, Enterobacterales isolates, ATCC 700603, MBL1, ESBL1, ATCC BAA1705 and KPC1, and P. aeruginosa isolates PA2 and PA4. Selected antibacterial agents were unique to the group of bacteria, for instance, antibiotics chosen for VRE isolates were vancomycin and linezolid. Finally, a representative metal complex from each different metal-containing series was selected including the very active tdda-phen family, Cu-tdda-phen, Mn-tdda-phen and Ag-tdda-phen. When drugs are combined, their effects on bacterial cells may be amplified, slightly enhanced, weakened, or have no effect at all, so the drugs may show synergistic, additive, indifferent or antagonistic interactions, respectively. On the basis of their FIC index, each combination was categorized as synergistic (≤ 0.5), additive (> 0.5 to 1), indifferent (> 1 to < 2) or antagonistic (≥ 2), according to the EUCAST guidelines [47]. Ideally, for the combination of metal complex with antibiotic, a synergistic was desired.
Combination effects in selected Gram-positive isolates
Methicillin-resistant Staphylococcus aureus (MRSA)
Ciprofloxacin is a bactericidal antibiotic of the fluoroquinolone class that target DNA replication [57] and gentamicin is a clinically significant aminoglycoside antibiotic that inhibits protein synthesis [58]. All three metal-tdda-phen complexes in combination with ciprofloxacin produced an indifferent effect against the clinical isolates, MRSA1 and MRSA2 (Table S 5). This means that the inhibitory effect of the combined agents is the same as that of the more active drug alone, this being the metal-tdda-phen complexes. When the complexes were co-administered with gentamicin, the combination was synergistic, in terms of the FICI value. In this context, the inhibitory effect against the bacterium in the combination was more potent than that of the individual agents alone.
Vancomycin-resistant Enterococci (VRE)
Vancomycin, a glycopeptide, exerts its bactericidal effect by binding to d-alanyl-d-alanine residues of the bacterial cell wall and preventing polymerization of peptidoglycans [59]. Linezolid is the first synthetic oxazolidinone antibiotic with a unique mechanism of action as it appears to block initiation of protein production [60]. All combinations of vancomycin or linezolid with the three metal-tdda-phen complexes against the clinical isolates, VRE1 and VRE6, produced indifferent effects (Table S 6).
Combination effects in Gram-negative strains
Enterobacterales isolates
Ceftazidime, is a third-generation cephalosporin antibiotic that exerts its bactericidal action by inhibiting enzymes responsible for cell wall synthesis primarily through penicillin-binding protein 3 (PBP3) [61]. Meropenem is a broad-spectrum antibacterial agent of the carbapenem class that inhibits cell wall synthesis also through binding to PBP targets [62]. The strains representing the test Enterobacterales group were ATCC 700603, ATCC BAA1705, ESBL1, MBL1 and KPC1 isolates (Table S 7). Co-exposure of ceftazidime with Cu-tdda-phen or Mn-tdda-phen, and the combinations of all of the metal-tdda-phen complexes with meropenem, caused an indifferent effect with all strains (the inhibitory rate of the combined agents was the same as that of the more active drug alone, that being the metal-tdda-phen complex). The addition of Ag-tdda-phen to ceftazidime also had an indifferent effect against ESBL1 and KPC1 strains. However, the same combination against ATCC 700603, MBL1 and ATCC BAA1705 produced an additive effect (combination of agents did not increase the inhibitory effect to an extent that was better than that of administering the concentration of the more active single drug alone). The same effect was observed with the combinations of Cu-tdda-phen, Mn-tdda-phen and Ag-tdda-phen with gentamicin against ESBL1. There have been numerous reports of simple silver or silver nanoparticles (AgNPs) restoring activity of ineffective antibiotics against multidrug-resistant strains [63–65]. One report stated the combination of AgNPs with ceftazidime were synergistic against 62.50% of examined ESBL + K. pneumoniae isolates, and confirming the inhibition of β-lactamase enzymes in isolates exposed to AgNPs [66].
Pseudomonas aeruginosa
When the clinical isolates PA2 and PA4 were tested with the metal-tdda-phen complexes in tandem with meropenem and gentamicin the results were indifferent and synergistic, respectively (Table S 8).
Whole-genome sequencing of Gram-negative Pseudomonas aeruginosa for resistance properties to selected metal-tdda-phen complexes
Wild type P. aeruginosa strain PAO1 was exposed to sub-lethal concentrations of lead metal-tdda-phen complexes so as to induce resistance properties (Fig. 1). This generated distinct strains that were denoted as PAO1_Mn, PAO1_Cu, and PAO1_Ag, when exposed to Mn-tdda-phen, Cu-tdda-phen and Ag-tdda-phen, respectively. Whole-genome sequencing (WGS) was performed on all strains and the genomes were subsequently analyzed using the bioinformatics programme ‘Geneious Prime’.
Various mutations were identified upon comparing the untreated control strain (PAO1_NT) to the metal-tdda-phen-treated strains (PAO1_Cu, PAO1_Mn and PAO1_Ag) (Table S 9). One variant identified between all metal-tdda-phen exposed strains was situated in an unnamed gene that encodes for a hypothetical protein that is linked to a carbon–nitrogen hydrolase containing protein. A BLAST search and computational predictions suggest that the protein exhibits N-carbamoylputresceine amidase activity [67]. This protein is a crucial component in the polyamine biosynthetic pathway, indicating that resistance to the metal-tdda-phen complexes may be acquired through alterations in the activity levels of this pathway. Mutations in agmatine deiminase and N-carbamoylputrescine amidase can directly influence the rate at which polyamines are produced. Arginine deiminase, GatB of the aspartyl/glutamyl-tRNA amidotransferase complex and ɣ-glutamyl phosphate reductase can all indirectly contribute to an altered polyamine biosynthetic rate [68]. The remaining mutations (Table S 9) were aligned to specific pathways and mechanisms, as discussed below.
Mutations associated with cellular respiration
Genome analysis suggest that alterations to energy metabolism pathways contributed to the development of bacterial resistance. Amino acid altering single nucleotide polymorphisms (SNPs) occurred in various unspecified oxidoreductases and known oxidases and dehydrogenases in metal-tdda-phen-treated strains. These enzymes are heavily involved in cellular respiration [69, 70]. In situations, where electron acceptors in oxidative phosphorylation are unavailable, the protein D-lactate dehydrogenase may act as a temporary electron sink [71]. In addition, recent studies have demonstrated the ability of D-lactate dehydrogenase to act as an electron transferring agent, transporting electrons from NADH to quinones present in the plasma membrane [72]. A mutation in the gene encoding for D-lactate dehydrogenase, ldhA, was identified in the analysis. In addition, a SNP was identified in an unspecified cytochrome c oxidase which acts as a terminal electron acceptor but also has other functions in bacteria such as promoting virulence and biofilm growth [73]. Both of these mutations indicate that cellular respiration was affected by the metal-tdda-phen complexes.
Mutations associated with polyamine biosynthetic pathway
Amino acid substitutions were identified in agmatine deiminase and N-carbamoylputrescine amidase (CPA), respectively. An inhibitory mutation in agmatine deiminase would prevent the formation of N-carbamoylputrescine, and therefore, no mutation would be required in CPA as it would not have a substrate on which to act. Similarly, the arginine biosynthetic pathway involves the conversion of glutamate into arginine through a series of consecutive enzymatic reactions [74]. Mutations were identified in arginine deiminase, GatB of the aspartyl/glutamyl-tRNA amidotransferase complex and ɣ-glutamyl phosphate reductase. Arginine deiminase and ɣ-glutamyl phosphate reductase catalyse the conversion of arginine to citrulline and N-acetyl-glutamyl-5-phosphate to N–acetyl-glutamyl-5-semialdehyde, respectively [74]. These reactions are essential steps in the arginine biosynthetic pathway. GatB is involved in the synthesis of glutamine which is a precursor to glutamate [75]. Amino acid substitutions in each of these enzymes further support the previous postulation that an enhanced rate of polyamine biosynthesis could contribute to the resistance of the PAO1 strain to the three metal-tdda-phen complexes.
Mutations associated with virulence factors
Bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) is the principle second messenger involved in the regulation of cell cycle, differentiation, virulence, motility, biofilm formation and dispersion [76, 77]. It is synthesized from two GTP molecules by diguanylate cyclases (DGC), and is degraded by phosphodiesterases (PDE). Variants in PDE, PprA, WspC, RhlA and alginate lyases were identified in metal-tdda-phen-treated strains, suggesting that changes occurred in the biofilm life cycle. In addition, WspC is a methyltransferase that promotes the activation of the Wsp pathway. This pathway is involved in the regulation of c-di-GMP concentration [78, 79]. Similarly, the gene pprA encodes the histidine kinase sensor, PprA, for the two-component system PprA–PprB. This system is associated with biofilm formation during high-stress conditions. PprA is responsible for the activation of the two-component system and a mutation in pprA could indicate that the activity status of the system was altered as a resistance strategy toward the metal-tdda-phen complexes [80, 81]. A mutation in rhlA was identified, which is a gene that codes for rhamnosyltransferase subunit A that acts as a key enzyme in the biosynthesis of rhamnolipid, a secondary metabolite that is important for the maintenance of mature biofilms [82]. We have previously reported the anti-biofilm activity of these metal-tdda-phen complexes against P. aeruginosa strains, isolated from Cystic Fibrosis patients, in both in vitro [22] and in vivo scenarios [83]. A SNP in an alginate lyase domain-containing protein was also observed in both PAO1_Cu and PAO1_Mn strains. This mutation resulted in an arginine residue being substituted for a glutamine residue. Alginate is a critical component of biofilms, providing the thick mucoid consistency that facilitates protection against the environment and stressors. Alginate lyase proteins degrade alginate and this mutation may reduce the enzyme's efficiency, allowing alginate levels to rise and promoting biofilm formation [84, 85].
SNPs were identified in other virulence factors such as nalC, which is a transcriptional regulator responsible for the control of the mexAB-oprM operon [86], encoding the primary efflux pump of P. aeruginosa, MexAB–OprM [87]. The MexAB–OprM system is responsible for the resistance to quinolones, macrolides, chloramphenicol, tetracyclines, lincomycin, and β-lactam antibiotics [88]. A mutation in this protein resulted in an arginine residue replacing a serine residue. Another notable variant was present in XqhA, a protein that increases specificity of the type II secretion system (T2SS) [89]. T2SS is known to secrete PlcH, a hemolytic toxin in which another mutation was identified causing the substitution of a serine with an alanine [90]. Finally, a mutation resulting in the replacement of an asparagine with a lysine occurred in the highly conserved bacterial protein, ClpB. This protein is vital in the disaggregation of proteins during high stress conditions [91], suggesting that the metal-tdda-phen complexes may have triggered protein aggregation within the bacterial cell.
Discussion
Here, we investigated the antibacterial capabilities of copper(II), manganese(II), and silver(I) complexes containing dicarboxylate ligands and phen in panels of clinical isolates derived from Irish hospitals and further investigated the potential resistance mechanisms by whole-genome sequencing (WGS) of our lead complexes in the representative Gram-negative organism, P. aeruginosa. With Gram-positive and -negative bacteria, their distinction lies in the composition of the cell envelope. The scaffold of the Gram-positive cell wall consists of a thick layer of peptidoglycan polymer embedded with teichoic and lipoteichoic acids that are anchored to the cell membrane. Teichoic acids are long anionic glycopolymers that bind cations contributing to bacterial cell surface charge and hydrophobicity, which in turn affects the interaction of antibiotics and host defences [92]. In contrast, and in the absence of teichoic acid, the Gram-negative cell wall consists of a thin layer of peptidoglycan; however, the outer membrane encloses this. This layer is effectively a second lipid bilayer containing amphiphilic lipopolysaccharide (LPS), phospholipids and outer membrane proteins [93]. Porins are β-barrel structures that form channels to orchestrate the movement of small hydrophilic molecules across the outer membrane [94], and efflux pumps are membrane-bound proteins which are responsible for the extrusion of a variety of solutes. Therefore, the outer membrane is a very effective and selective permeability barrier and a significant obstacle in the development of antibacterial agents that are effective against Gram-negative bacteria [55, 95]. In addition to this intrinsic resistance, acquired resistance is developing rapidly, creating a further impediment in the treatment of diseases caused by these pathogens [96–98].
Our present investigations have shown that, overall, the metal complexes that incorporate the phen ligand demonstrated superior antibacterial toxicity when compared to their non-phen precursors, metal-free phen, metal-free dicarboxylic acids or simple metal salts. The greater activity profiles of metal-phen complexes or metal-phendione complexes (phendione is a derivative of phen), in comparison with their non phen analogues has previously been reported against a range of microorganisms [23, 24, 30, 31, 53]. Moreover, the metal-phen complexes that contained the 3,6,9-trioxaundecanedioate (tdda) bridging dianionic ligand maintained their potency, to varying degrees, across both the Gram–positive and Gram–negative panels (Figs. 2 and 3). The tdda ligand enhances the water solubility of the metal complexes, strengthening their hydrophilicity and potentially increasing their uptake into the bacterial cell and thus their subsequent antibacterial action [99, 100]. Although generally the inclusion of the phen ligand in the complex formulations is key to their antibacterial action, the general exception to this was the Ag(I) complexes which were found to be active in both their phen and non-phen containing forms. Ag(I) compounds have well-documented multimodal bactericidal properties, displaying a broad spectrum of activity across both classes of bacteria [101, 102]. Ag(I) ions interact with the bacterial cell envelope and destabilize the membrane [103, 104], couple with nucleic acids and proteins [105], and inhibit metabolic pathways [106, 107]. Although the Ag(I) ion is generally not regarded as being redox active, the generation of reactive oxygen species (ROS) also attributes to its antibacterial activity [13, 101]. However, it is thought that the production of ROS indirectly occurs through the perturbation of the respiratory electron transfer chain [108], Fenton chemistry following destabilization of Fe–S clusters or displacement of iron [109] and inhibition of anti-ROS defences by thiol–silver bond formation [110]. The antibacterial potential of Ag(I) is influenced by the composition of the cell wall, the thick negatively charged peptidoglycan layer in Gram-positive bacteria attracts/binds the metal cations and retards their entry [101, 111]. The complexation of metal ions to a hydrophobic chelating ligand, such as phen, encases the cations in a hydrophobic sleeve and enables their penetration through the cell wall and membrane of a bacterium, thus presenting the complex to internal target biomolecules which ultimately inhibits cell growth or even triggers cell death [15]. The heightened activity of phen-containing Ag(I) complexes, compared to their non-phen precursors, was evident in the present work with both the Gram-positive (Fig. 2) and Gram-negative panels (Fig. 3). Ag(I) complexed to phen or a phen-type ligand (e.g., phendione) have presented with additional routes in which they exert their toxicity against microorganisms, such as interacting with double stranded DNA [36] or suppressing virulence [35]. Cu(II) and Mn(II)-phen complexes have been reported to be avid producers of ROS [112] which is thought to cause cell membrane damage and thiol depletion. Oxidative and thiol stress promotes the release metal ions (Fe, Zn and Cu) from metalloproteins, increasing their intracellular concentration initiating Fenton-type chemistry which then stimulates further ROS generation [113]. This, coupled with intercalation of the complexes with bacterial DNA, would cause deformation and cleavage of the nucleic acid [53, 112, 114] producing cascade effects that would eventually lead to bacterial cell death. These previous observations substantiate the hypothesis that the current metal-tdda-phen complexes, producing high intracellular levels of ROS, affect cellular respiration (Table S 9). Various mutations were detected in the mutant genome of the metal-tdda-phen-treated P. aeruginosa representative strain, PAO1, causing amino acid changes within proteins involved in the polyamine biosynthetic pathway. Polyamines have demonstrated the ability to reduce oxidative damage caused by ROS [115]. As previously mentioned, Cu(II), Mn(II) and Ag(I)-phen complexes generate free radicals which are highly reactive and unstable. Polyamines act as ROS scavengers, stabilizing ROS and preventing ROS-induced damage to DNA, lipids and proteins. Recent findings suggest that these organic cations may also upregulate genes associated with the enzymatic degradation of ROS, such as catalases and superoxide dismutases. Superoxide dismutases have the ability to degrade superoxide radicals, while catalases can degrade hydrogen peroxide [116, 117].
Due to the increasing rate of AMR, metals and metal complexes have not only been investigated as alternatives to antibiotics but also as adjuvants. There have been numerous reports on the capacity of metals or metal-bearing compounds to synergise and potentiate antibiotics within both in vitro and in vivo models [56, 118–121]. Within the present study, all three metal-tdda-phen complexes potentiated gentamicin (an aminoglycoside) activity in clinical isolates of MRSA, EBSL and P. aeruginosa in terms of their fractional inhibitory concentration (FIC) index. Aminoglycosides are bactericidal antibiotics that inhibit protein synthesis by binding with a high affinity to the aminoacyl-tRNA site (A site) within the 30S ribosomal subunit, thereby inhibiting the translation process and producing truncated proteins and affecting the cell wall composition. This increases membrane permeability and subsequently heightens uptake of the drug [122]. In studies using strains of E. coli, Herisse et al. reported a tenfold increase in antimicrobial activity of aminoglycosides (gentamicin, tobramycin, kanamycin, and streptomycin) when co-administered with AgNO3 [118]. Aminoglycosides cross the cell membrane via proton motive forces, and the Ag(I) ion enhanced their toxicity by acting independently of this process. Morones-Ramirez et al. also reported the synergistic combination of AgNO3 with β-lactams, aminoglycosides, and quinolones against E. coli, and they suggested that this was due to intensified ROS production [56]. One or both of the above-mentioned mechanisms could also be the reason why the present metal-tdda-phen complexes enhanced the activity of gentamicin, and this warrants further investigation.
Conclusion
In conclusion, of the spectrum of metal complexes assessed those incorporating the phen ligand had superior activity to their non-phen derivatives. In addition, the three metal-phen complexes incorporating the 3,6,9-trioxaundecanedioate (tdda) ligand broadly maintained activity across the bacterial panel of both classes, and these complexes also re-sensitized, gentamicin-resistant isolates to the antibiotic. The genomes of mutant P. aeruginosa strains treated to the metal-tdda-phen (metal = Cu(II), Mn(II), and Ag(I)) complexes eluded to novel and potentially multimodal mechanisms by which the test complexes exert their toxicity. The encouraging results emanating from the current study suggests that future pharmacological, toxicological and pharmacokinetic investigations are warranted for the metal-tdda-phen complexes.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 514 kb)
Data availability
The authors confirm that the data supporting the findings of this study are available within the article. However, data can be stored on the TUDublin central repository Arrow.
Declarations
Conflict of interest
The authors declare no conflict of interest.
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References
1. Theuretzbacher U Bush K Harbarth S Critical analysis of antibacterial agents in clinical development Nat Rev Microbiol 2020 18 286 298 10.1038/s41579-020-0340-0 32152509
2. Butler M Gigante V Sati H Analysis of the clinical pipeline of treatments for drug-resistant bacterial infections: despite progress, more action is needed Antimicrob Agents Chemother 2022 66 1 39 10.1128/aac.01991-21
3. Destoumieux-Garzón D Mavingui P Boetsch G The one health concept: 10 years old and a long road ahead Front Vet Sci 2018 5 1 13 10.3389/fvets.2018.00014 29417054
4. Cassini A Högberg LD Plachouras D Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European economic area in 2015: a population-level modelling analysis Lancet Infect Dis 2019 19 56 66 10.1016/S1473-3099(18)30605-4 30409683
5. Theuretzbacher U Gottwalt S Beyer P Analysis of the clinical antibacterial and antituberculosis pipeline Lancet Infect Dis 2019 19 40 50 10.1016/S1473-3099(18)30513-9
6. Organisation for Economic Co-operation and Development (2020) Antimicrobial resistance. tackling the burden in the European union. Eur Cent Dis Prev Control:1–20.
7. O'Neill J (2014) Antimicrobial resistance: tackling a crisis for the health and wealth of nations. The review on antimicrobial resistance
8. Murray C Ikuta K Sharara F Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis Lancet 2022 399 629 655 10.1016/S0140-6736(21)02724-0 35065702
9. Pelfrene E Botgros R Cavaleri M Antimicrobial multidrug resistance in the era of COVID-19: a forgotten plight? Antimicrob Resist Infect Control 2021 10 1 21 10.1186/s13756-021-00893-z 33407871
10. World Health Organization (2017) Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-resistant bacterial infections, including tuberculosis. [Accessed 25 March 2019]
11. World Health Organization (2020) Antibacterial agents in clinical and preclinical development. 2021. [Accessed 11 Feburary 2022]
12. Matos De Opitz CL, Sass P (2020) Tackling antimicrobial resistance by exploring new mechanisms of antibiotic action. Future Microbiol 15:703–708.
13. Lemire J Harrison J Turner RJ Antimicrobial activity of metals: mechanisms, molecular targets and applications Nat Rev Microbiol 2013 11 371 384 10.1038/nrmicro3028 23669886
14. Frei A Zuegg J Elliott A Metal complexes as a promising source for new antibiotics Chem Sci 2020 11 2627 2639 10.1039/C9SC06460E 32206266
15. Viganor L Howe O McCarron P The antibacterial activity of metal complexes containing 1,10-phenanthroline: potential as alternative therapeutics in the era of antibiotic resistance Curr Top Med Chem 2016 17 1280 1302 10.2174/1568026616666161003143333
16. Evans A Kavanagh K Evaluation of metal-based antimicrobial compounds for the treatment of bacterial pathogens J Med Microbiol 2021 70 1 18 10.1099/jmm.0.001363
17. Claudel M Schwarte J Fromm K New antimicrobial strategies based on metal complexes Chemistry 2020 2 849 899 10.3390/chemistry2040056
18. Frei A Metal complexes, an untapped source of antibiotic potential? Antibiotics 2020 9 1 10 10.3390/antibiotics9020090
19. Boros E Dyson PJ Gasser G Classification of metal-based drugs according to their mechanisms of action Chem 2020 6 41 60 10.1016/j.chempr.2019.10.013 32864503
20. Dwyer F Reid I Shulman A The biological actions of 1,10-phenanthroline and 2,2[prime]-bipyridine hydrochlorides, quartnery salts and metal chelates and related compounds Aust J Exp Biol Med 1969 47 203 218 10.1038/icb.1969.21
21. Ahmed M Rooney D McCann M Synthesis and antimicrobial activity of a phenanthroline-isoniazid hybrid ligand and its Ag+ and Mn2+ complexes Biometals 2019 32 671 682 10.1007/s10534-019-00204-5 31230149
22. O’Shaughnessy M McCarron P Viganor L The antibacterial and anti-biofilm activity of metal complexes incorporating 3,6,9-trioxaundecanedioate and 1,10-phenanthroline ligands in clinical isolates of Pseudomonas aeruginosa from Irish cystic fibrosis patients Antibiotics 2020 9 1 22 10.3390/antibiotics9100674
23. Gandra R McCarron P Fernandes M Antifungal potential of copper(II), manganese(II) and silver(I) 1,10-phenanthroline chelates against multidrug-resistant fungal species forming the Candida haemulonii Complex: Impact on the planktonic and biofilm lifestyles Front Microbiol 2017 8 1 10 10.3389/fmicb.2017.01257 28197127
24. Granato M Gonçalves D Seabra S 1,10-phenanthroline-5,6-dione-based compounds are effective in disturbing crucial physiological events of Phialophora verrucosa Front Microbiol 2017 8 1 9 10.3389/fmicb.2017.00076 28197127
25. Granato M Mello T Nascimento R Silver(I) and copper(II) complexes of 1,10-phenanthroline-5,6-dione against Phialophora verrucosa: a focus on the interaction with human macrophages and Galleria mellonella larvae Front Microbiol 2021 12 1 12 10.3389/fmicb.2021.641258
26. Vargas Rigo G Petro-Silveira B Devereux M Anti-Trichomonas vaginalis activity of 1,10-phenanthroline-5,6-dione-based metallodrugs and synergistic effect with metronidazole Parasitology 2019 146 1179 1183 10.1017/S003118201800152X 30207253
27. Lima A Elias C Oliveira S Anti-Leishmania braziliensis activity of 1,10-phenanthroline-5,6-dione and its Cu(II) and Ag(I) complexes Parasitol Res 2021 120 3273 3285 10.1007/s00436-021-07265-x 34363115
28. Papadia P Margiotta N Bergamo A Platinum(II) complexes with antitumoral/antiviral aromatic heterocycles: effect of glutathione upon in vitro cell growth inhibition J Med Chem 2005 48 3364 3371 10.1021/jm0500471 15857142
29. Chang E Simmers C Knight D Cobalt complexes as antiviral and antibacterial agents Pharmaceuticals 2010 3 1711 1728 10.3390/ph3061711 27713325
30. Viganor L Galdino A Nunes A Anti-Pseudomonas aeruginosa activity of 1,10-phenanthroline-based drugs against both planktonic- and biofilm-growing cells J Antimicrob Chemother 2016 71 128 134 10.1093/jac/dkv292 26416778
31. Ventura R Galdino A Viganor L Antimicrobial action of 1,10-phenanthroline-based compounds on carbapenemase-producing Acinetobacter baumannii clinical strains: efficacy against planktonic- and biofilm-growing cells Braz J Microbiol 2020 51 1703 1710 10.1007/s42770-020-00351-9 32737867
32. Vianez Peregrino I Ferreira Ventura R Borghi M Antibacterial activity and carbapenem re-sensitizing ability of 1,10-phenanthroline-5,6-dione and its metal complexes against KPC-producing Klebsiella pneumoniae clinical strains Lett Appl Microbiol 2021 73 139 148 10.1111/lam.13485 33843058
33. Gandra R McCarron P Viganor L In vivo activity of copper(II), manganese(II), and silver(I) 1,10-phenanthroline chelates against Candida haemulonii using the Galleria mellonella model Front Microbiol 2020 11 1 15 10.3389/fmicb.2020.00470 32082274
34. McCann M Santos A Da Silva B In vitro and in vivo studies into the biological activities of 1,10-phenanthroline, 1,10-phenanthroline-5,6-dione and its copper(II) and silver(I) complexes Toxicol Res 2012 1 47 54 10.1039/c2tx00010e
35. Galdino A Viganor L De Castro A Disarming Pseudomonas aeruginosa virulence by the inhibitory action of 1,10-phenanthroline-5,6-dione-based compounds: Elastase B (lasB) as a chemotherapeutic target Front Microbiol 2019 10 1 16 10.3389/fmicb.2019.01701 30728808
36. Galdino A Viganor L Pereira M Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa J Biol Inorg Chem 2022 27 201 213 10.1007/s00775-021-01922-3 35006347
37. McCann S McCann M Casey R Manganese(II) complexes of 3,6,9-trioxaundecanedioic acid (3,6,9-tddaH2): X-ray crystal structures of [Mn(3,6,9-tdda)(H2O)2]·2H2O and {[Mn(3,6,9-tdda)(phen)2·3H2O]·EtOH}n Polyhedron 1997 16 4247 4252 10.1016/S0277-5387(97)00233-7
38. Kellett A Howe O O’Connor M Radical-induced DNA damage by cytotoxic square-planar copper(II) complexes incorporating o-phthalate and 1,10-phenanthroline or 2,2′-dipyridyl Free Radic Biol Med 2012 53 564 576 10.1016/j.freeradbiomed.2012.05.034 22659117
39. McCann M Cronin J Devereux M Copper(II) complexes of heptanedioic acid (hdaH2) and octanedioic acid (odaH2): X-ray crystal structures OF [Cu(η2-hda)(phen)2]·11H2O and [Cu(η2-oda)(phen)2]·12H2O (phen = 1,10-Phenanthroline) Polyhedron 1995 14 2379 2387 10.1016/0277-5387(95)00075-4
40. Devereux M, McCann M, Cronin J, et al. (1999) Binuclear and polymeric copper(II) dicarboxylate complexes: syntheses and crystal structures of [Cu2(pda)(phen)4](ClO4)2.5H2O.C2H5OH, [Cu2(oda)(phen)4](ClO4)2.2.67H2O.C2H5OH. Polyhedron 18:2141–2148
41. McCann M Casey M Devereux M Syntheses, X-ray crystal structures and catalytic activities of the manganese(II) butanedioic acid complexes Polyhedron 1997 16 2547 2552 10.1016/S0277-5387(97)00002-8
42. Geraghty M McCann M Casey M Synthesis and catalytic activity of manganese (II) complexes of pentanedioic acid; X-ray crystal structure of [Mn(phen)2(H20)2][Mn(O2C(CH 2)3CO2)(phen)2H2O](O2C(CH2)3CO2)·12H2O(phen=1,10-phenanthroline) Inorganica Chim Acta 1998 277 257 262 10.1016/S0020-1693(97)06160-4
43. McCann M, Casey M, Devereux M, et al. (1997) Manganese(II) complexes of hexanedioic and heptanedioic acids: X-ray crystal structures of [Mn(O2C(CH2)4CO2(phen)2H2O]·7H2O and [Mn(phen)2(H2O)2][Mn(O2C(CH2)5CO2)[phen)2H2O](O2C(CH2)5CO2)·12.5H2O. Polyhedron 16:2741–2748
44. Thornton L Dixit V Assad L Water-soluble and photo-stable silver(I) dicarboxylate complexes containing 1,10-phenanthroline ligands: Antimicrobial and anticancer chemotherapeutic potential, DNA interactions and antioxidant activity J Inorg Biochem 2016 159 120 132 10.1016/j.jinorgbio.2016.02.024 26986979
45. European Committee on Antimicrobial Susceptibility Testing. Antimicrobial susceptibility testing EUCAST disk diffusion method. 2017. [Accessed 17 September 2018] http://www.eucast.org.
46. Odds FC Synergy, antagonism, and what the chequerboard puts between them J Antimicrob Chemother 2003 52 1 2 10.1093/jac/dkg301 12805255
47. European Committee on Antimicrobial Susceptibility Testing Terminology relating to methods for the determination of susceptibility of bacteria to antimicrobial agents Clin Microbiol Infect 2000 6 503 508 10.1046/j.1469-0691.2000.00149.x 11168186
48. Gautam S, KC R, Leong K, et al. (2019) A step-by-step beginner’s protocol for whole genome sequencing of human bacterial pathogens. J Biol Methods 6:1–9
49. European Committee on Antimicrobial Susceptibility Testing. The european committee on antimicrobial susceptibility testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 7.1, 2017. [Accessed 17 September 2018] http://www.eucast.org.
50. European Committee on Antimicrobial Susceptibility Testing. European Committee on Antimicrobial Susceptibility Testing Routine and extended internal quality control as recommended by EUCAST. Version 7.0, 2017. [Accessed 17 September 2018] http://www.eucast.org.
51. Magiorakos A Srinivasan A Carey R Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance Clin Microbiol Infect 2012 18 268 281 10.1111/j.1469-0691.2011.03570.x 21793988
52. Devereux M, Mccann M, Leon V et al. (2000) Synthesis and biogical activity of manganese (II) complexes of phtalic and isophtalic acid: X-ray crystal structures of [Mn(ph)(phen)2(H2O)].4H2O, [Mn(phen)2(H2O)2]2(Isoph)2(phen).12H2O and [Mn(isoph)(bipy)]4.2.75bipy. Met Based Drugs 7:275–88.
53. McCarron P McCann M Devereux M Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs Front Microbiol 2018 9 1 10 10.3389/fmicb.2018.01432 29403456
54. Levison M Levison J Pharmacokinetics and pharmacodynamics of antibacterial agents Infect Dis Clin North Am 2009 23 791 815 10.1016/j.idc.2009.06.008 19909885
55. Impey R Hawkins D Sutton J Overcoming intrinsic and acquired resistance mechanisms associated with the cell wall of Gram-negative bacteria Antibiotics 2020 9 1 19 10.3390/antibiotics9090623
56. RubenMorones-Ramirez J Winkler J Spina C Silver enhances antibiotic activity against Gram-negative bacteria Sci Transl Med 2013 5 1 21
57. Correia S Poeta P Hébraud M Mechanisms of quinolone action and resistance: where do we stand? J Med Microbiol 2017 66 551 559 10.1099/jmm.0.000475 28504927
58. Magnet S Blanchard J Molecular insights into aminoglycoside action and resistance Chem Rev 2005 105 477 497 10.1021/cr0301088 15700953
59. Lee T Pang S Abraham S Antimicrobial-resistant CC17 Enterococcus faecium: the past, the present and the future J Glob Antimicrob Resist 2019 16 36 47 10.1016/j.jgar.2018.08.016 30149193
60. Chen H Du Y Xia Q Role of linezolid combination therapy for serious infections: review of the current evidence Eur J Clin Microbiol Infect Dis 2020 39 1043 1052 10.1007/s10096-019-03801-x 31898798
61. Testa R Cantón R Giani T In vitro activity of ceftazidime, ceftaroline and aztreonam alone and in combination with avibactam against European Gram-negative and Gram-positive clinical isolates Int J Antimicrob Agents 2015 45 641 646 10.1016/j.ijantimicag.2014.12.033 25748553
62. Zandi T Townsend C Competing off-loading mechanisms of meropenem from an l d-transpeptidase reduce antibiotic effectiveness PNAS 2021 118 1 7 10.1073/pnas.2008610118
63. She P, Zhou L, Li S et al. (2019) Synergistic microbicidal effect of auranofin and antibiotics against planktonic and biofilm-encased S. aureus and E. faecalis. Front Microbiol 10:1–12.
64. Liang X Luan S Yin Z Recent advances in the medical use of silver complex Eur J Med Chem 2018 157 62 80 10.1016/j.ejmech.2018.07.057 30075403
65. Zou L Wang J Gao Y Synergistic antibacterial activity of silver with antibiotics correlating with the upregulation of the ROS production Sci Rep 2018 8 1 11 10.1038/s41598-018-29313-w 29311619
66. Panáček A Smékalová M Večeřová R Silver nanoparticles strongly enhance and restore bactericidal activity of inactive antibiotics against multiresistant Enterobacteriaceae Colloids Surf 2016 142 392 399 10.1016/j.colsurfb.2016.03.007
67. UniProt. hemE - Uroporphyrinogen decarboxylase - Pseudomonas aeruginosa (strain ATCC 15692/DSM 22644/CIP 104116/JCM 14847/LMG 12228/1C / PRS 101/PAO1)—hemE gene and; protein.
68. Sekula B Dauter Z Structural study of agmatine iminohydrolase from Medicago truncatula, the second enzyme of the agmatine route of putrescine biosynthesis in plants Front Plant Sci 2019 10 1 14 10.3389/fpls.2019.00320 30723482
69. Alford M Baghela A Yeung A NtrBC regulates invasiveness and virulence of Pseudomonas aeruginosa during high-density infection Front Microbiol 2020 11 1 17 10.3389/fmicb.2020.00773 32082274
70. Lee J Oh S Bhattacharya S The plasticity of the pyruvate dehydrogenase complex confers a labile structure that is associated with its catalytic activity PLoS ONE 2021 15 1 17
71. Kasai T Suzuki Y Kouzuma A Roles of d-lactate dehydrogenases in the anaerobic growth of Shewanella oneidensis MR-1 on sugars Appl Environ Microbiol 2019 85 1 11 10.1128/AEM.02668-18
72. Lin Y Cornell W Jo J The Pseudomonas aeruginosa complement of lactate dehydrogenases enables use of d- and L-lactate and metabolic cross-feeding MBio 2018 9 1 18 10.1128/mBio.00961-18
73. Jo J Cortez K Cornell W An orphan cbb3-type cytochrome oxidase subunit supports Pseudomonas aeruginosa biofilm growth and virulence Elife 2017 6 1 10 10.7554/eLife.30205
74. Majumdar R Barchi B Turlapati SA Glutamate, ornithine, arginine, proline, and polyamine metabolic interactions: the pathway is regulated at the post-transcriptional level Front Plant Sci 2016 7 65 78 10.3389/fpls.2016.00078 26904043
75. Friederich M Timal S Powell C Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder Nat Commun 2018 9 1 14 10.1038/s41467-018-06250-w 29317637
76. Valentini M Gonzalez D Mavridou DA Lifestyle transitions and adaptive pathogenesis of Pseudomonas aeruginosa Curr Opin Microbiol 2018 41 15 20 10.1016/j.mib.2017.11.006 29166621
77. Valentini M Filloux A Biofilms and cyclic di-GMP (c-di-GMP) signaling: lessons from Pseudomonas aeruginosa and other Bacteria J Biol Chem 2016 291 12547 12555 10.1074/jbc.R115.711507 27129226
78. Maunders E Welch M Matrix exopolysaccharides; the sticky side of biofilm formation FEMS Microbiol Lett 2017 364 1 10 10.1093/femsle/fnx120
79. Cai Y Webb JS Optimization of nitric oxide donors for investigating biofilm dispersal response in Pseudomonas aeruginosa clinical isolates Appl Microbiol Biotechnol 2020 104 8859 8869 10.1007/s00253-020-10859-7 32865612
80. Bhagirath A Li Y Patidar R Two component regulatory systems and antibiotic resistance in gram-negative pathogens Int J Mol Sci 2019 20 1 30 10.3390/ijms20071781
81. Wang C Chen W Xia A Carbon starvation induces the expression of PprB-regulated genes in Pseudomonas aeruginosa Appl Environ Microbiol 2019 85 1 17 10.1128/AEM.01705-19
82. Thi MTT Wibowo D Rehm BHA Pseudomonas aeruginosa biofilms Int J Mol Sci 2020 21 1 25 10.3390/ijms21228671
83. O’Shaughnessy M Piatek M McCarron P In vivo activity of metal complexes containing 1,10-phenanthroline and 3,6,9-trioxaundecanedioate ligands against Pseudomonas aeruginosa infection in Galleria mellonella larvae Biomedicines 2022 10 1 22 10.3390/biomedicines10020222
84. Moradali M Ghods S Rehm B Pseudomonas aeruginosa lifestyle: a paradigm for adaptation, survival, and persistence Front Cell Infect Microbiol 2017 7 1 39 10.3389/fcimb.2017.00039 28149830
85. Blanco-Cabra N Paetzold B Ferrar T Characterization of different alginate lyases for dissolving Pseudomonas aeruginosa biofilms Sci Rep 2020 10 1 10 10.1038/s41598-020-66293-2 31913322
86. Braz V Furlan J Fernandes A Mutations in NalC induce MexAB-OprM overexpression resulting in high level of aztreonam resistance in environmental isolates of Pseudomonas aeruginosa FEMS Microbiol Lett 2016 363 1 16 10.1093/femsle/fnw166
87. Barbosa C Mahrt N Bunk J The genomic basis of rapid adaptation to antibiotic combination therapy in Pseudomonas aeruginosa Mol Biol Evol 2021 38 449 464 10.1093/molbev/msaa233 32931584
88. Scoffone V Trespidi G Barbieri G Role of RND efflux pumps in drug resistance of cystic fibrosis pathogens Antibiotics 2021 10 1 25 10.3390/antibiotics10070863
89. Michel G Durand E Filloux A XphA/XqhA, a novel GspCD subunit for type II secretion in Pseudomonas aeruginosa J Bacteriol 2007 189 3776 3783 10.1128/JB.00205-07 17351035
90. Pena RT Blasco L Ambroa A Relationship between quorum sensing and secretion systems Front Microbiol 2019 10 1 19 10.3389/fmicb.2019.01100 30728808
91. Alam A Bröms J Kumar R The role of ClpB in bacterial stress responses and virulence Front Mol Biosci 2021 8 1 8 10.3389/fmolb.2021.668910
92. Brown S Santa Maria J Walker S Wall teichoic acids of Gram-positive bacteria Annu Rev Microbiol 2013 67 313 336 10.1146/annurev-micro-092412-155620 24024634
93. Okuda S Sherman D Silhavy T Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model Nat Rev Microbiol 2016 14 337 345 10.1038/nrmicro.2016.25 27026255
94. Silhavy T Kahne D Walker S The bacterial cell envelope Cold Spring Harb Perspect Biol 2010 2 1 16 10.1101/cshperspect.a000414
95. Zgurskaya H López C Gnanakaran S Permeability barrier of Gram-negative cell envelopes and approaches to bypass it ACS Infect Dis 2016 1 512 522 10.1021/acsinfecdis.5b00097
96. Peterson E Kaur P Antibiotic resistance mechanisms in bacteria: Relationships between resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogens Front Microbiol 2018 9 1 21 10.3389/fmicb.2018.02928 29403456
97. Pang Z Raudonis R Glick B Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies Biotechnol Adv 2019 37 177 192 10.1016/j.biotechadv.2018.11.013 30500353
98. Khan M Stapleton F Summers S Antibiotic resistance characteristics of Pseudomonas aeruginosa isolated from keratitis in Australia and India Antibiotics 2020 9 1 16 10.3390/antibiotics9090600
99. Ng N Leverett P Hibbs D The antimicrobial properties of some copper(II) and platinum(II) 1,10-phenanthroline complexes Dalt Trans 2013 42 3196 3209 10.1039/C2DT32392C
100. Ng N Wu M Jones C The antimicrobial efficacy and DNA binding activity of some copper(II) complexes of 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline and 1,2-diaminocyclohexane J Inorg Biochem 2016 162 62 72 10.1016/j.jinorgbio.2016.06.006 27293146
101. Domínguez A Algaba R Canturri A Antibacterial activity of colloidal silver against Gram-negative and Gram-positive bacteria Antibiotics 2020 9 1 10
102. Wang H Wang M Xu X Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance Nat Commun 2021 12 1 16 33397941
103. Jung W Koo H Kim K Antibacterial activity and mechanism of action of the silver ion in Staphylococcus aureus and Escherichia coli Appl Environ Microbiol 2008 74 2171 2178 10.1128/AEM.02001-07 18245232
104. McQuillan J Groenaga Infante H Stokes E Silver nanoparticle enhanced silver ion stress response in Escherichia coli K12 Nanotoxicology 2012 6 857 866 10.3109/17435390.2011.626532 22007647
105. Arakawa H Neault J Tajmir-Riahi H Silver(I) complexes with DNA and RNA studied by fourier transform infrared spectroscopy and capillary electrophoresis Biophys J 2001 81 1580 1587 10.1016/S0006-3495(01)75812-2 11509371
106. Gordon O Slenters T Brunetto P Silver coordination polymers for prevention of implant infection: thiol interaction, impact on respiratory chain enzymes, and hydroxyl radical induction Antimicrob Agents Chemother 2010 54 4208 4218 10.1128/AAC.01830-09 20660682
107. Wang H Yan A Liu Z Deciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli PLOS Biol 2019 17 1 31 10.1371/journal.pbio.3000292
108. Gu M Imlay J The SoxRS response of Escherichia coli is directly activated by redox-cycling drugs rather than by superoxide Mol Microbiol 2011 4 1136 1150 10.1111/j.1365-2958.2010.07520.x
109. Barras F Aussel L Ezraty B Silver and antibiotic, new facts to an old story Antibiotics 2018 7 1 10 10.3390/antibiotics7030079
110. Saulou-Bérion C Gonzalez I Enjalbert B Escherichia coli under ionic silver stress: an integrative approach to explore transcriptional, physiological and biochemical responses PLoS ONE 2015 10 1 25 10.1371/journal.pone.0145748
111. Dakal T Kumar A Majumdar R Mechanistic basis of antimicrobial actions of silver nanoparticles Front Microbiol 2016 7 1 17 10.3389/fmicb.2016.01831 26834723
112. Kellett A O’Connor M McCann M Water-soluble bis(1,10-phenanthroline) octanedioate Cu2+ and Mn2+ complexes with unprecedented nano and picomolar in vitro cytotoxicity: promising leads for chemotherapeutic drug development Med Chem Comm 2011 2 579 584 10.1039/c0md00266f
113. Schramm F Schroeder K Jonas K Protein aggregation in bacteria FEMS Microbiol Rev 2019 44 54 72 10.1093/femsre/fuz026
114. Ng N Wu M Aldrich-Wright J The cytotoxicity of some phenanthroline-based antimicrobial copper(II) and ruthenium(II) complexes J Inorg Biochem 2018 180 61 68 10.1016/j.jinorgbio.2017.11.022 29247868
115. Seo S Kim Y Park K Increasing polyamine contents enhances the stress tolerance via reinforcement of antioxidative properties Front Plant Sci 2019 10 1 13 10.3389/fpls.2019.01331 30723482
116. Van Acker H Coenye T The role of reactive oxygen species in antibiotic-mediated killing of bacteria Trends Microbiol 2017 25 456 466 10.1016/j.tim.2016.12.008 28089288
117. Guillouzo A Guguen-Guillouzo C Antibiotics-induced oxidative stress Curr Opin Toxicol 2020 20 23 28 10.1016/j.cotox.2020.03.004
118. Herisse M Duverger Y Martin-Verstraete I Silver potentiates aminoglycoside toxicity by enhancing their uptake Mol Microbiol 2017 105 115 126 10.1111/mmi.13687 28383153
119. Garza-Cervantes J Chávez-Reyes A Castillo E Synergistic antimicrobial effects of silver/transition-metal combinatorial treatments Sci Rep 2017 7 1 16 10.1038/s41598-017-01017-7 28127051
120. Kim J Pitts B Stewart P Comparison of the antimicrobial effects of chlorine, silver ion, and tobramycin on biofilm Antimicrob Agents Chemother 2008 52 1446 1453 10.1128/AAC.00054-07 18195062
121. Chen F Moat J McFeely D Biguanide iridium(III) complexes with potent antimicrobial activity J Med Chem 2018 61 7330 7344 10.1021/acs.jmedchem.8b00906 30070838
122. Kohanski M Dwyer D Wierzbowski J Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death Cell 2008 135 679 690 10.1016/j.cell.2008.09.038 19013277
| 36484826 | PMC9734640 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Biol Inorg Chem. 2022 Dec 9;:1-19 | utf-8 | J Biol Inorg Chem | 2,022 | 10.1007/s00775-022-01979-8 | oa_other |
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Environ Sci Pollut Res Int
Environ Sci Pollut Res Int
Environmental Science and Pollution Research International
0944-1344
1614-7499
Springer Berlin Heidelberg Berlin/Heidelberg
36474034
24596
10.1007/s11356-022-24596-z
Research Article
Ensuring environmental inclusion in developing countries: the role of macroeconomic policies
Batool Zakia [email protected]
1
Bhatti Arshad Ali [email protected]
2
Rehman Abdul [email protected]
3
1 grid.444798.2 0000 0004 0607 5732 Department of Economics, National University of Modern Languages (NUML), Islamabad, 44000 Pakistan
2 grid.411727.6 0000 0001 2201 6036 School of Economics, IIIE, International Islamic University, Islamabad, 44000 Pakistan
3 grid.108266.b 0000 0004 1803 0494 College of Economics and Management, Henan Agricultural University, Zhengzhou, 450002 China
Responsible Editor: Arshian Sharif
7 12 2022
112
22 9 2022
1 12 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
In every society, there exist disadvantaged groups who have failed constantly to take part in the development of the economy and reap the benefits of economic growth as well. Along with economic and social factors, environmental factors are also accountable in making inclusion a challenge for the marginalized group. Contaminated drinking water, inappropriate sanitation systems, and pollution are the factors that affect health and wellbeing of the poor class by affecting their productivity. Thus, the lack of a clean environment leads the poor section towards further poverty and income inequality. Since the 2030 Agenda for Sustainable Development emphasizes three components to achieve sustainable development, namely economic, social, and environmental, this study inspects the role of macroeconomic policies in ensuring an inclusive clean environment in developing countries. Moreover, it considers the composite effect of fiscal policy and monetary policy on environmental inclusion by including interactive terms. This investigation uses FE-2SLS on a panel of 51 developing countries for the period of 1995–2019 to analyse the impact of macroeconomic policies on environmental inclusion. The study provides empirical evidence that fiscal and monetary policy has the potential to ensure an inclusive clean environment in developing countries. The findings imply that the macroeconomic policy actions depend on each other. Furthermore, governments in developing regions are required to cut nondeveloping expenditures and use expansionary monetary policy to promote green growth.
Keywords
Environmental inclusion
Fiscal policy
Monetary policy
CO2 emission
FE-2SLS
==== Body
pmcIntroduction
While running on the path of economic growth, many individuals lag in the race due to a lesser number of opportunities available to them and thus have been thrown into a passive position. There are always individuals or groups in a society that are unable to engage in economic growth and hence do not benefit from it. Environmental factors, in addition to economic and social ones, are to blame for the marginalized minority’s difficulties assimilating into mainstream society. According to the report by the WHO (2014), between 2030 and 2050, climate change may cause approximately 250,000 deaths each year. On the other hand, contaminated drinking water, inappropriate sanitation systems, and pollution are the factors that affect the health and well-being of the poor class. It is observed that 1 out of 4 people do not have access to safe drinking water whereas almost half of the global population lacks access to safely managed sanitation facilities. At the start of the COVID-19 pandemic, three out of ten individuals across the world were unable to wash their hands with soap and water in their own homes.1 The sixth goal of SDGs emphasizes improving access to safe drinking water and sanitary facilities for all particularly vulnerable groups. Environmental justice is required in every economy because environmental ills affect unprivileged groups disproportionately. According to Inclusion Cornwall,2 natural environment helps to engage marginalized and isolated people; thus, environmental inclusion is necessary to make them participate in the growth process. It is a concept that focuses on not just only reducing pollution’s impact on the poor but also promoting fair access to nature for all.
The inverted U-shaped connection between environmental degradation and per capita income is explained by the Environmental Kuznets curve (EKC hereinafter), which states that environmental quality deteriorates during the early stages of economic development but improves in tandem with rising levels of economic success (Grossman and Krueger 1991; Stern et al. 1996). Environmental circumstances, on the other hand, affect economic growth, and poor environmental quality hinders many individuals from contributing to the growth process by reducing their productivity. The poorer sectors of the economy are more vulnerable to the negative consequences of environmental degradation, therefore providing a safe and green environment for everyone ensures that everyone has an equal opportunity to participate in the economic process. The human body’s exposure to harmful particles in water and air causes a variety of ailments, which reduces workers’ productivity by harming their health. People living in rural areas mostly rely on carbon-emitting energy sources, such as solid fuels which affect their health and reduce their productivity and cause an increase in health expenditures (Ahmad et al. 2021a).
The macroeconomic policy instruments can play their role in ensuring an inclusive environment. The developing economies have been using fiscal instruments just to raise revenue figures or to facilitate investor class so that a heave in economic growth could be realized. On the other hand, the government’s regarding its spending schemes has social and environmental outcomes as well. The increased government spending results in an increase in aggregate demand which stimulates the economic activities and use of natural resources. The excessive use of fuel, coal, and natural gas as sources of energy is needed to accomplish the growth targets which results in environmental degradation. The consequence of government spending on the environment also depends on whether the economy perceives the environment as a public or a luxury thing (Yilanci and Pata 2021). If the environment is perceived as a public good, environmental degradation will occur as a result of economic activities because market participants will not consider environmental aspects while carrying out market activities, and then the role of government to protect the environment through environmental regulations and pollution taxes becomes relevant (Hua et al. 2018; Moshiri and Daneshmand 2020). Alternatively, environmental deterioration hinders economic development (Ahmad et al. 2021b).
Monetary policy measures also affect the environment by affecting aggregate demand and corresponding market activities. The interest rate management ability of monetary policy contributes to a smooth interest rate over the economic cycles and thus brings about consistency and sustainability in economic growth. According to Qingquan et al. (2020), a country’s monetary policy is aimed at controlling inflation and sustaining long-term interest rates, and the changes in interest rate affect the industrial use of energy, aggregate demand, and financial development which eventually results in pollution. Monetary policy can also affect the well-being of economic agents through the channel of credit supply. The availability of credit on easy terms facilitates investors to move towards new and innovative projects. If enterprises are charged a higher credit rate for using innovative technologies, fewer new businesses would be started. However, rising CO2 levels may occur from the growing usage of obsolete and less environmentally friendly technologies. Conversely, it influences welfare projects, such as basic water and sanitation infrastructure, through the interest rate channel.
Since achieving a sustainable environment is the seventh Millennium Development Goal (hereinafter MDG) and the 2030 Agenda for Sustainable Development emphasizes three components to achieve sustainable development, namely, economic, social, and environmental, this study inspects the role of macroeconomic policies in ensuring an inclusive clean environment in the developing countries. At first, we planned for the study to include all developing countries throughout the globe; however, data availability issues forced us to leave out several countries. By creating an index of inclusive clean environment for developing countries worldwide, this study adds to the current literature. The second aspect of this investigation that makes it unique is that it looks at how both fiscal and monetary policies affect the positive environment. In addition, the analysis incorporates interactive factors to account for the combined effect of fiscal policy and monetary policy on environmental inclusion.
Literature review
Many economies have ignored environmental damage because of their desire for rapid economic expansion. It is well acknowledged that economic expansion and poverty have a detrimental impact on environmental quality (Costantini and Martini 2010). Many studies have used different proxies to measure environmental sustainability; for example, Ahmed et al. (2022a) use ecological footprint for environmental sustainability while Ahmed et al. (2022b) use CO2 reduction for environmental sustainability. On the one hand, Can and Ahmed (2022) have used renewable energy as a proxy for sustainable development, while Ahmed et al. (2022b) used per labor aggregate output for sustainable development. For environmental degradation, Jiang et al. (2022), Rehman et al. (2022a. 2022d), and Adebayo and Rjoub (2022) used CO2 emissions. While many studies in the literature have identified urbanization, energy consumption, financial development, ICT, and agricultural activities as determinants of environmental degradation (Batool et al. 2022; Zhao et al. 2022; Rehman et al. 2022b, 2022c), several studies in the literature have addressed the environmental issue in the context of inclusive development. Wan and Zhuang (2015) presented a survey report on inclusive growth in which the economic, social, and environmental elements of inclusive growth were explored. The environmental component takes into account environmental issues such as safe drinking water, sanitation, and clean air, all of which can influence unprivileged groups’ productivity and, as a result, their ability to participate in the growth process. Sanitation facilities, water supplies, greenhouse gas emissions, forest areas, and fossil fuel usage are considered indicators of the environmental dimension. The components were scored using the linear scoring technique, and the components were aggregated using the simple arithmetic mean.
The World Bank (1992) introduced the concept of the development-environment nexus which explains the two-way causal links between the two. According to some studies, economic progress has a progressive influence on environmental inclusiveness in terms of provision of the clean drinking water and sanitary facilities to masses; however, air pollution and sulphur dioxide emissions harm the environment (Shafik 1994). A report by the WHO (2010) emphasizes the matter that in developing countries the cause of young children’s mortality and chronic pulmonary diseases among adults is indoor combustion of fuels and being shortage of access to advanced energy resources. Thus, to have sustainable and inclusive economic growth, improvement, and maintenance of environmental quality is very essential. According to the United Nations (2018), emerging economies are facing the challenge of maintaining environmental quality and dealing with climate change in order to attain sustainability. Thus, the world’s attention is increasingly turning to environmental challenges coming from excessive resource use, mass production, diminished forests, and polluted seas, all of which have an impact on the climate (Zhang et al. 2022).
Many factors are responsible for environmental exclusion and among those factors; fiscal and monetary instruments have the tendency to affect the level of exclusion. Many researchers have suggested fiscal reforms to ensure a sustainable environment for all; for example, the resource allocation can be done to achieve environmental goals such as provision of drinking water and sanitation services and forest restoration and pollution can be controlled through the taxation (Lopez and Palacios 2010; Jones and Yoo 2011; Harris 2013; Callahan and Pisano 2014). Government spending affects the income distribution and social wellbeing of individuals and raises the public awareness about environmental challenges and thus affects the environmental quality (Halkos and Paizanos 2013). Schrecongost et al. (2020) worked on inclusive sanitation approach and suggested that there is need of public projects that are financially viable to pursue equitable, inclusive, and sustained services in urban areas. On the other hand, Sanogo (2019) argues that fiscal decentralization affects the provision of public services, for example, health, water, and sanitation in rural areas. However, to control air pollution, Kamal et al. (2021) suggest that entrepreneurs should be encouraged to adopt environmentally friendly technology through tax incentive policies while the carbon tax is found effective in reducing CO2 emissions (Liu et al. 2017; Freire-González and Ho 2019; Ojha et al. 2020). However, the study of Halkos and Paizanos (2016) investigated the impact of both taxes and government expenditures on CO2 emissions and concluded that deficit-financed government spending is more successful in improving the environment than deficit-financed taxes.
On the other hand, monetary policy also affects the level of inclusiveness through its channels and many researchers found a negative link between interest rate and environmental degradation (Alola 2019; Isiksal et al. 2019; Qingquan et al. 2020). Based on the association among environmental degradation and interest rate; many studies found a positive relationship between interest rate and environmental degradation that suggests lowering the interest rate to control environmental degradation (Muhafidin 2020; Åström et al. 2019; Pradeep 2022). The positive association emerges because lower interest rates relieve the private sector’s financial restrictions. This leads to more money going into carbon-efficient technology and environment-friendly projects which causes the environment to improve. While working on the same line, Chan (2020) does not find any empirical evidence of the relationship between monetary policy and the environment. Numerous economists used the term green financing to highlight the role of monetary policy in protecting the environment, that is, lowering the interest rate on green loans supports green financing and innovations that lead to improvement in environmental quality (Dikau and Volz 2021; Debrah et al. 2022; Desalegn et al. 2022). Many researchers have considered both fiscal and monetary policy instruments to analyze the effect of macroeconomic policies on the environment (Mughal et al. 2021; Mahmood et al. 2022; Zeraibi et al. 2022).
The past literature provides a sufficient amount of evidence on how fiscal and monetary policy affects the environment. Some of the studies have shown that expansionary macroeconomic policies affect the environment quality while the rest have shown the adverse effect of macroeconomic policies on the environment. However, very few studies have discussed macroeconomic policies in the context of environmental inclusion which is aimed at providing a suitable and green environment for all. Furthermore, the interaction influence of macroeconomic policies on environmental inclusion in emerging economies throughout the globe is a gap in the literature. As a result, this study fills a research vacuum by examining the combined influence of fiscal and monetary mechanisms on environmental inclusion.
Methodology for the construction of environmental inclusion
This section explains the indicators of environmental inclusion and the methodology to construct the index of environmental inclusion. The indicators of environmental inclusion include access to drinking water, sanitation, forest area, and less consumption of fossil fuel energy as these will make an improvement in the health conditions and reduce hazardous deaths. The majority of people living in rural regions lack access to water supplies and sanitary facilities and rely on fossil fuel energy, while the forest is fast diminishing as the pace of urbanisation rises, exposing the environment to pollution. The World Bank indicates that in 2019, around 90 percent of the population has access to water sources whereas 65 percent population has access to sanitation facilities. The proportion of the population having access to water and sanitation in low- and middle-income economies is 90 and 66 percent respectively whereas in rich countries the figure is around 99.5 percent for access to water and sanitation. According to a study by PCRWR,3 84 percent of the total population in Pakistan is deprived of safe drinking water. According to World Bank data, 1.91 percent of Pakistan’s total land area is still forested, although the proportion of fossil fuel usage is steadily growing.
As discussed earlier, this study assumes four indicators of environmental inclusion that measure the access of people to basic facilities that ensure a clean environment. To measure the first indicator, sanitation, WDI’s data on the percentage of the population having access to improved sanitation facilities has been used. The provision of these sanitation facilities helps to prevent human contact from human excreta, and the facilities include a flush system, ventilated improved pit latrine, and composting toilet, to measure water source data on the percentage of the population having access to improved drinking water sources released by the World Bank Data. It includes the provision of tap water connections on-premises, public taps, tube wells, boring water, protected springs, and rainwater collection. For the third indicator, forest area as a percentage of the land area is used. It is an indicator that mainly focuses on environmental sustainability. Forest area includes all types of terrain that have tree stands (either natural or planted) of at least 5 m in situ. It does not matter whether these tree stands are productive or not, but these do not include tree stands in agricultural production systems. The last indicator in this category is the consumption of fossil fuel energy. To measure this indicator, WDI’s data on the consumption of fossil fuel energy as a percentage of total energy use has been used. Consumption of fossil fuel energy includes the consumption of coal, petroleum, oil, and natural gas products.
Except for fossil fuel energy consumption, increasing values of all the indicators contributes positively towards the improvement of the environment; therefore, inverse of fossil fuel energy consumption is taken in this study. The summary of the descriptive statistics of the indicators is given in Table 1, whereas the preliminary analysis of pairwise correlations and Bonferroni level of significance are given in Table 6 in Appendix. The descriptive statistics in Table 1 show that the average forest area in the developing region from 1995 to 2019 is 346000 conversely the minimum value is 515. The consumption of fossil fuel energy in the developing world has reached 100 percent whereas the average consumption has been 61.426 percent. It is a good indicator that in developing regions the maximum value of access to water and sanitation is 100 percent but the average values of access to water and sanitation are 80.552 and 62.21 due to the reason that people in some of the developing countries, for example, Peru, Senegal, and Venezuela, do not have access to drinking water and sanitation facilities.Table 1 Descriptive statistics of the indicators of the environmental inclusion
Variable Mean Std. Dev Min Max
Forest area 346,000 773,000 515 5,300,000
Fossil fuel consumption 61.426 28.012 0.293 100
Access to water 80.552 18.872 9.13 100
Access to sanitation 62.21 28.758 1.781 100
For the construction of the environmental inclusion index, this study uses PCA. Mooi et al. (2018) state PCA gives consistent information subject to significant correlations. After the normalization of indicators, PCA is employed, and the Eigenvalues and factor loadings are reported in Tables 7 and 8 in Appendix respectively. The Eigenvalue of the first component is greater than 1; therefore, this study considers the first component only. The factor loadings of the first component are used as weights, and then the indicators are multiplied by their respective weights. The KMO statistic is 0.7323 which indicates that our data is well-suited for principal component analysis. Employing relative weight for each of the indicators and the following step is aggregation, and the linear-sum-of weighted normalized indicators are applied for aggregation.
Model of the study
Environment inclusiveness refers to the situation where a clean and green environment is available to everyone irrespective of whether they live in a rural or urban area and their income status. A clean environment can be perceived as public good since it meets the characteristic of public good, that is, nonrivalry and nonexcludable. To make a clean environment available for all, the government can play its role through fiscal instruments. The pattern of taxation and government expenditures can be designed to achieve the goals of a green environment. Green tax causes many industrialists to employ production techniques that cause less harm to the environment. López et al. (2011) explain that government spending oriented on public and social goods reduces pollution because it leads to human capital that affects environmental quality positively whereas Mohammed Saud et al. (2019) are of the view that government expenditure can affect the environment through three effects, that is, scale, composition and technical and the first effect results in environmental degradation while other two effects put a positive impact on the environment. The projects on water and sanitation may improve access to a clean environment for the deprived section of the economy, while green tax promotes energy-efficient technology and discourages deforestation.
Monetary policy also has the tendency to affect the level of environmental inclusion. Faria (1998) explains that monetary policy can affect the environment by minimizing transaction costs. Based on the Environmental-Kuznets-Curve hypothesis, both monetary and fiscal policy can indirectly affect environmental degradation by affecting the level of economic activities and the effect varies according to the income; that is, the effect of these policies on environmental degradation is positive in low-income countries and negative for rich countries. Xiaocang and Yaorong (2007) confirm that monetary policy through the expansion of bank credit causes an increase in physical capital and income while affecting the environment negatively whereas Munasinghe and Cruz (1995) explain that macroeconomic policies through the inflation channel affect the poor and cause them to rely on marginal land resulting in deforestation. The increased consumer prices also make access to gas and electricity difficult for the poor; thus, they use fuel wood and animal dug as an alternative. Combes et al. (2015), on the other hand, investigate how, in developing countries where deforestation and seigniorage are the government’s revenue options, tight monetary policy through a reduction in seigniorage can have a negative effect on environmental quality by increasing the rate of deforestation to compensate for missing revenues. Monetary policy, particularly interest rate policy, may have an impact on environmental inclusion through influencing investment in fundamental human rights such as education, health, access to safe drinking water, and sanitation.
Considering the theoretical link between macroeconomic policies and the environment, this study analyzes the composite impact of fiscal and monetary policy on the environment using panel data. One of the advantages of using panel data is that it allows us to have a larger number of observations and thus more degrees of freedom, which can lead to meaningful conclusions (Raj and Baltagi 2012). It also allows the researcher to cope with heterogeneities across time and cross-sections. Hsiao (2022) also discusses several benefits, including reducing the influence of excluded variables and exploring dynamic interactions. Thus, we have the following model:1 EIit=σ1+σ2Mit+σ3Fit+σ4Zit+σ5Mit·Fit+vi+λt+ui
In Eq. (1), EI is the index of environmental inclusion, M is the money supply, F is the fiscal policy instrument, that is, government expenditure, M·F is the interactive term, Z is the set of control variables, and vi and λt are the cross country and cross-time effects respectively. In this research, the variables are expressed in log form. The data on all variables are collected from the WDI (World Development Indicators) database. The effect of monetary policy on environmental inclusion given fiscal policy thus can be explained as follows:2 ∂EI∂M=α2+α5F
However, the conditional effect of fiscal policy on inclusive growth given the different levels of monetary policy is as follows:3 ∂EI∂F=α3+α5M
As we are using panel data of 51 countries (a list of countries is given in Appendix Table 9) for the period 1995–2019, to handle the issue of endogeneity, this study employs the FE-2SLS technique while POLS is applied for robustness check. To test the validity of instruments in FE-2SLS, Hansen’s J test is used with the null hypothesis of “instruments are valid”. The FE-2SLS model assumes no autocorrelation and heteroscedasticity; however, the existence of heteroscedasticity and autocorrelation can affect the results. To avoid the problem of missing observations for many economic series, we have collected data from 1995 to 2019. Data on institutional quality has been collected from ICRG; data on the human capital index is taken from FRED, while data on the rest of the variables of the model is gathered from WDI.
Results and discussion
Before moving to estimation, we have drawn a scatter plot of the environmental inclusion and government expenditure which is given in Fig. 1. The graph does not indicate a clear positive or negative relationship while it can be concluded that at low levels of government expenditures, environmental inclusiveness improves while at a higher level, environmental inclusion shows a decline. The nonlinear relation signifies that initially, an increase in government expenditures causes the provision of basic human needs, that is, water and sanitation but higher expenditures through increased economic activities increase the need for energy and pollute the air because developing countries cannot abruptly jump to advance techniques of energy efficiency and unwilling depends on fossil fuel energy consumptions. On the other hand, increased economic activities also reduce the forest area and hurt the green economy.Fig. 1 Environmental inclusion and government expenditures
The scatter plot of the relationship between environmental inclusion and money supply is given in Fig. 2. The graph shows a positive relationship between money supply and environment inclusiveness. An increase in the money supply by affecting the interest rate reduces the cost of production and encourages investors to use environment-friendly methods of production. The availability of credit for green financing also helps the economies to have a clean and inclusive environment.Fig. 2 Environmental inclusion and money supply
Initially, this study investigates the effect of fiscal and monetary instruments on inclusive environment separately in models 1 and 2 respectively, and then the interactive role of fiscal and monetary policy is considered in model 3. Model 1 examines the impact of government expenditures on environmental inclusion. Since the scatter plot exhibits a nonlinear relationship between environmental inclusion and government expenditures, we have included the square of government spending in the model (Table 2).Table 2 Impact of macroeconomic policies on environmental inclusion
Model 1 Model 2 Model 3
POLS FE-2SLS POLS FE-2SLS POLS FE-2SLS
M 0.248***
(0.000)
0.231***
(0.000)
− 0.316
(0.355)
0.412
(0.390)
G 2.032***
(0.000)
2.500***
(0.000)
0.472
(0.642)
0.780*
(0.071)
G2 − 0.404***
(0.000)
− 0.510***
(0.000)
− 0.111
(0.624)
− 0.56*
(0.058)
G*M 0.447
(0.111)
− 0.111*
(0.098)
G2*M − 0.086
(0.156)
0.020*
(0.081)
HCI 1.147***
(0.000)
1.091***
(0.000)
1.137***
(0.000)
0.968***
(0.000)
0.998***
(0.000)
1.038***
(0.000)
IQ 0.255***
(0.000)
0.255***
(0.000)
0.190***
(0.000)
0.340***
(0.000)
0.164***
(0.000)
0.102
(0.498)
Trade − 0.197***
(0.000)
− 0.200***
(0.000)
− 0.184***
(0.000)
− 0.13***
(0.000)
− 0.189***
(0.000)
− 0.200***
(0.000)
Constant − 4.789***
(0.000)
− 5.182***
(0.000)
− 2.465***
(0.000)
− 2.200***
(0.000)
− 2.065*
(0.080)
− 4.522***
(0.000)
No. of obs 1147 936 1147 921 1147 876
No. of instruments 10 11 14
R-square 0.60 0.593 0.61 0.68 0.667 0.656
F-Stat 52.733***
(0.000)
176.100***
(0.000)
167.763***
(0.000)
192.360***
(0.000)
233.323***
(0.000)
187.894***
(0.000)
Hansen’s J test 0.008
(0.927)
2.513
(0.113)
0.315
(0.574)
Environmental inclusion index is a dependent variable; G specifies the government spending; G2 indicates the square of government spending; HCI show the human capital index; IQ demonstrates the institutional Quality, and Trade is trade openness. Hansen’s J test uncovers that the instruments are effective. Parentheses uncover the p values
*, **, and *** indicate the significance level at 10%, 5%, and 1% respectively
Human capital and institutional quality, which served as controls in the POLS and 2SLS model, were shown to have a favourable effect on environmental inclusion, whereas trade had a negative effect. These findings are consistent with previous research. According to Southgate and Basterrechea (1992), human capital building and scientific base in rural regions contribute to environmentally sound economic growth, whereas regarding institutional quality, studies by Bhattarai and Hamming (2002) and Sulaiman et al. (2017) suggest that a better quality of institution improves environmental quality by reducing the rate of deforestation. Many studies, notably Hettige et al. (1992), imply that trade openness drives emerging economies to specialise in goods that demand more labour and natural resources, causing environmental harm.
Since model 1 involves the linear and square terms of government expenditure, we take the derivative of the Eq. 4 w.r.t government expenditure to analyze the ultimate influence of government expenditures on the environment inclusion and the derivatives are as follows:4 EIit=α0+α1Git+α2Git2+α3′Zit+vi+uit
5 ∂EI∂G=α1+2.α2Git
The derivative implies that the impact of G on EI is nonlinear, and it is conditional on the different levels of G; therefore, this study uses the 25th, 50th, and 75th percentiles of government spending. Table 3 shows the impact of government expenditure on the environmental inclusion. The result of POLS indicates that low levels of government expenditures affect the environment positively and significantly, but at a high level, the effect of government expenditure on the environment becomes insignificant while the FE-2SLS model shows a significant positive role of government expenditures on environmental inclusiveness that turned out to be insignificant at the median level of expenditures while at a higher level, government expenditures contribute to environmental inclusion negatively. This finding is consistent with the findings of Lopez et al. (2011), who found that there are two types of government spending: government spending on public goods and government spending on private goods, the latter of which includes subsidies for fossil fuel production and energy consumption, and thus a higher proportion of private spending in total government spending contributes to the deterioration of environmental quality while an equal proportion of public spending does not seem to.Table 3 Impact of government expenditures on environmental inclusion
Govt. Expenditure POLS FE-2SLS
P25 = 2.337 0.067***
(0.000)
0.192***
(0.000)
P50 = 2.540 0.046***
(0.011)
− 0.014
(0.674)
P75 = 2.760 0.022
(0.361)
− 0.237***
(0.000)
*, **, and *** indicate the significance level at 10%, 5%, and 1% respectively. P25, P50, and p75 are the 25th, 50th, and 75th percentiles
To evaluate the role of the money supply in advancing environmental inclusiveness, model 2 examines the impact of the money supply on environmental inclusion and the results are reported in Table 2. Results indicate that trade is affecting the environment negatively in the case of the 2SLS model while the POLS model shows that trade affects environmental inclusion negatively. The models of POLS and 2SLS show a positive and significant impact of money supply on environmental inclusiveness, and this result is in accordance with the study of Moran and Queralto (2018) that emphasizes that monetary policy by lowering the cost helps firms to make innovations and also motivates the organizations to initiate the welfare projects and for marginalized groups and help them purchase energy-efficient technologies whereas energy efficiency results in an eco-friendly environment (Riti and Shu 2016), while Chishti et al. 2021 have found that expansionary monetary policy affects the environment negatively.
To assess the interactive role of fiscal and monetary policy on environmental inclusion, we have included the interactive term and the results of model 3 are also reported in Table 2. Results indicate that human capital exerts a positive impact in promoting environment inclusiveness whereas, except the 2SLS model, the coefficient of institutional quality is positive and significant in all models. The results of the POLS and 2SLS model show that trade openness affect the environmental inclusion of economic growth negatively. To analyze the impact of money supply given different levels of government expenditures and the impact of government expenditures at different levels of money supply, the derivatives of the model for money supply and government expenditures are given as follows:6 EIit=β0+β1Mit+β2Git+β3Git2+β4M∗Git+β5M∗Git2+β6′Zit+vi+uit
7 ∂EI∂M=β1+β4Git+β5.G2
8 ∂EI∂G=β2+β3.2.Git+β4.Mit+β52.M∗Git
The derivative of Eq. 6 w.r.t M shows that the impact of money supply on environmental inclusion is conditional on the levels of G, while the derivative for G indicates that the effect of government expenditures on the environmental inclusion depends on the levels of government spending and money supply. To examine the ultimate effect of the money supply given government spending, the 25th, 50th, and 75th percentiles of government expenditures have been considered and the results are given in Table 4. The results of POLS and 2SLS models show a positive and significant effect of money supply on environment inclusiveness at all levels of government expenditures; however, higher levels of government expenditures reduce the effectiveness of money supply because now the role of the money supply is to correct the distortionary effects of fiscal policy measures and finance the expenditures. This finding is consistent with López et al. (2011) research, which contends that a high amount of government spending causes the scale effect and the income effect, both of which have a detrimental impact on the environment.Table 4 Impact of money supply given government expenditures
Govt. expenditure POLS FE-2SLS
P25 = 2.337 0.280***
(0.000)
0.279***
(0.000)
P50 = 2.540 0.263***
(0.000)
0.278***
(0.000)
P75 = 2.760 0.261***
(0.000)
0.279***
(0.000)
*, **, and *** indicate the significance level at 10%, 5%, and 1% respectively
To evaluate the impact of government expenditures given money supply on environmental inclusion, the 25th, 50th, and 75th percentile levels of the money supply are used for analysis and the results are given in Table 5.Table 5 Impact of government expenditures given money supply
Money Supply POLS FE-2SLS
G = P25 = 2.337
P25 = 3.438 0.112***
(0.005)
0.154***
(0.000)
P50 = 3.798 0.128***
(0.001)
0.152***
(0.000)
P75 = 4.118 0.142***
(0.001)
0.149***
(0.000)
G = P50 = 2.540
P25 = 3.438 − 0.052
(0.154)
− 0.042
(0.304)
P50 = 3.798 − 0.049
(0.103)
− 0.041
(0.179)
P75 = 4.118 − 0.045
(0.145)
− 0.041
(0.192)
G = P75 = 2.760
P25 = 3.438 − 0.23***
(0.000)
− 0.254***
(0.000)
P50 = 3.798 − 0.24***
(0.000)
− 0.251***
(0.000)
P75 = 4.118 − 0.25***
(0.000)
− 0.248***
(0.000)
*, **, and *** indicate the significance level at 10%, 5%, and 1% respectively
Results show that a low level of government expenditures at all levels of money supply affects environmental inclusion positively whereas the impact of median-level expenditure on the environment is insignificant on the other hand high government expenditure is observed to affect environmental inclusion negatively at all levels of the money supply. This result is in contrast with the study of Ercolano and Romano (2018) who observed that government spending affects the environment positively in EU countries while the finding of this study is in accordance with the view of Bernauer and Koubi (2006) that highlight that an increase in the size of government expenditure affects the environment negatively. The increasing proportion of government expenditures on subsidies given for fossil fuel production and energy consumption increases carbon emission and leaves the government of developing countries with fewer funds to spend on basic facilities like access to safe drinking water and basic sanitation facilities which eventually affects the environment inclusion negatively.
Conclusion and policy recommendations
An inclusive environment means a clean, healthy, and green environment irrespective of whether they belong to an urban or rural area. This study inspects the role of macroeconomic policies in ensuring an inclusive clean environment in the developing countries and considers the composite impact of fiscal policy and monetary policy on environmental inclusion by including interactive terms. The study uses FE-2SLS on a panel of 51 developing countries to analyze the impact of macroeconomic policies on environmental inclusion. The findings show that the macroeconomic policy actions depend on each other. Based on the findings, we conclude that low levels of government spending positively influence environmental inclusion whereas high levels of government spending adversely affect environmental inclusion since it is the content of government spending that counts rather than the magnitude of spending. Spending more on private goods, such as subsidies for fossil fuel consumption and energy consumption, has a negative impact on the environment; however, education expenditures help people understand the importance of environmental quality, while welfare projects improve access to water and sanitation for the marginalized group.
An increase in the money supply also helps to improve the inclusive environment because through interest rates and credit channels it encourages firms to make innovations and invest in R&D so that energy-efficient and environment-friendly production techniques could be adopted. The money supply is observed to affect environmental inclusion positively given low levels of government expenditures because, at high levels of government expenditure, the scale effect emerges and reduces the positive effect of the money supply.Since results show that monetary policy affects environmental inclusion significantly, for an inclusive clean and green environment, this study suggests that microfinance schemes should be promoted in developing countries because the extension of credit to low to moderate-income groups to help them to start environment-friendly small-scale projects will help to ensure an inclusive clean environment in the region. Also, the monetary authorities should provide funds at lower interest rates for low-carbon projects.
Since high levels of expenditures are found to affect environmental inclusion negatively, therefore, instead of increasing overall expenditure, the government in developing countries should spend more on environment-friendly sectors including education, health, water, sanitation, and green transportation and infrastructure.
Regarding coordination of fiscal and monetary policy, expansionary monetary policy given to low- to median-level government spending is found to be an effective strategy for environmental inclusion; therefore, governments in developing regions are required to cut nondeveloping expenditure and use expansionary monetary policy to promote green growth.
Future research may focus on investigating the effect of disaggregated government consumption on environmental inclusion. Furthermore, instruments of monetary policy can be used to clearly understand the channel of monetary policy through which it affects the environmental inclusion.
Appendix
Table 6 Pair-wise correlation coefficients
Forest area Fossil-fuel consumption Access to water Access to sanitation
Forest area 1.0000
Fossil-fuel consumption − 0.0750*
(0.0610)
1.0000
Access to water − 0.1701*** (0.0000) 0.7579*** (0.0000) 1.0000
Access to sanitation − 0.2052***
(0.0000)
0.7020*** (0.0000) 0.8149*** (0.0000) 1.0000
*, **, and *** show 10, 5, and 1 percent levels of significance respectively
Table 7 Eigen values of the components
Component Eigenvalue Difference Proportion Cumulative
Comp1 2.520 1.520 0.630 0.630
Comp2 1.000 0.696 0.250 0.880
Comp3 0.304 0.128 0.076 0.956
Comp4 0.176 0.044 1.000
Table 8 Factor loadings of each component
Variable Comp1 Comp2 Comp3 Comp4
Forest area − 0.044 0.997 0.060 0.022
Fossil fuel consumption 0.563 − 0.028 0.795 0.226
Access to water 0.590 0.055 − 0.194 − 0.782
Access to sanitation
KMO: 0.7323
0.577 0.047 − 0.572 0.581
Table 9 List of countries
1 Algeria 14 Cote d'Ivoire 27 Israel 40 Peru
2 Angola 15 Dominican Republic 28 Jamaica 41 Philippines
3 Bangladesh 16 Ecuador 29 Korea Rep 42 Senegal
4 Bolivia 17 Egypt Arab Rep 30 Malaysia 43 South Africa
5 Botswana 18 El Salvador 31 Mexico 44 Sri Lanka
6 Brazil 19 Ethiopia 32 Mongolia 45 Thailand
7 Cameroon 20 Ghana 33 Morocco 46 Togo
8 Chile 21 Guatemala 34 Mozambique 47 Tunisia
9 China 22 Haiti 35 Namibia 48 Turkey
10 Colombia 23 Honduras 36 Nicaragua 49 Uruguay
11 Congo Dem. Rep 24 India 37 Pakistan 50 Venezuela RB
12 Congo Rep 25 Indonesia 38 Panama 51 Zambia
13 Costa Rica 26 Iran Islamic Rep 39 Paraguay
Author contribution
Zakia Batool is responsible for the conceptualization, investigation, methodology, formal analysis, visualization, and writing the original draft. Arshad Ali Bhatti and Abdul Rehman are assigned to the supervision, investigation, visualization, review, and editing and made suggestions for the manuscript.
Data Availability
Data available on request from the authors.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
1 WHO/UNICEF JPM report “Progress on household drinking water, sanitation and hygiene 2000–2020”.
2 https://inclusioncornwall.co.uk/about-us/what-is-inclusion/environmental-inclusion-2/
3 Pakistan Council of Research in Water Resources (2017).
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Adebayo TS Rjoub H A new perspective into the impact of renewable and nonrenewable energy consumption on environmental degradation in Argentina: a time–frequency analysis Environ Sci Pollut Res 2022 29 11 16028 16044 10.1007/s11356-021-16897-6
Ahmad M Akram W Ikram M Shah AA Rehman A Chandio AA Jabeen G Estimating dynamic interactive linkages among urban agglomeration, economic performance, carbon emissions, and health expenditures across developmental disparities Sustain Prod Consum 2021 26 239 255 10.1016/j.spc.2020.10.006
Ahmad M, Li H, Anser MK, Rehman A, Fareed Z, Yan Q, Jabeen G (2021b) Are the intensity of energy use, land agglomeration, CO2 emissions, and economic progress dynamically interlinked across development levels? Energy & Environment 32(4):690–721
Ahmed Z Ahmad M Alvarado R Sinha A Shah MI Abbas S Towards environmental sustainability: Do financial risk and external conflicts matter? J Clean Prod 2022 371 133721 10.1016/j.jclepro.2022.133721
Ahmed Z Ahmad M Murshed M Shah MI Mahmood H Abbas S How do green energy technology investments, technological innovation, and trade globalization enhance green energy supply and stimulate environmental sustainability in the G7 countries? Gondwana Res 2022 112 105 115 10.1016/j.gr.2022.09.014
Alola AA The trilemma of trade, monetary and immigration policies in the United States: accounting for environmental sustainability Sci Total Environ 2019 658 260 267 10.1016/j.scitotenv.2018.12.212 30577021
Åström S Kiesewetter G Schöpp W Sander R Andersson S Investment perspectives on costs for air pollution control affect the optimal use of emission control measures Clean Technol Environ Policy 2019 21 3 695 705 10.1007/s10098-018-1658-4
Batool Z Raza SMF Ali S Abidin SZU ICT, renewable energy, financial development, and CO2 emissions in developing countries of East and South Asia Environ Sci Pollut Res 2022 29 23 35025 35035 10.1007/s11356-022-18664-7
Bernauer T, Koubi V (2006). States as providers of public goods: how does government size affect environmental quality?. Available at SSRN 900487
Bhattarai M, Hamming M (2002) Governance, economic policy, and the Environmental Kuznets Curve for natural tropical forests. In The Second World Congress of Environmental and Resource Economist, Monterrey Bay
Callahan, R. F., & Pisano, M. (2014). Aligning fiscal and environmental sustainability. In Elgar Companion to Sustainable Cities (pp. 154–165). Edward Elgar Publishing. 10.4337/9780857939999.00013
Can M Ahmed Z Towards sustainable development in the European Union countries: does economic complexity affect renewable and non-renewable energy consumption? Sustain Dev 2022 10.1002/sd.2402
Chan YT Are macroeconomic policies better in curbing air pollution than environmental policies? A DSGE approach with carbon-dependent fiscal and monetary policies Energy Policy 2020 141 111454 10.1016/j.enpol.2020.111454
Chishti MZ Ahmad M Rehman A Khan MK Mitigations pathways towards sustainable development: assessing the influence of fiscal and monetary policies on carbon emissions in BRICS economies J Clean Prod 2021 292 126035 10.1016/j.jclepro.2021.126035
Combes JL Motel PC Minea A Villieu P Deforestation and seigniorage in developing countries: a tradeoff? Ecol Econ 2015 116 220 230 10.1016/j.ecolecon.2015.03.029
Costantini V Martini C The causality between energy consumption and economic growth: a multi-sectoral analysis using non-stationary cointegrated panel data Energy Economics 2010 32 3 591 603 10.1016/j.eneco.2009.09.013
Debrah C Chan APC Darko A Green finance gap in green buildings: a scoping review and future research needs Build Environ 2022 207 108443 10.1016/j.buildenv.2021.108443
Desalegn G Fekete-Farkas M Tangl A The effect of monetary policy and private investment on green finance: evidence from Hungary J Risk Financial Manag 2022 15 3 117 10.3390/jrfm15030117
Dikau S Volz U Central bank mandates, sustainability objectives and the promotion of green finance Ecol Econ 2021 184 107022 10.1016/j.ecolecon.2021.107022
Ercolano S Romano O Spending for the environment: general government expenditure trends in Europe Soc Indic Res 2018 138 3 1145 1169 10.1007/s11205-017-1695-0
Faria JR Environment, growth and fiscal and monetary policies Econ Model 1998 15 1 113 123 10.1016/S0264-9993(97)00016-3
Freire-González J Ho MS Carbon taxes and the double dividend hypothesis in a recursive-dynamic CGE model for Spain Econ Syst Res 2019 31 2 267 284 10.1080/09535314.2019.1568969
Grossman, G., & Krueger, A. (1991). Environmental impacts of a North American free trade agreement (No. 3914). National Bureau of Economic Research, Inc. 10.3386/w3914
Halkos GE Paizanos EΑ The effect of government expenditure on the environment: an empirical investigation Ecol Econ 2013 91 48 56 10.1016/j.ecolecon.2013.04.002
Halkos GE Paizanos EΑ The effects of fiscal policy on CO2 emissions: evidence from the USA Energy Policy 2016 88 317 328 10.1016/j.enpol.2015.10.035
Harris JM (2013) Green Keynesianism: Beyond standard growth paradigms (No. 1434–2016–118840)
Hettige H, Lucas RE, Wheeler D (1992) The toxic intensity of industrial production: global patterns, trends, and trade policy. Am Econ Rev, 478–481
Hsiao C Analysis of panel data 2022 Cambridge University Press
Hua Y Xie R Su Y Fiscal spending and air pollution in Chinese cities: identifying composition and technique effects China Econ Rev 2018 47 156 169 10.1016/j.chieco.2017.09.007
Isiksal AZ Samour A Resatoglu NG Testing the impact of real interest rate, income, and energy consumption on Turkey’s CO2 emissions Environ Sci Pollut Res 2019 26 20 20219 20231 10.1007/s11356-019-04987-5
Jiang Y Batool Z Raza SMF Haseeb M Ali S ZainUlAbidin S Analyzing the asymmetric effect of renewable energy consumption on environment in STIRPAT-Kaya-EKC framework: a NARDL approach for China Int J Environ Res Public Health 2022 19 12 7100 10.3390/ijerph19127100 35742348
Jones RS, Yoo B (2011). Korea's Green Growth Strategy: Mitigating Climate Change and Developing New Growth Engines (No. 798). OECD Publishing
Kamal M Usman M Jahanger A Balsalobre-Lorente D Revisiting the role of fiscal policy, financial development, and foreign direct investment in reducing environmental pollution during globalization mode: evidence from linear and nonlinear panel data approaches Energies 2021 14 21 6968 10.3390/en14216968
Liu X Zhang S Bae J The impact of renewable energy and agriculture on carbon dioxide emissions: investigating the environmental Kuznets curve in four selected ASEAN countries J Clean Prod 2017 164 1239 1247 10.1016/j.jclepro.2017.07.086
Lopez, R. E., & Palacios, A. (2010). Have government spending and energy tax policies contributed to make Europe environmentally cleaner? (No. 1667–2016–136345)
López R Galinato GI Islam A Fiscal spending and the environment: theory and empirics J Environ Econ Manag 2011 62 2 180 198 10.1016/j.jeem.2011.03.001
Mohammed Saud MA Guo P Haq IU Pan G Khan A Do government expenditure and financial development impede environmental degradation in Venezuela? PloS one 2019 14 1 e0210255 10.1371/journal.pone.0210255 30629649
Moshiri S, Daneshmand A (2020). How effective is government spending on environmental protection in a developing country? An empirical evidence from Iran. J Econ Stud. 10.1108/JES-12-2018-0458
Mahmood H Adow AH Abbas M Iqbal A Murshed M Furqan M The fiscal and monetary policies and environment in GCC countries: analysis of territory and consumption-based CO2 emissions Sustainability 2022 14 3 1225 10.3390/su14031225
Mughal N Kashif M Arif A Guerrero JWG Nabua WC Niedbała G Dynamic effects of fiscal and monetary policy instruments on environmental pollution in ASEAN Environ Sci Pollut Res 2021 28 46 65116 65126 10.1007/s11356-021-15114-8
Muhafidin D The role of fiscal policy and monetary policy in environmental degradation in Indonesia Int J Energy Econ Policy 2020 10 3 504 10.32479/ijeep.9586
Munasinghe M Cruz W Economywide policies and the environment 1995 Washington DC World Bank
Mooi E, Sarstedt M, Mooi-Reci I (2018). Principal component and factor analysis. In Market research (pp. 265–311). Springer, Singapore
Moran P Queralto A Innovation, productivity, and monetary policy J Monet Econ 2018 93 24 41 10.1016/j.jmoneco.2017.10.006
Ojha VP Pohit S Ghosh J Recycling carbon tax for inclusive green growth: a CGE analysis of India Energy Policy 2020 144 111708 10.1016/j.enpol.2020.111708
Pradeep S Role of monetary policy on CO2 emissions in India SN Bus Econ 2022 2 1 1 33 10.1007/s43546-021-00175-1
Qingquan J Khattak SI Ahmad M Ping L A new approach to environmental sustainability: assessing the impact of monetary policy on CO2 emissions in Asian economies Sustain Dev 2020 28 5 1331 1346 10.1002/sd.2087
Raj B, Baltagi BH (Eds.) (2012) Panel data analysis. Springer Science & Business Media
Rehman A, Alam MM, Ozturk I, Alvarado R, Murshed M, Işık C, Ma H (2022a). Globalization and renewable energy use: how are they contributing to upsurge the CO2 emissions? A global perspective. Environ Sci Pollut Res, 1-14. 10.1007/s11356-022-22775-6
Rehman A Alam MM Alvarado R Işık C Ahmad F Cismas LM Pupazan MCM Carbonization and agricultural productivity in Bhutan: Investigating the impact of crops production, fertilizer usage, and employment on CO2 emissions J Clean Prod 2022 375 134178 10.1016/j.jclepro.2022.134178
Rehman A Ma H Khan MK Khan SU Murshed M Ahmad F Mahmood H The asymmetric effects of crops productivity, agricultural land utilization, and fertilizer consumption on carbon emissions: revisiting the carbonization-agricultural activity nexus in Nepal Environ Sci Pollut Res 2022 29 26 39827 39837 10.1007/s11356-022-18994-6
Rehman A Radulescu M Cismas LM Alvarado R Secara CG Tolea C Urbanization, economic development, and environmental degradation: investigating the role of renewable energy use Sustainability 2022 14 15 9337 10.3390/su14159337
Riti JS Shu Y Renewable energy, energy efficiency, and eco-friendly environment (R-E5) in Nigeria Energy, Sustain Soc 2016 6 1 1 16
Sanogo T Does fiscal decentralization enhance citizens’ access to public services and reduce poverty? Evidence from Côte d’Ivoire municipalities in a conflict setting World Dev 2019 113 204 221 10.1016/j.worlddev.2018.09.008
Schrecongost A Pedi D Rosenboom JW Shrestha R Ban R Citywide inclusive sanitation: a public service approach for reaching the urban sanitation SDGs Front Environ Sci 2020 8 19 10.3389/fenvs.2020.00019
Shafik N (1994) Economic development and environmental quality: an econometric analysis. Oxford economic papers, 757–773
Southgate D, Basterrechea M (1992). Population growth, public policy and resource degradation: the case of Guatemala. Ambio, 460–464
Stern DI Common MS Barbier EB Economic growth and environmental degradation: the environmental Kuznets curve and sustainable development World Dev 1996 24 7 1151 1160 10.1016/0305-750X(96)00032-0
Sulaiman C Abdul-Rahim AS Mohd-Shahwahid HO Chin L Wood fuel consumption, institutional quality, and forest degradation in sub-Saharan Africa: evidence from a dynamic panel framework Ecol Ind 2017 74 414 419 10.1016/j.ecolind.2016.11.045
United Nations (UN) (2018). Sustainable development goals (SDGs). http://un.org. Accessed 12 Aug 2022
Wan G Zhuang J Making growth more inclusive 2015 In Managing the middle-income transition Edward Elgar Publishing
World Bank. (1992). World development report 1992: development and the environment. The World Bank
World Health Organization WHO guidelines for indoor air quality: selected pollutants 2010 Regional Office for Europe World Health Organization
World Health Organization. (2014). Global status report on noncommunicable diseases 2014 (No. WHO/NMH/NVI/15.1). World Health Organization
Xiaocang X, Yaorong Z (2007) Analysis on the relationship between environmental quality, economic growth and monetary policy in China. Social Sciences in Xinjiang
Yilanci V, Pata UK (2021). On the interaction between fiscal policy and CO2 emissions in G7 countries: 1875–2016. J Environ Econ Policy, 1-22. 10.1080/21606544.2021.1950575
Zeraibi A Ahmed Z Shehzad K Murshed M Nathaniel SP Mahmood H Revisiting the EKC hypothesis by assessing the complementarities between fiscal, monetary, and environmental development policies in China Environ Sci Pollut Res 2022 29 16 23545 23560 10.1007/s11356-021-17288-7
Zhang D, Ozturk I, Ullah S (2022). Institutional factors-environmental quality nexus in BRICS: a strategic pillar of governmental performance. Economic Research-EkonomskaIstraživanja, 1-13. 10.1080/1331677X.2022.2037446
Zhao S Hafeez M Faisal CMN Does ICT diffusion lead to energy efficiency and environmental sustainability in emerging Asian economies? Environ Sci Pollut Res 2022 29 8 12198 12207 10.1007/s11356-021-16560-0
| 36474034 | PMC9734668 | NO-CC CODE | 2022-12-14 23:28:30 | no | Environ Sci Pollut Res Int. 2022 Dec 7;:1-12 | utf-8 | Environ Sci Pollut Res Int | 2,022 | 10.1007/s11356-022-24596-z | oa_other |
==== Front
Curr Psychol
Curr Psychol
Current Psychology (New Brunswick, N.j.)
1046-1310
1936-4733
Springer US New York
4059
10.1007/s12144-022-04059-x
Article
Pains and gains of feedback source: the dual effects of subordinates’ feedback-seeking events on leaders’ work engagement
Zhang Wei [email protected]
1
Wang Bin [email protected]
2
Qian Jing [email protected]
3
Liu Yixin [email protected]
2
1 grid.20513.35 0000 0004 1789 9964 School of Government, Beijing Normal University, 100875 Beijing, China
2 grid.39436.3b 0000 0001 2323 5732 School of Management, Shanghai University, 200444 Shanghai, China
3 grid.20513.35 0000 0004 1789 9964 Business School, Beijing Normal University, 100875 Beijing, China
3 12 2022
111
19 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Despite the well documented research on workplace feedback-seeking behavior from the seeker’s perspective, limited attention has been devoted to the feedback source—the individual providing the feedback. Drawing from the affective events theory (AET), we developed a theoretical model and examined the potential impacts on leaders (i.e., the feedback source) when asked for feedback by subordinates. We conducted a 5-day experience sampling study with 106 leaders. Research findings revealed that subordinates’ feedback-seeking events (SFSE) was positively related to leaders’ positive and negative affect; SFSE had a positive indirect effect on leaders’ daily work engagement through increased positive affect, and a negative indirect effect through increased negative affect. In addition, the relationship between SFSE and affective reactions was moderated by emotion suppression, such that leaders with higher levels of emotion suppression experienced less positive affect elicited by SFSE. This study helps to enrich the workplace feedback-seeking literature by examining how and when responding to feedback seeking influences feedback sources’ emotional and work experiences.
Keywords
Feedback-seeking events
Feedback source
Work engagement
Emotion suppression
Affective events theory
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 71672012 72102140 Wang Bin Qian Jing
==== Body
pmcIntroduction
Feedback-seeking behavior refers to “(the) conscious devotion of effort toward determining the correctness and adequacy of behaviors for attaining valued end states” (Ashford, 1986, p 466). Previous studies have shown that feedback-seeking behavior is beneficial for feedback seekers (see a meta-analysis, Anseel et al., 2015), such as enhancing their performance (Lan et al., 2020), building positive images in the workplace (Chun et al., 2018), promoting individual learning and growth (Anseel, 2017), improving creativity (Sung & Choi, 2021), and reinforcing their identification as well as the fit with their jobs and organizations (Bauer et al., 2019; Young & Steelman, 2014).
However, few studies have focused on the potential influence of being asked for feedback on the feedback source (Ashford et al., 2016, for exceptions see Krasman, 2018; Krasman & Kotlyar, 2019). This lack of attention to feedback sources is surprising given that feedback episodes are dynamic and contain interpersonal interactions between the seekers and givers (i.e., the source) (Anseel et al., 2018). In this case, feedback-seeking behavior will have an impact on both sides (i.e., not only on the seekers but also the sources) involved in this dynamic process (Anseel et al., 2015; Ashford et al., 2016). For example, Minnikin et al. (2021) posited that responding to feedback seeking behavior from others consumed the time and energy of the feedback source. Considering the important role of feedback sources in determining the quality of feedback (Lechermeier & Fassnacht, 2018), an in-depth exploration on the reactions of sources to feedback-seeking behavior is needed.
Moreover, prior research has paid little attention to the instant reactions and subsequent work experience of the feedback source (Ashford et al., 2016), leaving it unclear whether being asked for feedback will enhance or destroy sources’ experience at work through their instant reactions. Indeed, one possible and important type of sources reactions is affective reactions, as affections largely derived from work events and determined an individual’s work state (Bledow et al., 2011; Weiss & Cropanzano, 1996). On the one hand, sources may enjoy the process of being asked for feedback, as they can gather valuable information in line with their own work goals from the interactive feedback process (Moss & Martinko, 1998). These positive reactions may then raise sources’ feelings and keep them in a good state at work. On the other hand, being asked and responding to feedback need sources to allocate resources such as time and energy (Minnikin et al., 2021), which may hinder their own goal progress (Koopman et al., 2016). This resource-consuming and interrupting process may disturb feedback sources and their following work experiences (Koopman et al., 2016). In this way, feedback seeking behavior may have a complex and mixed blessing (i.e., both positive and negative) on feedback sources’ work experiences. As such, we aim to apply a balanced perspective to explore the immediate affective reactions of sources after encountering feedback seeking behavior, as well as their subsequent work experiences.
To do so, we applied AET to examine the affective reactions of the feedback source after encountering feedback seeking events (Weiss & Cropanzano, 1996). We especially focused on leaders’ reactions to the feedback seeking behavior from subordinates, as leaders usually act as feedback sources while subordinates are usually seekers in the feedback seeking process (Ashford, 1993). Therefore, we conceptualized subordinates’ feedback seeking behavior as a type of work event (i.e., SFSE) that leaders encountered in their daily work, which then influence their affective reactions. Specifically, when leaders could obtain useful information from SFSE, such as subordinates’ work progress and problems, they may experience stronger positive affect (i.e., higher level positive affect and less negative affect). In contrast, when leaders experienced interruption and resource consumption that obstructed their own goals after encountering SFSE, they may experience stronger negative affect. The positive and negative affects leaders experienced through SFSE will further increase or decrease their daily work state, such as work engagement (i.e., a positive and motivational state that is characterized by vigor, dedication, and absorption, Schaufeli et al., 2002), respectively. The reason why we consider work engagement is that it is not only good for leaders’ mental health but also an important predictor for leader effectiveness (Lanaj et al., 2019; Qin et al., 2018).
Considering the central role of affect in AET, we further expect the moderating role of one emotion regulation strategy (i.e., emotion suppression) in the relationship between SFSE and affective reactions (Matta et al., 2014). Emotion suppression is a stable individual difference that refers to the tendencies of individuals to inhibit his/her true emotion expression (Diefendorff & Richard, 2003). Individuals with higher emotion suppression tendencies, are not only unable to remove negative emotions, but also put themselves into a poor-resource situation (Gross & John, 2003). In this vein, we posit that emotion suppression lightens the positive affect, while aggravates the negative affect elicited by SFSE.
To test our theoretical model of how and when SFSE influences leaders’ daily emotional and work experiences (see Fig. 1), we conducted a study applying experience sampling methodology. This research contributes to the current literature in several ways. First, by focusing on the sources’ perspective, we extend the literature on the outcomes of feedback seeking behavior. Second, by combining the positive and negative affective reactions into one theoretical model, we demonstrate the mixed roles of SFSE and provide a more comprehensive view to explain feedback seeking and responding process (i.e., the dynamic and interactive process). Finally, by including emotion suppression as the boundary condition, we further highlight the central roles of affects in AET, and offer a trajectory of leaders’ affective reactions and emotion regulation when dealing with daily work events.
Fig. 1 The theoretical model
Theory and hypotheses
Subordinates’ feedback seeking as an affective event
In the organizational context, AET contends that work events can elicit affective reactions (i.e., positive and negative affect) that influence subsequent work attitudes and behaviors (Weiss & Cropanzano, 1996). More specifically, positive work events lead to positive affect through facilitating goal attainment, and negative work events lead to negative affect through obstructing goals progress (Weiss & Cropanzano, 1996). Advancing the opposite valences about workplace events, recent studies demonstrated that certain events have mixed influences on affective reactions, especially when the events contained interactions between two or more parties (Liu et al., 2022). For example, research has indicated that workplace friendship and participating in organizational citizenship behavior (OCB) has both costs and benefits for employees (Koopman et al., 2016; Methot et al., 2016). Align with this, it is feasible for us to explore both the positive and negative affective reactions of feedback sources to SFSE, as this event involves interactions between leaders and subordinates and has the potentials in stimulating and hindering leaders’ daily goal progress.
Although AET was originally developed to infer the attitude and behavior consequences of affective reactions (Weiss & Cropanzano, 1996), a later review posited that affects aroused by work events also influence individual cognitive functions, such as flexibility, attentional focus, and motivational fit (Ashton-James & Ashkanasy, 2005). As work engagement refers to an affective and cognitive state (Schaufeli et al., 2002), and contains attitudinal, energetic and involvement components (Bledow et al., 2011), it can also be explained by AET. In summary, we aim to examine the dual effects of SFSE on leaders’ affective affections, and then their work engagement based on AET.
SFSE and leader’s emotional experiences
Positive affect refers to a pleasant emotional state in which individuals feel active, enthusiastic, and alert, whereas negative affect reflects the degree to which individuals experience tension, anxiety, and worry (Watson et al., 1988). Previous studies have shown that positive affect and negative affect are independent of each other (Bledow et al., 2011). In this vein, individuals could experience these two affects simultaneously. More specifically, individuals would perceive more positive affect and less negative affect when encountering events that align with their goals and would perceive more negative affect and less positive affect when encountering events that hindering their goals (Liu et al., 2022; Weiss & Cropanzano, 1996). As SFSE not only involves valuable information that advances the work goals of leaders and the entire team but also has the potential to disturb leaders’ work pace and leave behind their planned goals, it may determine leaders’ affective reactions.
First, we expect leaders to perceive positive affect based on the functions of SFSE on their own and team goals. In detail, one of the most important roles leaders need to play in their daily work is to direct and motivate their subordinates to achieve higher performance (Rosen et al., 2019). SFSE provides leaders with such opportunities to acknowledge the progress of their subordinates’ work and team work, as well as the chances to implement their guidance and influence as a leader (Heen & Stone, 2014). Besides, research has indicated that part of leaders’ job performance depends on their employees (Moss & Martinko, 1998). In this vein, SFSE works on facilitating the goal attainment of leaders and induces their positive affective reactions. Research has provided indirect support for this view, indicating that dealing with task-centered rather than task-independent emails from subordinates disturbs leaders less in their daily goal progress (Rosen et al., 2019).
Second, we assume a positive relation between SFSE and leaders’ negative affect, as SFSE may hinder leaders’ personal goals. Specifically, despite responding to subordinates’ needs, leaders also have other responsibilities (e.g., making personal decisions) to complete (Lanaj et al., 2019). While responding to and dealing with SFSE consume the limited time and attention of leaders, which would obstruct leaders’ goal progress and then evoke negative affect (Rosen et al., 2019). To support this view, Lanaj and Jennings (2020) found that being responsive to personal help requests from subordinates puts leaders in a bad mood on a daily basis. Accordingly, we propose the following hypotheses:
Hypothesis 1a: SFSE will be positively related to leaders’ positive affect.
Hypothesis 1b: SFSE will be positively related to leaders’ negative affect.
The mediating role of affective reactions
Work engagement is an active working state for leaders, which is characterized by vigor, dedication, and absorption (Schaufeli et al., 2002). According to AET and previous research, work engagement may also fluctuate with affective reactions (Bledow et al., 2011). While a systematic review of work engagement has concluded that job resources are “the most important predictors of work engagement (Bakker et al., 2014, p 393)”, and positive affects help broaden and build resources (Ouweneel et al., 2012), while negative affects narrow the resources allocation (Bledow et al., 2011), we expect a positive relationship between positive affect and work engagement and a negative relationship between negative affect and work engagement respectively. Indeed, previous studies have provided support for this proposition, with Ouweneel et al. (2012) found an increase in work engagement owing to positive affect and Bledow et al. (2011) found a decrease in work engagement owing to negative affect. Accordingly, we propose the following hypotheses:
Hypothesis 2a: Positive affect will be positively related to leaders’ daily work engagement.
Hypothesis 2b: Negative affect will be negatively related to leaders’ daily work engagement.
Altogether, combining Hypotheses 1a and 1b, which posited the positive relationship between SFSE and affective reactions (i.e., positive affect (Hypothesis 1a) and negative affect (Hypothesis 1b)), with Hypotheses 2a and 2b, which assumed the positive relationship between positive affect and work engagement (Hypothesis 2a), as well as the negative relationship between negative affect and work engagement (Hypothesis 2b), we argue that SFSE will influence leaders’ work engagement via increasing their positive or negative affect. Accordingly, we propose the following hypotheses:
Hypothesis 3a: SFSE will have a positive indirect effect on leaders’ daily work engagement via positive affect.
Hypothesis 3b: SFSE will have a negative indirect effect on leaders’ daily work engagement via negative affect.
Moderating effects of leaders’ emotion suppression
Emotion suppression reflects the extent to which individuals inhibit expressing his or her true feelings (Diefendorff & Richard, 2003). While emotion suppression is usually regarded as a stable individual difference, examining its moderating roles also aligns with the proposition of AET, which contends that there are individual differences in affective reactions to the same work events (Weiss & Cropanzano, 1996). Indeed, emotion suppression has been proven to be a resource-consuming emotion regulation strategy and is ineffective in alleviating negative affect (Gross, 2015; Gross & John, 2003). Therefore, we propose that emotion suppression may decrease the positive affect aroused by SFSE because of its consumption of resources, and may increase the negative affect aroused by SFSE owing to its nature in resource-consuming and its inability in lightening negative affect.
Specifically, leaders with high levels of emotion suppression tend to conceal their true feelings by inhibiting negative affect while displaying positive affect (Diefendorff & Richard, 2003). This emotion regulation process needs them to invest resources and leads to a poor cope capacity (Brotheridge & Grandey, 2002). Besides, while emotion suppression has little effect on releasing the negative affect (Gross & John, 2003), it accordingly fails to reduce the negative affect derived from SFSE. Therefore, the positive affect elicited by SFSE will be buffered, and the negative affect elicited by SFSE will be strengthened for this type leader.
In contrast, leaders with low levels of emotion suppression tend to express their feelings authentically (Diefendorff & Richard, 2003), and expressing emotion in this way does not cause additional drains on their own resources. Leaders of this type will react normally (i.e., perceive positive and negative affect at the original level) when experiencing SFSE. To support these propositions, Zhou et al. (2019) found that employees who comply with display rules (i.e., suppress negative emotions and express positive emotions) experience stronger negative affect from workplace incivility compared to employees who do not comply with the rules. Therefore, we propose the following hypotheses:
Hypothesis 4a: Emotion suppression will moderate the relationship between SFSE and positive affect, such that this relationship is weaker for leaders with higher levels of emotion suppression.
Hypothesis 4b: Emotion suppression will moderate the relationship between SFSE and negative affect, such that this relationship is stronger for leaders with higher levels of emotion suppression.
Method
Participants and procedures
We recruited part-time MBA students at a university in northern China as participants. We first introduced the background and purpose of our research project to MBA students and clarified the voluntary nature of this project. Participants had to meet the following criteria: (1) hold a leadership position1 and supervise at least one subordinate; (2) have a full-time job; (3) have no business trips within 5 working days of the daily investigation. To increase the response rate, we used a random lottery (with management books as prizes) to motivate participants to complete the surveys. In addition, participants can also obtain a research report at the end of the project.
We collected data in two phases, using the experience sampling methodology (ESM) via online surveys hosted by WeChat, a popular messaging app in China. In the first phase, we sent a baseline survey to participants, asking them to report their demographic information and emotion suppression. In the second phase, which was about a week after phase one, we collected data twice a day for 5 consecutive workdays. Specifically, we sent the first daily survey at 3 p.m. (Time 1), which was used to measure daily SFSE, positive affect and negative affect. We sent the second daily survey at 6 p.m. (Time 2), asking participants to report their daily work engagement. For each time, participants were given a one-hour window to respond to the survey.
Of the 119 participants that initially signed up for our research project, 13 of them quit the research project due to personal reasons. The remaining 106 individuals provided the final 5042 day-level data points with a response rate of 84.7% (out of a possible 595 total data points). The final sample consisted of 106 leaders who were employed in a variety of industries, including technology, finance, internet, education, consulting, and sales. Within that sample, 53.8% of the participants were males, the average age was 33.81 years (SD = 5.09), and the average tenure of leadership was 4.86 years (SD = 3.59). Most of them (57.5%) held bachelor’s degrees, and had ten subordinates on average (SD = 9.72).
Measures
The measures we used were originally constructed in English. We performed a standard translation and back-translation procedure to ensure cross-cultural consistency (Brislin, 1980). All the scales were rated on a 7-point Likert scale and, unless otherwise indicated, 1 to 7 represented “strongly disagree” to “strongly agree”.
Between-individual measurement
Emotion suppression
We measured emotion suppression in the baseline survey using a four-item scale developed by Diefendorff and Richard (2003). Sample items are “I control my emotions and make sure they are appropriate” and “I conceal negative emotions about tasks and others”. The α of this scale was 0.80.
Within-individual measurement
SFSE
To measure the intensity of SFSE experienced by leaders in their daily work, we adopted the feedback-seeking behavior scale developed by Ashford and Tsui (1991). The scale contained three items, and a sample item is “Today my subordinates asked me for feedback about his or her performance”. Participants rated each item on a 7-point Likert scale, with 1 to 7 representing “Never” to “More than five times”. The average α across five days was 0.93.
Positive affect and negative affect
We used Watson et al.’s (1988) twelve-item PANAS scale to measure leaders’ positive affect and negative affect. Sample items are “interested” and “enthusiastic” for positive affect, and “worried” and “irritable” for negative affect. The average α across five days was 0.92 for positive affect, and 0.93 for negative affect.
Work engagement
We measured work engagement using a three-item scale adopted by Rich et al. (2010). Sample items are “Today I exerted a lot of energy on the job” and “Today I was absorbed by the job”. The average α across five days was 0.95.
Control variables
Following previous research (e.g., Vogel et al., 2022), we controlled the study day (coded with 1 to 5) to remove common methods bias.
Analytic strategy
Due to the nested structure of our data (i.e., multiple days nested within leaders, and the within-individual variance proportion of our study variables ranged from 37.1 to 52.7%, indicating the feasibility in using multilevel analysis, see Table 1), we conducted a multilevel path analysis using Mplus 8.3 to test our hypotheses. Specifically, the between-individual cross-level moderator (i.e., leaders’ emotion suppression) was modeled at level 2, and the within-individual variables (i.e., SFSE, leaders’ positive and negative affect, and leaders’ work engagement) were modeled at level 1 using random slopes. In addition, following Enders and Tofighi (2007), we group-mean centered the within-individual variables and grand-mean centered the between-individual variables to distinguish the variances between different levels.
Table 1 Percentage of within-individual variance among the daily variables
Variables Within-individual variance(σ2) Between-individual variance(τ) Percentage of within-individual variance(%)
SFSE (T1) 1.17 1.05 52.7%
Leaders’ positive affect (T1) 0.47 0.64 42.2%
Leaders’ negative affect (T1) 0.63 0.79 44.6%
Leaders’ work engagement (T2) 0.47 0.79 37.1%
Nlevel−1=504, Nlevel−2=106. The percentage of within-individual variance was calculated as r=σ2/(σ2+τ); T1 represents the variable measured at time 1 survey, i.e., 3 p.m., T2 represents the variable measured at time 2 survey, i.e., 6 p.m
We conducted two independent statistical models to test the hypotheses. Model 1 (M1) was used to test the mediating effect of positive and negative affect. Following Preacher et al. (2010), we ran two parallel mediating path analyses (i.e., 1–1 (1) -1 mediating model) at within- and between-individual levels, and examined the indirect effect by calculating the product of the path coefficients (i.e., the coefficients from the independent variable to the mediating variable, and from the mediating variable to the outcome variable) using Model Constraint command at the within-individual level. Based on Model 1, Model 2 (M2) included emotion suppression to test the cross-level moderating effect. Specifically, we set the random slopes between SFSE and leaders’ positive affect and negative affect as dependent variables and ran a linear regression on emotion suppression to examine the moderating role of emotion suppression.
Results
We conducted a multilevel confirmatory factor analysis (CFA) to examine the discrimination of the studied variables. The results in Table 2 demonstrated that the five factors model (SFSE, leaders’ positive affect, leaders’ negative affect, leaders’ work engagement, and leaders’ emotion suppression) had a better fit (χ2 = 875.12, df = 406, CFI = 0.94, TLI = 0.93, RMSEA = 0.05, SRMRwithin = 0.05, SRMRbetween =0.08) than the other three competitive models, indicating that variables in this study had good discriminant validity.
Table 2 Results of confirmatory factor analysis for studied variables
Models χ2 df Δχ2/Δdf CFI TLI RMSEA SRMRwithin SRMRbetween
Five factors SFSE, PA, NA, WE, ES 857.12 406 -- 0.94 0.93 0.05 0.05 0.08
Four factors SFSE, PA + NA, WE, ES 1920.04 413 1062.92***/7 0.79 0.76 0.08 0.20 0.34
Three factors SFSE, PA + NA + WE, ES 3431.56 418 2574.44***/12 0.58 0.53 0.12 0.19 0.23
Two factors SFSE + PA + NA + WE, ES 4461.31 421 3604.19***/15 0.43 0.37 0.13 0.21 0.24
Nlevel−1=504, Nlevel−2=106. SFSE = subordinates’ feedback-seeking events, PA = leaders’ positive affect, NA = leaders’ negative affect, WE = leaders’ work engagement, and ES = leaders’ emotion suppression; “+” means to combine two or more factors into a single factor
Table 3 summarizes the means, standard deviations, internal consistency reliabilities, and correlations among the studied variables. The results indicated that SFSE was positively correlated with leaders’ positive affect (r = .10, p < .001) and negative affect (r = .12, p < .001); leaders’ positive affect (r = .11, p < .001) and negative affect (r = − .08, p < .001) were positively and negatively correlated with leaders’ work engagement respectively. These results provided initial support for Hypotheses 1a to 2b.
Table 3 Descriptive statistics and correlations among studied variables
Variables M SD 1 2 3 4 5 6 7
Level 1
1. SFSE (T1) 2.42 1.48 (0.93) 0.34*** 0.31*** 0.26*** 0.20*** − 0.03 0.16
2. Positive affect (T1) 4.74 1.04 0.10*** (0.92) − 0.16 0.80*** 0.38*** − 0.15 0.31**
3. Negative affect (T1) 2.82 1.18 0.12*** − 0.11*** (0.93) − 0.22*** − 0.20* 0.47*** − 0.36***
4. Work engagement (T2) 4.85 1.10 0.08** 0.11*** − 0.08*** (0.95) 0.36*** − 0.13 0.35***
5. study day 3.00 2.00 0.14* 0.03 − 0.06 − 0.05 -- -- --
Level 2
6. Emotion suppression 5.56 0.71 -- -- -- -- -- −− (0.80)
Nlevel−1=504, Nlevel−2=106. The part below the diagonal is the correlation coefficient among within-individual variables with group-mean centered, and the part above the diagonal is the correlation coefficient among between-individual variables. * p < .05, ** p < .01, ***p < .001
Tests of hypotheses
Within-individual hypotheses
M1 was used to test Hypothesis 1 to Hypothesis 3, which posited that SFSE had indirect effects on leaders’ work engagement via positive and negative affect. As shown in Table 4, SFSE was positively related to leaders’ positive affect (B = 0.11, SE = 0.03, p < .001), and was positively related to leaders’ negative affect (B = 0.14, SE = 0.04, p < .001) after controlling the demographic variables. Thus, Hypothesis 1a and Hypothesis 1b were supported. Additionally, leaders’ positive affect was positively related to work engagement (B = 0.22, SE = 0.05, p < .001), and leaders’ negative affect was negatively related to work engagement (B = − 0.13, SE = 0.04, p < .01), therefore Hypothesis 2a and Hypothesis 2b were supported.
Table 4 Multilevel path analysis results for mediation test (M1)
Predictors Positive affect Negative affect Work engagement
B SE B SE B SE
Independent variable
SFSE 0.11*** 0.03 0.14*** 0.04 0.08** 0.03
Mediators
Positive affect 0.22*** 0.05
Negative affect − 0.13** 0.04
Control variable
Study day 0.01 0.02 − 0.04 0.03
Within-individual residual variance 0.46*** 0.03 0.61*** 0.04 0.40*** 0.03
Between-individual residual variance 0.57*** 0.10 0.71*** 0.12 0.18*** 0.05
Nlevel−1=504, Nlevel−2=106. * p < .05, ** p < .01, ***p < .001
To confirm mediating roles of positive and negative affect, we calculated the product of the path coefficients using the Model Constraint command in Mplus. Results indicated that the indirect effect of the relationship between SFSE and leaders’ work engagement through positive affect was 0.024 (SE = 0.01, p < .01, 95% CI [0.006, 0.042]), the indirect effect of the relationship between SFSE and leaders’ work engagement through negative affect was − 0.018 (SE = 0.01, p < .05, 95% CI [-0.034, -0.003]). Thus, Hypotheses 3a and 3b were also supported. To further explain the relationship between SFSE and work engagement, we calculated the difference between the positive indirect and negative indirect effects, and the total effect (i.e., two indirect effects plus the direct effect) of SFSE on work engagement. Results showed that the difference between the positive path (i.e., positive affect as the mediator) and the negative path (i.e., negative affect as the mediator) was 0.042 (SE = 0.01, p < .001, 95% CI [0.023, 0.062]); and the total effect was 0.087 (SE = 0.03, p < .01, 95% CI [0.025, 0.149]), indicating an offsetting effect of positive indirect effect on the negative indirect effect and a positive effect of SFSE on work engagement.
Between-individual hypotheses
Based on M1, we tested the cross-level interaction hypotheses (i.e., Hypotheses 4a and 4b) by including leaders’ emotion suppression into the statistical model (i.e., M2). As shown in Table 5, the interaction term of SFSE and leaders’ emotion suppression was negative and significant (B = − 0.05, SE = 0.02, p < .05), Thus, Hypothesis 4a was supported by the data. When taking negative affect as the dependent variable, the interaction term of SFSE and leaders’ emotion suppression was not significant (B = − 0.02, SE = 0.03, ns.), Hypothesis 4b, therefore, was not supported by the data.
Table 5 Multilevel path analysis results for moderation test (M2)
Predictors Positive affect Negative affect Work engagement
B SE B SE B SE
Intercept 4.70*** 0.11 2.93*** 0.12 4.94*** 0.11
Independent variables
SFSE 0.05 0.05 0.12* 0.06 0.08** 0.03
Emotion suppression − 0.00 0.01 0.00 0.01
Emotion suppression × SFSE − 0.05* 0.02 − 0.02 0.03
Mediators
Positive affect 0.25*** 0.05
negative affect − 0.14** 0.04
Control variables
Study day 0.01 0.02 − 0.03 0.03 − 0.04† 0.02
Within-individual residual variance 0.41*** 0.03 0.55*** 0.04 0.41*** 0.03
Between-individual residual variance 0.63*** 0.11 0.81*** 0.13 0.69*** 0.12
Outcomes Positive affect Negative affect
Values of moderator Estimate SE 95% CI Estimate SE 95% CI
+ 1 SD 0.01 0.06 [-0.106, 0.126] 0.11 0.07 [-0.028, 0.238]
-1 SD 0.09† 0.04 [0.000, 0.173] 0.13* 0.05 [0.031, 0.227]
Difference − 0.08** 0.03 [-0.142, − 0.011] − 0.02 0.04 [-0.100, 0.052]
Nlevel−1=504, Nlevel−2=106. † p < .1, * p < .05, ** p < .01, ***p < .001
To further explain the moderating effect of leaders’ emotion suppression, following Cohen and Cohen (1983), we conducted regression analyses at one standard deviation above and below the mean of emotion suppression and depicted the relationship between SFSE and leaders’ negative affect. As shown in Fig. 2, the relationship between SFSE and positive affect was significant and positive (simple slope = 0.09, t = 2.00, p < .05) when leaders’ emotion suppression was at lower levels; however, this relationship was not significant when leaders’ emotion suppression was at higher levels (simple slope = 0.01, t = 0.23, ns).
Fig. 2 Moderating effect of emotion suppression on the relationship between SFSE and positive affect
Supplemental analysis
To further expand the model, we examined whether emotion suppression can moderate the indirect effect of the relationship between SFSE on work engagement via positive affect (i.e., the moderated mediating effect). According to Edwards and Lambert (2007), we calculated the indirect effect of SFSE on leaders’ work engagement through positive affect at higher (+ 1 SD) and lower (-1 SD) levels of emotion suppression. The results showed that this indirect effect was marginally significant when emotion suppression was low (indirect effect = 0.022, SE = 0.01, p = .07, 95% CI [-0.027, 0.032]), but not significant when emotion suppression was high (indirect effect = 0.002, SE = 0.02, ns), and the difference between these two indirect effects was significant (indirect effect = − 0.019, SE = 0.01, p < .05, 95% CI [-0.037, − 0.001]), providing support for the moderated mediated effect.
Discussion
Drawing upon the AET (Weiss & Cropanzano, 1996), we developed and tested a model explaining how and when experiencing SFSE affects leaders’ emotional experiences and daily work engagement. Findings from a daily diary survey on 106 leaders for 5 workdays revealed that SFSE had a dual effect on leaders (i.e., feedback source). On the bright side, SFSE elicited leaders’ positive affect, which in turn increased their daily work engagement. On the other hand, SFSE also elicited negative affect, which in turn decreased leaders’ daily work engagement. Moreover, our research results supported the moderating role of leaders’ emotion suppression on the relationship between SFSE and positive affect, with higher levels of emotion suppression hindering the positive affect derived from SFSE.
Theoretical implications
Our study has important theoretical implications. First, we extend workplace feedback-seeking literature by shifting the predominant focus from the feedback seeker to the feedback source. Research has indicated that organizational phenomena (e.g., leadership style) which contain social interaction processes will impact both embedded sides (e.g., Lanaj et al., 2016; Liu et al., 2022). As feedback seeking and responding are interactive by nature (Ashford et al., 2016), a source-centric view of feedback seeking behavior is needed. Our findings suggest that SFSE elicits leasers’ affective reactions, which in turn influence their daily work state. As such, we highlight the source’s perspective in feedback seeking and responding process and enrich the outcomes of feedback seeking behavior.
Second, our research focuses on the paradox traits of SFSE, extending AET theory by examining the positive and negative affective reactions in one theoretical model. Prior research has indicated that certain work events, behaviors, or characteristics have both bright and dark effects on employees’ or team results (Koopman et al., 2016; Liu et al., 2022). We advance this research line by suggesting that SFSE has a balanced effect (i.e., both positive and negative) on leaders’ affective reactions. Besides, research on feedback seeking behavior has demonstrated the potential positive and negative impacts of this behavior on sources separately (Krasman, 2018; Krasman & Kotlyar, 2019), we contribute to these studies by offering a comprehensive perspective of the conflict influences.
Finally, we provide a new contingency view (i.e., emotion suppression) on the relationship between work events and the affective reactions of leaders. Previous studies have demonstrated that personal traits such as big-five personality (Lanaj et al., 2016) and self-control (Rosen et al., 2019) could influence leaders’ reactions to certain work events. However, few studies have focused on leaders’ emotion regulation in this relationship. By demonstrating the moderating role of emotion suppression on the relationship between SFSE and positive affect, we highlight the central roles of emotions in AET and provide a holistic picture involving both affective reactions and emotion regulation in the process of handling work events.
Practical implications
This study also has important practical implications. First, organizations should pay attention to leaders’ responses to SFSE and improve their abilities to deal with SFSE. While our findings suggest that SFSE has both positive and negative effects on leaders’ affective reactions and daily work experience, organizations can take steps to help leaders focus more on the positive aspects of SFSE, such as by encouraging leaders to engage in positive self-reflection (Lanaj et al., 2019), think deeply about the possible benefits of feedback-seeking behavior to subordinates, themselves and the team. Moreover, organizations could also provide relevant trainings aimed at developing leaders’ self-regulation and self-control (Rosen et al., 2019), eventually improving their abilities to handle SFSE.
Secondly, organizations should take measures to develop leaders’ emotion regulation abilities. Owing to the hindering moderating effect of emotion suppression, organizations should spend effort in judging and improving leaders’ emotion regulation orientation. This could be done through two ways. First, when organizations recruit or select leaders, it should involve candidates’ differences in emotion regulation in the assessment criteria. Second, organizations can provide courses related to emotion regulation, such as guiding leaders to express real emotions through deep acting or cognitive reappraisal (Alam & Singh, 2021; Matta et al., 2014).
Finally, our findings also shed light on the management of daily feedback seeking behavior. Specifically, due to the possible interrupting effects of SFSE on leaders’ goal progress and negative effect, organizations should guide this behavior, such as instructing employees to fully consider the motivations and purposes for the feedback seeking (Minnikin et al., 2021), or providing formal feedback seeking area and setting regularly time for feedback seeking.
Limitations and future directions
This study, inevitably, has some limitations. First, this study measured leaders’ positive and negative affects at fixed time points (i.e., interval-based sampling), which make us unable to capture leaders’ immediate emotional responses after SFSE. Future studies are encouraged to measure instant affective reactions by applying event-based measurement (e.g., Wijewardena et al., 2017).
Second, this study only focused on the frequency of SFSE, neglecting the content of feedback seeking. Based on our proposition, when the content of SFSE is more related to leaders’ goal achievement, it will arouse stronger positive rather than negative affect. In contrast, when the content is less related to leaders’ goal achievement, it will arouse stronger negative rather than positive affect (Lanaj & Jennings, 2020). In this vein, future research will benefit from distinguishing the content of SFSE, and then providing a more detailed examination between SFSE and affective reactions.
Third, this study only examined one possible boundary condition (i.e., emotion suppression) in the relationship between SFSE and affective reactions. Other factors such as perspective taking, and leadership experience will also play role in this process, as leaders with these traits have higher coping abilities (Chun et al., 2018; Ku et al., 2015). Notably, the moderating role of emotion suppression on the relationship between SFSE and negative affect was not supported by our data. One possible reason may exist in the inability of this emotion regulation in dealing with negative affect (Gross & John, 2003). The other emotion regulation strategy (i.e., reappraisal) would play a more important role in the process of negative affective reactions (Gross & John, 2003). Future studies thus are encouraged to explore more boundary conditions in work events and affective reactions relationship.
Finally, this study mainly focused on the effect of SFSE on leaders’ work engagement. Future research could move beyond the current focus on affective reactions and work engagement by investigating how SFSE will shape leadership behaviors such as daily transformational leadership (Rosen et al., 2019), moving its results to employee even team level.
Conclusion
The results from the current study indicate that SFSE has dual effects on leaders daily work engagement via the increased positive affect and negative affect; individual difference (i.e., emotion suppression) released the positive relationship between SFSE and positive affect. Our findings contribute to FSB literature on how FSB influences the emotional responses and attitudes of feedback sources.
Author contributions
WZ and BW contributed to conception and design of the study. JQ and YL organized the database. WZ performed the statistical analysis and wrote the first draft of the manuscript. BW wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
Funding
This work was supported by National Natural Science Foundation of China (Grant Number: 71662017 and 72102140) and Shanghai Pujiang Program (21PJC057).
Data availability
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Declarations
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards with written informed consent from all subjects. All data were collected before the COVID-19. This research was approved by the Research Committee at the Business School, Beijing Normal University.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
1 If the student does not have a leader position, he/she are encouraged to recommend his/her direct leader to us.
2 For 92 leaders providing 5 days of surveys (i.e., 460 daily observations) and 14 leaders providing 2–4 days of surveys, and the 14 leaders providing a total of 44 daily observations.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Alam, M., & Singh, P. (2021). Performance feedback interviews as affective events: an exploration of the impact of emotion regulation of negative performance feedback on supervisor–employee dyads. Human Resource Management Review, 31(2). 10.1016/j.hrmr.2019.100740.
Anseel F Agile learning strategies for sustainable careers: a review and integrated model of feedback-seeking behavior and reflection Current Opinion in Environmental Sustainability 2017 28 51 57 10.1016/j.cosust.2017.07.001
Anseel F Beatty AS Shen W Lievens F Sackett PR How are we doing after 30 years? A meta-analytic review of the antecedents and outcomes of feedback-seeking behavior Journal of Management 2015 41 1 318 348 10.1177/0149206313484521
Anseel F Vossaert L Corneillie E Like ships passing in the night: toward a truly dyadic perspective on feedback dynamics Management Research 2018 16 4 334 342 10.1108/MRJIAM-12-2017-0794
Ashford SJ Feedback-seeking in individual adaptation: a resource perspective Academy of Management Journal 1986 29 3 465 487 10.5465/256219
Ashford, S. J. (1993). The feedback environment: an exploratory study of cue use. Journal of Organizational Behavior, 14(3). 10.1002/job.4030140302
Ashford SJ De Stobbeleir K Nujella M To seek or not to seek: is that the only question? Recent developments in feedback-seeking literature Annual Review of Organizational Psychology and Organizational Behavior 2016 3 1 213 239 10.1146/annurev-orgpsych-041015-062314
Ashford SJ Tsui AS Self-regulation for managerial effectiveness: the role of active feedback seeking Academy of Management Journal 1991 34 2 251 280 10.2307/256442
Ashton-James, C. E., & Ashkanasy, N. M. (2005). What lies beneath? A process analysis of affective events theory. Research on emotion in Organizations, (Vol. 1, p. 23-26). Emerald Group Publishing Limited.
Bakker AB Demerouti E Sanz-Vergel AI Burnout and work Engagement: the JDR Approach Annual Review of Organizational Psychology and Organizational Behavior 2014 1 389 411 10.1146/annurev-orgpsych-031413-091235
Bauer, T. N., Perrot, S., Liden, R. C., & Erdogan, B. (2019). Understanding the consequences of newcomer proactive behaviors: The moderating contextual role of servant leadership. Journal of Vocational Behavior, 112(October 2018), 356–368. 10.1016/j.jvb.2019.05.001
Bledow R Schmitt A Frese M Kühnel J The affective shift model of work engagement Journal of Applied Psychology 2011 96 6 1246 1257 10.1037/a0024532 21766997
Brislin RW Translation and content analysis of oral and written material Handbook of Cross-Cultural Psychology 1980 2 2 349 444
Brotheridge CM Grandey AA Emotional labor and burnout: comparing two perspectives of “people work” Journal of Vocational Behavior 2002 60 1 17 39 10.1006/jvbe.2001.1815
Chun JU Lee D Sosik JJ Leader negative feedback-seeking and leader effectiveness in leader-subordinate relationships: the paradoxical role of subordinate expertise Leadership Quarterly 2018 29 4 501 512 10.1016/j.leaqua.2017.11.001
Cohen, J., & Cohen, P. (1983). Applied multiple regression/correlation analysis for the behavioral sciences. Erlbaum. 10.2307/2064799
Diefendorff JM Richard EM Antecedents and consequences of emotional display rule perceptions Journal of Applied Psychology 2003 88 2 284 294 10.1037/0021-9010.88.2.284 12731712
Edwards JR Lambert LS Methods for integrating moderation and mediation: a general analytical framework using moderated path analysis Psychological Methods 2007 12 1 1 22 10.1037/1082-989X.12.1.1 17402809
Enders, C. K., & Tofighi, D. (2007). Centering predictor variables in cross-sectional multilevel models: A new look at an old issue. Psychological Methods, 12(2), 121–138. 10.1037/1082-989X.12.2.121
Gross JJ Emotion regulation: current status and future prospects Psychological Inquiry 2015 26 1 1 26 10.1080/1047840X.2014.940781
Gross JJ John OP Individual differences in two emotion regulation processes: implications for Affect, Relationships, and well-being Journal of Personality and Social Psychology 2003 85 2 348 362 10.1037/0022-3514.85.2.348 12916575
Heen, S., & Stone, D. (2014). Find the coaching in criticism. Harvard Business Review, (JAN-FEB). 10.2469/dig.v44.n3.10
Koopman J Lanaj K Scott BA Integrating the bright and dark sides of OCB: a daily investigation of the benefits and costs of helping others Academy of Management Journal 2016 59 2 414 435 10.5465/amj.2014.0262
Krasman J Getting to the “Source” of Feedback-Seeking: impact of feedback-seeking on Supervisor stress International Journal of Human Resource Studies 2018 8 3 103 10.5296/ijhrs.v8i3.12706
Krasman, J., & Kotlyar, I. (2019). The impact of feedback-seeking on sources’ job satisfaction: a study of canadian Supervisors. Journal of Organizational Psychology, 19(2). 10.33423/jop.v19i2.2052.
Ku G Wang CS Galinsky AD The promise and perversity of perspective-taking in organizations Research in Organizational Behavior 2015 35 79 102 10.1016/j.riob.2015.07.003
Lan J Huo Y Cai Z Wong CS Chen Z Lam W Uncovering the impact of triadic relationships within a team on job performance: an application of balance theory in predicting feedback-seeking behaviour Journal of Occupational and Organizational Psychology 2020 93 3 654 686 10.1111/joop.12310
Lanaj K Foulk TA Erez A Energizing leaders via self-reflection: a within-person field experiment Journal of Applied Psychology 2019 104 1 1 18 10.1037/apl0000350 30321029
Lanaj K Jennings RE Putting leaders in a bad mood: the affective costs of helping followers with personal problems Journal of Applied Psychology 2020 105 4 355 371 10.1037/apl0000450 31478714
Lanaj K Johnson RE Lee SM Benefits of transformational behaviors for leaders: a daily investigation of leader behaviors and need fulfillment Journal of Applied Psychology 2016 101 2 237 251 10.1037/apl0000052 26348475
Lechermeier J Fassnacht M How do performance feedback characteristics influence recipients’ reactions? A state-of-the-art review on feedback source, timing, and valence effects Management Review Quarterly 2018 68 2 145 193 10.1007/s11301-018-0136-8
Liu, Y., Song, Y., Trainer, H., Carter, D., Zhou, L., Wang, Z., & Chiang, J. T. (2022). Feeling negative or positive about fresh blood? Understanding veterans’ affective reactions toward newcomer entry in teams from an affective events perspective. Journal of Applied Psychology, online. 10.1037/apl0001044
Matta FK Erol-Korkmaz HT Johnson RE Biçaksiz P Significant work events and counterproductive work behavior: the role of fairness, emotions, and emotion regulation Journal of Organizational Behavior 2014 35 7 920 944 10.1002/job.1934
Methot JR Lepine JA Podsakoff NP Christian JS Are workplace friendships a mixed blessing? Exploring tradeoffs of Multiplex Relationships and their Associations with Job Performance Personnel Psychology 2016 69 2 311 355 10.1111/peps.12109
Minnikin A Beck JW Shen W Why do you ask? The Effects of Perceived Motives on the effort that managers allocate toward delivering feedback Journal of Business and Psychology 2021 10.1007/s10869-021-09776-x
Moss SE Martinko MJ The effects of performance attributions and outcome dependence on leader feedback behavior following poor subordinate performance Journal of Organizational Behavior 1998 19 3 259 274 10.1002/(SICI)1099-1379(199805)19:3<259::AID-JOB839>3.0.CO;2-T
Ouweneel E Le Blanc PM Schaufeli WB van Wijhe CI Good morning, good day: a diary study on positive emotions, hope, and work engagement Human Relations 2012 65 9 1129 1154 10.1177/0018726711429382
Preacher KJ Zyphur MJ Zhang Z A general multilevel SEM framework for assessing multilevel mediation Psychological Methods 2010 15 3 209 233 10.1037/a0020141 20822249
Qin X Huang M Johnson RE Hu Q Ju D The short-lived benefits of abusive supervisory behavior for actors: an investigation of recovery and work engagement Academy of Management Journal 2018 61 5 1951 1975 10.5465/amj.2016.1325
Rich BL Lepine JA Crawford ER Job engagement: antecedents and effects on job performance Academy of Management Journal 2010 53 3 617 635 10.5465/amj.2010.51468988
Rosen CC Simon LS Gajendran RS Johnson RE Lee HW Joanna L Boxed in by your inbox: implications of daily E-mail demands for managers’ leadership behaviors Journal of Applied Psychology 2019 104 1 19 33 10.1037/apl0000343 30221954
Schaufeli WB Salanova M Bakker AB Gonzales-Roma V The measurement of Engagement and Burnout: a two sample confirmatory factor Analytic Approach Journal of Happiness Studies 2002 3 71 92 10.1023/A:1015630930326
Sung SY Choi JN Do you value or worry about feedback? Tradeoffs between cost and value perceptions and dual feedback-seeking strategies toward creativity Journal of Organizational Behavior 2021 42 7 950 963 10.1002/job.2524
Vogel RM Rodell JB Agolli A Daily engagement and productivity: the importance of the speed of engagement Journal of Applied Psychology 2022 107 9 1579 1599 10.1037/apl0000958 34647778
Watson D Clark LA Tellegen A Development and validation of brief measures of positive and negative affect: the PANAS scales Journal of Personality and Social Psychology 1988 54 6 1063 1070 10.1037/0022-3514.54.6.1063 3397865
Weiss HM Cropanzano R Affective events theory: a theoretical discussion of the structure, causes and consequences of affective experiences at work Research in Organizational Behavior 1996 18 1 74
Wijewardena N Härtel CEJ Samaratunge R Using humor and boosting emotions: an affect-based study of managerial humor, employees’ emotions and psychological capital Human Relations 2017 70 11 1316 1341 10.1177/0018726717691809
Young SF Steelman LA The role of feedback in supervisor and workgroup identification Personnel Review 2014 43 2 228 245 10.1108/PR-01-2013-0006
Zhou ZE Meier LL Spector PE The spillover effects of coworker, supervisor, and outsider workplace incivility on work-to-family conflict: a weekly diary design Journal of Organizational Behavior 2019 40 9–10 1000 1012 10.1002/job.2401
| 0 | PMC9734672 | NO-CC CODE | 2022-12-14 23:28:30 | no | Curr Psychol. 2022 Dec 3;:1-11 | utf-8 | Curr Psychol | 2,022 | 10.1007/s12144-022-04059-x | oa_other |
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BDJ In Pract
Bdj in Practice
2057-3308
2520-8675
Nature Publishing Group UK London
1825
10.1038/s41404-022-1825-5
Interview
'Technology enables us to take better care of our patients and lighten our work loads'
Westgarth David [email protected]
BDJ In Practice, London, United Kingdom
5 12 2022
2022
35 12 1011
© British Dental Association 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
issue-copyright-statement© British Dental Association 2022
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pmcBDJ In Practice spoke to Claire Nightingale, Dentex partner at Queens Gate Orthodontics and NHS Consultant at Watford General Hospital and Jamie Morley, Leadership Coach and Author, about the problems facing orthodontists, the future of the specialty - and one solution available to improve their patients' experience
What are the main problems orthodontists face as we head into 2023?
CN I think all sectors within which orthodontics is provided have their unique challenges. NHS orthodontists are dealing with the backlog caused by COVID-19, poor UOA values and difficulties in finding specialist orthodontists, particularly outside of London. Recruitment and workforce issues are rife across dentistry, and we're no exception. Specialist orthodontists are highly trained but the value the NHS places on remunerating that skill set is low. I was recently told that specialist orthodontists are like 'gold dust', but at the same time, young orthodontists seem to have to work in multiple sites to fill a month of employment - how those two things can be equally true is a conundrum to me. Additionally, orthodontists, and their teams, have lost their jobs within practices that have lost their NHS contract. This is a cruel evolution in healthcare provision.
In the private sector, I've observed a significant change in referral patterns as general dental practices either employ in-house orthodontists or prefer to provide the treatment themselves, often with clear aligners. An estimated 70% of Invisalign providers nationally are GDPs which reduces referrals to specialist orthodontists. Consequently, I worry that patients may not be getting the benefit of a comprehensive discussion of treatment options, including referrals to NHS hospitals for orthognathic treatment.
Finally, I have concerns that we're not training orthodontists to work with modern technology that's being used in private practice, where digital scanners have replaced impressions and increasingly, I'm managing complex malocclusions with Invisalign. On the NHS, I can still only train orthodontists to use traditional techniques, such as metal fixed braces and functional appliances.
What are the current trends within the profession?
CN Treatment opportunities are very much moving towards clear aligners, as well as the integration of artificial intelligence within orthodontics. Technology enables us to take better care of our patients and lighten our work loads. Dental Monitoring is one such advancement and has revolutionised my practice.
I need to reiterate the problem of investment - with a widening discrepancy between what can be achieved in private practice and on the NHS. Take imaging technology, for example. Are there enough consultant dental radiologists to report on cone beam CT scans that, ideally, I'd like to prescribe for every patient with complex impacted teeth? Intra-oral scanners are a basic necessity in private practice but providing multiple scanners for hospital units is unlikely to happen within existing NHS budgets.
JM Globally, you can point to the economic and cost-of-living crisis. This will impact the profession - patients will have less disposable income, and to a degree private practice may be adversely affected.
That said, if you look at this through the prism of being a headwind, there are several tailwinds and positive trends to counterbalance the headwind. There's still an incredible level of demand for good, aesthetically pleasing teeth and smiles, so the demand will remain. With the challenges Claire spells out - especially for NHS orthodontists - patients don't want to wait for their treatment. There are too many instances of huge waiting lists for that to be a realistic possibility, so how do you make the most of that opportunity?
Dental Monitoring provides a quality, convenient platform for practitioners to free up their time and offer a level of service their patients expect. Time is becoming as much of a valuable commodity as money, and Dental Monitoring offers just that.
There's plenty of chatter about the remote management of orthodontic patients. What are your views on this, and can it be done safely and effectively?
CN Yes, it can. In my opinion, Dental Monitoring improves patient care. I'm almost at the point of concluding that it shouldn't be an optional extra; rather it's becoming a necessity. The treatment progress is assessed on a weekly basis, rather than every six to eight weeks, by AI, which is more acute than the human eye at picking up lost attachments or modules, for example. Problems are flagged up immediately, there's better dialogue between patients and their practitioner and a human being still makes the clinical decisions.
AI isn't flawless and doesn't pick up all problems, but it reduces unnecessary patient attendances and makes the necessary visits more purposeful. The orthodontist and team are still very involved from start to finish.
JM An accurate, initial assessment is critical - it means you can put that patient on the right track from very early in the process. There's a tendency to baulk at new ways of doing things, yet if it works for the patient and the practitioner, it has to be considered seriously. As always, it's all about the patient and their safety, and increased remote management can provide that.
What are the advantages and disadvantages of remote monitoring?
JM Chair time for the practice and wins for the patient, especially from a convenience perspective, would be high up on my lists. It's a process that takes a change in outlook - dentists will naturally think not seeing a patient is a bad thing. If you're constantly on top of the patient from afar, providing convenience for the patient and opening up chair time for new patients, that's a win for everyone.
CN For me, it's about working smarter, but not compromising on quality or patient safety as a result. It's been transformative. How was it possible for Queen's Gate Orthodontics to win 'Best Practice, UK' in 2020 and then to become the 'Most Transformed Practice' in the UKI in May 2022? I attribute this largely to embracing Dental Monitoring after the pandemic, in addition to being more adventurous with treating difficult malocclusions with Invisalign and other digital changes.
I audited our workflow to see how effective it was. I discovered that we'd saved 290 in-person appointments, equivalent to approximately 19 days' worth of work, between our previous analogue clinical practice (2019) and our digital practice (2021). The increased 'white space' in my diary enables new patients to be seen more quickly, for treatment problems to be addressed early, and for the team to have a better work/life balance, in addition to the ability to increase our caseloads.
The cost-of-living crisis is making its way into the wider profession. Is there any way practices and practitioners can effectively safeguard themselves against taking large hits?
JM There is only so much you can do to cut costs in a safe and effective way - once you tip over the precipice, it becomes dangerous. Once the rocky period is over, you're then not in a position to recover quickly, so ultimately it's not going to help in the long run.
That's not to say don't be sensible with costs - you have to be. If there's a way to grow the business in a positive, convenient and easy way, it's important you're in a position to invest and do so.
What does the future hold for the specialty?
JM Like in any forms of life, the more differentiated you are from someone providing the same service, the better. Orthodontists need to stand out and be different and lean on their vast experience in the field when compared to their GDP colleagues.
CN I think it's a bit bleak. There will always be a clinical need for specialist orthodontists, but as GDPs increase their orthodontic caseload, what will the workforce look like and who will treat dental disease? I fear for orthodontic therapists, for example, who risk being the last ones in and first ones out as recognised roles within the dental team. Their roles are prime for being replaced by technology, and I think the Australian model of a triple dental hygienist, dental therapist and orthodontic therapy qualification would be a welcome change to GDC registration.
The marketplace is becoming crowded, as younger GDPs wish to keep to low-risk procedures such as align, bleach and bond. Specialist orthodontists need to maintain this skill set to keep up with the competition and keep their social media profile high to connect directly with the public, as the traditional referral pathway becomes redundant. ◆
Bios Claire Nightingale, a highly experienced and multiple prize-winning orthodontist, including 'Most Transformed Practice' in the Invisalign UKI Awards, 2022, 'Best Practice, UK, 2020' in the Dentistry Awards and 'Orthodontist of the Year, London, 2019' in the GHP Private Healthcare Awards, qualified as a dentist from Newcastle University (1989) and completed her specialist training as an orthodontist at Bristol University (1996). She is the Dentex partner at Queens Gate Orthodontics and combines private practice in South Kensington, London, with an NHS Consultant post at Watford General Hospital.
Jamie Morley is a leadership coach with over 20 years experience of leading teams within businesses including 17 years at Johnson & Johnson and 7 years at Align Technology where he was the General Manager for UK & Ireland. Jamie has a degree in Business Studies from Sheffield Hallam University and an MSc in Coaching & Behavioural Change from Henley Business School where he developed his ability to help others change and evolve. In 2018 Jamie set up Fitting Leadership which provides leadership training and coaching focusing specifically on the Orthodontic and dental sector.
| 0 | PMC9734675 | NO-CC CODE | 2022-12-14 23:28:30 | no | BDJ In Pract. 2022 Dec 5; 35(12):10-11 | utf-8 | null | null | null | oa_other |
==== Front
ZDM
ZDM
Zdm
1863-9690
1863-9704
Springer Berlin Heidelberg Berlin/Heidelberg
1449
10.1007/s11858-022-01449-0
Original Paper
Keeping pace with innovations in data visualizations: A commentary for mathematics education in times of crisis
http://orcid.org/0000-0003-4947-0540
Lim Vivian Y. [email protected]
1
Peralta Lee Melvin M. 2
Rubel Laurie H. 3
Jiang Shiyan 4
Kahn Jennifer B. 5
Herbel-Eisenmann Beth 2
1 grid.212340.6 0000000122985718 CUNY Guttman Community College, New York, USA
2 grid.17088.36 0000 0001 2150 1785 Michigan State University, East Lansing, USA
3 grid.18098.38 0000 0004 1937 0562 University of Haifa, Haifa, Israel
4 grid.40803.3f 0000 0001 2173 6074 North Carolina State University, Raleigh, USA
5 grid.26790.3a 0000 0004 1936 8606 University of Miami, Coral Gables, USA
8 12 2022
110
31 10 2022
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The mathematical medium of data visualization and other data representations (DV) has served as a primary means of communicating about the COVID-19 crisis. DVs about the pandemic are highly visible across news journalism and include an increasingly innovative and diverse set of representational forms. These representational forms employ multimodal, interactive, and narrative elements, among others, that create new possibilities for data storytelling. Building on current efforts to expand the teaching and learning of data practices in K-12 mathematics education, we argue that innovative DVs create new opportunities for teaching and learning mathematics, particularly during times of crisis. We illustrate our argument using three examples of innovative DVs from news journalism. We discuss how these DVs could serve as complementary resources alongside conventional graphs to support students as they use mathematics and mathematical representations to make sense of crises such as the COVID-19 pandemic. Our commentary seeks to bring current trends in data representation to bear in mathematics education. Leveraging such trends offers artifacts useful for teaching and opens up space for elevating emotion and experience as important aspects of mathematics curricula.
Keywords
Data visualization
Emotion
COVID-19
Pedagogical affordances
==== Body
pmcIntroduction
At the time of our writing, the world continues to contend with COVID-19. Mathematics is used to picture this and other crises (Skovsmose, 2021), in part through the use of data visualizations and other data representations (DVs).1 New digital platforms and tools enable multimodal representational features in DVs, including audio, video, or animation, as well as interactive features. These representational forms extend beyond conventional graphs (e.g., static bar or line graphs; Sheiber, 2017). New representational forms allow for enhanced data storytelling as well as the integration of art and activism (e.g., Chalabi, 2020; Lupi & Posavec, 2016). On one hand, the prevalence of DVs and data-driven arguments about COVID-19 in news journalism (Kwon et al., 2021) provides artifacts ripe for mathematics curricula through their connections to mathematics topics such as percent and number, rates of change, probability, and modeling. On the other hand, since data and DVs are a key resource for understanding, framing, and solving problems, as well as communicating their solutions (Boyd & Crawford, 2012; Stenliden et al., 2019), data literacies are crucial for education about the pandemic and for its resolution (Aguilar & Castaneda, 2021; da Silva et al., 2021). Moreover, the very prevalence of DVs signals a need that they become more central to mathematics education. In this commentary, we argue that innovative DV forms can broaden opportunities for mathematics learning. Multimodal, interactive, and narrative elements, among others, enable new forms of DVs to tell stories about crises in more explicitly visceral and emotionally engaging ways than conventional graphs. Our purpose is not to argue that conventional graphs should be replaced but rather to consider new visualization forms as equally valuable resources for mathematics learning, particularly during times of crisis.
Innovative DV forms offer pedagogical affordances with respect to the goal of using mathematics to help students make sense of their own and others’ lives during times of crises. Such a goal includes the use of mathematics to understand crises such as the COVID-19 pandemic on an aggregate level but also to make sense of crises on an individual level with an emphasis on emotion as well as intrapersonal and interpersonal experiences. These different approaches to using mathematics to make sense of crises are not opposites, but rather complementary and interrelated. Konold et al. (2015) argue that while statistics is “fundamentally about the behavior of aggregates” (p. 322), students should be able to move flexibly between seeing data through an individual, point-wise perspective and through an aggregate, global perspective, based on the purposes and questions at hand. Individual-based perspectives can ground truth and instantiate, challenge, interrogate, or build towards aggregate trends, while aggregate views are necessary for seeking patterns or conducting statistical analyses (Ben-Zvi & Arcavi, 2001).
In this commentary, we convey that innovative DV forms offer alternative and potentially complementary ways to make sense of the world through data, particularly during times of crisis. We highlight opportunities for mathematics educators to recognize the plurality of representations in DVs, to understand the affordances that particular DVs can contribute to instructional goals, and to curate sets of representations that most effectively work together towards those instructional goals. In the first part of this commentary, we provide a brief overview of related literature about DVs in mathematics education and about newer forms of DVs. Then, we present the idea of pedagogical affordances as a lens through which to analyze the particular opportunities presented by different forms of DVs. Next, we introduce three examples of DVs from news journalism that are viscerally and emotionally engaging in different ways, discuss their pedagogical affordances for mathematics teaching and learning, and suggest possibilities for pairing innovative DVs with conventional graphs in generative ways. Finally, we discuss how these three examples suggest new possibilities for using DVs in mathematics education during times of crises.
Data visualization and mathematics education
DVs in mathematics education
DVs appear in K-12 mathematics education in terms of graph reading and writing, with graphs as tools for data analysis, data representation, and communication. At the elementary level, students are typically introduced to bar graphs, circle graphs, dotplots, and scatter plots; at the middle and high school levels, this expands to include graphs of functions and, sometimes, other plots (e.g., box-and-whiskers plots; Bargagliotti et al., 2020). The latest PISA Mathematics Framework (OECD, 2018), for example, emphasizes graphing as a tool for analysis, problem-solving, and for communicating one’s thinking efficiently and abstractly. There is also a growing emphasis on mathematical representations more generally, especially with respect to mathematical modeling, a domain that includes data analysis and statistical modeling (Ben-Zvi et al., 2018; Biehler et al., 2018; Burkhardt, 2018; Maass et al., 2019; Schukajlow et al., 2018). The U.S. PreK-12 Guidelines for Assessment and Instruction in Statistics Education II, for example, note that evolutions in technology have produced “amazing data visualization tools” and “unconventional representations” (Bargagliotti et al., 2020, pp. 11, 95). In that document, however, the focus is on extracting conventional statistical information from newer representational forms, rather than on highlighting how these representations could add opportunities for learning. In short, there is potential to tap into the expanded range of DVs and benefit from their affordances.
DVs in news journalism
DVs are social texts that tell stories from specific points of view (Rubel et al., 2021). Data journalists have become increasingly intentional about attending to audiences’ bodies and emotions to more fully capture the experiences of people with respect to real-world phenomena and better engage audiences through data (see e.g., Cairo, 2016; Chalabi, 2020; McCandless, 2000). These trends can be seen as a revival of DV practices prevalent in the nineteenth century, when appeals to emotion were embraced (see Brasseur, 2005 for examples from Florence Nightingale; Battle-Baptiste & Russet, 2018 for examples from W.E.B. Du Bois). Kostelnick (2016) refers to that period as a golden age of statistical graphics, in how designers broke traditional design conventions by making abundant use of color and narrative elements. Such practices were subsequently rejected in the twentieth century through modernist movements that insisted on minimalism and Enlightenment-era appeals to rationality over feeling (Kennedy & Hill, 2018; Kostelnick, 2016).
Today, there is widespread acknowledgement that DVs are storytelling devices that can evoke emotions and engage the body (Kennedy & Hill, 2018; Kostelnick, 2016; Matuk et al., 2022). In particular, interactivity allows readers to interact with data in more ways and can readily evoke emotional and visceral responses (Cairo, 2016; Kennedy & Engebretsen, 2020). Interactivity includes the layering of multimedia (i.e., audio, images, text, video; Hill & Bradshaw, 2018), incorporating dynamic features (e.g., hovering that shows tooltips, zooming in and out, time sliders, adding filters and search functionality; Segel & Heer, 2010), and shifting the perspective or the dimensions of the data display (e.g., manipulating a data dashboard or expanding or shrinking a data table). These features are thought to provoke emotional responses by engaging readers’ senses (e.g., fear; Oh & Hwang, 2021), drawing readers in closer proximity to the data by allowing them to customize the data display or explore it using their bodies (e.g., Roberts & Lyons, 2020), or allowing readers to receive real-time flows of information (see Kostelnick, 2016).
We subsequently consider how innovative DVs, as storytelling devices designed to capture people’s engagement in new ways, can be leveraged for mathematics education. Through three examples and the lens of pedagogical affordances, we illustrate how multimodal, interactive, and narratively compelling DVs create opportunities for sensemaking about crises and for learning mathematics.
Pedagogical affordances
Mathematics teachers can excerpt DVs from news journalism to support students to use mathematics to understand real world events and crises. In the process of curating these resources, teachers take numerous considerations into account, including their beliefs and convictions about education, their instructional goals, their understandings of their students, the availability of materials, and their school context (see Pepin et al., 2017; Remillard & Heck, 2014). While excerpting DVs for classroom use, mathematics teachers must consider what instructional possibilities they offer. These possibilities can be understood in terms of affordances.
Gibson’s (1986) concept of affordances describes the relationship that exists between an acting agent and its surrounding environment. The affordance of an object is what it allows an acting agent to do (Norman, 2013), such as the case of a coffee mug handle that allows a person to pick up a hot mug without burning their hand. This concept depends not only on the object's properties but also on the acting agent and the context. Certain acting agents may not be able to use a mug handle—for example, a mug handle may be unusable by some animals or a person with a broken finger—the handle may not be perceptible, or the acting agent may not understand how to use or wish to use the handle. Thus, affordances are relational phenomena, not standalone properties of objects removed from their conditions of use (Norman, 2013). Affordances do not guarantee action (Dindyal et al., 2021), and the likelihood that an affordance becomes actualized may depend on issues of discoverability, accessibility, and feedback (Norman, 2013).
Nagashima et al. (2020) discusses the notion of pedagogical affordances as the "properties of an instructional tool that could help achieve instructional goals, or that would put a limit on achieving the goals" (p. 1). The affordance of an instructional tool depends on the teachers’ instructional goals, which shape what constitutes an affordance and how such affordance is perceived and activated (Nagashima et al., 2020). For instance, if a mathematics teachers’ instructional goal is to support students in understanding the importance of equally scaled axes on a graph, then a DV that includes a scaled axis serves as an affordance toward that goal. However, if the teacher does not make that goal explicit, the affordance offered by the DV may not be perceived by students or activated in the course of instruction. Pedagogical affordances therefore can describe the instructional possibilities created by text, diagrams, or graphs that conceptualize real-world phenomena in various modes (Wu & Puntambekar, 2012). Studying the affordances of a representation includes considering how it prompts individuals to relate displayed information to their own lives, identify and name their feelings about a social issue or natural phenomena, examine familiar concepts in new forms, and form connections between topics.
We seek to convey the potential of innovative DVs for mathematics education by highlighting the instructional possibilities that such DVs afford. In the following section, we examine three examples of DVs from news journalism focused on the COVID-19 pandemic and highlight complementary pedagogical affordances offered by conventional representations of the same data. These examples are not comprehensive and are but an initial sampling of innovative DVs that have emerged in news journalism and other forms of public media.
Three examples of DVs
Example 1: Bui and Badger (2020)
Bui and Badger’s (2020) DV, published in the New York Times, models levels of audible noise in New York City (NYC) using data gathered by street-level microphones (see Fig. 1). The DV is a line graph that depicts sound levels between February 2019 and May 2020 to contrast sound levels from before the pandemic with the lockdown in March 2020. Audio clips from two points are layered on top of the graph, which are activated when a user clicks on images of sound waves corresponding with the clips. These audio clips illustrate, in a particular way, the impact of the pandemic’s first vicious wave in NYC.Fig. 1 Screenshot from Bui and Badger’s (2020) DV depicting sound levels in New York City before and during the pandemic
Because the audio clips are layered as attached to two points on the graph, the representation does not detract from the pedagogical affordances of a traditional line graph. Figure 1 still utilizes a coordinate system to denote data values and trends. The audio clips provide audible embellishment that highlights the intended contrast. Furthermore, the audio clips bridge a gap between the line graph as a model of changes in sound levels and the meaning of individual points on the graph (what a street sounds like at a particular sound level). In other words, the audio clips can serve as a scaffold for readers to connect the line graph to the phenomenon that it is modeling––the varying levels of street sound in NYC from before the pandemic to its first lockdown. The audio clips thus add dimension to the line graph by offering a means of experiencing the quantified measures with auditory senses.
The choice to represent and include audio in Bui and Badger’s (2020) DV is not arbitrary—it provides an opportunity for meaningful connection to people’s experiences during lockdown. The quiet in the streets demonstrated in this DV, produced by the constrained mobility in response to public health recommendations, marks the deep human estrangement and loneliness that was experienced in that period. The integration of audio alongside the visual representations invites the reader to not just see but to hear and feel how that loneliness sounded. Different from framing human mobility as dangerous with humans as disease vectors, this DV highlights the social meaning of mobility and, as was the case, the social meaning of limited mobility. Bui and Badger’s (2020) DV opens space for mutual acknowledgement and engagement with feelings like loneliness and isolation that have accompanied the pandemic (Dutta, 2021).
By integrating sound into their DV, Bui and Badger (2020) establish a sensory and emotional connection between the reader, the mathematics, and the phenomenon. In so doing, they call into question conventions in mathematics education that focus only on visual representations of data. The inclusion of audio in the DV challenges the notion that all types of raw data (in this case, audio) should ultimately be formatted according to a quantitative scale that can be plotted and shows how other forms of data can be integrated in meaningful ways. One could imagine a DV embedding continuous audio corresponding with a graph to enable readers to experience a dataset’s variability, or even using audio alone as a model for a data set, even data that is not about sound (see data sonification, Beans, 2017). We note that audio is only one example of an alternative medium that can enhance or serve as a mathematical representation. One can also imagine a DV that invites the reader to feel the data through other senses, for example through fluctuations in temperature or different types and intensities of smells.
Example 2: Hart (2021)
Hart's (2021) 500,000 Lives Lost DV (see Fig. 2), published in Reuters, conveys the number of people in the United States who died from COVID-19 as of February 2021. The interactive DV uses points to represent each individual life, points which amass along a vertical timeline. The points fluctuate in their density over time in correspondence with waves of the pandemic. Hart engages the reader interactively through touch: readers must scroll down to view the entire vertical timeline. Each flowing point represents a person’s death, and the quantification of aggregated deaths is visualized through the amassing of these individual points; the spacing of the dots has the effect of generating a visual sense of accumulation rather than on conveying exact magnitudes.Fig. 2 Screen shot from Hart’s (2021) 500,000 Lives Lost DV. Permission pending
Hart's (2021) DV is not amenable for precisely measuring values or rates; however, the graduated density of the dots, which fluctuate between narrow and wide clusters over time, produces a visual and tactile experience that can likely support the learning of concepts like rate of change. Points representing individual deaths are not evenly spaced out and there is no marked axis for the reader to determine aggregates by date. Yet extreme values become evident through the scrolling, as the intermittent dots turn into a line of dots and then quickly to a thick, dense, and wavy band of dots. At the same time, Hart reminds the reader of the individual lives lost that are at the core of the aggregated data, and how these lives relate to the collective. On the left side, the DV includes mini-obituaries of some individuals that provide names, ages, and some details about their lives. On the right side, the DV anchors the magnitude of 500,000 relative to numbers of lives lost during select historical milestone events. These techniques further remind readers of the human and social significance of the data on an individual and societal level. Layering aggregate data and meaningful individual qualitative data, setting up comparisons with memorable historical events, and framing the magnitude of lives lost through individual dots, are techniques that anthropomorphize data (i.e., anthropographics, Sorapure, 2022).
Fig. 3 Reproduction of Fig. 2 using a conventional graphical display (U.S. CDC COVID-19 Data Tracker). The data and data representation in Fig. 3 comes from the U.S. Center for Disease Control’s (CDC) COVID-19 Data Tracker, which allows users to create customizable bar graphs that display COVID-19 related data based on a chosen date range. Figure 3 shows the daily number of such deaths reported to the CDC between February 6, 2020 and February 22, 2021, which is the same statistic and date range as in Hart’s (2021) DV
Figure 3 represents a similar dataset but uses a conventional bar and line graph representation. Deaths are organized by date and aggregated into thin vertical bars scaled according to magnitude. The entire time interval is compactly expressed in a single frame, displaying the entire distribution all at once and making it easier to observe overall patterns. This representation is conducive for identifying extreme values, intervals on which the graph is increasing, and other kinds of rates of change.
Pairing conventional graphs like Fig. 3 with innovative ones like Hart’s (2021) DV can provide opportunities for learning in terms of making important mathematical connections. For example, connections can be drawn toward the different ways that time is represented, the variety in how axes are used, different levels of or need for precision, and the relationship between representations of individual values (in this case, lives lost) and aggregate measures. Other connections can be drawn between increasing/decreasing intervals and slope values that are more conveniently calculated using Fig. 3––but often elusive in meaning to beginner graph readers––with the cascading density of points in Hart’s DV. Similar connections can be drawn regarding extreme values and how they are represented in each DV. These mathematical connections can create opportunities for a deeper understanding of not just the mathematical concepts but what they represent––in this case, the widespread pain and loss related to COVID-19.
Example 3: Chalabi (2020)
Chalabi's (2020) Companies that have profited from the pandemic, published in The Guardian, stays within the parameters of visual modality; however, it challenges conventions by mixing conventional mathematical representations (i.e., a bar graph) with political illustrations for the purpose of activism through storytelling (see Fig. 4). Chalabi represents several U.S. retail companies’ additional profits in 2020 compared to the previous year using a nontraditional bar graph whereby the bars are composed of illustrated images of workers stacked on top of each other on their hands and knees. Illustrations of the executives wearing suits representing each company stand on the backs atop each stack of kneeling workers. Chalabi’s DV is an example of how a DV can be used to tell complex, compelling stories that render the DV emotionally engaging. The spatial positions of the people shown in the DV (workers on hands-and-knees as compared to company owners standing on top) draw attention to the inequality, social hierarchy, and inhumanity connected with the excess profits that corporations experienced during the COVID-19 pandemic. Chalabi’s DV instantiates that visualizing data can enable mathematics to be used to challenge injustices.Fig. 4 Company profits during the pandemic (Chalabi, 2020)
Chalabi’s (2020) DV makes clear how traditional DVs tend to obscure human dimensions related to who benefits and who are exploited by current arrangements. In the case of capitalism, it relies on invisible labor and the invisibility of that labor is reinforced by how typical DVs essentially hide it from view. Chalabi’s DV, however, shows corporate profits while highlighting the labor that makes these profits possible. The DV, together with the accompanying text, is intentional in narrating that companies’ huge profits were only made possible by the workers taking risks on the front lines during the pandemic. The DV subtly allows reference to other aspects of the context, like the owners’ genders and race—nearly all of the leaders of these companies seem to be White men (though it misses the opportunity to highlight the genders and races of workers).
By making human bodies and their identities visible, Chalabi’s (2020) DV affords the instructional possibility of highlighting the connection between income inequality, particularly in the context of crises, with gender and race. These instructional possibilities may open up conversations in which students can reflect on their own identities and lived experiences during crises, such as may be the case for students who were required to work, or whose family members were required to work, during the COVID-19 pandemic. In this sense, the mathematics classroom may become more than a space for students to understand the technical dimensions of crises, but also a space where students can use mathematical representations to make sense of their lived experiences and view them in social context.
Figure 5 shows the same data but in a traditional bar graph and is ripe for conventional statistical analyses such as finding various measures of central tendency. The simplicity and reproducibility of this graph enables its ease of production or modification. A teacher might consider remaking Fig. 5 so that the y-axis is unevenly scaled to demonstrate one way that graphs can be misleading. Chalabi’s (2020) DV is a bespoke design, and does not possess this same flexibility in terms of modification or reproducibility. The juxtaposition of Chalabi’s DV with Fig. 5, however, invites learning opportunities through their contrast. For instance, the narrative of Chalabi’s DV is foregrounded, exemplifying how DVs are always social texts with a particular perspective, whereas the narrative that is communicated through Fig. 5 is more ambiguous. The hand-drawn nature of the illustrations in Chalabi’s DV further accentuates that a person created the DV (Alamalhodaei et al., 2020). The reminder that people, not data, make the choices that determine how a DV is made can inspire additional voicing of stances on societal issues and can create opportunities for healing around these social issues, increase potential for mathematical power and agency, and improve relationships with mathematics (Kokka, 2018, 2022).
Fig. 5 Reproduction of Fig. 4 using a conventional graphical display (R). The authors created Fig. 5 using the ggplot2 library in the open-source statistical computing software package R. The authors used the same data source behind Chalabi’s (2020) DV (Brookings, 2020)
The conventional bar graph of Fig. 5 relies on a minimalist design style with simple bars, a grayscale color palette and precisely marked x- and y-axes. These design choices foreground the numerical qualities of the data—as opposed to its social, cultural, political, and ethical dimensions or context. The minimalist style of Fig. 5 is aligned with widespread practices in the DV community that minimize the use of color and other stylistic choices in order to present the “raw facts” of the dataset without any emotional appeal. The belief that data visualization should be minimalistic can be attributed to Tufte (2001), who believed that DVs should remove superfluous information to appeal to reason alone without the interference of emotional—and thus subjective—factors (D’Ignazio & Klein, 2020). It can be argued that Tufte’s design philosophy is the dominant paradigm for data visualization in mathematics curricula. Presenting both Chalabi’s (2020) DV alongside Fig. 5 as valid alternatives for making sense of crises through a mathematical representation offers the opportunity to thoughtfully accept, reject, or add nuance to this dominant paradigm or to consider in which situations one might be preferable. Finally, debates about the use of mathematical representations prompted by the contrast between these figures invite broader philosophical discussions about the nature of mathematics itself.
Discussion
The prominence of DVs in news journalism, which increasingly showcases innovations in DVs, creates new opportunities and calls for expanding the set of DVs that are incorporated into mathematics curricula. The preceding examples highlight the potential impact that such DVs might have on mediating mathematical engagement with social crises like the COVID-19 pandemic. All three examples combine aesthetic elements with mathematical qualities of space, variation, and quantity and generate pedagogical affordances that open up possibilities for shifting students’ relationships with and understandings of mathematics. This is especially true when such affordances are paired with those offered by conventional graphs.
All visualizations or other representations of complex phenomena are imperfect models of reality. As models, they make some elements of phenomena visible and render others invisible. Traditional graphs afford certain pedagogical opportunities but have not kept pace with the development of newer forms of DVs that seek to render phenomena visible in different ways. The examples of DVs in this commentary showcase multimodal, interactive, and narrative features, among others, that could create opportunities for students to construct their understanding of quantities and patterns in data from an alternative vantage point or sensory perspective. In addition to contributing to sensemaking, DVs with innovative features may provide opportunities to shift students’ relationships with mathematics by centering their identities, experiences, and agency in the mathematics classroom. Multimodal features, such as those found in Bui and Badger’s (2020) DV (Fig. 1), can enable teachers to direct students’ attention toward sensory dimensions of crises beyond the visual and, through multimedia technologies, invite students to experience these dimensions on a visceral level. Interactivity, such as that found in Hart’s (2021) DV (Fig. 2), can be used to position students as active participants in engaging with DVs. Illustrations, such as Chalabi’s (2020) DV (Fig. 4), can help students see the humans behind a data-driven story and thereby see themselves within the story. In these ways, the mathematics classroom can become a space for students not just to connect to but also grapple with the realities of their lived experiences during times of crisis, turning the mathematics classroom into a potential place for empowerment and healing (Kokka, 2018).
To emphasize, we do not argue for the elimination of conventional graphs from the mathematics curriculum. Instead, innovative DVs raise issues for researchers and practitioners to consider when selecting, adapting, and using DVs from popular media. Using innovative DVs in the classroom involves trade-offs, such as a loss of precision that might occur, for instance, by eliminating a visible axis in favor of enabling students to experience data through scrolling and touch. Just like conventional graphs, innovative DVs are only partial representations of reality. Nonetheless, solely presenting students with minimalist graphs in the name of precision or apparent neutrality can exact a price, such as removing the people most affected from the forefront of the representation. Including graphs that make the human creators and human impact (often an unequal impact) of crises visible can invite awareness and motivate critical questions.
Lastly, we do not claim that traditional graphical representations cannot be used to evoke emotion in learning settings, nor that using innovative DVs ensure emotional engagement. As Kennedy and Hill (2018) suggest, all DVs have emotional qualities, but some DVs are more explicit about these emotional qualities than others. Because pedagogical affordances do not guarantee action, we emphasize that exactly how a DV engages students depends not only on the features of the DV but also on the teacher’s decision making, the classroom culture, and the other aspects of the learning environment.
Conclusion
Emerging guidelines and research in statistics, data literacy, and data science education acknowledge the rise of innovative DVs (Bargagliotti et al., 2020) and encourage students to explore and create new means of visual expression that more fully capture lived experiences (Lee et al., 2022). Our commentary adds to this work by considering particular affordances of innovative DVs while situating how they might elicit emotion and experience as potentially generative aspects of making sense of crises through a mathematical lens. We argue for increased attention in mathematics education to innovative DVs. This is an opportunity for mathematics education to keep pace with contemporary trends in data representation. Moreover, this is an opportunity to expand what it means to use mathematics as a way to understand ourselves, one another, and broader aspects of society.
Funding
Although no funding was received to assist specifically with this work, Beth Herbel-Eisenmann was on assignment at the National Science Foundation while working on this manuscript. Any opinion, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of NSF.
Declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
1 In this commentary, we use the abbreviation DV to broadly encompass data visualizations and other data representations to include representations of data in visual, audio, tactile, and other forms.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Aguilar MS Castaneda A What mathematical competencies does a citizen need to interpret Mexico’s official information about the COVID-19 pandemic? Educational Studies in Mathematics 2021 108 227 248 10.1007/s10649-021-10082-9 34934238
Alamalhodaei, A., Alberda, A. P., & Feigenbaum A. (2020) Humanizing data through ‘data comics’: An introduction to graphic medicine and graphic social science. In M. Engebretsen & H. Kennedy (Eds.) Data visualization in society (pp. 347–365). Amsterdam University Press. 10.1515/9789048543137-025.
Bargagliotti, A., Franklin, C., Arnold, P., Gould, R., Johnson, S., Perez, L., & Spangler, D. A. (2020). PreK-12 guidelines for assessment and instruction in statistics education ii (GAISE II): A framework for statistics and DS education. NCTM & ASA.
Battle-Baptiste, W., & Rusert, B. (2018). W.E.B. Du Bois’s data portraits: Visualizing Black America. Princeton Architectural Press.
Beans C Science and culture: Musicians join scientists to explore data through sound Proceedings of the National Academy of Sciences 2017 114 18 4563 4565 10.1073/pnas.1705325114
Ben-Zvi D Arcavi A Junior high school students’ construction of global views of data and data representations Educational Studies in Mathematics 2001 45 35 65 10.1023/A:1013809201228
Ben-Zvi, D., Makar, K., & Garfield, J. (Eds.) (2018). International Handbook of Research in Statistics Education. Springer. 10.1007/978-3-319-66195-7.
Biehler R Frischemeier D Podworny S Elementary preservice teachers’ reasoning about statistical modeling in a civic statistics context ZDM-Mathematics Education 2018 50 7 1237 1251 10.1007/s11858-018-1001-x
Boyd, D., & Crawford, K. Critical questions for big data: Provocations for a cultural, technological, and scholarly phenomenon Information, Communication & Society 2012 15 5 662 679 10.1080/1369118X.2012.678878
Brasseur L Florence Nightingale's visual rhetoric in the rose diagrams Technical Communication Quarterly 2005 14 2 161 182 10.1207/s15427625tcq1402_3
Brookings (2020). Major retail companies’ COVID-19 compensation to workers during the pandemic: A ranking. Metropolitan Policy Program. https://www.brookings.edu/wp-content/uploads/2020/11/20201120_BrookingsMetro_Ranking-COVID19Compensation-OnePager-2.pdf.
Burkhardt H Ways to teach modeling—A 50 year study ZDM-Mathematics Education 2018 50 1/2 61 75 10.1007/s11858-017-0899-8
Bui, Q. & Badger, E. (2020). The coronavirus quieted city noise. Listen to what’s left. New York Times. https://www.nytimes.com/interactive/2020/05/22/upshot/coronavirus-quiet-city-noise.html.
Cairo, A. (2016). The truthful art: Data, charts, and maps for communication. New Riders.
Chalabi, M. (2020). The pandemic has been good to big US retail firms—to their workers, less so. Guardian. https://www.theguardian.com/news/datablog/2020/dec/29/us-retail-companies-workers-coronavirus-datablog.
Choy BH Dindyal J Productive teacher noticing and affordances of typical problems ZDM-Mathematics Education 2021 53 1 195 213 10.1007/s11858-020-01203-4
D'Ignazio C Klein LF Data feminism 2020 MIT Press
da Silva AS Barbosa MTS de Souza Velasque L da Silveira Barroso Alves, D., & Magalhães, M. N. The COVID-19 epidemic in Brazil: How statistics education may contribute to unravel the reality behind the charts Educational Studies in Mathematics 2021 108 269 289 10.1007/s10649-021-10112-6 34934244
Dindyal J Schack EO Choy BH Sherin MG Exploring the terrains of mathematics teacher noticing ZDM-Mathematics Education 2021 53 1 1 16 10.1007/s11858-021-01249-y
Dutta, S. (2021) Empathy through data: Loneliness through the lens of data visualization (Master’s thesis, OCAD University). Retrieved from http://openresearch.ocadu.ca/id/eprint/3331/.
Gibson JJ The ecological approach to visual perception 1986 Lawrence Erlbaum Associates
Hart, S. (2021). 500,000 lives lost: The scale of the COVID-19 death toll in the United States. Reuters. https://graphics.reuters.com/HEALTH-CORONAVIRUS/USA-CASUALTIES-CHRONOLOGY/xklpyomnrpg/.
Hill, S., & Bradshaw, P. (2018). Mobile-first journalism: Producing news for social and interactive media. Routledge.
Kennedy, H., & Engebretsen, M. (2020). Introduction: The relationships between graphs, charts, maps and meanings, feelings, engagements. In H. Kennedy & M. Engebretsen (Eds.), Data visualization in society (pp. 19–32). Amsterdam University Press. 10.2307/j.ctvzgb8c7.7
Kennedy H Hill RL The feeling of numbers: Emotions in everyday engagements with data and their visualisation Sociology 2018 52 4 830 848 10.1177/0038038516674675
Kokka K Healing-informed social justice mathematics: Promoting students’ sociopolitical consciousness and well-being in a mathematics classroom Urban Education 2018 54 9 1179 1209 10.1177/0042085918806947
Kokka K Toward a theory of affective pedagogical goals for social justice mathematics Journal for Research in Mathematics Education 2022 53 2 133 153 10.5951/jresematheduc-2020-0270
Konold C Higgins T Russell SJ Khalil K Data seen through different lenses Educational Studies in Mathematics 2015 88 305 325 10.1007/s10649-013-9529-8
Kostelnick C The re-emergence of emotional appeals in interactive data visualization Technical Communication 2016 63 2 116 135
Kwon ON Han C Lee C Lee K Kim K Jo G Yoon G Graphs in the COVID-19 news: A mathematics audit of newspapers in Korea Educational Studies in Mathematics 2021 108 183 200 10.1007/s10649-021-10029-0 34934226
Lee VR Pimentel DR Bhargava R D'Ignazio C Taking data feminism to school: A synthesis and review of pre-collegiate data science education projects British Journal of Educational Technology 2022 10.1111/bjet.13251
Lupi, G., & Posavec, S. (2016). Dear data. Chronicle Books.
Maass K Doorman M Jonker V Wijers M Promoting active citizenship in mathematics teaching ZDM-Mathematics Education 2019 51 991 1003 10.1007/s11858-019-01048-6
Matuk, C., Amato, A., & Davidesco, I. [Chairs] (2022). Data storytelling in the classroom. [Symposium]. 16th International Conference of the Learning Sciences, Hiroshima (Online).
McCandless D Information is beautiful 2000 Collins
Nagashima, T., Yang, K., Bartel, A., Silla, E., Vest, N., Alibali, M., & Aleven, V. (2020). Pedagogical affordance analysis: Leveraging teachers’ pedagogical knowledge to elicit pedagogical affordances and constraints of instructional tools. In The Interdisciplinarity of the Learning Sciences, 14th International Conference of the Learning Sciences (ICLS) 2020 (Vol. 3).
Norman, D. (2013). The design of everyday things: Revised and expanded edition. Basic books.
OECD (2018). PISA 2022 Mathematics Framework (Draft). https://pisa2022-maths.oecd.org/files/PISA-2022-Mathematics-Framework-Draft.pdf.
Oh J Hwang AH Interactive data visualization enhances preventive intentions in COVID-19 news stories: The mediating role of fear and the moderating role of political orientation Journal of Broadcasting & Electronic Media 2021 65 4 479 504 10.1080/08838151.2021.1999958
Pepin B Gueudet G Trouche L Refining teacher design capacity: Mathematics teachers' interactions with digital curriculum resources ZDM-Mathematics Education 2017 49 799 812 10.1007/s11858-017-0870-8
Remillard JT Heck DJ Conceptualizing the curriculum enactment process in mathematics education ZDM-Mathematics Education 2014 46 705 718 10.1007/s11858-014-0600-4
Roberts J Lyons L Examining spontaneous perspective taking and fluid self-to-data relationships in informal open-ended data exploration Journal of the Learning Sciences 2020 29 1 32 56 10.1080/10508406.2019.1651317
Rubel LH Nicol C Chronaki A A critical mathematics perspective on reading data visualizations: Reimagining through reformatting, reframing, and renarrating Educational Studies in Mathematics 2021 108 3 249 268 10.1007/s10649-021-10087-4 34934245
Schukajlow S Kaiser G Stillman G Empirical research on teaching and learning of mathematical modeling: A survey on the current state-of-the-art ZDM-Mathematics Education 2018 50 5 18 10.1007/s11858-018-0933-5
Segel E Heer J Narrative visualization: Telling stories with data IEEE Transactions on Visualization and Computer Graphics 2010 16 6 1139 1148 10.1109/TVCG.2010.179 20975152
Shahin, F. (2021). Seeing data, feeling data: The visual language of numbers in Mona Chalabi’s Instagram infographics. iJournal, 6(2). 10.33137/ijournal.v6i2.36455
Sheiber, N. (2017). How Uber uses psychological tricks to push its drivers' buttons. The New York Times. https://www.nytimes.com/interactive/2017/04/02/technology/uber-drivers-psychological-tricks.html.
Skovsmose O Mathematics and crises Educational Studies in Mathematics 2021 108 369 383 10.1007/s10649-021-10037-0 34934225
Sorapure M Anthropographics in COVID-19 simulations Big Data & Society 2022 9 1 1 10.1177/20539517221098414
Stenliden L Bodén U Nissen J Students as producers of interactive data visualizations—Digitally skilled to make their voices heard Journal of Research on Technology in Education 2019 51 2 101 117 10.1080/15391523.2018.1564636
Tufte, E. R. (2001). The visual display of quantitative information (2nd ed.). Graphics Press.
Wu HK Puntambekar S Pedagogical affordances of multiple external representations in scientific processes Journal of Science Education and Technology 2012 21 6 754 767 10.1007/s10956-011-9363-7
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A mid-term follow-up with a lung ultrasonographic score correlates with the severity of COVID-19 acute phase
Perrone Tiziano 1
Falaschi Francesco 1
Meloni Federica 2
Ballesio Alessia 1
Sabatini Umberto 1
Lenti Marco Vincenzo 1
Melazzini Federica 1
Lettieri Sara 2
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1
1 grid.419425.f 0000 0004 1760 3027 Department of Internal Medicine and Medical Therapeutics, University of Pavia, Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy
2 grid.8982.b 0000 0004 1762 5736 Department of Respiratory Disease, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
3 grid.8982.b 0000 0004 1762 5736 Department of Infectious Disease, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
4 grid.419425.f 0000 0004 1760 3027 Direzione Medica di Presidio, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
5 grid.419425.f 0000 0004 1760 3027 Biometry and Clinical Epidemiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
6 grid.8982.b 0000 0004 1762 5736 Division of Cardiology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
5 12 2022
16
27 7 2022
21 10 2022
© The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Lung ultrasound (LUS) has rapidly emerged in COVID-19 diagnosis and for the follow-up during the acute phase. LUS is not yet used routinely in lung damage follow-up after COVID-19 infection. We investigated the correlation between LUS score, and clinical and laboratory parameters of severity of SARS-COV-2 damage during hospitalization and at follow-up visit. Observational retrospective study including all the patients discharged from the COVID-19 wards, who attended the post-COVID outpatient clinic of the IRCCS Policlinico San Matteo in April–June 2020. 115 patients were enrolled. Follow-up visits with LUS score measurements were at a median of 38 days (IQR 28–48) after discharge. LUS scores were associated with the length of hospitalization (p < 0.001), patients’ age (p = 0.036), use of non-invasive ventilation (CPAP p < 0.001 or HFNC p = 0.018), administration of corticosteroids therapy (p = 0.030), and laboratory parameters during the acute phase (WBC p < 0.001, LDH p < 0.001, CRP p < 0.001, D-dimer p = 0.008, IL-6 p = 0.045), and inversely correlated with lymphocyte count (p = 0.007). We found correlation between LUS score and both LDH (p = 0.001) and the antibody anti-SARS-CoV-2 titers (p value = 0.008). Most of these finding were confirmed by dichothomizing the LUS score (≤ 9 or > 9 points). We found a significantly higher LUS score at the follow-up in the patients with persistent dyspnea (7.00, IQR 3.00–11.00) when compared to eupnoeic patients (3.00, IQR 0–7.00 p < 0.001). LUS score at follow-up visit correlates with more severe lung disease. These findings support the hypothesis that ultrasound could be a valid tool in the follow-up medium-term COVID-19 lung damage.
Keywords
Imaging
Lung
Radiology
Viral infection
Ultrasound
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pmcIntroduction
Sonographic evaluation of COVID-19-induced lung damage has played a significant role since the first phases of the pandemic. Imaging follow-up of lung lesions after moderate-to-severe symptomatic COVID-19 has been suggested to help identifying patients who deserve a tighter clinical and rehabilitative care and who could benefit from further investigations or treatment [1]. Chest X-ray and Chest Computed Tomography Scan (CT-Scan) are the main imaging techniques used for such follow-up purposes [2] because of their wide use and the growing experience on SARS COV-2 infection patterns. Nevertheless, these techniques use ionizing radiation and their widespread use in large numbers of patients leads to a potential radiological harm [3]. Lung Ultrasound (LUS) has been widely used in emergency settings as a low cost, harm free and practical tool for ruling out respiratory failure differential diagnosis. LUS has rapidly emerged in COVID-19 diagnosis process and follow-up especially in the acute phase, when a rapid assessment of lung involvement is required at the critically ill patients’ bedside [4, 5]. However, LUS is not yet used routinely in follow-up of moderate-to-severe COVID-19 infection. The well-known operator dependability of ultrasound techniques can be at least partially addressed using scores and standardized lung scan procedures, as proposed by Soldati et al. [6]. In this study, we investigate the correlation between LUS scores and the severity of COVID-19 infection adding elements for the reliability of LUS as a potential substitute to chest X-ray and CT scan in COVID-19 patients’ follow-up.
The aim of the study is to evaluate the association between LUS score (considered on a continuous scale or dichotomized) and clinical and laboratory parameters of severity of SARS-COV-2 damage during hospitalization and at follow-up visit.
Materials and methods
Patients
In this retrospective study, we enrolled all consecutive outpatients, discharged from the Internal Medicine, Pneumology and Infectious Diseases wards, who attended the post-COVID outpatient clinic of the IRCCS Policlinico San Matteo, starting from April 27, 2020 until June 10, 2020. The inclusion criteria were having had an infection by SARS-CoV-2 during the first wave of the pandemic, an age greater than 18 years, and the ability to provide informed consent. Denial of informed consent was the only exclusion criterium. A total of 115 patients meeting the inclusion criteria were enrolled.
Demographic and clinical parameters
Clinical parameters considered were age, sex, length of hospital stay, time from discharge to outpatient evaluation, type of ventilation required (HFNC, CPAP), medical therapy during admission (corticosteroids, remdesivir, tocilizumab, hyperimmune plasma, heparin), and comorbidities already present upon admission. The above-mentioned parameters were obtained from the medical records.
Blood tests
Worst biomarkers levels were considered as follows:lymphocytes: the lowest absolute value
WBC, LDH, CRP, D-dimer, fibrinogen, and IL-6: the highest values.
Anti-SARS-COV-2 antibodies’ titer was determined at follow-up visit (Diasorin, Cypress, CA, USA) and a higher titer was considered as index of more severe disease [7, 8].
Sonographic technique
The outpatient sonographic evaluation was performed by experienced sonographers (at least 3 years of lung ultrasound practice) using an Esaote MyLab Twice with a convex probe. According to the protocol, an abdominal preset was applied with the following features: 10 cm depth, total gain 50%, and placement of the focus on the pleural line.
LUS score
Patients underwent a sonographic assessment following the protocol proposed by Soldati et al. [6]. Briefly, 14 different areas of the chest wall were evaluated, and ten (10) s clips were recorded to allow further revision. Patients were in supine position, with a 45°angle grade of the bed for anterior and lateral scans and sitting position for posterior scans. Sonographers avoided cosmetic filters or specific presets, and did not use harmonic corrections, nor contrast nor compounding, the saturation phenomena were avoided by setting the gain and reducing mechanical index. During the sonographic examination, possible pleural effusion or cava vein dilatation was assessed. Each scan was associated with a given score from 0 to 3 according to the following:Score 0: Regular pleural line. “A” lines are visible
Score 1: Small interruptions of the pleural line, isolated vertical artifacts underlying.
Score 2: Significant pleural line irregularities, pleura looks interrupted. Subpleural consolidations are documented associated with small white lung areas as pre-consolidative phase.
Score 3: Completely altered pleural line, diffuse white lung and tissue-like patterns.
At the end of the sonographic examination, the total LUS score was calculated by the sum of the 14 scores. Every clip was collected and consequently evaluated by an experienced sonographer with more than 15 years of experience in lung ultrasound.
Spirometry
The “Sensor Medics V MAX 22” spirometer was used at the post-COVID outpatient control for respiratory function tests (FEV1, FVC, FEV1/FVC, and DLCO measurements). Data analysis was conducted according the ATS/ERS guidelines [9, 10].
Statistical analysis
We used the Stata software, version 16.1, for all computations (StataCorp, College Station. TX, USA). All tests are two-sided and a p value < 0.05 is considered statistically significant. We described continuous data with the mean and standard deviation (SD) or the median and interquartile range (IQR) and categorical data as counts and percent. For the purpose of the analysis, to identify patients with the highest lung impairment, we dichotomized the total LUS score at its upper quartile (≤ 9/> 9). We computed the Spearman R and its 95% confidence interval (95% CI) to measure the association of continuous variables and the total LUS score and the Mann–Whitney U test to compare the LUS score between categorical variables. Finally, we compared patients with high and low LUS score with the Mann–Whiney U test or the Fisher exact test, for the continuous and categorical variables, respectively.
Ethical aspects
Patients signed informed consent on a form approved by the Ethical Committee of IRCCS Policlinico San Matteo, Pavia.
Results
Among the 115 patients enrolled in the study, 88 (76.5%) were male; age of patients and number of days between symptom onset, hospitalization, discharge, and follow-up are summarized in Table 1. Outpatients complained fatigue at the follow-up visit in 57% of cases and dyspnea in 37% of cases; patients less frequently (< 4%) complained other symptoms like chest pain, palpitations, cough, anosmia, and gastrointestinal disorders. Patients' median LUS score was 4, with an interquartile range (IQR) of 2–9. The distribution of LUS scores at the follow-up visit is represented in Fig. 1.Table 1 Description of enrolled population: age, number of comorbidities, days between symptom onset, hospitalization, discharge, and follow-up
Age, mean ± SD 62 ± 11.5
Number of comorbidities, median (IQR) 2 (1–2)
Days between symptom onset and hospitalization, median (IQR) 7 (6–10)
Days of hospitalization, median (IQR) 13 (10–21)
Days between discharge and follow-up, median (IQR) 38 (28–48)
Days between hospitalization and follow-up, median (IQR) 57 (43–65)
SD standard deviation, IQR interquartile range
Fig. 1 Distribution of the LUS score at the follow-up visit in enrolled patients
By dividing patients according to the LUS score (using the 75th percentile of 9 as the threshold), we obtained a group of 26 patients with LUS score > 9 and a group of 89 patients with LUS score ≤ 9. Median LUS score was higher in males than in females (5.0 IQR 2.00–9.50 vs. 3.00 IQR 1.00. 5.00), but not significantly (p value = 0.132). The proportion of patients with LUS score greater than 9 was also not significantly different among males and females (respectively, 25% and 15%, p value = 0.308). The correlation between age, length of stay, discharge-follow-up time, and LUS score by Spearman’s RHO and dichotomizing at LUS score more than 9 is summarized in Table 2.Table 2 Correlation between age, days of hospitalization and discharge-follow-up time, age expressed as mean ± standard deviation, length of stay, and discharge-follow-up time expressed in median (interquartile range)
Variable Spearman RHO (95% CI) p Value LUS score > 9 LUS score ≤ 9 p Value
Age (N = 115) 0.195 (0.013–0.365) 0.036 65.7 ± 11.2 61.4 ± 11.5 0.116
Length of stay (days) (N = 115) 0.34 (0.163–0.489) < 0.001 16.50 (12.00–27.00) 12 (9–18) 0.022
Discharge-follow-up time (days) (N = 114) − 0.218 (− 0.386 to − 0.035) 0.020 29.5 (20.0–40.0) 40 (31.00–48.50) 0.008
Among the risk factors, only onco-hematological disease at the admission is associated with the LUS score (p = 0.040). No association was observed with other risk factors nor with comorbidities (i.e., smoking status, hypertension, cardiovascular disease, cerebrovascular diseases, diabetes, chronic kidney diseases, asthma, COPD, tumors, immunodepression, iatrogenic immunosuppression, rheumatological diseases, psychiatric diseases, non-vascular neurological diseases, endocrine diseases excluding diabetes, and obesity).
Median LUS score at the follow-up visits for patients requiring non-invasive ventilation (CPAP and high-flow nasal cannula) is summarized in Table 3.Table 3 Average of the LUS score according to the ventilator therapies used at hospitalization
Type of non-invasive ventilation
CPAP HFNC
Yes = 44 No = 71 Yes = 45 No = 70
LUS score (median, IQR) 6.00 (3.00–11.00) 3.00 (0.00–8.00) 5.00 (3.00–11.00) 3.00 (0.00–8.00)
p Value 0.008 0.018
CPAP continuous positive airway pressure, HFNC high-flow nasal cannula oxygen therapy, IQR interquartile range
Comparable results were observed by dichotomizing the LUS score > 9 and ≤ 9 (p value 0.01 for CPAP and 0.04 for HFNC). No significant differences were found between average LUS scores for patients undergoing different medical treatments (Tocilizumab, Remdesivir, Plasma, Steroid, Heparin in prophylactic dosage, Heparin in therapeutic dosage), except for those who were administered corticosteroids (median LUS score of 7.3 ± 5.6 vs. 5.1 ± 5.2 in untreated patients, p value = 0027. Most of the laboratory parameters (the worst value during hospitalization) showed a significant correlation with LUS score at the time of the first follow-up visit, as shown in Table 4. Similar significant associations were observed dichotomizing the LUS score (> 9 and ≤ 9) except for lymphocyte count and D-dimer. Conversely, blood tests performed in the follow-up visit did not show any correlation with LUS score except for LDH (Spearman’s Rho 2.93, p value = 0.0015), even by dichotomizing the score at > 9 o ≤ 9 (p = 0.035). We furthermore observed a correlation between the antibody titers and LUS score at follow-up (N = 91, Rho = 0.277, p value = 0.0078), also when dichotomized by LUS score > 9, p = 0.037. A higher median LUS score was assessed in patients with dyspnea ((7.00, IQR 3.00–11.00) when compared to eupnoeic patients (3.00, IQR 0–7.00 p < 0.001). The persistence of fatigue showed a non-significant association with the LUS score (6.62 ± 5.81 vs. 4.63 ± 4.67, p = 0.079). By dichotomizing the LUS score (> 9 vs. ≤ 9), we did not observe any significant correlation for persistent dyspnea or fatigue (p = 0.113 and p = 0.184, respectively).Table 4 Correlation between biochemical parameters (WBC, lymphocytes, LDH, CRP, D-dimer, fibrinogen, IL-6) at the worst value during hospitalization and LUS score at follow-up
N Rho spearman (95% CI) p Value
WBC (× 103/µl) 114 0.333 (0.157–0.489) < 0.001
Lymphocytes (× 103/µl) 114 − 0.253 (− 0.417 to − 0.072) 0.007
LDH (mU/ml) 109 0.343 (0.165–0.499) < 0.001
CRP (mg/dl) 110 0.3151 (0.136–0.474) < 0.001
D-dimer (ug/l) 24 0.5289 (0.159–0768) 0.008
Fibrinogen (mg/dl) 27 0.1175 (− 0.275 to 0.476) 0.559
IL-6 (pg/ml) 16 0.5060 (0.014–0.801) 0.045
We did not find a correlation between LUS score and spirometry variables among the 50 patients that underwent the respiratory function test, as shown in Table 5. Criteria for execution of spirometry were persistence of dyspnea, evidence of oxygen saturation below 95% at rest, and necessity of oxygen support. Similar results were achieved by dichotomizing the LUS score by 9 (FEV1 p = 0.348, FEV1/FVC p = 0.630, DLCO p = 0.325).Table 5 Correlation of spirometric parameters with LUS score at follow-up
N Rho spearman (95% CI) p Value
FEV1 (% pred) 50 − 0.028 (− 0.304 to 0.252) 0.848
FEV1/FVC (%) 50 − 0.076 (− 0.347 to 0.207) 0.599
DLCO (%) 49 − 0.101 (− 0.372 to 0.185) 0.488
FEV-1 forced expiratory volume in the first second, FVC forced vital capacity, DLCO diffusing capacity of lung for CO (carbon monoxide)
Discussion
According to our results, length of hospitalization was significantly correlated with the total LUS score. To explain this finding, it can be reasonably assumed that a longer hospital stay indicates a more severe disease and therefore a more critical lung damage, persisting up to follow-up.
An inverse correlation was found between LUS score and time from discharge to the outpatient visit, similarly to other studies [11] that described a complete resolution of lung damage (21% at 1 month, 69% at 3 months after hospital discharge). These findings highlight the progressive recovery process from COVID-19 lung damage after weeks and months from the acute disease. Within our study population, age was significantly correlated with total LUS score, and we speculate that elderly might likely be affected by several comorbidities (i.e., heart failure, lung diseases) and faced a more severe form of SARS COV-2 infection [12, 13].
Our data also suggest a statistically significant correlation between non-invasive ventilation (CPAP or HFNC) and LUS score at follow-up control. We speculate that patients requiring CPAP non-invasive ventilation suffered from more severe pneumonia; hence, lung damage sequelae might persist longer at a higher degree; a less likely theory is that parenchymal alterations might represent CPAP-induced lung damage; this hypothesis is even less likely for HFNC that less likely harm the lungs.
We did not consider the consequences of mechanical ventilation on lungs, because in this population, only 7 patients underwent oro-tracheal intubation and the mean age of that subgroup was lower than the mean age of the rest of the group undergoing other types of oxygen treatments. Moreover, intubated patients had longer hospital stay and a longer lapse to control visit; therefore, lung damage could have had more time to improve.
Among the COVID-19 infection treatments analyzed, only corticosteroids therapy correlates with LUS score, also when dichotomized, probably because steroids were mainly administered to patients with severe respiratory impairment before it became a standard treatment. Similarly, in those initial phases of the COVID-19 pandemic, patients with critical lung involvement were administered higher anticoagulant doses of heparin (LMWH) and that could explain the positive correlation with LUS score.
A very interesting finding is that almost all blood inflammation and lung damage biomarkers (WBC, CRP, LDH, D-Dimer, IL-6) correlate with LUS score, most of these also when score was dichotomized by 9 points. Only lymphocyte count had an inverse relationship with LUS score, which further confirms the hypothesis that LUS score is a valid measure of lung damage: in fact, lower lymphocyte count is associated with more severe COVID-19 as demonstrated in other studies [14, 15].
Previous studies showed that more severe pneumonia patients develop higher titers of anti-SARS-CoV2 [7, 8], and also in our limited data, we observe that neutralizing antibodies titer at the outpatient visit strongly correlates with higher LUS scores.
LUS score correlated also with persistent dyspnea at follow-up. When LUS score was dichotomized by 9, results did not show any relevant difference among the subgroups; on the other hand, when dichotomized by 7, LUS score allowed the identification of patients with and without dyspnea (p = 0.006). Using the same cut-off, fatigue appeared significantly more frequent in the > 7 LUS score patient subgroup (p = 0.041).
In contrast, spirometry parameters did not seem in correlation with LUS score; potential explanations for this are the following: a selection bias for more symptomatic patients that underwent the testing, the non-obstructive pattern of COVID-19 lung damage, and a similarity to other radiology test in which the lung imaging persists altered after lung function has restored [16].
Indeed, our study has some limitations. This is an observational study that can therefore only provide speculations for further studies. Population of the study was quite selected, as we included patients discharged alive and able to attend outpatient visits a probable bias toward more fit patients; nevertheless, the study shows interesting correlations between COVID-19 severity and LUS score that could have been even more evident if a wider range of severity of the disease had been represented. The follow-up visit was performed at various time intervals after discharge (median of 38 days, IQR 28–48 days) and, as we have shown that time influences the persistence of lung damage; nonetheless, this demonstrates that the associations of COVID-19 severity markers with LUS score remain true in a follow-up setting with a timing not strictly controlled. Additionally, only a minority of patients underwent CT scan, and thus, we were unable to compare this datum to the LUS score. The time-to-CT widely varied among patients, making it impossible to interpret any meaningful correlation with LUS sore. Only more symptomatic patients underwent CT, thus not representing the entire cohort. Future studies should focus on comparing LUS with CT scan. Finally, our data missed some other possible COVID-19 severity indexes (as P/F during admission or worst blood oxygen saturation); however, the multiple and consensual associations of many different severity markers with LUS score seems to us sufficiently convincing.
Our findings consistently suggest that LUS score at follow-up visit (1–2 months after the hospital admission) correlates with more severe lung disease, according to clinical and biochemical markers both during acute phase and at the follow-up. These findings support the hypothesis that ultrasound represents a valid tool for assessing medium-term COVID-19 lung damage. Further studies are needed to evaluate the utility of sonography in the long-term follow-up of COVID-19 patients. Our findings suggest that a possible cut-off to identify patients with more severe persistent lung damage could be in the 7–9 points range of LUS score. This cut-off needs to be prospectively validated in a large cohort of COVID-19 patients.
Author contributions
All authors participated in the drafting of the manuscript or critical revision of the manuscript for important intellectual content and provided approval of the final submitted version. All authors approved the final version of the paper.
Funding
None.
Declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval and consent to participate
The study was approved by the local ethics committee (Fondazione IRCCS Policlinico San Matteo) and all patients provided written informed consent.
Human and animal rights
The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Tiziano Perrone and Francesco Falaschi are co-first authors.
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References
1. Lee KS Wi YM Residual lung lesions at 1-year CT after COVID-19 Radiology 2021 302 720 10.1148/radiol.2021212350 34609154
2. Larici AR Cicchetti G Marano R COVID-19 pneumonia: current evidence of chest imaging features, evolution and prognosis Chin J Acad Radiol 2021 4 229 240 10.1007/s42058-021-00068-0 33969266
3. Brenner DJ Hall EJ Computed tomography—an increasing source of radiation exposure N Engl J Med 2007 357 2277 2284 10.1056/NEJMra072149 18046031
4. Gaspardone C Meloni C Preda A Lung ultrasound in COVID-19 a role beyond the acute phase? J Ultrasound Med 2021 40 503 511 10.1002/jum.15425 32770687
5. Peixoto AO Costa RM Uzun R Applicability of lung ultrasound in COVID-19 diagnosis and evaluation of the disease progression: a systematic review Pulmonology 2021 27 529 562 10.1016/j.pulmoe.2021.02.004 33931378
6. Soldati G Smargiassi A Inchingolo R Proposal for international standardization of the use of lung ultrasound for patients with COVID-19: a simple, quantitative, reproducible method J Ultrasound Med 2020 39 1413 1419 10.1002/jum.15285 32227492
7. Garcia-Beltran WF Lam EC Astudillo MG COVID-19-neutralizing antibodies predict disease severity and survival Cell 2021 184 476 488 10.1016/j.cell.2020.12.015 33412089
8. Hansen CB Jarlhelt I Pérez-Alós L SARS-CoV-2 antibody responses are correlated to disease severity in COVID-19 convalescent individuals J Immunol 2021 206 109 117 10.4049/jimmunol.2000898 33208457
9. Miller MR Hankinson J Brusasco V ATS/ERS task force. Standardisation of spirometry Eur Respir J 2005 26 319 338 10.1183/09031936.05.00034805 16055882
10. Graham BL Brusasco V Burgos F ERS/ATS standards for single-breath carbon monoxide uptake in the lung Eur Respir J 2017 3 49
11. Hernández-Píriz A Tung-Chen Y Jiménez-Virumbrales D Importance of lung ultrasound follow-up in patients who had recovered from coronavirus disease 2019: results from a prospective study J Clin Med 2021 10 3196 10.3390/jcm10143196 34300362
12. Smorenberg A Peters EJ van Daele P How does SARS-CoV-2 targets the elderly patients? A review on potential mechanisms increasing disease severity Eur J Intern Med 2021 83 1 5 10.1016/j.ejim.2020.11.024 33303345
13. Sherwani S Khan MWA Cytokine response in SARS-CoV-2 infection in the elderly J Inflamm Res 2020 13 737 747 10.2147/JIR.S276091 33116752
14. Tavakolpour S Rakhshandehroo T Wei EX Lymphopenia during the COVID-19 infection: what it shows and what can be learned Immunol Lett 2020 225 31 32 10.1016/j.imlet.2020.06.013 32569607
15. Lee J Park SS Kim TY Lymphopenia as a biological predictor of outcomes in COVID-19 patients: a nationwide cohort study Cancers 2021 13 471 10.3390/cancers13030471 33530509
16. Bruns AH Oosterheert JJ El Moussaoui R Pneumonia recovery: discrepancies in perspectives of the radiologist, physician and patient J Gen Intern Med 2010 25 203 206 10.1007/s11606-009-1182-7 19967464
| 36469248 | PMC9734680 | NO-CC CODE | 2022-12-14 23:28:30 | no | Intern Emerg Med. 2022 Dec 5;:1-6 | utf-8 | Intern Emerg Med | 2,022 | 10.1007/s11739-022-03144-0 | oa_other |
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Scientometrics
Scientometrics
Scientometrics
0138-9130
1588-2861
Springer International Publishing Cham
4574
10.1007/s11192-022-04574-5
Article
YouTube and science: models for research impact
http://orcid.org/0000-0002-6046-4638
Shaikh Abdul Rahman [email protected]
Alhoori Hamed [email protected]
Sun Maoyuan [email protected]
grid.261128.e 0000 0000 9003 8934 Northern Illinois University, DeKalb, USA
7 12 2022
123
31 8 2021
9 9 2022
© Akadémiai Kiadó, Budapest, Hungary 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Video communication has been rapidly increasing over the past decade, with YouTube providing a medium where users can post, discover, share, and react to videos. There has also been an increase in the number of videos citing research articles, especially since it has become relatively commonplace for academic conferences to require video submissions. However, the relationship between research articles and YouTube videos is not clear, and the purpose of the present paper is to address this issue. We created new datasets using YouTube videos and mentions of research articles on various online platforms. We found that most of the articles cited in the videos are related to medicine and biochemistry. We analyzed these datasets through statistical techniques and visualization, and built machine learning models to predict (1) whether a research article is cited in videos, (2) whether a research article cited in a video achieves a level of popularity, and (3) whether a video citing a research article becomes popular. The best models achieved F1 scores between 80% and 94%. According to our results, research articles mentioned in more tweets and news coverage have a higher chance of receiving video citations. We also found that video views are important for predicting citations and increasing research articles’ popularity and public engagement with science.
Keywords
Social media
YouTube
Societal impact
Research impact
Science of science
MetaScience
Machine learning
Altmetrics
Scientometrics
Scholarly communication
http://dx.doi.org/10.13039/100000001 National Science Foundation SMA-2022443 Shaikh Abdul Rahman http://dx.doi.org/10.13039/100000001 National Science Foundation IIS-2002082 Alhoori Hamed
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pmcIntroduction
Social media platforms have seen tremendous growth and changed communication paradigms in the past decade, with information posted online within seconds and shared through multiple channels worldwide almost instantaneously. Immensely popular platforms such as Twitter, Facebook, and YouTube have shifted information-sharing on the internet from a largely one-way process of posting information to a proprietary website to one in which information becomes available rapidly through many websites and user accounts and in many forms and iterations, and in which responses to original content can be voiced and shared broadly based on a few manual clicks or via a preset automated process. This shift has seen trillions of posts, tweets, and video uploads on multiple platforms, which have had a far-reaching impact on most, if not all, areas of human endeavor-including scholarly research. Video communication has rapidly increased on social media sites such as YouTube, Instagram, Twitter, and Facebook. Launched in 2005, YouTube, in particular, has played a vital role in increasing video communication. In regard to scholarly work, research outcomes from this venue are increasingly being shared on several social media platforms. Further, it is by no means unusual for YouTube video descriptions to include citations of research articles, which could play an important role in disseminating research. In this paper, we analyze those video citations to better understand how research is being disseminated through such a new way of citation and the implications of this kind of sharing.
In addition to the traditional citation-based analysis, it is necessary to track web-driven scholarly interactions and measure the impact of research beyond scholarly communities. Altmetrics or alternative metrics (Sugimoto et al., 2017) specifically track scholarly mentions on online platforms to analyze and measure the impact of scholarly products. Altmetrics track many different metrics, including, for example, users who have read or shared an article, even though those users may not formally cite it. Altmetrics could be used to measure the broader impact of a research article through many channels and even measure scholarly impact by predicting citations (Thelwall & Nevill, 2018; Akella et al., 2021). As a result, there is a movement toward digital libraries and publishers providing altmetrics on their websites. Several researchers have analyzed altmetrics and their potential for measuring societal impact. For example, Bornmann et al. (2019) used altmetrics data from the UK Research Excellence Framework (REF) in a case study designed to assess the validity of altmetrics and found that they have the potential to capture societal impact in relation to several distinct perspectives. In the present paper, we demonstrate our use of these social media metrics and features from altmetrics gathered from different platforms to further understand the role of YouTube video citations in the dissemination and societal impact of research.
Social media has become the primary source for real-time updates of various kinds of news worldwide, and YouTube is the principal site for video sharing (Susarla et al., 2012). Snelson et al. (2012) found that although YouTube is the most prolific online video-sharing platform, it is also the most under-researched social media platform. Every minute, more than 500 hours of video are uploaded to YouTube, which gets billions of views all over the world (YouTube, 2021). This popularity has resulted in YouTube ranking as the second most viewed website globally, outranked only by Google (Alexa, 2021). The platform’s usability and functionality allow a wide range of videos to be shared by users of all skill levels worldwide, who can then interact with others who like, dislike, and/or comment on the videos. Those posting content create a channel on YouTube as an organizing principle and showcase their video content, and others can choose to subscribe in order to receive updates when new videos are posted. Diverse fields of videos disseminating real-time information related to entertainment, health, music, sports, education, and news are uploaded by different channels. Recently, there has been an increase in the use of YouTube due to the dissemination of information related to the recent global pandemic, COVID-19 (Suciu, 2021; Rodriguez, 2021).
The global COVID-19 pandemic has disrupted the lives of most people, requiring significant changes in many everyday practices. Social and professional activities worldwide have adapted new methods and processes to meet the challenges associated with these changes. In the academic world, as in other realms, annual conferences and society meetings are hosting events virtually (Falk & Hagsten, 2021) in order to continue the exchanges that foster research progress in those venues. This unique experience has provided unexpected opportunities for the research community to reach wider audiences and improve diversity, equity, and novelty (Price, 2020; Liu et al., 2022; Kousha et al., 2022). Beehler and Griffiths (2020) hosted the 20th annual meeting of Interdisciplinary Nineteenth-Century Studies (INCS) online and shared the steps they took and the challenges they faced in hosting the conference in that context. Among many important points, the researchers asked the hosts to record the conference events and post the videos online to continue the discussion after the event. They also encouraged the presenters and other attendees to circulate appropriate hashtags on social media, share discussions, and broadcast the event’s news. Similarly, Bonifati et al. (2020) shared their experience of hosting a joint conference online and provided a number of suggestions for doing so successfully, including implementing the practice of making videos of the presentations available to the public by posting them online after the conference. In such contexts, videos were mostly uploaded to the conference’s YouTube channel and often cited one or more articles in their description. In addition, many conferences require a video submission (CHI, 2021; AAO, 2021), and given that this is the case, there is a need to analyze and understand the characteristics and impact of these video citations within and beyond the scholarly community now that they are also available to the public.
The idea of YouTube videos citing research literature is relatively new and has enormous potential to improve the visibility and dissemination of research, leading to greater societal and scholarly impact in the long term. However, there are far fewer studies on the relationship between research articles and scientific YouTube videos compared to the relationship between such articles and other social media platforms. To understand and analyze this impact, we consider the following research questions: What is the relationship between scientific YouTube videos and research articles? And what video categories and scientific subjects are most popular on YouTube?
Can we build machine learning models to predict the societal and scholarly impact related to YouTube videos? If so, what are the important features and characteristics?
To answer these questions, we analyzed the citations of research articles in videos on YouTube. We collected datasets from YouTube and Altmetric.com and used statistical and visualization techniques to understand the trends and discover patterns in the datasets. We combined the collected datasets and built machine learning models to predict three target variables. First, we built classification models to predict whether a research article has received a YouTube video citation. These video citations may influence the popularity of the research article, so it is vital to identify the features that are most important for contributing to the prediction of video mentions of research articles. Second, the prediction of citations of a research article is essential to assessing its scholarly impact. To understand the contribution of videos to this impact, we built our second machine learning model to predict citations of a research article using social media mentions and features from videos citing the article on YouTube. Third, the number of views of a video indicates the popularity of its content. To identify the social media features that are most important in attracting these views, we built our third machine learning model, which draws on social media features to predict the number of views for a video citing a research article on YouTube. In summary, our contributions include: One of the first studies that examines the relationship between scientific YouTube videos and research articles.
An investigation of the societal and scholarly impact, characteristics, and popularity of YouTube videos through visualization, statistical techniques, and machine learning models.
A novel dataset of research articles and YouTube videos that researchers can use to study the effects of scientific YouTube videos on the scientific community and the public.
Related work
Users’ social interactions in the online world generate new forms of data that can be extracted and analyzed by developing new models to find undiscovered patterns beneficial to advances in research. The traditional analytical approach through scholarly citations limits measuring the impact within these scholarly boundaries. In contrast, altmetrics (Sud & Thelwall, 2014; Bornmann, 2014; Shaikh & Alhoori, 2019) can measure the impact of research in a more diverse way across multiple platforms and can help us to understand the direct and indirect impact of scholarly research. On this point, according to Weller et al. (2015), the proper use of altmetrics can help disseminate new scientific innovations to the public. Researchers have recently employed social media metrics to gauge public reaction to scientific findings (Freeman et al., 2019, 2020; Shahzad & Alhoori, 2022; Shahzad et al., 2022).
Now a feature of many people’s daily lives, YouTube has undeniably changed information-sharing worldwide. Since YouTube’s launch, researchers have studied the platform’s relationship with and impact on many aspects of daily life. For example, in a review of articles related to YouTube and health care, Madathil et al. (2015) found that health information is increasingly conveyed through YouTube, given that the platform offers a setting for users worldwide to upload, view, and communicate health information. Further, as an educational tool in nursing education (Agazio & Buckley, 2009; Johnston et al., 2018), the platform has been used to stimulate active learning on the part of students and enhance health care learning. Chtouki et al. (2012) found that YouTube videos can be a useful source of free educational content that improves student performance. In a study designed to assess the effectiveness of YouTube videos on a given anatomy problem, Jaffar (2012) found that 98% of the 91 medical students used YouTube extensively, and 92% agreed it helped them learn about anatomy. June et al. (2014) conducted research with a sample of 50 students to assess their critical-thinking skills and interactive activities while using videos on YouTube. According to the results, YouTube has vast potential as a learning tool because it enhances the students’ experience and improves their critical-thinking skills.
Due to the massive quantity of content on YouTube, it is generally difficult for most contributors to reach a vast audience. Therefore, there is no guarantee that posting content will create an impact. For this reason, the relative popularity of videos has become a research focus with the goal of determining the features that are principally responsible for a video achieving a high level of popularity. According to Susarla et al. (2012), older YouTube accounts with more videos posted have a greater chance of having an impact than do newer accounts with fewer videos. In an assessment of the effect of content-agnostic factors on video popularity, Borghol et al. (2012) found that views of videos shared previously by the uploader and video age are critical factors in determining video popularity. Figueiredo et al. (2014) used Amazon Mechanical Turk to evaluate YouTube videos and found that high-quality content resulted in tremendous popularity. To analyze the factors affecting the popularity of videos focused on science communication on YouTube, Welbourne and Grant (2016) studied 390 videos of this kind uploaded to 39 channels on the platform and extracted popularity metrics such as view count, comment count, subscriber count, share count, and rating. They found that user-generated content was more popular than professionally generated content. Brodersen et al. (2012) examined more than 20 million YouTube videos to determine the relationship between video popularity and geographic locality by analyzing the views from a spatial locality instead of a global locality. They found that the videos have a strong geographic interest, and around 50% of the videos had gained more than 70% of their views from a single region. Khan and Vong (2014) analyzed top viral videos by building an empirical model to understand how videos achieve virality and the relationship between different aspects such as social and non-social capital. They found that along with view count, offline social capital and network dynamics are the strongest contributors to virality.
Several models have been proposed to predict the popularity of videos on YouTube. Pinto et al. (2013) proposed two regression models to predict the popularity of videos using two YouTube video datasets. They found that variables such as the number of comments, ratings, and users who favorited the video are usually positively correlated with the number of views and do not help the regression model. Instead, information related to the user who posted the video and the subscriber count proved most useful. Hovden (2013) conducted an early study that investigated the productivity and impact of the top video channels on YouTube by applying h-index and g-index bibliometrics. Music video-based channels had a high impact appearing in the g-index rankings, whereas video blogs and mini-shows ranked top in the h-index rankings. They found that these metrics were best if used to compare channels of a related field. Yu et al. (2015) collected 172,000 videos from YouTube and proposed popularity phases to describe a YouTube video’s lifecycle. They found multiple stages of popularity with increases and decreases over several months for most videos, with phases related to content and popularity. Ma et al. (2017) proposed a Lifetime Aware Regression Model (LARM) to predict long-term video popularity using early accessible features such as views, likes, dislikes, comments, and video categories. They used two YouTube datasets to validate their model and found that it outperformed other baselines by up to 20% in terms of the prediction error reduction rate. Trzciński and Rokita (2017) proposed a Support Vector Regression model with Gaussian radial basis functions to predict the popularity of videos on YouTube and Facebook. They found that social features are more strongly associated with video popularity predictions than visual features.
Most of the previous research on YouTube focuses on the potential use of the platform as a tool for communicating information on health, politics, or science and as a means for providing education for students to facilitate learning. Researchers have built models to predict the popularity of videos on YouTube through metadata about the videos, and they have conducted surveys and performed literature reviews to understand users’ behavior. Most research to date has not explored the connection between YouTube videos and research outcomes. Based on our research, the present paper is one of the first in which the relationship between research articles and YouTube videos is analyzed through a range of social media features.
Methodology
Data collection and preprocessing
The data for this study came from two sources: Altmetric.com and YouTube. We analyzed these datasets individually and then combined them to form final datasets consisting of several features, which consist of social media mentions of the research articles and the metadata of the YouTube videos citing the research articles, as shown in Table 1 and Table 2. Using these datasets, we applied visualization techniques and statistical models for analysis and built machine learning models to predict important features in the dataset.Fig. 1 Data collection process
The data collection process for this research is shown in Figure 1. We extracted 500,000 random research articles from the Altmetric API, which includes metadata of the research articles and mentions of research outputs on various social media networks. We named this dataset A1; it includes research articles cited in videos as well as research articles not cited in videos. Descriptions of the features in this dataset are presented in Table 1.Table 1 Altmetric features of datasets A1 and A2
Feature Feature description
Altmetric ID Unique ID for each research article
Title Title of a research article
Publication date Publication date of a research article
Mendeley readers Number of times a reference to a research article is archived on Mendeley
Scopus subjects Subjects of the research article
News Number of times a research article is mentioned in news contexts
Twitter Number of times an article has been tweeted on Twitter
Facebook Number of times an article is shared on Facebook
Policy Number of times an article is shared in policy documents
GooglePlus Number of times an article is shared on Google Plus
Reddit Number of times an article is mentioned on Reddit
Blogs Number of times an article is mentioned or featured in blogs
Patent Number of times an article is mentioned or featured in patents
Wikipedia Number of times an article is cited on Wikipedia
Video citations Number of times an article is mentioned in the description of videos (i.e., cited) on YouTube
Citation Number of times a research article is cited based on Dimensions.ai
YouTube links List of YouTube video links citing the publication (dataset A2)
YouTube citation Binary variable indicating whether or not the publication is cited on YouTube. This is the target variable for Model 1 and is used in dataset A1
Scholarly citation Binary variable indicating whether the publication has more citations than the median number of citations, which is 27 for all publications in dataset A2. This is the target variable for Model 2 and is used in dataset A2
The Altmetric dataset provided the number of videos in which an article was cited with links to those videos. We checked all those links and verified they belonged to the YouTube platform. Each video on YouTube cited research articles through the description of the video uploaded to the channel. If the value of the feature Video was greater than 0, then we set the target variable to 1. Otherwise, we set the target variable to 0. We named this binary feature, which served as a target variable, “YouTube Citation.”
To further explore articles cited in videos, we selected all the research articles in altmetric.com that are cited by at least one video on YouTube. Using the Altmetric API, we collected research articles cited by video along with the list of video links citing the publication. We found a total of 160,283 research articles cited in videos on YouTube. We extracted these articles and created dataset A2, which comprises Altmetric IDs (a unique ID for each research article), metadata of those research articles, and post counts from various social media platforms, as shown in Table 1. The features are the same for both datasets with the exception of the target variable, which is “YouTube Citation” for A1 and “Scholarly Citation” for A2. Of the original 160,283 research articles in dataset A2, 9,659 records did not have valid video links. We, therefore, removed these records, resulting in a final count of 150,624. The Scopus subjects of the research articles were split to include only the major subjects, and the sub-subjects were removed. A total of 22 unique major subjects were analyzed further, as described in Sect. 3.4. For 21,905 research articles, no major subject or sub-subject was defined. We, therefore, converted these empty values to “Other” subjects.
We then created dataset B through the video links collected in dataset A2 under “YouTube Links” by extracting the videos’ metadata through the YouTube API. There were 94,130 unique video links in dataset B, of which 199 video links were unavailable, leaving 93,931 videos with available links and containing the YouTube video ID or link, the title of the video, views, likes, dislikes, description, the number of comment counts, and cited IDs of Altmetric articles. It is important to note that an article could be cited in more than one video and that one video could cite more than one article. Dataset B contains only the metadata of videos citing research articles, as shown in Table 2.Table 2 Features from YouTube
Feature Feature description
Link YouTube unique link or ID of video
Cited ID Altmetric IDs of cited research articles
Title Title of YouTube video
Views Total views of a YouTube video
Likes Total likes of a YouTube video
Dislikes Total dislikes of a YouTube video
SubNo Total subscriber count of the channel posting the video
Pubdate Publication date of the video
Description Description of the video as provided by the channel
Video Category Category of the video as stated by the uploader
Comments Number of comments posted on the YouTube video
Video Views Binary variable indicating whether or not the video has more than the median number of views, which is 1,139 for all the videos in dataset B. This is the target variable for Model 3.
In dataset B, of the 93,931 videos, 11,710 had no “Likes” values, and 2,553 had null values in the Likes feature, which both were converted to 0 “Likes .” Similarly, 42,673 videos had no “Dislikes,” and 2,554 null values in the Dislike feature were converted to 0 “Dislikes.” In addition, 64 videos had no “Views” in the Views feature and were converted to 0 “Views.” The channel subscriber count is presented in a textual form such as “1.2M” or “330K” and was converted appropriately to integer values. Features such as “Views,” “Likes,” “Dislikes,” “Subno,” and “Comments” were converted into integers from strings. For the feature “Pubdate,” there were 4 null values and 2,823 values that included “Premiered on Date,” which were changed to a date format from a string. We checked the “Category” feature of videos and found 15 categories out of the 29 major categories on YouTube TechPostPlus (2019). There were 2,126 “Category” values different from the 15 categories, which we changed to the “Undefined” category.
Approach
In our approach to answering RQ1, we use dataset A1 to build our first machine learning model to predict video citation. Analyzing the important features of the first model helped us further explore the relationship between videos and articles and is also an indirect indicator of popularity. The analysis of dataset A1 revealed a class-imbalance problem while building the machine learning model, as 84% of research articles were not cited in videos. This shows that the majority of articles are not cited in videos, but popular articles might be cited in videos. For the binary feature “YouTube Citation,” the class 0 value denoting a research article not cited in videos contained 419,886 records, whereas class 1 indicating a research article cited in videos had 80,114 records.
In a real-world classification of any given dataset, the classes have a high chance of imbalance. Thus, the classes are not relatively equal in number, i.e., one of the class values is higher than the others. However, there are several techniques to resolve this issue. A class-imbalance problem can be resolved by either oversampling the minority class or undersampling the majority class. The goal was to process the imbalanced data before feeding it into the classifier and, in this way, overcome the fact that the classifier is more sensitive to the majority class and less sensitive to the minority class, resulting in the prediction of the majority class. A limitation of oversampling a minority class in an imbalanced dataset is that it could lead to overfitting, as the existing values are copied in this technique. The concern with undersampling is that essential data can be missed.
We applied a hybrid method to dataset A1, combining random oversampling and undersampling techniques. In the case of oversampling applied to the dataset, the minority class samples were increased to equal 0.5 of the majority class samples. After oversampling the dataset, we applied undersampling in which the majority class samples were downsampled to equal 0.8 of the minority class samples. The class label counts from the dataset that resulted from applying the hybrid method were as follows: 262,428 for class 0, which denotes a research article not cited in videos, and 209,943 for class 1, which denotes a research article. This reduced the effect of the class-imbalance problem for dataset A1. We then applied all the classification models to the resulting dataset A1 to determine which model performed best.
To answer RQ2, we combined dataset B with dataset A2 to create datasets C1 and C2, our final datasets, which we used in building models to predict article citations and video views, respectively. The second model used dataset C1 and the features utilized are shown in Table 4. The feature “Scholarly Citation" described in Table 1 is the target variable for the second model, which represents article citations. Citation analysis of articles is one of the indicators of scholarly impact and can help identify the important features related to scholarly impact through videos on YouTube. The final model is built using dataset C2 and the features utilized are shown in Table 4. The feature “Video views" is the target feature for the third model described in Table 2. Views of a YouTube video are associated with popularity and are a potential indicator of societal impact. Important features of the model can help in examining features related to societal impact through views of videos. A description of all the datasets and available features is shown in Table 3.Table 3 Metadata about the Datasets utilized in our work. ( * =features averaged over all research articles; ** = features averaged over all videos citing research articles)
Dataset Description Features
A1 Random 500,000 Research articles from Altmetric.com Altmetric ID, Title, Publication Date, Scopus Subjects, Video Citation, Citation, News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Patent, Blogs, Wikipedia, YouTube Citation
A2 All 150,624 Research articles from Altmetric.com cited in available videos (YouTube) Altmetric ID, Title, Publication Date, Scopus Subjects, Video Citation, Citation, News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Patent, Blogs, Wikipedia, YouTube Links, Scholarly Citation
B All 93,931 available videos citing research articles Link, Title, Views, Likes, Dislikes, SubNo, Pubdate, Description, Video Category, Comments, Video Views, Cited Altmetric IDs
C1 150,624 Research articles with metadata of all videos citing articles Altmetric ID, Title, Publication Date, Scopus Subjects, Video Citation, Citation, News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Scholarly Citation, Patent, Blogs, Wikipedia, Video Views*, Video Likes*, Video Dislikes*, Video SubNo*, Video Comments*
C2 93,931 YouTube videos with metadata of articles cited by each video Link, Title, Views, Likes, Dislikes, SubNo, Pubdate, Description, Video Category, Comments, Video Views, Video Citation**, Citation**, News**, Twitter**, Facebook**, Policy**, Google+**, Reddit**, Mendeley Readers**, Patent**, Blogs**, Wikipedia**
To determine the importance of video citations for popularity or increasing the citations of a research article, we combined datasets A2 and B to form dataset C1, which consists of all the research articles cited by a video on YouTube with the links to the videos and the metadata of those videos citing that research article. Dataset C1 was created by adding video metadata from dataset B to its link present in the Video links of dataset A2. The final dataset C1 comprises 150,624 research articles cited by 93,931 unique video links. The features of the videos in dataset C1 have multiple values, as each research article had video citations ranging from 1 to 814 videos. Numerous videos can cite an article, and each video has different values for its features. Therefore, in building our models, we averaged the values of all the features of the YouTube videos citing a research article. For example, for a research article cited by three videos with respective view counts of 35634, 2733, and 1, we determined a single average value of 12,794.34.
To further analyze the YouTube videos citing research articles, we combined datasets B and A2 to create dataset C2, which consists of 93,931 YouTube videos citing 150,624 research articles, along with the metadata of the videos and the altmetric information of the research articles cited in the video descriptions. Dataset C2 was created by adding altmetric data from dataset A2 to its altmetric ID present in the feature for the cited ID in dataset B. The altmetrics features in dataset C2 have multiple values, as each YouTube video cited numerous research articles ranging from 1 to 82. Therefore, we averaged the numerical features for the research articles. For example, if a video cites five research articles and those articles had Twitter mentions such as 80, 63, 31, 27, 15, they were averaged to a single value of 43.2. It is important to note that in dataset C1, an article could be cited by multiple videos, whereas in dataset C2, a single video could cite numerous articles. For data exploration, we used datasets A1, A2, B, and C1, whereas in building the machine learning models, we used only datasets A1, C1, and C2. The resulting datasets are publicly available as a comma-separated-value file (CSV)1.
The datasets used in building the models differ from one another and are presented in Table 4, along with features utilized in each model and the target variable. Given its correlation with Mendeley Readers, we removed Citations from dataset A1. For Model 3, in dataset C2, Citations and Blogs were removed as they are correlated with other features. For each model, we used Scikit-learn (Pedregosa et al., 2011) to implement classification models such as Bernoulli Naive Bayes, Random Forest, Decision Tree, and K-Nearest Neighbors (KNN). For the machine learning models, we applied k-fold cross-validation to the dataset and average evaluation metrics over 20 folds. To evaluate each model, we used the metrics precision, recall, F1-score, and accuracy. The four models are described along with the evaluation metrics. We report the essential features in building all the models to identify the importance of those attributes in relation to the target variables and our research questions.Table 4 Datasets, features, and target variable considered for all models (* =features averaged over all research articles; ** = features averaged over all videos citing research articles)
Model Dataset Features Target
1. A1 News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Patent, Blogs, Wikipedia YouTube Citation
2. C1 Mendeley Readers, Twitter, Facebook, Policy, Google+, Patent, Wikipedia, Video Citations, Video views**, Subno**, Comments** Scholarly Citation
3. C2 Mendeley Readers*, Video Mentions*, Facebook*, Google+*, Twitter*, Wikipedia*, Policy*, Patent*, Reddit*, Video Category, SubNo Video Views
Results
We report the results of our work in two parts. The first part describes the exploration of the dataset, which helps answer RQ1. The second part deals with building machine learning models to predict different metrics for answering RQ2. We provide an analysis of the datasets through visualization and statistical techniques in the first part and then build classification models for the second part.
Data exploration
Fig. 2 Number of records of Scopus subjects by year in dataset A2
Fig. 3 Number of video mentions for Scopus subjects in dataset A2
To explore the second part of RQ1 and identify the popular subjects of articles cited in videos, we analyzed the research articles in dataset A2 and found that an increasing number of research articles have been cited in videos in the last two decades (Figure 2). The articles most cited in videos each year were the “Medical and Health Sciences” Scopus subject. As the data was collected at the end of 2020, we can see a drop in the number of research articles cited in videos in 2019 and 2020 compared to previous years. This could mean that articles tend not to be cited in videos shortly after publication, with citations of this kind taking time to accrue. We also found that research articles with the Scopus subjects Medical and Health Sciences, Biological Sciences, and Psychology and Cognitive Sciences had the highest number of video mentions in comparison to other subjects (Figure 3). This indicates that most of the research articles cited in the videos were related to medicine and biochemistry. The citation count for these subjects was also higher than for other subjects.Fig. 4 Number of YouTube videos in each category per year
Fig. 5 Video views of YouTube categories
The popular video categories on YouTube citing research articles can be seen in Figure 4. We can see that an increasing number of videos have cited research articles in the last decade. The majority of the videos citing research articles are categorized as Education, Science & Technology, or People & Blogs. It is also worth noting that People & Blogs was the third-highest category of videos to cite research articles, even though most of the research articles cited belong to Medicine & Biochemistry. Figure 5 shows the number of views of YouTube videos in dataset B based on the video category. The most-viewed videos citing research articles are categorized as Science & Technology and Education due to the high number of these videos in the dataset. Even though fewer videos were categorized as Entertainment in dataset B, this category garnered the fourth-highest view count.Fig. 6 Correlation matrix for all the numerical features in dataset C1
To explore the relationship between articles and video features, we plotted a correlation matrix between the features to answer RQ1. Based on the correlation matrix of the features in dataset C1, we can observe that Likes and Dislikes are highly correlated with Views (Figure 6). To reduce complexity while building our machine learning models, we removed highly correlated features, i.e., features with a correlation greater than 0.5. Thus, we removed Likes and Dislikes as they had a correlation of 0.85 and 0.53, respectively, keeping only video Views as the sole feature relating to the videos. We also removed Blog as it had a 0.61 correlation with News, and Citation was also removed due to its correlation of 0.59 with Mendeley Readers.
Building models
Fig. 7 Classification results for Model 1
Fig. 8 Important features for the Random Forest classifier for Model 1
To explore the relationship between articles and videos as well as predict the impact of popularity, we predicted whether an article was cited in at least one video on YouTube. This identified important social media features of an article influencing YouTube citation. In the first model, Random Forest yielded the best results, as shown in Figure 7, achieving an accuracy level of 0.95 and an F1-score of 0.94. Decision Tree performed second best with an accuracy of 0.92 and an F1-score of 0.91. Figure 8 shows the feature importance of the Random Forest classifier in predicting video citations. Twitter and News were the most important features, followed by Mendeley Readers and Blog.Fig. 9 Classification results for Model 2
Fig. 10 Important features for the Random Forest classifier for Model 2
To predict whether an article will reach a level of popularity or scholarly impact, we built the second model to answer RQ2. For the second model, Random Forest performed the best overall, with an accuracy level and an F1-score of 0.80. KNN performed second best with an accuracy level of 0.75 and an F1-score of 0.78. Figure 9 shows the evaluation metrics of the classification models built on dataset C1 to predict the binary target variable. Figure 10 shows feature importance in the model built by the Random Forest classifier. We can see that the average number of Video Views citing a research article is the second-most important feature, after Mendeley Readers, in classifying citations of research articles.Fig. 11 Classification results for Model 3
Fig. 12 Most important features for the Random Forest classifier for Model 3
We built the third model with the features and the target variable mentioned in Table 4 to answer RQ2. The third model correlates video popularity and societal impact. The Video Category feature was converted to numerical features using One Hot Encoding. Figure 11 shows the results of the classifiers: Random Forest again performed best, achieving an accuracy level of 0.81 and an F1-score of 0.80, and KNN performed second best with an accuracy level of 0.79 and an F1-score of 0.78. Figure 12 shows feature importance in the model built by the Random Forest classifier. SubNo and Mendeley Readers were the most important features in building the model.
Discussion
Video citations of research articles may help increase the popularity of the articles in the research community and eventually increase citations of research articles. In this study, we analyzed citations of research articles in the descriptions of videos on YouTube. The rise of video citations over recent years, along with the increasing number of conferences requiring a video submission of accepted scholarly research, have paved the way to identify important features that contribute to the popularity and impact of research through the results found in Sects. 4.1 and 4.2. It is essential to analyze these video citations and the social media mentions of research articles to identify the crucial factors that improve the popularity of videos and research articles. We collected data from YouTube and Altmetric to discover hidden patterns and explore the relationship between research articles and video citations. We combined the datasets, analyzed them using visualization techniques, and built machine learning models to predict important target variables. For the analysis, we examined the combined datasets in relation to research articles and videos, which led us to build three datasets to predict video citations, video views, and citations of research articles.
From our analysis of the large A1 dataset of research articles, we found that around three-quarters of the dataset’s research articles were not cited in videos. In Sect. 4.1, we found that research related to Medicine and Biochemistry received the highest number of video citations. We also found that most of the videos citing research articles were in either the Science & Technology or the Education category. Videos categorized as Entertainment mentioned fewer research articles but attracted the fourth-highest number of views after Science & Technology, Education, and People & Blogs. This result suggests that scientific results are being used for entertainment and educational purposes. Through our analysis of the video dataset B, we found positive correlations between the number of video views, likes, and dislikes, as seen in Figure 6. This is self-evident since users usually view a video before adding a like or dislike. This is also in line with findings reported by Welbourne and Grant (2016) and Pinto et al. (2013), who found that other video metadata such as likes, dislikes, and comment counts are highly correlated with video views. Given these correlations, we removed all these features from consideration, with the exception of the video views feature. However, contrary to previous findings, the comment count did not have a high correlation with views of scientific videos, as seen in Figure 6. This hesitancy to comment publicly on scientific videos could be related to the hesitancy to comment publicly on research articles. Around 80% of researchers considered that their comments might affect their reputation or how others perceive them (Hemminger & TerMaat, 2014).
For our second part of the study, as can be seen in Sect. 4.2, we considered four classification algorithms-Bernoulli Naive Bayes, Random Forest, Decision Tree, and K-Nearest Neighbors-and applied them to each of the three cases to predict three target variables. We evaluated the models based on precision, recall, accuracy, and F1-score. Prediction of whether a research article is cited in a video is the first model of our study for which we used social media mentions of the research article to predict a binary variable indicating video citation. Twitter Mentions and News Mentions of research articles were important factors that contributed to attracting a video citation for a research article. Research articles mentioned in news and tweets cause buzz across the internet and have a high chance of being cited in videos. Citations show the importance and usefulness of a research article and are a strong indication of its popularity. The second model in this study predicted the binary variable, indicating whether a research article had more citations than the median of all the citations of research articles in the dataset. We found that Mendeley Readership and Video Views contributed greatly to this scholarly impact prediction. This result is in line with previous studies in which Mendeley readership is found to be important for predicting citation counts (Thelwall & Nevill, 2018). However, Video Views are a new feature that plays a vital role in garnering citations, reaching wider audiences, and fostering the popularity and impact of research articles. Our third model predicted Video Views. We found that the subscriber count of a channel, Mendeley Readers, and Twitter Mentions of research articles were important in predicting views of videos citing those research articles. This shows that the number of followers for a YouTube channel plays an essential role in the number of scientific video views. Random Forest achieved the best results for all the models built in this study.
A limitation of this study is that it relied on social media features from a single source Altmetric.com. It also does not consider other related factors, such as the textual content of the research or the video content. Another limitation of our work is that the built models did not consider the temporal nature of the features present in the various datasets, which needs continuous data collection. We also assumed that citations and views could be considered indicators of scholarly and societal impact, respectively, whereas other factors can also influence these impacts. Moreover, the prediction of the target feature of the models can only be applicable after the accumulation of important social media features, which is a cold-start problem. Furthermore, we used multiple visualizations to explore trends and patterns in our collected datasets. One possible improvement for further studies is to relate and synthesize information from these visualizations (Sun et al., 2021a, b; Shaikh et al., 2022), which may be help gain some more in-depth insights.
Our process offers insight into ways to make improvements in future iterations by incorporating some traditional factors such as the h-index of authors, scholarly venues, and temporal features that have been useful in other studies. Additionally, it would be helpful to distinguish between subjects and research fields to provide a basis for building models for individual areas that would, in turn, improve the results. Furthermore, we considered Dimensions Citations, and it would be worthwhile to check other sources such as Google Scholar. Another direction to explore is the use of research in videos. Do the videos include results drawn principally from the abstract, methods, or results section? Further, the reasons for including references to research articles in videos remain unexplored. For example, do the videos cite research to promote content, provide a message within the video, increase public trust in the content, sell a product, or even spread misinformation? Lastly, our results could be compared with research focused on measuring and predicting other types of societal impact, such as in economic, political, and health areas.
Conclusion and future work
In this study, we analyzed the impact of YouTube on research by building classification models to predict video citations, scholarly citations, and video views. We found that fewer research articles were cited in videos in a large dataset of research articles. Most of the articles cited in videos belonged to the Medicine and Biochemistry categories. These subjects also have the highest number of video citations in comparison to other subjects. The number of video citations has been increasing in recent years, with most of the videos citing research articles categorized as Science & Technology, Education, and People & Blogs. Science & Technology and Education are the categories of videos that garnered the most views. We found a high-to-mid correlation among views, likes, dislikes, and the subscriber count of videos. We also observed that Random Forest performed the best of all the models built on the datasets. We found that News mentions and Twitter mentions of a research article are important factors in determining a research article’s video citation. Another important finding of the study is that the view count of a video was an important feature in predicting a research article’s citations. For future work, we plan to use more textual and temporal features of the videos and articles. We will study the topics of videos citing research articles and the relationship between the video categories and the research articles’ subjects.
Acknowledgements
This research is supported in part by NSF Grants SMA-2022443, IIS-2002082, and the Research and Artistry Opportunity Grant from Northern Illinois University.
1 https://zenodo.org/record/4691941.
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References
AAO. (2021). Video submission instructions for aao. Retrieved April 04, 2021 from https://www.aao.org/annual-meeting/presenter/video-submission-instructions
Agazio J Buckley KM An untapped resource: using youtube in nursing education Nurse educator 2009 34 1 23 28 10.1097/01.NNE.0000343403.13234.a2 19104342
Akella AP Alhoori H Kondamudi PR Freeman C Zhou H Early indicators of scientific impact: Predicting citations with altmetrics Journal of Informetrics 2021 15 2 101128 10.1016/j.joi.2020.101128
Alexa. (2021). Alexa - top sites. Retrieved April 01, 2021 from https://www.alexa.com/topsites/
Beehler, B., & Griffiths, D. (2020). Going viral: Taking your conference online for covid-19. Retrieved April 03, 2021 from https://www.insidehighered.com/advice/2020/03/16/how-shift-your-conference-online-light-coronavirus-opinion
Bonifati, A., Guerrini, G., Lutz, C., Martens, W., Mazilu, L., Paton, N., Salles, M. A. V., Scholl, M. H., & Zhou, Y. (2020). Holding a conference online and live due to covid-19.
Borghol, Y., Ardon, S., Carlsson, N., Eager, D., & Mahanti, A. (2012). The untold story of the clones. Proceedings of the 18th ACM SIGKDD international conference on Knowledge discovery and data mining - KDD ’12.
Bornmann L Do altmetrics point to the broader impact of research? an overview of benefits and disadvantages of altmetrics Journal of Informetrics 2014 8 4 895 903 10.1016/j.joi.2014.09.005
Bornmann L Haunschild R Adams J Do altmetrics assess societal impact in a comparable way to case studies? an empirical test of the convergent validity of altmetrics based on data from the uk research excellence framework (ref) Journal of Informetrics 2019 13 1 325 340 10.1016/j.joi.2019.01.008
Brodersen, A., Scellato, S., & Wattenhofer, M. (2012). Youtube around the world: Geographic popularity of videos. In Proceedings of the 21st International Conference on World Wide Web, WWW ’12, page 241–250, New York, NY, USA. Association for Computing Machinery.
CHI. (2021). Technical requirements and guidelines for videos at chi. Retrieved April 04, 2021 from https://chi2021.acm.org/for-authors/presenting/papers/technical-requirements-and-guidelines-for-videos-at-chi
Chtouki, Y., Harroud, H., Khalidi, M., & Bennani, S. (2012). The impact of youtube videos on the student’s learning. In 2012 International Conference on Information Technology Based Higher Education and Training (ITHET), pp. 1–4.
Falk MT Hagsten E When international academic conferences go virtual Scientometrics 2021 126 1 707 724 10.1007/s11192-020-03754-5 33230351
Figueiredo, F., Almeida, J. M., Benevenuto, F., & Gummadi, K. P. (2014). Does content determine information popularity in social media? a case study of youtube videos’ content and their popularity. In Proceedings of the SIGCHI Conference on Human Factors in Computing Systems, CHI ’14, page 979-982, New York, NY, USA. Association for Computing Machinery.
Freeman, C., Alhoori, H., & Shahzad, M. (2020). Measuring the diversity of facebook reactions to research. Proc. ACM Hum.-Comput. Interact., 4(GROUP).
Freeman, C., Roy, M. K., Fattoruso, M., & Alhoori, H. (2019). Shared feelings: Understanding Facebook reactions to scholarly articles. In 2019 ACM/IEEE Joint Conference on Digital Libraries (JCDL), pp. 301–304.
Hemminger BM TerMaat J Annotating for the world: Attitudes toward sharing scholarly annotations Journal of the Association for Information Science and Technology 2014 65 11 2278 2292 10.1002/asi.23124
Hovden R Bibliometrics for internet media: Applying the h-index to youtube Journal of the American Society for Information Science and Technology 2013 64 11 2326 2331 10.1002/asi.22936
Jaffar AA Youtube: An emerging tool in anatomy education Anatomical Sciences Education 2012 5 3 158 164 10.1002/ase.1268 22383096
Johnston AN Barton MJ Williams-Pritchard GA Todorovic M Youtube for millennial nursing students; using internet technology to support student engagement with bioscience Nurse Education in Practice 2018 31 151 155 10.1016/j.nepr.2018.06.002 29906632
June S Yaacob A Kheng YK Assessing the use of youtube videos and interactive activities as a critical thinking stimulator for tertiary students: An action research International Education Studies 2014 7 56 67 10.5539/ies.v7n8p56
Khan G Vong S Virality over youtube: an empirical analysis Internet Res. 2014 24 629 647 10.1108/IntR-05-2013-0085
Kousha K Thelwall M Bickley M The high scholarly value of grey literature before and during covid-19 Scientometrics 2022 127 6 3489 3504 10.1007/s11192-022-04398-3 35615527
Liu M Bu Y Chen C Xu J Li D Leng Y Freeman RB Meyer ET Yoon W Sung M Jeong M Lee J Kang J Min C Song M Zhai Y Ding Y Pandemics are catalysts of scientific novelty: Evidence from covid-19 Journal of the Association for Information Science and Technology 2022 73 8 1065 1078 10.1002/asi.24612 35441082
Ma, C., Yan, Z., & Chen, C. W. (2017). Larm: A lifetime aware regression model for predicting youtube video popularity. In Proceedings of the 2017 ACM on Conference on Information and Knowledge Management, CIKM ’17, pp. 467-476, New York, NY, USA. Association for Computing Machinery.
Madathil KC Rivera-Rodriguez AJ Greenstein JS Gramopadhye AK Healthcare information on youtube: A systematic review Health Informatics Journal 2015 21 3 173 194 10.1177/1460458213512220 24670899
Pedregosa F Varoquaux G Gramfort A Michel V Thirion B Grisel O Blondel M Prettenhofer P Weiss R Dubourg V Vanderplas J Passos A Cournapeau D Brucher M Perrot M Duchesnay Édouard Scikit-learn: Machine learning in python Journal of Machine Learning Research 2011 12 85 2825 2830
Pinto, H., Almeida, J. M., & Gonçalves, M. A. (2013). Using early view patterns to predict the popularity of youtube videos. In Proceedings of the Sixth ACM International Conference on Web Search and Data Mining, WSDM ’13, pp. 365–374, New York, NY, USA. Association for Computing Machinery.
Price, M. (2020). As covid-19 forces conferences online, scientists discover upsides of virtual format. Retrieved April 03, 2021 from https://www.sciencemag.org/careers/2020/04/covid-19-forces-conferences-online-scientists-discover-upsides-virtual-format
Rodriguez, S. (2021). Youtube is social media’s big winner during the pandemic. Retrieved April 06, 2021 from https://www.cnbc.com/2021/04/07/youtube-is-social-medias-big-winner-during-the-pandemic.html
Shahzad M Alhoori H Public reaction to scientific research via twitter sentiment prediction Journal of Data and Information Science 2022 7 1 97 124 10.2478/jdis-2022-0003
Shahzad M Alhoori H Freedman R Rahman SA Quantifying the online long-term interest in research Journal of Informetrics 2022 16 2 101288 10.1016/j.joi.2022.101288
Shaikh, A. R., & Alhoori, H. (2019). Predicting patent citations to measure economic impact of scholarly research. In 2019 ACM/IEEE Joint Conference on Digital Libraries (JCDL), pp. 400–401.
Shaikh, A. R., Koop, D., Alhoori, H., & Sun, M. (2022). Toward systematic design considerations of organizing multiple views. In 2022 IEEE VIS conference.
Snelson C Rice K Wyzard C Research priorities for youtube and video-sharing technologies: A delphi study British Journal of Educational Technology 2012 43 1 119 129 10.1111/j.1467-8535.2010.01168.x
Suciu, P. (2021). Youtube remains the most dominant social media platform. Retrieved June 05, 2021 from https://www.forbes.com/sites/petersuciu/2021/04/07/youtube-remains-the-most-dominant-social-media-platform/?sh=284719d36322
Sud P Thelwall M Evaluating altmetrics Scientometrics 2014 98 2 1131 1143 10.1007/s11192-013-1117-2
Sugimoto CR Work S LariviÃre V Haustein S Scholarly use of social media and altmetrics: A review of the literature Journal of the Association for Information Science and Technology 2017 68 9 2037 2062 10.1002/asi.23833
Sun, M., Namburi, A., Koop, D., Zhao, J., Li, T., & Chung, H. (2021a). Towards systematic design considerations for visualizing cross-view data relationships. IEEE Transactions on Visualization and Computer Graphics.
Sun, M., Shaikh, A. R., Alhoori, H., & Zhao, J. (2021). Sightbi: Exploring cross-view data relationships with biclusters. IEEE Transactions on Visualization and Computer Graphics, 28(1), 54–64.
Susarla A Oh J-H Tan Y Social networks and the diffusion of user-generated content: Evidence from youtube Information Systems Research 2012 23 1 23 41 10.1287/isre.1100.0339
TechPostPlus (2019). Youtube video categories list. Retrieved April 05, 2021 from https://techpostplus.com/youtube-video-categories-list-faqs-and-solutions/
Thelwall, M., & Nevill, T. (2018). Could scientists use altmetric.com scores to predict longer term citation counts? Journal of Informetrics, 12(1):237-248.
Trzciński T Rokita P Predicting popularity of online videos using support vector regression IEEE Transactions on Multimedia 2017 19 11 2561 2570 10.1109/TMM.2017.2695439
Welbourne DJ Grant WJ Science communication on youtube: Factors that affect channel and video popularity Public Understanding of Science 2016 25 6 706 718 10.1177/0963662515572068 25698225
Weller, K., Welpe, I. M., Wollersheim, J., Ringelhan, S., & Osterloh, M. (2015). Social Media and Altmetrics: An Overview of Current Alternative Approaches to Measuring Scholarly Impact, pp. 261–276. Springer
YouTube. (2021). Press - youtube. Retrieved April 01, 2021 from https://www.youtube.com/about/press/
Yu, H., Xie, L., & Sanner, S. (2015). The lifecyle of a youtube video: Phases, content and popularity. In ICWSM.
| 0 | PMC9734683 | NO-CC CODE | 2022-12-14 23:28:30 | no | Scientometrics. 2022 Dec 7;:1-23 | utf-8 | Scientometrics | 2,022 | 10.1007/s11192-022-04574-5 | oa_other |
==== Front
Scientometrics
Scientometrics
Scientometrics
0138-9130
1588-2861
Springer International Publishing Cham
4574
10.1007/s11192-022-04574-5
Article
YouTube and science: models for research impact
http://orcid.org/0000-0002-6046-4638
Shaikh Abdul Rahman [email protected]
Alhoori Hamed [email protected]
Sun Maoyuan [email protected]
grid.261128.e 0000 0000 9003 8934 Northern Illinois University, DeKalb, USA
7 12 2022
123
31 8 2021
9 9 2022
© Akadémiai Kiadó, Budapest, Hungary 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Video communication has been rapidly increasing over the past decade, with YouTube providing a medium where users can post, discover, share, and react to videos. There has also been an increase in the number of videos citing research articles, especially since it has become relatively commonplace for academic conferences to require video submissions. However, the relationship between research articles and YouTube videos is not clear, and the purpose of the present paper is to address this issue. We created new datasets using YouTube videos and mentions of research articles on various online platforms. We found that most of the articles cited in the videos are related to medicine and biochemistry. We analyzed these datasets through statistical techniques and visualization, and built machine learning models to predict (1) whether a research article is cited in videos, (2) whether a research article cited in a video achieves a level of popularity, and (3) whether a video citing a research article becomes popular. The best models achieved F1 scores between 80% and 94%. According to our results, research articles mentioned in more tweets and news coverage have a higher chance of receiving video citations. We also found that video views are important for predicting citations and increasing research articles’ popularity and public engagement with science.
Keywords
Social media
YouTube
Societal impact
Research impact
Science of science
MetaScience
Machine learning
Altmetrics
Scientometrics
Scholarly communication
http://dx.doi.org/10.13039/100000001 National Science Foundation SMA-2022443 Shaikh Abdul Rahman http://dx.doi.org/10.13039/100000001 National Science Foundation IIS-2002082 Alhoori Hamed
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pmcIntroduction
Social media platforms have seen tremendous growth and changed communication paradigms in the past decade, with information posted online within seconds and shared through multiple channels worldwide almost instantaneously. Immensely popular platforms such as Twitter, Facebook, and YouTube have shifted information-sharing on the internet from a largely one-way process of posting information to a proprietary website to one in which information becomes available rapidly through many websites and user accounts and in many forms and iterations, and in which responses to original content can be voiced and shared broadly based on a few manual clicks or via a preset automated process. This shift has seen trillions of posts, tweets, and video uploads on multiple platforms, which have had a far-reaching impact on most, if not all, areas of human endeavor-including scholarly research. Video communication has rapidly increased on social media sites such as YouTube, Instagram, Twitter, and Facebook. Launched in 2005, YouTube, in particular, has played a vital role in increasing video communication. In regard to scholarly work, research outcomes from this venue are increasingly being shared on several social media platforms. Further, it is by no means unusual for YouTube video descriptions to include citations of research articles, which could play an important role in disseminating research. In this paper, we analyze those video citations to better understand how research is being disseminated through such a new way of citation and the implications of this kind of sharing.
In addition to the traditional citation-based analysis, it is necessary to track web-driven scholarly interactions and measure the impact of research beyond scholarly communities. Altmetrics or alternative metrics (Sugimoto et al., 2017) specifically track scholarly mentions on online platforms to analyze and measure the impact of scholarly products. Altmetrics track many different metrics, including, for example, users who have read or shared an article, even though those users may not formally cite it. Altmetrics could be used to measure the broader impact of a research article through many channels and even measure scholarly impact by predicting citations (Thelwall & Nevill, 2018; Akella et al., 2021). As a result, there is a movement toward digital libraries and publishers providing altmetrics on their websites. Several researchers have analyzed altmetrics and their potential for measuring societal impact. For example, Bornmann et al. (2019) used altmetrics data from the UK Research Excellence Framework (REF) in a case study designed to assess the validity of altmetrics and found that they have the potential to capture societal impact in relation to several distinct perspectives. In the present paper, we demonstrate our use of these social media metrics and features from altmetrics gathered from different platforms to further understand the role of YouTube video citations in the dissemination and societal impact of research.
Social media has become the primary source for real-time updates of various kinds of news worldwide, and YouTube is the principal site for video sharing (Susarla et al., 2012). Snelson et al. (2012) found that although YouTube is the most prolific online video-sharing platform, it is also the most under-researched social media platform. Every minute, more than 500 hours of video are uploaded to YouTube, which gets billions of views all over the world (YouTube, 2021). This popularity has resulted in YouTube ranking as the second most viewed website globally, outranked only by Google (Alexa, 2021). The platform’s usability and functionality allow a wide range of videos to be shared by users of all skill levels worldwide, who can then interact with others who like, dislike, and/or comment on the videos. Those posting content create a channel on YouTube as an organizing principle and showcase their video content, and others can choose to subscribe in order to receive updates when new videos are posted. Diverse fields of videos disseminating real-time information related to entertainment, health, music, sports, education, and news are uploaded by different channels. Recently, there has been an increase in the use of YouTube due to the dissemination of information related to the recent global pandemic, COVID-19 (Suciu, 2021; Rodriguez, 2021).
The global COVID-19 pandemic has disrupted the lives of most people, requiring significant changes in many everyday practices. Social and professional activities worldwide have adapted new methods and processes to meet the challenges associated with these changes. In the academic world, as in other realms, annual conferences and society meetings are hosting events virtually (Falk & Hagsten, 2021) in order to continue the exchanges that foster research progress in those venues. This unique experience has provided unexpected opportunities for the research community to reach wider audiences and improve diversity, equity, and novelty (Price, 2020; Liu et al., 2022; Kousha et al., 2022). Beehler and Griffiths (2020) hosted the 20th annual meeting of Interdisciplinary Nineteenth-Century Studies (INCS) online and shared the steps they took and the challenges they faced in hosting the conference in that context. Among many important points, the researchers asked the hosts to record the conference events and post the videos online to continue the discussion after the event. They also encouraged the presenters and other attendees to circulate appropriate hashtags on social media, share discussions, and broadcast the event’s news. Similarly, Bonifati et al. (2020) shared their experience of hosting a joint conference online and provided a number of suggestions for doing so successfully, including implementing the practice of making videos of the presentations available to the public by posting them online after the conference. In such contexts, videos were mostly uploaded to the conference’s YouTube channel and often cited one or more articles in their description. In addition, many conferences require a video submission (CHI, 2021; AAO, 2021), and given that this is the case, there is a need to analyze and understand the characteristics and impact of these video citations within and beyond the scholarly community now that they are also available to the public.
The idea of YouTube videos citing research literature is relatively new and has enormous potential to improve the visibility and dissemination of research, leading to greater societal and scholarly impact in the long term. However, there are far fewer studies on the relationship between research articles and scientific YouTube videos compared to the relationship between such articles and other social media platforms. To understand and analyze this impact, we consider the following research questions: What is the relationship between scientific YouTube videos and research articles? And what video categories and scientific subjects are most popular on YouTube?
Can we build machine learning models to predict the societal and scholarly impact related to YouTube videos? If so, what are the important features and characteristics?
To answer these questions, we analyzed the citations of research articles in videos on YouTube. We collected datasets from YouTube and Altmetric.com and used statistical and visualization techniques to understand the trends and discover patterns in the datasets. We combined the collected datasets and built machine learning models to predict three target variables. First, we built classification models to predict whether a research article has received a YouTube video citation. These video citations may influence the popularity of the research article, so it is vital to identify the features that are most important for contributing to the prediction of video mentions of research articles. Second, the prediction of citations of a research article is essential to assessing its scholarly impact. To understand the contribution of videos to this impact, we built our second machine learning model to predict citations of a research article using social media mentions and features from videos citing the article on YouTube. Third, the number of views of a video indicates the popularity of its content. To identify the social media features that are most important in attracting these views, we built our third machine learning model, which draws on social media features to predict the number of views for a video citing a research article on YouTube. In summary, our contributions include: One of the first studies that examines the relationship between scientific YouTube videos and research articles.
An investigation of the societal and scholarly impact, characteristics, and popularity of YouTube videos through visualization, statistical techniques, and machine learning models.
A novel dataset of research articles and YouTube videos that researchers can use to study the effects of scientific YouTube videos on the scientific community and the public.
Related work
Users’ social interactions in the online world generate new forms of data that can be extracted and analyzed by developing new models to find undiscovered patterns beneficial to advances in research. The traditional analytical approach through scholarly citations limits measuring the impact within these scholarly boundaries. In contrast, altmetrics (Sud & Thelwall, 2014; Bornmann, 2014; Shaikh & Alhoori, 2019) can measure the impact of research in a more diverse way across multiple platforms and can help us to understand the direct and indirect impact of scholarly research. On this point, according to Weller et al. (2015), the proper use of altmetrics can help disseminate new scientific innovations to the public. Researchers have recently employed social media metrics to gauge public reaction to scientific findings (Freeman et al., 2019, 2020; Shahzad & Alhoori, 2022; Shahzad et al., 2022).
Now a feature of many people’s daily lives, YouTube has undeniably changed information-sharing worldwide. Since YouTube’s launch, researchers have studied the platform’s relationship with and impact on many aspects of daily life. For example, in a review of articles related to YouTube and health care, Madathil et al. (2015) found that health information is increasingly conveyed through YouTube, given that the platform offers a setting for users worldwide to upload, view, and communicate health information. Further, as an educational tool in nursing education (Agazio & Buckley, 2009; Johnston et al., 2018), the platform has been used to stimulate active learning on the part of students and enhance health care learning. Chtouki et al. (2012) found that YouTube videos can be a useful source of free educational content that improves student performance. In a study designed to assess the effectiveness of YouTube videos on a given anatomy problem, Jaffar (2012) found that 98% of the 91 medical students used YouTube extensively, and 92% agreed it helped them learn about anatomy. June et al. (2014) conducted research with a sample of 50 students to assess their critical-thinking skills and interactive activities while using videos on YouTube. According to the results, YouTube has vast potential as a learning tool because it enhances the students’ experience and improves their critical-thinking skills.
Due to the massive quantity of content on YouTube, it is generally difficult for most contributors to reach a vast audience. Therefore, there is no guarantee that posting content will create an impact. For this reason, the relative popularity of videos has become a research focus with the goal of determining the features that are principally responsible for a video achieving a high level of popularity. According to Susarla et al. (2012), older YouTube accounts with more videos posted have a greater chance of having an impact than do newer accounts with fewer videos. In an assessment of the effect of content-agnostic factors on video popularity, Borghol et al. (2012) found that views of videos shared previously by the uploader and video age are critical factors in determining video popularity. Figueiredo et al. (2014) used Amazon Mechanical Turk to evaluate YouTube videos and found that high-quality content resulted in tremendous popularity. To analyze the factors affecting the popularity of videos focused on science communication on YouTube, Welbourne and Grant (2016) studied 390 videos of this kind uploaded to 39 channels on the platform and extracted popularity metrics such as view count, comment count, subscriber count, share count, and rating. They found that user-generated content was more popular than professionally generated content. Brodersen et al. (2012) examined more than 20 million YouTube videos to determine the relationship between video popularity and geographic locality by analyzing the views from a spatial locality instead of a global locality. They found that the videos have a strong geographic interest, and around 50% of the videos had gained more than 70% of their views from a single region. Khan and Vong (2014) analyzed top viral videos by building an empirical model to understand how videos achieve virality and the relationship between different aspects such as social and non-social capital. They found that along with view count, offline social capital and network dynamics are the strongest contributors to virality.
Several models have been proposed to predict the popularity of videos on YouTube. Pinto et al. (2013) proposed two regression models to predict the popularity of videos using two YouTube video datasets. They found that variables such as the number of comments, ratings, and users who favorited the video are usually positively correlated with the number of views and do not help the regression model. Instead, information related to the user who posted the video and the subscriber count proved most useful. Hovden (2013) conducted an early study that investigated the productivity and impact of the top video channels on YouTube by applying h-index and g-index bibliometrics. Music video-based channels had a high impact appearing in the g-index rankings, whereas video blogs and mini-shows ranked top in the h-index rankings. They found that these metrics were best if used to compare channels of a related field. Yu et al. (2015) collected 172,000 videos from YouTube and proposed popularity phases to describe a YouTube video’s lifecycle. They found multiple stages of popularity with increases and decreases over several months for most videos, with phases related to content and popularity. Ma et al. (2017) proposed a Lifetime Aware Regression Model (LARM) to predict long-term video popularity using early accessible features such as views, likes, dislikes, comments, and video categories. They used two YouTube datasets to validate their model and found that it outperformed other baselines by up to 20% in terms of the prediction error reduction rate. Trzciński and Rokita (2017) proposed a Support Vector Regression model with Gaussian radial basis functions to predict the popularity of videos on YouTube and Facebook. They found that social features are more strongly associated with video popularity predictions than visual features.
Most of the previous research on YouTube focuses on the potential use of the platform as a tool for communicating information on health, politics, or science and as a means for providing education for students to facilitate learning. Researchers have built models to predict the popularity of videos on YouTube through metadata about the videos, and they have conducted surveys and performed literature reviews to understand users’ behavior. Most research to date has not explored the connection between YouTube videos and research outcomes. Based on our research, the present paper is one of the first in which the relationship between research articles and YouTube videos is analyzed through a range of social media features.
Methodology
Data collection and preprocessing
The data for this study came from two sources: Altmetric.com and YouTube. We analyzed these datasets individually and then combined them to form final datasets consisting of several features, which consist of social media mentions of the research articles and the metadata of the YouTube videos citing the research articles, as shown in Table 1 and Table 2. Using these datasets, we applied visualization techniques and statistical models for analysis and built machine learning models to predict important features in the dataset.Fig. 1 Data collection process
The data collection process for this research is shown in Figure 1. We extracted 500,000 random research articles from the Altmetric API, which includes metadata of the research articles and mentions of research outputs on various social media networks. We named this dataset A1; it includes research articles cited in videos as well as research articles not cited in videos. Descriptions of the features in this dataset are presented in Table 1.Table 1 Altmetric features of datasets A1 and A2
Feature Feature description
Altmetric ID Unique ID for each research article
Title Title of a research article
Publication date Publication date of a research article
Mendeley readers Number of times a reference to a research article is archived on Mendeley
Scopus subjects Subjects of the research article
News Number of times a research article is mentioned in news contexts
Twitter Number of times an article has been tweeted on Twitter
Facebook Number of times an article is shared on Facebook
Policy Number of times an article is shared in policy documents
GooglePlus Number of times an article is shared on Google Plus
Reddit Number of times an article is mentioned on Reddit
Blogs Number of times an article is mentioned or featured in blogs
Patent Number of times an article is mentioned or featured in patents
Wikipedia Number of times an article is cited on Wikipedia
Video citations Number of times an article is mentioned in the description of videos (i.e., cited) on YouTube
Citation Number of times a research article is cited based on Dimensions.ai
YouTube links List of YouTube video links citing the publication (dataset A2)
YouTube citation Binary variable indicating whether or not the publication is cited on YouTube. This is the target variable for Model 1 and is used in dataset A1
Scholarly citation Binary variable indicating whether the publication has more citations than the median number of citations, which is 27 for all publications in dataset A2. This is the target variable for Model 2 and is used in dataset A2
The Altmetric dataset provided the number of videos in which an article was cited with links to those videos. We checked all those links and verified they belonged to the YouTube platform. Each video on YouTube cited research articles through the description of the video uploaded to the channel. If the value of the feature Video was greater than 0, then we set the target variable to 1. Otherwise, we set the target variable to 0. We named this binary feature, which served as a target variable, “YouTube Citation.”
To further explore articles cited in videos, we selected all the research articles in altmetric.com that are cited by at least one video on YouTube. Using the Altmetric API, we collected research articles cited by video along with the list of video links citing the publication. We found a total of 160,283 research articles cited in videos on YouTube. We extracted these articles and created dataset A2, which comprises Altmetric IDs (a unique ID for each research article), metadata of those research articles, and post counts from various social media platforms, as shown in Table 1. The features are the same for both datasets with the exception of the target variable, which is “YouTube Citation” for A1 and “Scholarly Citation” for A2. Of the original 160,283 research articles in dataset A2, 9,659 records did not have valid video links. We, therefore, removed these records, resulting in a final count of 150,624. The Scopus subjects of the research articles were split to include only the major subjects, and the sub-subjects were removed. A total of 22 unique major subjects were analyzed further, as described in Sect. 3.4. For 21,905 research articles, no major subject or sub-subject was defined. We, therefore, converted these empty values to “Other” subjects.
We then created dataset B through the video links collected in dataset A2 under “YouTube Links” by extracting the videos’ metadata through the YouTube API. There were 94,130 unique video links in dataset B, of which 199 video links were unavailable, leaving 93,931 videos with available links and containing the YouTube video ID or link, the title of the video, views, likes, dislikes, description, the number of comment counts, and cited IDs of Altmetric articles. It is important to note that an article could be cited in more than one video and that one video could cite more than one article. Dataset B contains only the metadata of videos citing research articles, as shown in Table 2.Table 2 Features from YouTube
Feature Feature description
Link YouTube unique link or ID of video
Cited ID Altmetric IDs of cited research articles
Title Title of YouTube video
Views Total views of a YouTube video
Likes Total likes of a YouTube video
Dislikes Total dislikes of a YouTube video
SubNo Total subscriber count of the channel posting the video
Pubdate Publication date of the video
Description Description of the video as provided by the channel
Video Category Category of the video as stated by the uploader
Comments Number of comments posted on the YouTube video
Video Views Binary variable indicating whether or not the video has more than the median number of views, which is 1,139 for all the videos in dataset B. This is the target variable for Model 3.
In dataset B, of the 93,931 videos, 11,710 had no “Likes” values, and 2,553 had null values in the Likes feature, which both were converted to 0 “Likes .” Similarly, 42,673 videos had no “Dislikes,” and 2,554 null values in the Dislike feature were converted to 0 “Dislikes.” In addition, 64 videos had no “Views” in the Views feature and were converted to 0 “Views.” The channel subscriber count is presented in a textual form such as “1.2M” or “330K” and was converted appropriately to integer values. Features such as “Views,” “Likes,” “Dislikes,” “Subno,” and “Comments” were converted into integers from strings. For the feature “Pubdate,” there were 4 null values and 2,823 values that included “Premiered on Date,” which were changed to a date format from a string. We checked the “Category” feature of videos and found 15 categories out of the 29 major categories on YouTube TechPostPlus (2019). There were 2,126 “Category” values different from the 15 categories, which we changed to the “Undefined” category.
Approach
In our approach to answering RQ1, we use dataset A1 to build our first machine learning model to predict video citation. Analyzing the important features of the first model helped us further explore the relationship between videos and articles and is also an indirect indicator of popularity. The analysis of dataset A1 revealed a class-imbalance problem while building the machine learning model, as 84% of research articles were not cited in videos. This shows that the majority of articles are not cited in videos, but popular articles might be cited in videos. For the binary feature “YouTube Citation,” the class 0 value denoting a research article not cited in videos contained 419,886 records, whereas class 1 indicating a research article cited in videos had 80,114 records.
In a real-world classification of any given dataset, the classes have a high chance of imbalance. Thus, the classes are not relatively equal in number, i.e., one of the class values is higher than the others. However, there are several techniques to resolve this issue. A class-imbalance problem can be resolved by either oversampling the minority class or undersampling the majority class. The goal was to process the imbalanced data before feeding it into the classifier and, in this way, overcome the fact that the classifier is more sensitive to the majority class and less sensitive to the minority class, resulting in the prediction of the majority class. A limitation of oversampling a minority class in an imbalanced dataset is that it could lead to overfitting, as the existing values are copied in this technique. The concern with undersampling is that essential data can be missed.
We applied a hybrid method to dataset A1, combining random oversampling and undersampling techniques. In the case of oversampling applied to the dataset, the minority class samples were increased to equal 0.5 of the majority class samples. After oversampling the dataset, we applied undersampling in which the majority class samples were downsampled to equal 0.8 of the minority class samples. The class label counts from the dataset that resulted from applying the hybrid method were as follows: 262,428 for class 0, which denotes a research article not cited in videos, and 209,943 for class 1, which denotes a research article. This reduced the effect of the class-imbalance problem for dataset A1. We then applied all the classification models to the resulting dataset A1 to determine which model performed best.
To answer RQ2, we combined dataset B with dataset A2 to create datasets C1 and C2, our final datasets, which we used in building models to predict article citations and video views, respectively. The second model used dataset C1 and the features utilized are shown in Table 4. The feature “Scholarly Citation" described in Table 1 is the target variable for the second model, which represents article citations. Citation analysis of articles is one of the indicators of scholarly impact and can help identify the important features related to scholarly impact through videos on YouTube. The final model is built using dataset C2 and the features utilized are shown in Table 4. The feature “Video views" is the target feature for the third model described in Table 2. Views of a YouTube video are associated with popularity and are a potential indicator of societal impact. Important features of the model can help in examining features related to societal impact through views of videos. A description of all the datasets and available features is shown in Table 3.Table 3 Metadata about the Datasets utilized in our work. ( * =features averaged over all research articles; ** = features averaged over all videos citing research articles)
Dataset Description Features
A1 Random 500,000 Research articles from Altmetric.com Altmetric ID, Title, Publication Date, Scopus Subjects, Video Citation, Citation, News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Patent, Blogs, Wikipedia, YouTube Citation
A2 All 150,624 Research articles from Altmetric.com cited in available videos (YouTube) Altmetric ID, Title, Publication Date, Scopus Subjects, Video Citation, Citation, News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Patent, Blogs, Wikipedia, YouTube Links, Scholarly Citation
B All 93,931 available videos citing research articles Link, Title, Views, Likes, Dislikes, SubNo, Pubdate, Description, Video Category, Comments, Video Views, Cited Altmetric IDs
C1 150,624 Research articles with metadata of all videos citing articles Altmetric ID, Title, Publication Date, Scopus Subjects, Video Citation, Citation, News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Scholarly Citation, Patent, Blogs, Wikipedia, Video Views*, Video Likes*, Video Dislikes*, Video SubNo*, Video Comments*
C2 93,931 YouTube videos with metadata of articles cited by each video Link, Title, Views, Likes, Dislikes, SubNo, Pubdate, Description, Video Category, Comments, Video Views, Video Citation**, Citation**, News**, Twitter**, Facebook**, Policy**, Google+**, Reddit**, Mendeley Readers**, Patent**, Blogs**, Wikipedia**
To determine the importance of video citations for popularity or increasing the citations of a research article, we combined datasets A2 and B to form dataset C1, which consists of all the research articles cited by a video on YouTube with the links to the videos and the metadata of those videos citing that research article. Dataset C1 was created by adding video metadata from dataset B to its link present in the Video links of dataset A2. The final dataset C1 comprises 150,624 research articles cited by 93,931 unique video links. The features of the videos in dataset C1 have multiple values, as each research article had video citations ranging from 1 to 814 videos. Numerous videos can cite an article, and each video has different values for its features. Therefore, in building our models, we averaged the values of all the features of the YouTube videos citing a research article. For example, for a research article cited by three videos with respective view counts of 35634, 2733, and 1, we determined a single average value of 12,794.34.
To further analyze the YouTube videos citing research articles, we combined datasets B and A2 to create dataset C2, which consists of 93,931 YouTube videos citing 150,624 research articles, along with the metadata of the videos and the altmetric information of the research articles cited in the video descriptions. Dataset C2 was created by adding altmetric data from dataset A2 to its altmetric ID present in the feature for the cited ID in dataset B. The altmetrics features in dataset C2 have multiple values, as each YouTube video cited numerous research articles ranging from 1 to 82. Therefore, we averaged the numerical features for the research articles. For example, if a video cites five research articles and those articles had Twitter mentions such as 80, 63, 31, 27, 15, they were averaged to a single value of 43.2. It is important to note that in dataset C1, an article could be cited by multiple videos, whereas in dataset C2, a single video could cite numerous articles. For data exploration, we used datasets A1, A2, B, and C1, whereas in building the machine learning models, we used only datasets A1, C1, and C2. The resulting datasets are publicly available as a comma-separated-value file (CSV)1.
The datasets used in building the models differ from one another and are presented in Table 4, along with features utilized in each model and the target variable. Given its correlation with Mendeley Readers, we removed Citations from dataset A1. For Model 3, in dataset C2, Citations and Blogs were removed as they are correlated with other features. For each model, we used Scikit-learn (Pedregosa et al., 2011) to implement classification models such as Bernoulli Naive Bayes, Random Forest, Decision Tree, and K-Nearest Neighbors (KNN). For the machine learning models, we applied k-fold cross-validation to the dataset and average evaluation metrics over 20 folds. To evaluate each model, we used the metrics precision, recall, F1-score, and accuracy. The four models are described along with the evaluation metrics. We report the essential features in building all the models to identify the importance of those attributes in relation to the target variables and our research questions.Table 4 Datasets, features, and target variable considered for all models (* =features averaged over all research articles; ** = features averaged over all videos citing research articles)
Model Dataset Features Target
1. A1 News, Twitter, Facebook, Policy, Google+, Reddit, Mendeley Readers, Patent, Blogs, Wikipedia YouTube Citation
2. C1 Mendeley Readers, Twitter, Facebook, Policy, Google+, Patent, Wikipedia, Video Citations, Video views**, Subno**, Comments** Scholarly Citation
3. C2 Mendeley Readers*, Video Mentions*, Facebook*, Google+*, Twitter*, Wikipedia*, Policy*, Patent*, Reddit*, Video Category, SubNo Video Views
Results
We report the results of our work in two parts. The first part describes the exploration of the dataset, which helps answer RQ1. The second part deals with building machine learning models to predict different metrics for answering RQ2. We provide an analysis of the datasets through visualization and statistical techniques in the first part and then build classification models for the second part.
Data exploration
Fig. 2 Number of records of Scopus subjects by year in dataset A2
Fig. 3 Number of video mentions for Scopus subjects in dataset A2
To explore the second part of RQ1 and identify the popular subjects of articles cited in videos, we analyzed the research articles in dataset A2 and found that an increasing number of research articles have been cited in videos in the last two decades (Figure 2). The articles most cited in videos each year were the “Medical and Health Sciences” Scopus subject. As the data was collected at the end of 2020, we can see a drop in the number of research articles cited in videos in 2019 and 2020 compared to previous years. This could mean that articles tend not to be cited in videos shortly after publication, with citations of this kind taking time to accrue. We also found that research articles with the Scopus subjects Medical and Health Sciences, Biological Sciences, and Psychology and Cognitive Sciences had the highest number of video mentions in comparison to other subjects (Figure 3). This indicates that most of the research articles cited in the videos were related to medicine and biochemistry. The citation count for these subjects was also higher than for other subjects.Fig. 4 Number of YouTube videos in each category per year
Fig. 5 Video views of YouTube categories
The popular video categories on YouTube citing research articles can be seen in Figure 4. We can see that an increasing number of videos have cited research articles in the last decade. The majority of the videos citing research articles are categorized as Education, Science & Technology, or People & Blogs. It is also worth noting that People & Blogs was the third-highest category of videos to cite research articles, even though most of the research articles cited belong to Medicine & Biochemistry. Figure 5 shows the number of views of YouTube videos in dataset B based on the video category. The most-viewed videos citing research articles are categorized as Science & Technology and Education due to the high number of these videos in the dataset. Even though fewer videos were categorized as Entertainment in dataset B, this category garnered the fourth-highest view count.Fig. 6 Correlation matrix for all the numerical features in dataset C1
To explore the relationship between articles and video features, we plotted a correlation matrix between the features to answer RQ1. Based on the correlation matrix of the features in dataset C1, we can observe that Likes and Dislikes are highly correlated with Views (Figure 6). To reduce complexity while building our machine learning models, we removed highly correlated features, i.e., features with a correlation greater than 0.5. Thus, we removed Likes and Dislikes as they had a correlation of 0.85 and 0.53, respectively, keeping only video Views as the sole feature relating to the videos. We also removed Blog as it had a 0.61 correlation with News, and Citation was also removed due to its correlation of 0.59 with Mendeley Readers.
Building models
Fig. 7 Classification results for Model 1
Fig. 8 Important features for the Random Forest classifier for Model 1
To explore the relationship between articles and videos as well as predict the impact of popularity, we predicted whether an article was cited in at least one video on YouTube. This identified important social media features of an article influencing YouTube citation. In the first model, Random Forest yielded the best results, as shown in Figure 7, achieving an accuracy level of 0.95 and an F1-score of 0.94. Decision Tree performed second best with an accuracy of 0.92 and an F1-score of 0.91. Figure 8 shows the feature importance of the Random Forest classifier in predicting video citations. Twitter and News were the most important features, followed by Mendeley Readers and Blog.Fig. 9 Classification results for Model 2
Fig. 10 Important features for the Random Forest classifier for Model 2
To predict whether an article will reach a level of popularity or scholarly impact, we built the second model to answer RQ2. For the second model, Random Forest performed the best overall, with an accuracy level and an F1-score of 0.80. KNN performed second best with an accuracy level of 0.75 and an F1-score of 0.78. Figure 9 shows the evaluation metrics of the classification models built on dataset C1 to predict the binary target variable. Figure 10 shows feature importance in the model built by the Random Forest classifier. We can see that the average number of Video Views citing a research article is the second-most important feature, after Mendeley Readers, in classifying citations of research articles.Fig. 11 Classification results for Model 3
Fig. 12 Most important features for the Random Forest classifier for Model 3
We built the third model with the features and the target variable mentioned in Table 4 to answer RQ2. The third model correlates video popularity and societal impact. The Video Category feature was converted to numerical features using One Hot Encoding. Figure 11 shows the results of the classifiers: Random Forest again performed best, achieving an accuracy level of 0.81 and an F1-score of 0.80, and KNN performed second best with an accuracy level of 0.79 and an F1-score of 0.78. Figure 12 shows feature importance in the model built by the Random Forest classifier. SubNo and Mendeley Readers were the most important features in building the model.
Discussion
Video citations of research articles may help increase the popularity of the articles in the research community and eventually increase citations of research articles. In this study, we analyzed citations of research articles in the descriptions of videos on YouTube. The rise of video citations over recent years, along with the increasing number of conferences requiring a video submission of accepted scholarly research, have paved the way to identify important features that contribute to the popularity and impact of research through the results found in Sects. 4.1 and 4.2. It is essential to analyze these video citations and the social media mentions of research articles to identify the crucial factors that improve the popularity of videos and research articles. We collected data from YouTube and Altmetric to discover hidden patterns and explore the relationship between research articles and video citations. We combined the datasets, analyzed them using visualization techniques, and built machine learning models to predict important target variables. For the analysis, we examined the combined datasets in relation to research articles and videos, which led us to build three datasets to predict video citations, video views, and citations of research articles.
From our analysis of the large A1 dataset of research articles, we found that around three-quarters of the dataset’s research articles were not cited in videos. In Sect. 4.1, we found that research related to Medicine and Biochemistry received the highest number of video citations. We also found that most of the videos citing research articles were in either the Science & Technology or the Education category. Videos categorized as Entertainment mentioned fewer research articles but attracted the fourth-highest number of views after Science & Technology, Education, and People & Blogs. This result suggests that scientific results are being used for entertainment and educational purposes. Through our analysis of the video dataset B, we found positive correlations between the number of video views, likes, and dislikes, as seen in Figure 6. This is self-evident since users usually view a video before adding a like or dislike. This is also in line with findings reported by Welbourne and Grant (2016) and Pinto et al. (2013), who found that other video metadata such as likes, dislikes, and comment counts are highly correlated with video views. Given these correlations, we removed all these features from consideration, with the exception of the video views feature. However, contrary to previous findings, the comment count did not have a high correlation with views of scientific videos, as seen in Figure 6. This hesitancy to comment publicly on scientific videos could be related to the hesitancy to comment publicly on research articles. Around 80% of researchers considered that their comments might affect their reputation or how others perceive them (Hemminger & TerMaat, 2014).
For our second part of the study, as can be seen in Sect. 4.2, we considered four classification algorithms-Bernoulli Naive Bayes, Random Forest, Decision Tree, and K-Nearest Neighbors-and applied them to each of the three cases to predict three target variables. We evaluated the models based on precision, recall, accuracy, and F1-score. Prediction of whether a research article is cited in a video is the first model of our study for which we used social media mentions of the research article to predict a binary variable indicating video citation. Twitter Mentions and News Mentions of research articles were important factors that contributed to attracting a video citation for a research article. Research articles mentioned in news and tweets cause buzz across the internet and have a high chance of being cited in videos. Citations show the importance and usefulness of a research article and are a strong indication of its popularity. The second model in this study predicted the binary variable, indicating whether a research article had more citations than the median of all the citations of research articles in the dataset. We found that Mendeley Readership and Video Views contributed greatly to this scholarly impact prediction. This result is in line with previous studies in which Mendeley readership is found to be important for predicting citation counts (Thelwall & Nevill, 2018). However, Video Views are a new feature that plays a vital role in garnering citations, reaching wider audiences, and fostering the popularity and impact of research articles. Our third model predicted Video Views. We found that the subscriber count of a channel, Mendeley Readers, and Twitter Mentions of research articles were important in predicting views of videos citing those research articles. This shows that the number of followers for a YouTube channel plays an essential role in the number of scientific video views. Random Forest achieved the best results for all the models built in this study.
A limitation of this study is that it relied on social media features from a single source Altmetric.com. It also does not consider other related factors, such as the textual content of the research or the video content. Another limitation of our work is that the built models did not consider the temporal nature of the features present in the various datasets, which needs continuous data collection. We also assumed that citations and views could be considered indicators of scholarly and societal impact, respectively, whereas other factors can also influence these impacts. Moreover, the prediction of the target feature of the models can only be applicable after the accumulation of important social media features, which is a cold-start problem. Furthermore, we used multiple visualizations to explore trends and patterns in our collected datasets. One possible improvement for further studies is to relate and synthesize information from these visualizations (Sun et al., 2021a, b; Shaikh et al., 2022), which may be help gain some more in-depth insights.
Our process offers insight into ways to make improvements in future iterations by incorporating some traditional factors such as the h-index of authors, scholarly venues, and temporal features that have been useful in other studies. Additionally, it would be helpful to distinguish between subjects and research fields to provide a basis for building models for individual areas that would, in turn, improve the results. Furthermore, we considered Dimensions Citations, and it would be worthwhile to check other sources such as Google Scholar. Another direction to explore is the use of research in videos. Do the videos include results drawn principally from the abstract, methods, or results section? Further, the reasons for including references to research articles in videos remain unexplored. For example, do the videos cite research to promote content, provide a message within the video, increase public trust in the content, sell a product, or even spread misinformation? Lastly, our results could be compared with research focused on measuring and predicting other types of societal impact, such as in economic, political, and health areas.
Conclusion and future work
In this study, we analyzed the impact of YouTube on research by building classification models to predict video citations, scholarly citations, and video views. We found that fewer research articles were cited in videos in a large dataset of research articles. Most of the articles cited in videos belonged to the Medicine and Biochemistry categories. These subjects also have the highest number of video citations in comparison to other subjects. The number of video citations has been increasing in recent years, with most of the videos citing research articles categorized as Science & Technology, Education, and People & Blogs. Science & Technology and Education are the categories of videos that garnered the most views. We found a high-to-mid correlation among views, likes, dislikes, and the subscriber count of videos. We also observed that Random Forest performed the best of all the models built on the datasets. We found that News mentions and Twitter mentions of a research article are important factors in determining a research article’s video citation. Another important finding of the study is that the view count of a video was an important feature in predicting a research article’s citations. For future work, we plan to use more textual and temporal features of the videos and articles. We will study the topics of videos citing research articles and the relationship between the video categories and the research articles’ subjects.
Acknowledgements
This research is supported in part by NSF Grants SMA-2022443, IIS-2002082, and the Research and Artistry Opportunity Grant from Northern Illinois University.
1 https://zenodo.org/record/4691941.
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References
AAO. (2021). Video submission instructions for aao. Retrieved April 04, 2021 from https://www.aao.org/annual-meeting/presenter/video-submission-instructions
Agazio J Buckley KM An untapped resource: using youtube in nursing education Nurse educator 2009 34 1 23 28 10.1097/01.NNE.0000343403.13234.a2 19104342
Akella AP Alhoori H Kondamudi PR Freeman C Zhou H Early indicators of scientific impact: Predicting citations with altmetrics Journal of Informetrics 2021 15 2 101128 10.1016/j.joi.2020.101128
Alexa. (2021). Alexa - top sites. Retrieved April 01, 2021 from https://www.alexa.com/topsites/
Beehler, B., & Griffiths, D. (2020). Going viral: Taking your conference online for covid-19. Retrieved April 03, 2021 from https://www.insidehighered.com/advice/2020/03/16/how-shift-your-conference-online-light-coronavirus-opinion
Bonifati, A., Guerrini, G., Lutz, C., Martens, W., Mazilu, L., Paton, N., Salles, M. A. V., Scholl, M. H., & Zhou, Y. (2020). Holding a conference online and live due to covid-19.
Borghol, Y., Ardon, S., Carlsson, N., Eager, D., & Mahanti, A. (2012). The untold story of the clones. Proceedings of the 18th ACM SIGKDD international conference on Knowledge discovery and data mining - KDD ’12.
Bornmann L Do altmetrics point to the broader impact of research? an overview of benefits and disadvantages of altmetrics Journal of Informetrics 2014 8 4 895 903 10.1016/j.joi.2014.09.005
Bornmann L Haunschild R Adams J Do altmetrics assess societal impact in a comparable way to case studies? an empirical test of the convergent validity of altmetrics based on data from the uk research excellence framework (ref) Journal of Informetrics 2019 13 1 325 340 10.1016/j.joi.2019.01.008
Brodersen, A., Scellato, S., & Wattenhofer, M. (2012). Youtube around the world: Geographic popularity of videos. In Proceedings of the 21st International Conference on World Wide Web, WWW ’12, page 241–250, New York, NY, USA. Association for Computing Machinery.
CHI. (2021). Technical requirements and guidelines for videos at chi. Retrieved April 04, 2021 from https://chi2021.acm.org/for-authors/presenting/papers/technical-requirements-and-guidelines-for-videos-at-chi
Chtouki, Y., Harroud, H., Khalidi, M., & Bennani, S. (2012). The impact of youtube videos on the student’s learning. In 2012 International Conference on Information Technology Based Higher Education and Training (ITHET), pp. 1–4.
Falk MT Hagsten E When international academic conferences go virtual Scientometrics 2021 126 1 707 724 10.1007/s11192-020-03754-5 33230351
Figueiredo, F., Almeida, J. M., Benevenuto, F., & Gummadi, K. P. (2014). Does content determine information popularity in social media? a case study of youtube videos’ content and their popularity. In Proceedings of the SIGCHI Conference on Human Factors in Computing Systems, CHI ’14, page 979-982, New York, NY, USA. Association for Computing Machinery.
Freeman, C., Alhoori, H., & Shahzad, M. (2020). Measuring the diversity of facebook reactions to research. Proc. ACM Hum.-Comput. Interact., 4(GROUP).
Freeman, C., Roy, M. K., Fattoruso, M., & Alhoori, H. (2019). Shared feelings: Understanding Facebook reactions to scholarly articles. In 2019 ACM/IEEE Joint Conference on Digital Libraries (JCDL), pp. 301–304.
Hemminger BM TerMaat J Annotating for the world: Attitudes toward sharing scholarly annotations Journal of the Association for Information Science and Technology 2014 65 11 2278 2292 10.1002/asi.23124
Hovden R Bibliometrics for internet media: Applying the h-index to youtube Journal of the American Society for Information Science and Technology 2013 64 11 2326 2331 10.1002/asi.22936
Jaffar AA Youtube: An emerging tool in anatomy education Anatomical Sciences Education 2012 5 3 158 164 10.1002/ase.1268 22383096
Johnston AN Barton MJ Williams-Pritchard GA Todorovic M Youtube for millennial nursing students; using internet technology to support student engagement with bioscience Nurse Education in Practice 2018 31 151 155 10.1016/j.nepr.2018.06.002 29906632
June S Yaacob A Kheng YK Assessing the use of youtube videos and interactive activities as a critical thinking stimulator for tertiary students: An action research International Education Studies 2014 7 56 67 10.5539/ies.v7n8p56
Khan G Vong S Virality over youtube: an empirical analysis Internet Res. 2014 24 629 647 10.1108/IntR-05-2013-0085
Kousha K Thelwall M Bickley M The high scholarly value of grey literature before and during covid-19 Scientometrics 2022 127 6 3489 3504 10.1007/s11192-022-04398-3 35615527
Liu M Bu Y Chen C Xu J Li D Leng Y Freeman RB Meyer ET Yoon W Sung M Jeong M Lee J Kang J Min C Song M Zhai Y Ding Y Pandemics are catalysts of scientific novelty: Evidence from covid-19 Journal of the Association for Information Science and Technology 2022 73 8 1065 1078 10.1002/asi.24612 35441082
Ma, C., Yan, Z., & Chen, C. W. (2017). Larm: A lifetime aware regression model for predicting youtube video popularity. In Proceedings of the 2017 ACM on Conference on Information and Knowledge Management, CIKM ’17, pp. 467-476, New York, NY, USA. Association for Computing Machinery.
Madathil KC Rivera-Rodriguez AJ Greenstein JS Gramopadhye AK Healthcare information on youtube: A systematic review Health Informatics Journal 2015 21 3 173 194 10.1177/1460458213512220 24670899
Pedregosa F Varoquaux G Gramfort A Michel V Thirion B Grisel O Blondel M Prettenhofer P Weiss R Dubourg V Vanderplas J Passos A Cournapeau D Brucher M Perrot M Duchesnay Édouard Scikit-learn: Machine learning in python Journal of Machine Learning Research 2011 12 85 2825 2830
Pinto, H., Almeida, J. M., & Gonçalves, M. A. (2013). Using early view patterns to predict the popularity of youtube videos. In Proceedings of the Sixth ACM International Conference on Web Search and Data Mining, WSDM ’13, pp. 365–374, New York, NY, USA. Association for Computing Machinery.
Price, M. (2020). As covid-19 forces conferences online, scientists discover upsides of virtual format. Retrieved April 03, 2021 from https://www.sciencemag.org/careers/2020/04/covid-19-forces-conferences-online-scientists-discover-upsides-virtual-format
Rodriguez, S. (2021). Youtube is social media’s big winner during the pandemic. Retrieved April 06, 2021 from https://www.cnbc.com/2021/04/07/youtube-is-social-medias-big-winner-during-the-pandemic.html
Shahzad M Alhoori H Public reaction to scientific research via twitter sentiment prediction Journal of Data and Information Science 2022 7 1 97 124 10.2478/jdis-2022-0003
Shahzad M Alhoori H Freedman R Rahman SA Quantifying the online long-term interest in research Journal of Informetrics 2022 16 2 101288 10.1016/j.joi.2022.101288
Shaikh, A. R., & Alhoori, H. (2019). Predicting patent citations to measure economic impact of scholarly research. In 2019 ACM/IEEE Joint Conference on Digital Libraries (JCDL), pp. 400–401.
Shaikh, A. R., Koop, D., Alhoori, H., & Sun, M. (2022). Toward systematic design considerations of organizing multiple views. In 2022 IEEE VIS conference.
Snelson C Rice K Wyzard C Research priorities for youtube and video-sharing technologies: A delphi study British Journal of Educational Technology 2012 43 1 119 129 10.1111/j.1467-8535.2010.01168.x
Suciu, P. (2021). Youtube remains the most dominant social media platform. Retrieved June 05, 2021 from https://www.forbes.com/sites/petersuciu/2021/04/07/youtube-remains-the-most-dominant-social-media-platform/?sh=284719d36322
Sud P Thelwall M Evaluating altmetrics Scientometrics 2014 98 2 1131 1143 10.1007/s11192-013-1117-2
Sugimoto CR Work S LariviÃre V Haustein S Scholarly use of social media and altmetrics: A review of the literature Journal of the Association for Information Science and Technology 2017 68 9 2037 2062 10.1002/asi.23833
Sun, M., Namburi, A., Koop, D., Zhao, J., Li, T., & Chung, H. (2021a). Towards systematic design considerations for visualizing cross-view data relationships. IEEE Transactions on Visualization and Computer Graphics.
Sun, M., Shaikh, A. R., Alhoori, H., & Zhao, J. (2021). Sightbi: Exploring cross-view data relationships with biclusters. IEEE Transactions on Visualization and Computer Graphics, 28(1), 54–64.
Susarla A Oh J-H Tan Y Social networks and the diffusion of user-generated content: Evidence from youtube Information Systems Research 2012 23 1 23 41 10.1287/isre.1100.0339
TechPostPlus (2019). Youtube video categories list. Retrieved April 05, 2021 from https://techpostplus.com/youtube-video-categories-list-faqs-and-solutions/
Thelwall, M., & Nevill, T. (2018). Could scientists use altmetric.com scores to predict longer term citation counts? Journal of Informetrics, 12(1):237-248.
Trzciński T Rokita P Predicting popularity of online videos using support vector regression IEEE Transactions on Multimedia 2017 19 11 2561 2570 10.1109/TMM.2017.2695439
Welbourne DJ Grant WJ Science communication on youtube: Factors that affect channel and video popularity Public Understanding of Science 2016 25 6 706 718 10.1177/0963662515572068 25698225
Weller, K., Welpe, I. M., Wollersheim, J., Ringelhan, S., & Osterloh, M. (2015). Social Media and Altmetrics: An Overview of Current Alternative Approaches to Measuring Scholarly Impact, pp. 261–276. Springer
YouTube. (2021). Press - youtube. Retrieved April 01, 2021 from https://www.youtube.com/about/press/
Yu, H., Xie, L., & Sanner, S. (2015). The lifecyle of a youtube video: Phases, content and popularity. In ICWSM.
| 36480044 | PMC9734685 | NO-CC CODE | 2022-12-14 23:28:30 | no | Z Rheumatol. 2022 Dec 8; 81(10):899 | latin-1 | Z Rheumatol | 2,022 | 10.1007/s00393-022-01297-z | oa_other |
==== Front
Appl Microbiol Biotechnol
Appl Microbiol Biotechnol
Applied Microbiology and Biotechnology
0175-7598
1432-0614
Springer Berlin Heidelberg Berlin/Heidelberg
36484827
12323
10.1007/s00253-022-12323-0
Applied Microbial and Cell Physiology
Deletion of gene OV132 attenuates Orf virus more effectively than gene OV112
Yamada Yumiko 1
Chuang Shih-Te 2
Tseng Ching-Yu 1
Liao Guan-Ru 1
Liu Shin-Wu 2
Tseng Yeu-Yang 3
Lin Fong-Yuan 4
http://orcid.org/0000-0002-1392-163X
Hsu Wei-Li [email protected]
1
1 grid.260542.7 0000 0004 0532 3749 Graduate Institute of Microbiology and Public Health, National Chung Hsing University, Taichung, Taiwan
2 grid.260542.7 0000 0004 0532 3749 Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
3 grid.1008.9 0000 0001 2179 088X WHO Collaborating Center for Reference and Research On Influenza, Peter Doherty Institute for Infection and Immunity, VIDRL, University of Melbourne, Melbourne, VIC Australia
4 grid.411432.1 0000 0004 1770 3722 Department of Animal Healthcare, Hungkuang University, Taichung, Taiwan
9 12 2022
117
8 8 2022
27 11 2022
30 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Abstract
Orf virus (ORFV), a Parapoxvirus in Poxviridae, infects sheep and goats resulting in contagious pustular dermatitis. ORFV is regarded as a promising viral vector candidate for vaccine development and oncolytic virotherapy. Owing to their potential clinical application, safety concerns have become increasingly important. Deletion of either the OV132 (encoding vascular endothelial growth factor, VEGF) or OV112 (encoding the chemokine binding protein, CBP) genes reduced ORFV infectivity, which has been independently demonstrated in the NZ2 and NZ7 strains, respectively. This study revealed that the VEGF and CBP gene sequences of the local strain (TW/Hoping) shared a similarity of 47.01% with NZ2 and 90.56% with NZ7. Due to the high sequence divergence of these two immunoregulatory genes among orf viral strains, their contribution to the pathogenicity of Taiwanese ORFV isolates was comparatively characterized. Initially, two ORFV recombinants were generated, in which either the VEGF or CBP gene was deleted and replaced with the reporter gene EGFP. In vitro assays indicated that both the VEGF-deletion mutant ORFV-VEGFΔ-EGFP and the CBP deletion mutant ORFV-CBPΔ-EGFP were attenuated in cells. In particular, ORFV-VEGFΔ-EGFP significantly reduced plaque size and virus yield compared to ORFV-CBPΔ-EGFP and the wild-type control. Similarly, in vivo analysis revealed no virus yield in the goat skin biopsy infected by ORFV-VEGFΔ-EGFP, and significantly reduced the virus yield of ORFV-CBPΔ-EGFP relative to the wild-type control. These results confirmed the loss of virulence of both deletion mutants in the Hoping strain, whereas the VEGF-deletion mutant was more attenuated than the CBP deletion strain in both cell and goat models.
Key points
• VEGF and CBP genes are crucial in ORFV pathogenesis in the TW/Hoping strain
• The VEGF-deletion mutant virus was severely attenuated in both cell culture and animal models
• Deletion mutant viruses are advantageous vectors for the development of vaccines and therapeutic regimens
Supplementary Information
The online version contains supplementary material available at 10.1007/s00253-022-12323-0.
Keywords
Parapoxvirus
Chemokine binding protein
Vascular endothelial growth factor
Pathogenesis
Attenuation
http://dx.doi.org/10.13039/501100004663 Ministry of Science and Technology, Taiwan 106-2313-B-005-039-MY3 NSTC-111-2313-B-005-043-MY3 Hsu Wei-Li
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pmcIntroduction
Orf virus (ORFV), the prototype species of the genus Parapoxvirus within the Poxviridae family, causes highly contagious skin lesions, referred to as orf, in several species of small ruminants, particularly sheep and goats. It consists of a double-stranded DNA molecule of roughly 138 kb long (Haig and Mercer 1998). ORFV is a zoonotic pathogen that occasionally infects humans (Haig and Mercer 1998). The disease is typically benign, with lesions that progress through a well-liked stage and create pustules within a few days. Rupture of the pustules results in ulcers and, subsequently, a thick and overlying crust that is shed within 4–6 weeks (Fleming et al. 2017). The mortality rate of ORFV infection can reach up to 10% in lambs and may be as high as 93% in kids (Hosamani et al. 2009). This high mortality in young animals was due to their inability to suck and consume nutrition properly (Hosamani et al. 2009). Wild-type ORFV transmission to adults can occur on scarred skin, but it always remains clinically unapparent, and in exceedingly rare cases, proliferative lesions are seen.
In common with other poxviruses, ORFV expresses a variety of immunomodulatory proteins (IMPs) responsible for regulating the host-innate and pro-inflammatory responses to infection (Weber et al. 2003). For the past years, the function(s) and the underlying mechanism(s) of the ORFV-encoded IMPs had been determined. Examples of these IMPs are a chemokine binding protein (CBP) (Fleming et al. 2017), an interleukin 10 homolog (ORFV127) (Fleming et al. 1997), an inhibitor of granulocyte-monocyte colony-stimulating factor and IL-2 (ORFV117) (Deane et al. 2000), an interferon (IFN)-resistance protein (OV20) (Tseng et al. 2015a), a homolog of vascular endothelial growth factor (VEGF) (Wise et al. 1999), and the immunomodulators of the nuclear factor-kappa (NF-κB) signaling pathway (Martins et al. 2017). Although these genes are mainly non-essential for ORFV replication in vitro, it has been noted that the VEGF, CBP, viral homologs of IL-10 (ORFV127), and NF-κB inhibitor ORFV121 are virulence factors that play a part in ORFV pathogenesis in the natural host (Fleming et al. 2017; Savory et al. 2000).
ORFV has been proposed as an ideal viral vector because of its immunomodulatory and biological properties (Rziha et al. 2000). ORFV possesses several unique qualities that make it suitable for the development of parapoxviruses as vectors for vaccine delivery (Friebe et al. 2011; Reguzova et al. 2020). Some of these features include a safety profile, restricted host range, and “exceptionally strong” induction of inflammation and the innate immune system (Martins et al. 2017). ORFV-based vaccines have provided protection against some viral infections, such as rabbit hemorrhagic disease virus (Rohde et al. 2011), classical swine fever (Voigt et al. 2007), Borna disease virus (Henkel et al. 2005), pseudorabies virus (Fischer et al. 2003), rabies virus (Amann et al. 2013), and influenza A virus (Rohde et al. 2013). The major advantage of using recombinant ORFV for vaccination is based on the fact that ORFV generally elicits only short-lived virus-specific immunity in its natural hosts, allowing frequent reinfection owing to the absence of virus-neutralizing antibodies (Reguzova et al. 2020). This feature allows repeated immunizations using ORFV recombinants to boost humoral immune responses against the inserted antigens.
Recently, several studies have demonstrated the oncolytic properties of ORFV in lung cancer (Rintoul et al. 2012) and colorectal cancer (Chen et al. 2021). Given these circumstances, safety is a priority. Several strategies have been used to ensure the safety of viral vectors. These include the selection of natural strains with lower virulence, development of highly attenuated strains (e.g., ORFV strain D1701) (Reguzova et al. 2020), inactivation of virulence factors such as vascular endothelial growth factor (VEGF) (Savory et al. 2000), and deletion of immunomodulatory viral genes (Fleming et al. 1997). Previous studies revealed that the deletion of either the chemokine binding protein (CBP) (Fleming et al. 2017) or VEGF gene (Savory et al. 2000) in the NZ7 and NZ2 strains, respectively, attenuated ORFV infection and presumably reduced the severity of the disease in the host (i.e., sheep). Although ORFV showed an excellent safety profile as a viral vector, there are still circumstances in which ORFV can impose severe infections in an immunocompromised individual when this virus will be applied for therapeutic purposes.
CBP, approximately 32 kDa, is expressed by the gene OV112 (approximately 861 bp) (Fleming et al. 2017), which is one of the virulence genes that can be detected early after the invasion of host cells by ORFV (Heidarieh et al. 2015). OV112 is located in highly variable terminal regions of the ORFV genome, and a high frequency of sequence variations of the OV112 gene has been noted among different strains (Heidarieh et al. 2015). For instance, the sequence of the ORFV NZ7 gene is 27 bp longer than that of its NZ2 counterpart. Moreover, sequence alignment with the NZ2 strain revealed three insertions in NZ7, and the amino acid identity of the CBP of NZ2 and NZ7 strains was only 78% (Seet et al. 2003). ORFV-CBP permits transient expression of the virus antigen in infected cells impeding the reactivation of cytokines and chemokines (McGuire et al. 2012). In addition, the recruitment and migration of dendritic cells and other immune cells to peripheral lymph nodes to activate an adaptive immune response are inhibited by the CBP of ORFV (Chen et al. 2020). Notably, viral CBP have no mammalian homologs (Lateef et al. 2010). In addition, the lack of regulation of immune cells can cause inhibition of the MHC class II pathway, affecting the recruitment and/or activation of cytotoxic T cells at the site of skin infection (Chen et al. 2020).
The viral VEGF protein is encoded by the OV132 gene (~ 462 bp), an early gene that is located in highly variable terminal regions at the right end of the conserved region of the ORFV genome (Tan et al. 2009). Genetic analysis showed that the ORFV OV132 gene was likely purloined from host organisms during evolutionary coexistence (Lyttle et al. 1994). Substantial sequence variations in VEGF genes between viral strains have been reported (Mercer et al. 2002). For instance, the amino acid sequences of the VEGF gene between the two New Zealand isolates, namely the OV NZ2 and NZ7 strains, showed only 41.1% identity, and surprisingly, little homology at the DNA level was found between the strains (Lyttle et al. 1994). Moreover, viral VEGF is characterized only in the genus Parapoxvirus of Poxviridea. Hence, it was postulated that these two ORFV strains acquired the VEGF gene by independent events and from different sources (Lyttle et al. 1994).
Viral VEGF is homologous to mammals and is one of the immunomodulatory proteins responsible for inhibiting the proliferation of host immunity (Wise et al. 1999). However, cellular VEGF is a regulatory protein actively involved in the elimination of tumors (Nash et al. 2006) and virus-infected cells (Achen et al. 1998), as well as in promoting the wound healing process (Shen Ni et al. 2013). A previous study suggested that ORFV-VEGF may stimulate the proliferation of epithelial cells which would enhance the formation of more viral and receptor binding sites for ORFV replication (Wise et al. 1999). In addition to viral replication, ORFV-VEGF protects the virus from the overall effects of immune responses and weakens the host antiviral response (Haig and McInnes 2002). This implies that ORFV-VEGF is responsible for promoting the intracellular replication of the virus by sabotaging the apoptotic activity of the host cell (Wise et al. 1999).
ORFV has emerged as an attractive vector candidate for vaccine development and has potential clinical applications in humans. To this end, the attenuation of ORFV is essential. As mentioned above, sequences of the two virulence determinants (i.e., CBP and VEGF) were substantial variables between viral strains, even for those isolated from the same countries. Moreover, the degree of attenuation between these two deletion ORFVs on their natural host was examined using different experimental designs and evaluation parameters. Hence, the current study aimed to comprehensively characterize the two recombinant ORFVs of the Hoping strain (isolated from Taiwan) with deletions of either the VEGF (OV132) or CBP (OV112) gene. To this end, the infection profile of these single gene-knockout viruses and also their clinical pathology in a natural host were comparatively analyzed in parallel with the ORFV containing wild-type genome. These results demonstrated that recombinant ORFV defective in either VEGF or CBP expression significantly reduced viral infection. Notably, compared with the CBP-null mutant virus, knockout of VEGF expression resulted in severe attenuation of ORFV infectivity in both cell culture and animal models.
Materials and methods
Cell maintenance
Human embryonic kidney cell line 293 T and goat fibroblast (abbreviated as FB) cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Gibco BRL, Life Technologies Corporation, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS) (GIBCO, Carlsbad USA, CA) and 1% penicillin–streptomycin (Gibco BRL). Cells were cultured at 37 °C and 5% CO2.
Viruses and infection
The ORFV-WT-EGFP (Hoping strain) was propagated in goat fibroblast cells (FB) as described previously (Lin et al. 2015). For infection, 80% confluent cell monolayers were incubated with ORFV at the indicated multiplicity of infection (MOI) in the infection medium (DMEM without FBS). After allowing 1 h for viral adsorption, the infection medium was replaced with fresh DMEM containing 2% FBS, and the vessels were returned to 37 °C with 5% FBS.
Construction of transfer vectors for generation of recombinant ORFVs
Two transfer vectors were constructed to prepare attenuated viruses. First, the transfer vector (pVEGF△-vvTK-eGFP) for ORFV with deletion of the VEGF gene was generated in several steps. Initially, a plasmid harboring flanking (upstream and downstream) sequences of OV132 was generated. DNA fragments containing downstream (namely, OV133) and upstream (i.e., OV131) sequences were amplified from ORFV genomic DNA by PCR with two primer sets comprising built-in restriction enzyme sequences, namely down-VEGF-BamH I-F/down-VEGF-EcoR I -R and up-VEGF-Hind III-F/up-VEGF-Xho I-R, respectively. To generate viruses with a screening marker (EGFP), the two ORFV DNA fragments trimmed with restriction enzymes were individually cloned upstream or downstream of the EGFP coding sequences in the pUC19-H5-EGFP plasmid (Tseng et al. 2015b) and linearized with enzymes compatible with the insert DNA fragments. The resulting plasmid was designated pUC19-VEGF-flanking. To equip recombinant ORFV with a selection marker, the thymidine kinase (vvTK) gene (554 bp) was amplified from the vaccinia virus using the primers vvTK-Nco I-F/vvTK-BamH I-R and further inserted into the slp-pETDuet plasmid. Subsequently, vvTK fused with poxvirus late promoter sequences (sLp) was generated by PCR using the primers slp-vvTK-Xba I-F and vvTK-Xba I-R, and the resulting amplicon (sLp-vvTK, 648 bp) was cloned into a pUC19-VEGF-flanking plasmid.
Using a similar strategy, another transfer vector (pCBPΔ-EGFP) was created. In brief, two fragments containing the right and left flanking sequences of the CBP gene (OV112) were placed upstream, or downstream of the EGFP coding sequences in the vector pUC19- H5-EGFP (Tseng et al. 2015b). Specifically, a fragment that spans 522 bp upstream of the CBP coding region was amplified by PCR using the primer set OV112-up-EcoRI-F/OV112-up-BamHI-R and cloned into the EcoR I and BamH I restriction sites of pUC19- H5-EGFP to generate the pUC19-H5-EGFP-upstream plasmid. Another fragment that spans 560 bp downstream of the CBP coding region was amplified using two primers, OV112-down-XhoI-F and OV112-down-HindIII-R, and then cloned into the vector pUC19-H5-EGFP-upstream at the Xho I and Hind III restriction sites. The final plasmid construct is referred to as pCBPΔ-EGFP.
All primers used to amplify the ORFV gene were designed based on ORFV sequences published in GenBank (accession number AY386264.1), and are summarized in Table 1.Table 1 Primer sequences used in this study
Primer name Sequence (5′–3′)
Up-VEGF-Hind III-F ATAAGCTTGACCCCAGAGGCCGCCGACTG
Up-VEGF-Xho I-F TTTCTCGAGCTCAAAGCCTATCCAGACAC
Down-VEGF-EcoR I-R CCGAATTCCGGTCACAATGTCGTATGAGGTG
Down-VEGF-BamH I-R TTTGGATCCGTCTGGGCACGCAATTTATT
slp-vvTK-Xba I-F GGATAACAATTCCCCTCTAGATTTTTTT
vvTK-Xba I-R GGGGTCTAGATTATGAGTCGATGTAACACTTTCTAC
vvTK-Nco l-F TTTCCATGGATGAACGGCGGACATATTC
vvTK-BamH l-R GGGGGGATCCTTATGAGTCGATGTAACACTTTCTAC
rVEGF-BamH I-F GGGGATCCTTCTGTTAATGAATGGATGCAAACATTAGG
rVEGF-Xho I-F GGGCTCGAGAACGACTACGGTTGTATTTCTTGTT
VEGF-F CCAGAATGCGTGTCTCAGGG
VEGF-R GTTACAGCAACCACTGCATCG
eGFP-F AAGGATCCATGGTGAGCAAGGGCGAG
eGFP-R TTGTCGACTTACTTGTACAGCTCGTCC
OV112-up-EcoRI-F GAATTCCCCGGCGACGGAGATCTC
OV112-up-BamHI-R ATTTATTGGATCCCCTGATTGTTGCAAGATTCCAGAG
OV112-down-XhoI-F CTCGAGGATGTTTTTATTCGGCAATATAATAGGTG
OV112-down-HindIII-R AAGCTTCCAGGCCCCACCTCCAC
OV112-F ATGAAGGCGNTGGTGTTG
OV112-R ATGGCCAGGGCTGAGGTTAAG
OV111-F ATTCGGCGACATGCTGTACGC
OV113-R CCCCACTTCCACCTCTACCTC
OV112-F1-F GGGGCATATGAAGGCGGTGGTGTTGTTG
OV112-F1-R GGCTCGAGATCCATTACGGAGTCTTC
OV112-F2-F GGCATATGGATAATGAATACATGTCTGCG
OV112-F2-R GGGCTCGAGGTTCGCAGATAAGTCCTG
OV112-F3-F TTTCATATGGCGAACGGCAGCTGGG
OV112-F3-R GGGCTCGAGCTTTCTGTTTACACTGGCG
OV112-F4-F GGGGCATATGAAGGCGGTGGTGTTGTTG
OV112-F4-R GGCTCGAGATCCATTACGGAGTCTTC
The underlined primer sequences highlight the restriction enzyme recognition sites
Generation of single-gene deletion orf viruses
Recombinant ORFV-VEGFΔ-EGFP and ORFV-CBPΔ-EGFP viruses were generated using a procedure adapted from the standard protocols used in the generation of vaccinia virus recombinants and previously described methods (Byrd and Hruby 2004; Marzook and Newsome 2019; Tseng et al. 2015b; Wyatt et al. 2017). HEK293T cells were infected with wild-type orf virus at an MOI of 0.05. At 1 hpi, infected cells were transfected with one of the transfer vectors, pVEGF△-vvTK-eGFP and pCBPΔ-EGFP, specific for generating recombinant orf viruses, ORFV-VEGFΔ-EGFP and ORFV-CBPΔ-EGFP with deletions of VEGF or CBP, respectively. Transfection was performed using Lipofectamine 2000 (Invitrogen, Thermo Fisher Scientific, Carlsbad, CA, USA) following the manufacturer’s instructions. Briefly, 3 µL of Lipofectamine 2000 per 1 µg of transfer vector was mixed, incubated at room temperature for 15 min, and added to the cells. After 6 h at 37 °C, the medium containing the transfection mix was removed and replaced with a complete growth medium (DMEM supplemented with 10% FBS). The recombinant virus was monitored for EGFP expression and collected 24–48 h after transfection by scraping cells off the plates and mixing them along with any floating cells in the culture followed by sonication. The cell lysate containing the orf virus was tenfold serially diluted and inoculated into the FB cells. The infected cell monolayer was overlaid with 1.2% methyl cellulose, and cell morphology was observed daily by fluorescence microscopy. Individual fluorescing plaques were selected and subjected to several rounds of plaque purification.
The total genomic DNA isolated from the recombinants per round of plaque purification was characterized using restriction endonuclease, PCR, and western blot analyses.
Genotyping of single-gene deletion orf viruses
The genotypes of the two recombinant viruses were validated using PCR. To confirm the deletion of the target gene, PCR with the primer set VEGF-F/VEGF-R or OV112-F/OV112-R was used to amplify VEGF and CBP, respectively, from the viral genome. Moreover, the presence of the inserted gene cassette in the ORFV-VEGFΔ-EGFP virus, including vvTK and EGFP, was further validated by PCR with the primer set vvTK-Nco l-F/vvTK-Xba I-R or eGFP-F/eGFP-R, respectively.
Additionally, restriction fragment length polymorphism (RFLP) analysis was conducted to confirm the ORFV-CBPΔ-EGFP genotype. To do so, a fragment spanning two open reading frames adjacent to OV 112 was amplified by PCR using primers OV111-F and OV113-R. Subsequently, ORFV-CBPΔ-EGFP and ORFV-WT-ORFV (2095 bp and 2024 bp, respectively) were reacted with a restriction enzyme, either Bgl II or Nco I. The RFLP pattern of ORFV-CBPΔ-EGFP was comparatively analyzed with that of ORFV-WT-ORFV. The primers used for genotyping are listed in Table 1.
Preparation of anti-serum for ORFV-VEGF and CBP
To confirm the deletion of the target genes, two antibodies against ORFV-VEGF and CBP proteins were generated to detect target gene expression. First, an immunogen is produced in prokaryotic cells. The VEGF gene was amplified from wild-type ORFV DNA by PCR using primers rVEGF-BamH I-F and rVEGF-Xho I-R. The PCR product was trimmed by BamH I and Xho I and cloned into pET32b linearized with the corresponding enzymes. Recombinant CBP was expressed in four fragments to increase the yield. The four fragments (OV112-F1 to -F4) with expected sizes of 224 bp, 228 bp, 224 bp, and 220 bp, which covered the whole region of the CBP protein, were individually amplified by PCR with primer sets (OV112-F1-F/OV112-F1-R ~ OV112-F4-F/OV112-F4-R, Table 1). Subsequently, the four amplicons were reacted with Nde I and Xho I enzymes and ligated with pET24a vectors linearized with compatible enzymes. Expression and purification of recombinant proteins (rVEGF, CBP F1-F4 fragments) followed the protocol established in our laboratory (Tseng et al. 2015b). Production of polyclonal anti-serum for VEGF and CBP was carried out by Yao-Hong Biotechnology, Inc. (Taipei, Taiwan).
Analysis of sequence variations and phylogenetic relationships
The chemokine binding protein and vascular endothelial growth factor protein sequences of orf virus reference strains isolated from different countries were downloaded from the NCBI GenBank database. To perform a comparative analysis of the sequences, related protein sequences were aligned using the CLUSTAL W multiple sequence alignment program, version 1.83, MegAlign module of Lasergene DNA Star software Pairwise.
The accession numbers of all the reference strains used in this study are summarized in Table 2.Table 2 Accession numbers of reference sequences
Name Gene Accession no Ref. no
TW/Hoping strain CBP OP056416 –
D1701 CBP HM133903 (McGuire et al. 2012)
NZ7 CBP AAR18811 (Seet et al. 2003)
NZ2 CBP ABA00630 (Mercer et al. 2006)
Bangalore/89/05/Goat CBP AWN09366 –
Hubei/2013 CBP AHJ61508 –
Malaysia/goat/2020 CBP UAJ23439 –
Ludhiana/50/Goat/2006 CBP AWN09367 –
Hyderabad/25/Sheep/2006 CBP AWN09365 –
Gujarat/SP26/Goat/2006 CBP AWN09364 –
Alwar/Goat/2008 CBP AWN09363 –
Shahjahanpur/82/Goat/2004 CBP AWN09360 –
PVNZ CBP QDO67043 (Sharif et al. 2019)
BPSV CBP AIY25487 –
Human VEGF-A VEGF NG_008732 (Eswarappa et al. 2014)
HLJ05 VEGF MK317956 –
VEGF-D VEGF JN603825 (de Castro et al. 2022)
D1701 VEGF HM133903 (McGuire et al. 2012)
ITC2 VEGF DQ012965.1 (Mercer et al. 2002)
ITTo VEGF DQ012964 (Mercer et al. 2002)
NA1-11 VEGF KF234407 –
NA17 VEGF MG674916 –
NP VEGF KP010355 (Chi et al. 2015)
NZ2 VEGF DQ184476 (Mercer et al. 2006)
HN3-12 VEGF KY053526 –
IA82 VEGF AY386263 (Delhon et al. 2004)
SJ1 VEGF KP010356 (Chi et al. 2015)
Pseudocowpox VEGF GQ329669 (Hautaniemi et al. 2010)
TW/Hoping strain VEGF OP056415 –
NZ7 VEGF S67522 (Lyttle et al. 1994)
Western blot analysis
Proteins were resolved by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and then electrophoretically transferred to a polyvinylidene difluoride (PVDF) membrane, followed by immunoblotting with diluted antibodies against viral proteins, F1L and VEGF (1:2500, homemade), EGFP (homemade 1:2000), and alpha-tubulin (Novusbio, 1:10,000) overnight at 4 °C. Goat anti-mouse or rabbit IgG conjugated with horseradish peroxidase (HRP) were used as secondary antibodies and incubated with the membrane for 1 h at room temperature. After the membrane was washed with 0.05% Tween 20 in PBS, the signal was detected using an enzyme-linked chemiluminescence assay (SuperSignal; Thermo Scientific). Images were captured using ImageQuant LAS 4000 (GE Healthcare, Uppsala, Sweden), and the intensity of each band was determined by densitometry (ImageJ, NIH).
Plaque assay
FB cells were seeded one night before infection and infected with tenfold serially diluted viruses. One hour post-adsorption, the infectious medium was replaced with 1.1% methylcellulose in DMEM with 2.5% FBS. Infection was monitored daily until a cytopathic effect (CPE) was observed (~ 14 days). The cells were fixed with 10% formaldehyde and stained with crystal violet.
Viral infection of goats
All animal experiments described in this study were approved by the National Chung Hsing University (NCHU) Animal Ethics Committee (IACUC No. 110–106). Animals were housed in an ABSL-2 facility at the Research Center for Animal Medicine, NCHU, Taiwan. The experiment design followed the method from Mercer’s laboratory (Fleming et al. 2017). Briefly, three 8-month-old Nubian goats, representing three repeats, were individually inoculated with one of the three orf viruses (ORFV-VEGFΔ-EGFP, ORFV-CBPΔ-EGFP, and ORFV-WT-EGFP) on the epidermis of each leg. An approximately 3-cm-long scratch was made in the skin of the legs using a bifurcated needle and infected by topical application of 100 μL of virus (106 pfu) or PBS only (no virus control). Virus-induced lesions were photographed daily for 10 days, and clinical scores were determined. The goats were examined for erythema, papule formation, pustule formation, and firmly attached scabs associated with scarified/infected areas of the skin. The clinical scores were determined by counting the discrete round raised papules with a creamy appearance that formed on the skin surface along the lines of scarification using magnified photographic images and the width of the lesions (1–10 mm) that formed when papules coalesced (days 5–7). Clinical scores ranged from 0 to 3 (0, “no clinical sign of inflammation nor papule on the skin”; 1, “mild to moderate inflammation and visible slight papule”; 2, “moderate to severe papule and mild vesicular”; and 3, “moderate to severe vesicular and moderate pustular to severe pustular”). The clinical scores utilized in this study were determined as per the pathogenesis of ORFV infection recommended by a qualified and experienced veterinarian. The clinical scores for all animals at all time points were determined by two qualified and experienced veterinarians.
Punch biopsies (3 mm) were performed on days 4, 7, and 10 post-infection. Blood samples were collected from the jugular vein of each animal before infection. The viral loads in the lesion were measured using a standard plaque assay or reverse transcription-polymerase chain reaction (RT-PCR).
Histology examination of goat skin by hematoxylin and eosin (H&E) staining
Skin biopsies (3 mm) from goats were fixed with 10% formalin and embedded in paraffin wax. Sections were cut at 4 μm, mounted on glass slides, and stained with H&E, as described by Feldman and Wolfe (2014).
Statistical analysis
Data are expressed as mean ± standard deviation. Student’s t test was used to determine significant differences. Statistical analysis was performed using GraphPad Prism version 8.00 (GraphPad Software). Statistical significance was set at p < 0.05 and is represented by the asterisk sign (*, **, and *** indicate p values < 0.05, 0.01, and 0.001, respectively).
Results
Sequence analysis of OV132 and OV112 of ORFV (Hoping strain)
Based on previous reports, sequences of ORFV genes encoding VEGF (OV132) and CBP (OV112) were highly variable, especially the OV132 gene. Hence, initially, the region consisting of the coding sequence as well as the flanking regions adjacent to the target gene of our local strain (TW/Hoping) was determined. Sequence analysis indicated that VEGF of the Hoping strain was phylogenetically close to NZ7 and distant from NZ2 (Figure S1). Overall, there was an approximately 9% sequence divergence in both genes between the TW/Hoping and NZ7 strains. Specifically, alignment of the nucleotide sequence indicated the OV132 gene of TW/Hoping shares 90.17% similarity with that of NZ7 and as low as 47.01% with that of NZ2 (Fig. 1A). NZ2 and NZ7 are the two model strains commonly used for the study of ORFV pathogenicity in goat models (Fleming et al. 2017; Savory et al. 2000). Compared with VEGF, a higher similarity was noticed in the OV112 gene that encodes CBP among different strains; as shown in Fig. 1B, there is approximately 90–91% of similarity between the Taiwanese (TW/Hoping) strain and the two model strains (Fig. 1B).Fig. 1 Sequence analysis of orf viruses. Sequence similarity in the OV132 (A) and OV112 (B) genes and various ORFV strains isolated from different countries were analyzed using the CLUSTAL W multiple sequence alignment program, version 1.83, of the MegAlign module of Lasergene DNA Star software Pairwise. The strains analyzed in this assay are summarized in Table 2
Generation of recombinant orf viruses with deletion of the OV132 or OV112 gene
Considering the high sequence variation between the NZ2 and NZ7 strains, it is important to evaluate the role of the two virulence factors involved in the TW/Hoping strain. To generate traceable ORFV, the enhanced green fluorescent protein (EGFP) reporter gene was inserted into the genome of ORFV (Hoping strain) to replace the entire coding region of the virulence genes, that is, either VEGF (Fig. 2A) or CBP (Fig. 3A), by means of homologous recombination. Moreover, the thymidine kinase (vvtk) gene of the vaccinia virus was inserted into the genome of the VEGF-deletion virus, which could serve as a selection marker for the subsequent run of recombinant virus manipulation (Lye and Wang 1996). After several rounds of plaque purification, viral DNA was extracted to confirm the genotype of these recombinant ORFVs, in comparison with that of ORFV-WT-EGFP, another reporter virus consisting of the EGFP gene inserted between the OV20 and OV21 loci of the wild-type viral genome that was previously established (Tseng et al. 2015b).Fig. 2 Generation and validation of recombinant ORFV with VEGF deletion. A Schematic representation of ORFV genomes and the expression cassette of the transfer vector for generation of VEGF-null mutant virus by homologous recombination between transfer vector DNA and the ORFV genome (Hoping strain). The genotype of the ORFV-VEGFΔ-EGFP virus was confirmed by the absence of OV132 (B) and the insertion of both vvTK and EGFP fragments (C) by PCR. Representative results demonstrating the deletion of OV132 (B) and the presence of vvTK and EGFP (C) in the genome of the ORFV-VEGFΔ-EGFP virus. The plaque of ORFV-VEGFΔ-EGFP was visualized using Giemsa staining (D) or direct fluorescent microscopy (E). The ORFV-VEGFΔ-EGFP virus that failed to express VEGF was validated by western blot analysis using an antibody specific for VEGF (F). F1L and actin served as quality controls for ORFV infection and cell condition, respectively. The viruses with wild-type genome, including parental WT virus (WT) or the one with insertion of a reporter gene (WT-EGFP), served as a control for genotyping and also for monitoring infection in panels B and C and D–F, respectively
Fig. 3 Generation and validation of recombinant ORFV with CBP deletion. A Schematic representation of ORFV genomes and the expression cassette of the transfer vector for generation of CBP-null mutant virus by homologous recombination between transfer vector DNA and the ORFV genome (Hoping strain). The genotype of the ORFV-CBPΔ-EGFP virus was confirmed by the absence of OV112 using PCR amplification (B). The identity and purity of the recombinant ORFV-CBPΔ-EGFP genome was validated using the RFLP-PCR profile (C). The plaque of ORFV-CBPΔ-EGFP was visualized using Giemsa staining (D) or direct fluorescent microscopy (E). The ORFV-CBPΔ-EGFP virus that failed to express CBP was validated by western blot analysis using an antibody specific for CBP (F). F1L and actin served as quality controls for ORFV infection and cell condition, respectively. The viruses with wild-type genome, including parental WT virus (WT) or the one with insertion of a reporter gene (WT-EGFP), served as a control for genotyping and also for monitoring infection in panels B and C and D–F, respectively
As indicated in Fig. 2B, the OV132 gene was deleted from the ORFV-VEGFΔ-EGFP genome. Moreover, fragments with the expected molecular weights of vvTK and EGFP were successfully amplified by PCR with gene-specific primers from the recombinant ORFV (Fig. 2C). Notably, the plaque size of ORFV-VEGFΔ-EGFP was smaller than that of ORFV-WT-EGFP, as visualized by the standard plaque assay (Fig. 2D) and fluorescence microscopy (Fig. 2E).
The ORFV-CBPΔ-EGFP virus was validated using strategies similar to those for the ORFV-VEGFΔ-EGFP virus. First, the OV112 was absent from the ORFV-CBPΔ-EGFP genome (lane CBPΔ in Fig. 3B). Moreover, since OV112 contains Bgl II, while EGFP has Nco I, replacement of the OV112 gene by insertion of the EGFP cassette altered the cutting pattern of the restriction enzyme. Hence, the identity and purity of the recombinant virus were confirmed by restriction fragment length polymorphism (RFLP). A fragment spanning OV111 to OV113 was amplified from the viral genome followed by digestion with either Bgl II or Nco I enzyme. As illustrated in Fig. 3C, compared with ORFV-WT-EGFP, the recombinant virus ORFV-CBPΔ-EGFP contains one additional Nco I site; therefore, Nco I digestion yielded two major fragments of 1233 bp and 778 bp, while there was only one major fragment observed in the wild-type virus. On the other hand, due to the presence of additional Bgl II sites in the wild-type viral genome, the reaction of this enzyme produced two fragments (1142 bp and 884 bp), which is distinct from the ORFV-CBPΔ-EGFP virus (Fig. 3C). Notably, unlike the ORFV-VEGFΔ-EGFP virus, the plaque size of the ORFV-CBPΔ-EGFP virus was similar to that of ORFV-WT-EGFP (Fig. 3D), and the expression of EGFP was stronger than that of ORFV-WT-EGFP (Fig. 3E). Among the three viruses, ORFV-VEGFΔ-EGFP demonstrated the weakest EGFP signal, whereas the ORFV-CBPΔ-EGFP virus showed the strongest EGFP expression.
Importantly, in addition to reporter gene expression, knockout of VEGF or CBP expression from recombinant viruses was confirmed. As shown in Figs. 2F and 3F, both viruses encoded the viral F1L protein, while VEGF and CBP proteins were not detected in ORFV-VEGFΔ-EGFP or ORFV-CBPΔ-EGFP viruses, respectively. Taken together, these data indicate the successful generation of recombinant orf viruses with deletion of either the VEGF or CBP genes.
Characterization of the recombinant ORFV in vitro
Next, the replication properties of these two single-gene deleted viruses (ORFV-VEGFΔ-EGFP and ORFV-CBPΔ-EGFP) were comparatively analyzed with an equivalent reporter virus containing the wild-type genome (ORFV-WT-EGFP) in primary goat fibroblast (FB) cells.
Replication profiles of CBPΔ-ORFV-EGFP and VEGFΔ-ORFV-EGFP recombinant viruses were first evaluated using two different infection doses, including a multiplicity of infection (MOI) of 0.1 and 1 to assess the multi-step growth (Fig. 4A, C, E) and single-step growth (Fig. 4B, D, F) of these viruses, respectively. Based on the green fluorescence signal observed under microscopy, a significant decrease in infection was observed in FB cells infected with VEGF-null mutant virus throughout the infection at both MOIs, when compared to ORFV-WT-EGFP or ORFV-CBPΔ-EGFP (Fig. 4A, B). At 24 hpi, infection of wild-type virus at 0.1 MOI had the strongest fluorescence signal. However, the expression of the reporter gene in cells infected with CBP-null ORFV was higher than that of cells infected with wild-type ORFV at a higher MOI or at 48 hpi (Fig. 4D).Fig. 4 Comparative characterization of the two recombinant ORFVs. FB cells were infected with the recombinant viruses at an MOI of 0.1 (A, C, E) or 1 (B, D, F) as indicated. The expression of the reporter gene was directly visualized using fluorescence microscopy (A). The protein expression profile (including viral proteins F1L and VEGF, the reporter GFP, and cellular tubulin) and the yield of virus progenies in cells infected with viruses for 24 and 48 hpi were determined by western blot analysis (C, D) and plaque assay (E, F), respectively. The experiments were conducted in triplicate. Bars represent the standard error of the mean. Student’s t test was performed, and statistical differences between the mean viral F1L protein or titers between ORFV-WT-EGFP and recombinant ORFV groups were considered significant at *p < 0.05, **p < 0.01, and ***p < 0.001. “n.s.” indicates no significance
Next, the accumulated expression level of viral protein was also evaluated; western blot analysis revealed that the expression level of viral F1L protein was significantly lower in ORFV-VEGFΔ-EGFP and ORFV-CBPΔ-EGFP as compared to that expressed in WT reporter virus at 24 hpi (Fig. 4C and 4D). Nevertheless, at a later time point of infection (48 hpi), the decreased F1L expression was only significant in infection with ORFV-VEGFΔ-EGFP at 1 MOI, compared with ORFV-WT-EGFP (Fig. 4D). Moreover, among the three viruses analyzed, ORFV-VEGFΔ-EGFP had the lowest yield of viral progenies at both infection doses and time points analyzed (Fig. 4E, F), which is in accordance with the trend observed in F1L protein levels. Interestingly, in comparison to ORFV-WT-EGFP, infection with 0.1 MOI of ORFV-CBPΔ-EGFP yielded a significantly lower titer at 24 hpi, while viral production was drastically elevated to an extent higher than that of ORFV-WT-EGFP at 48 hpi (Fig. 4E), which is consistent with the dynamic expression level of EGFP (Fig. 4A). Collectively, the deletion of VEGF significantly affected ORFV infection, whereas the absence of the CBP gene did not compromise the ability of ORFV to replicate in the cell culture.
Pathogenesis in goats
As previously described by Mercer et al., experimental infection of sheep with WT-ORFV (NZ7 strain) by scarification of the skin generally results in discrete papules and pustules that form along the scratch line (Fleming et al. 2017). The pathogenicity of these recombinant ORFV was comparatively analyzed in a goat model, the authentic host of ORFV. In this study, following the protocol described previously (Savory et al. 2000), each of the three goats was inoculated with 106 pfu/0.1 mL of ORFV (i.e., ORFV-VEGFΔ-EGFP, ORFV-CBPΔ-EGFP, ORFV-WT-EGFP virus) or PBS (mock-infected control) by smearing the virus at different scratch lines. Infected skin was photographed daily to record clinical pathology, and the clinical score was determined from the appearance and size of papules and pustules that developed along the scratch line as described in the “Materials and methods.” As shown in Fig. 5A, the gross pathology of the lesion in each animal infected with either the recombinant deletion virus or the wild-type virus showed no significant difference with respect to papule and pustule formation on days 4 and 7 post-infection.Fig. 5 Clinical course of ORFV infection in infected goats. The skin was inoculated with 106 pfu of ORFV-VEGFΔ-EGFP (VEGFΔ), ORFV-CBPΔ-EGFP (CBP.Δ), ORFV-WT-EGFP (WT) viruses, or PBS (mock infection). Gross pathology of ORFV lesions in goats 4 and 7 days post inoculation (dpi) (A). Viral production in the scarified skin of three goats infected with the three viruses at 7 and 10 dpi was measured using standard plaque assay (B). # indicates no virus titer. The average viral yield of defective ORFV relative to the ORFV-WT-EGFP titer in three goats was estimated and plotted (C). The bars represent the standard error of the mean. Student’s t test was performed, and statistical differences between the mean titers of viral shedding in the ORFV-WT-EGFP group and recombinant ORFV groups were considered significant at *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001
To estimate the production of infectious viruses during the course of infection in goats, 1.5-mm punch biopsies were taken, and viral titers at both 7- and 10-days post-infection (dpi) were determined. Notably, the ORFV-CBPΔ-EGFP titers were significantly lower than those of the ORFV-WT-EGFP strain (Fig. 5C). As summarized in Table 3, compared with the ORFV-WT-EGFP virus, ORFV-CBPΔ-EGFP titers were reduced by as much as 14-fold and 529-fold on 7 and 10 dpi, respectively. Furthermore, the titer of ORFV-CBPΔ-EGFP on the skin lesions declined from 7 to 10 dpi, whereas the wild-type virus remained at a similar level during this period (Table 3). Surprisingly, the production of infectious ORFV-VEGFΔ-EGFP virus particles on the scarified skin was undetectable (Fig. 5B). To confirm ORFV-VEGFΔ-EGFP replication during the study, we extracted viral DNA from ORFV-VEGFΔ-EGFP-infected tissues to determine the presence of viral RNA by RT-PCR using primers targeting the viral A32L gene, a gene that is used for molecular characterization of ORFV (Chan et al. 2009). The results confirmed the presence of ORFV-VEGFΔ-EGFP RNA with increasing signal intensity from 4 to 10 dpi (Figure S2). Overall, these results suggested that the deletion of either CBP or VEGF significantly impaired ORFV replication relative to that of the ORFV-WT-EGFP virus in goats. Moreover, ORFV-VEGFΔ-EGFP infection was more attenuated than ORFV-CBPΔ-EGFP infection in the goat model.Table 3 Viral yield was detected in the skin of the infected goats
Animal ID dpi Virus titer (PFU/mL) Fold reduction&
WT-EGFP CBP∆-EGFP VEGF∆-EGFP
G1 7 7.50 × 105 5.25 × 104 ND 14.3
10 9.25 × 104 1.75 × 102 ND 528.6
G2 7 2.25 × 104 3.0 × 103 ND 7.5
10 4.25 × 102 ND ND 425
G3 7 5.05 × 106 9.0 × 105 ND 5.61
10 2.25 × 105 3.0 × 102 ND 750
ND not detected
&ORFV-CBP∆-EGFP compared with ORFV-WT-EGFP
Histopathology analysis of lesions in infected goats
Skin tissues of goats infected with ORFV were analyzed using H&E staining. As mentioned previously, biopsies of the ORFV-VEGFΔ-EGFP, ORFV-CBPΔ-EGFP, and ORFV-WT-EGFP viruses were obtained from the scarified skin at 4 and 10 dpi. Histological examination of skin biopsies revealed hypergranulosis (thickened cornified layer, indicated by an arrow) and increased inflammatory infiltrate, most notably within the papillary dermis (Fig. 6, cropped as a rectangle), but also invading the epidermis, which was present in all infected animals. Moreover, characteristic histological changes associated with ORFV infection, including epidermal hyperplasia and hydrophobic degeneration of keratinocytes, were observed (Fig. 6). As early as 4 dpi, animals infected with ORFV-CBPΔ-EGFP (Fig. 6B) showed acanthosis (thickening of the stratum basal and stratum spinosum) and orthokeratotic hyperkeratosis (thickening of the stratum corneum), as well as hydropic ballooning degeneration, representing viral infection (indicated by an arrowhead), which represents the typical WT virus infection (Fig. 6A). The same histological features were observed in ORFV-VEGFΔ-EGFP virus infection (Fig. 6C). However, this was not observed in the mock-infected control group (Fig. 6G). At 10 dpi, similar histopathological changes were observed, although a slight decrease in acanthosis was noted in the infected tissue samples (Fig. 6D–F). Notably, these features were not observed in the mock-infected group.Fig. 6 Histopathology of skin biopsies of goats infected with ORFV. Histopathological examination of the ORFV-infected skin tissue. Sections from biopsy tissue infected with ORFV-WT-EGFP (A, E), ORFV-CBP∆-EGFP (B, F), and ORFV-VEGF∆-EGFP (C, G) at 4 and 10 dpi, or PBS-treated skin (D) were stained with hematoxylin and eosin (H&E stain). Typical histological features of ORFV-infected tissue, that is, dermal neutrophilic infiltration and hydropic ballooning degeneration, are indicated by dotted rectangles and arrowheads, respectively. Images were taken at 40 × magnification
Discussion
ORFV is an ideal vector for gene delivery and heterologous gene expression (Haig and Mercer 1998; Joshi et al. 2021; Reguzova et al. 2020). Hence, the safety profile remains a great concern when a viral vector is used as a medical platform, particularly for therapeutic purposes. ORFV encodes several proteins that modulate host immune responses to favor viral replication, either by inhibiting or enhancing inflammatory responses (Deane et al. 2000; Haig and McInnes 2002). Given their potent immunomodulatory properties, the roles of VEGF (Savory et al. 2000) and CBP (Fleming et al. 2017) in sheep have been individually described. However, since these studies used two different viral strains circulating in New Zealand (NZ2 and NZ7), it is difficult to objectively determine the contribution of these two genes. Moreover, as per our results (Fig. 1) and the aforementioned, remarkable divergence was found in sequences of both the CBP and VEGF genes within the ORFV species; for instance, the sequence of CBP (Seet et al. 2003) or VEGF (Lyttle et al. 1994) of the NZ7 strain shares only 78% or 41% identity with that of the NZ2 strain, respectively. The similarity of the VEGF gene between our local strain (TW/Hoping) and NZ2, the model strain used to define the function of VEGF, was 47.01%. Hence, the findings of the previous study might not be applicable to our local viral strain isolated from goats. Since the contribution of these genes to ORFV isolated from goats in Taiwan remains unknown, two null mutant orf viruses defective in the function of CBP or VEGF were generated to investigate their contribution to goat ORFV (Hoping strain) replication in vitro and pathogenesis in vivo. More importantly, the attenuation levels of these two functionally defective viruses were comparatively analyzed for the first time. The ORFV-VEGFΔ-EGFP virus was remarkably attenuated in both cell culture and goat models, whereas infection with the ORFV-CBPΔ-EGFP virus was significantly compromised only in an animal model.
The phenotype of the null mutant orf viruses established in the current study was distinct from those isolated from New Zealand in cell cultures. It has been reported that deletion of VEGF (Savory et al. 2000) or CBP (Fleming et al. 2017) did not cause viral attenuation in in vitro models. In the scenario of the VEGF-deletion virus, no discrepancy in either plaque size or growth kinetics was found between the WT and deletion virus in primary bovine testis cells (Savory et al. 2000). However, our study showed that the deletion of VEGF from ORFV (Hoping strain) led to a decrease in the size of viral plaques (Fig. 2D) and expression of the F1L viral protein (Fig. 4C, D). Importantly, a significant reduction in virus yield was observed in the ORFV-VEGFΔ-EGFP virus, as compared to the WT strain in goat fibroblast cells (Fig. 4E, F). Hence, the knockout of VEGF from ORFV (Hoping strain) affects viral propagation in primary cells derived from the natural host. Several factors may be involved in this inconsistent phenomenon while evaluating the function of virally encoded VEGF in cell cultures. First, the effect of VEGF may be dependent on the viral strain or in a cell type–specific manner. Mercer et al. studied the NZ2 strain of sheep ORFV (ovORFV) on bovine testis cells (Savory et al. 2000), whereas we depicted the role of viral VEGF in goat fibroblast cells using a goat ORFV (Hoping) strain. Moreover, in a previous study (Savory et al. 2000), the viral VEGF coding region was partially removed (i.e., 116 bp) from the ovVEGFΔ-virus, whereas ORFV-VEGFΔ-EGFP was a VEGF-null mutant ORFV. Although VEGF-like activity, including endothelial cell mitogenesis, vascular permeability, and activation of VEGF receptor-2, has not been detected in cells infected with ovVEGFΔ, whether viral VEGF could modulate viral infection by other mechanisms has not yet been determined.
On the other hand, unlike VEGF, CBP deletion in the ORFV genome decreased viral protein expression or viral yield only at an early time point (i.e., 24 hpi) of a lower dose (that is, 0.1 MOI) of infection (Fig. 4). Surprisingly, rapid growth kinetics were observed at 48 hpi; the green fluorescence level (Fig. 4A, B) and virus yield (Fig. 4E, F) of ORFV-CBPΔ-EGFP significantly exceeded those of viruses harboring the WT genome. The apparent attenuation effect of CBP-knockout on viral infection suggests that the CBP gene could be non-essential for ORFV replication in vitro, which is consistent with the results of previous studies using ovORFV with CBP-knockout (CBP-ko virus) (Fleming et al. 2017; Martins et al. 2021).
It is critical to validate the phenotype of mutant viruses in models using authentic animals. The effects of CBP and VEGF on ORFV biology and pathogenesis were investigated in a goat model. ORFV infections display lesions that are typically characterized by maculopapular and proliferative scabby lesions (Fleming et al. 2017; Haig and Mercer 1998). These lesions are usually self-limiting and resolve within 4–6 weeks. However, as shown in Fig. 5A, experimental goats did not present a progressive disease course in any group after virus inoculation; the inflammation on the lesion gradually diminished after 7 dpi. In a previous study, the NZ7 strain of ovORFV that induced large pustular lesions in sheep was chosen to characterize the virulence factors of ovORFV (Fleming et al. 2017). Furthermore, the goats in the current study were approximately 8 months old, which could not be as vulnerable to ORFV infection as young kids (Hosamani et al. 2009). Hence, we suspect that the indefinite gross lesion developed by infection with the ORFV Hoping strain is possibly due to the lower virulence as compared with ovORFV used in other research groups, or due to a lower susceptibility of experimental goats.
In the sheep model, efficient replication of ovVEGFΔ was observed throughout the time of infection, although the reduced pathology of the skin lesions was evidenced by rete ridge formation (Savory et al. 2000). Intriguingly, infectious virions were not detected in ORFV-VEGFΔ-EGFP-infected skin samples throughout the study (Fig. 5B, C). However, to rule out the under-detectable viral production in the skin biopsies due to the failure of initial viral inoculation, virus replication was further determined by detection of viral A32L RNA using reverse transcription-PCR. As shown in Figure S2, viral RNA was readily detectable, and the increase in viral RNA levels along with the infection time indicates the progression of ORFV-VEGFΔ-EGFP infection. Moreover, histological examination of skin biopsies revealed characteristic histological changes associated with ORFV infection, including epidermal hyperplasia, influx of inflammatory cells, and hydrophobic degeneration of keratinocytes, indicating a bonafide infection of the ORFV-VEGFΔ-EGFP. Collectively, these lines of evidence endorse a severe attenuation of ORFV (Hoping strain) in the absence of VEGF. Our findings in light of the animal model are consistent with those of Savory et al., wherein the inactivation of the viral VEGF function significantly affected the pathogenesis of ORFV in its natural host (Savory et al. 2000). The virus titer in ovVEGFΔ-infected lesions was approximately 20-fold lower than that in WT, and a milder lesion (based on the formation of vascularization and rete ridge) was observed on scarified skin infected with ovVEGF-Δ (Savory et al. 2000).
According to the viral yield in the goat model, the ORFV-CBPΔ-EGFP virus appeared to be less attenuated than the VEGF knockout virus. ORFV-CBPΔ-EGFP was less pathogenic than the WT strain, as evidenced by markedly reduced virus production in the infected cells and skin tissue (Fig. 5C, Table 3). CBP deletion in the ORFV Hoping strain displayed a reduction in virus titer by approximately 14-fold and 528-fold in goats compared to ORFV-WT-EGFP at 7 and 10 dpi, respectively (Table 3). In line with the results of Martins et al., clearance of CBP-knockout ORFV was faster than that of its parental strain (Martins et al. 2021). Despite the unapparent gross pathological changes, the skin histology examination showed a typical characteristic of ORFV infection (Fig. 5). Consistent with the findings of Fleming et al. (2017) and Martins et al. (2021), this suggests that the immunomodulatory function of CBP is important for ORFV infection, disease progression, and resolution in the natural host.
In the current study, deletion of the target gene was indubitably evidenced by the absence of CBP and VEGF protein expression in immunoblot analysis (Figs. 2F and 3F), whereas the phenotype of the knockout virus was confirmed by functional assays, such as receptor binding ability and cellular activities in previous studies (Fleming et al. 2017; Savory et al. 2000). Although reduced infectivity has been well demonstrated in ovVEGFΔ virus (with partial deletion of 116 bp of OV132), or CBP-ko ORFV, in comparison to its parental strain (ovORFV), the parameters used in those studies were not comparable to each other. Hence, the relative degree of attenuation of these recombinant viruses remains unclear. In the study of Savory et al., the attenuation of VEGF-gene deleted ORFV (ovVEGF-D) was evaluated by the formation of rete ridges, yield of virus progenies, histological comparison of infected tissues, and gross pathology, but clinical scoring in lesions was not performed (Savory et al. 2000). On the other hand, Fleming et al. (2017) highlight the attenuation of CBP-ko ORFV by estimating the clinical scores of infected skin lesions by histology analysis, the region of virus replication, and MHC-II by immunohistochemistry (IHC) assay. Following the same experimental design and based on the same criteria, this study demonstrated that ORFV-VEGFΔ-EGFP is less pathogenic than ORFV-CBPΔ-EGFP.
In conclusion, our study clearly showed that the VEGF and CBP genes are critical for the infection and virulence of ORFV (Hoping strain). Notably, recombinant ORFV defective in either VEGF or CBP expression significantly reduced viral infection; in particular, knockout of VEGF expression resulted in severe attenuation of ORFV infectivity in an animal model. As both VEGF and CBP have been clearly defined as virulence determinants for ORFV, deletion of these loci improve the overall safety of the ORFV vector platform. As evidenced in both cell culture and the natural goat host, deletion of the VEGF gene markedly reduced the yield of viral progenies, while the ability of intracellular viral propagation remained. This property renders the ORFV-VEGFΔ-EGFP virus an advantageous vector for the development of a live attenuated vaccine as well as for therapeutic regimens.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 162 KB)
Acknowledgements
This project was supported by the Ministry of Science and Technology of Taiwan (MOST-106-2313-B-005-039-MY3 and NSTC-111-2313-B-005-043-MY3).
Author contribution
WLH conceived of and designed the study. All of the authors conducted the experiments. WLH, STC, and YY analyzed the data. WLH and YY wrote the manuscript. WLH provided grants for this study. All of the authors have read and approved the manuscript.
Data availability
The data generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declarations
Ethical statement
All applicable international, national, and institutional guidelines for the care and use of animals were followed. The use of animals and experimental protocols were approved by the IACUC of the National Chung Hsing University (approval number: 110–106)
Conflict of interest
The authors declare no conflicts of interest.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Achen MG Jeltsch M Kukk E Makinen T Vitali A Wilks AF Alitalo K Stacker SA Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) Proc Natl Acad Sci U S A 1998 95 2 548 553 10.1073/pnas.95.2.548 9435229
Amann R Rohde J Wulle U Conlee D Raue R Martinon O Rziha HJ A new rabies vaccine based on a recombinant ORF virus (parapoxvirus) expressing the rabies virus glycoprotein J Virol 2013 87 3 1618 1630 10.1128/JVI.02470-12 23175365
Byrd CM Hruby DE Construction of recombinant vaccinia virus: cloning into the thymidine kinase locus Methods Mol Biol 2004 269 31 40 10.1385/1-59259-789-0:031 15114005
Chan KW Yang CH Lin JW Wang HC Lin FY Kuo ST Wong ML Hsu WL Phylogenetic analysis of parapoxviruses and the C-terminal heterogeneity of viral ATPase proteins Gene 2009 432 1–2 44 53 10.1016/j.gene.2008.10.029 19061942
Chen YL Hardman CS Yadava K Ogg G Innate lymphocyte mechanisms in skin diseases Annu Rev Immunol 2020 38 171 202 10.1146/annurev-immunol-082919-093554 32340577
Chen D Wang R Long M Li W Xiao B Deng H Weng K Gong D Liu F Luo S Hao W Identification of in vitro and in vivo oncolytic effect in colorectal cancer cells by Orf virus strain NA1/11 Oncol Rep 2021 45 2 535 546 10.3892/or.2020.7885 33416161
Chi X Zeng X Li W Hao W Li M Huang X Huang Y Rock DL Luo S Wang S Genome analysis of orf virus isolates from goats in the Fujian Province of southern China Front Microbiol 2015 6 1135 10.3389/fmicb.2015.01135 26557108
Deane D McInnes CJ Percival A Wood A Thomson J Lear A Gilray J Fleming S Mercer A Haig D Orf virus encodes a novel secreted protein inhibitor of granulocyte-macrophage colony-stimulating factor and interleukin-2 J Virol 2000 74 3 1313 1320 10.1128/jvi.74.3.1313-1320.2000 10627542
Delhon G Tulman ER Afonso CL Lu Z de la Concha-Bermejillo A Lehmkuhl HD Piccone ME Kutish GF Rock DL Genomes of the parapoxviruses ORF virus and bovine papular stomatitis virus J Virol 2004 78 1 168 177 10.1128/jvi.78.1.168-177.2004 14671098
Eswarappa SM Potdar AA Koch WJ Fan Y Vasu K Lindner D Willard B Graham LM DiCorleto PE Fox PL Programmed translational readthrough generates antiangiogenic VEGF-Ax Cell 2014 157 7 1605 1618 10.1016/j.cell.2014.04.033 24949972
Feldman AT Wolfe D Tissue processing and hematoxylin and eosin staining Methods Mol Biol 2014 1180 31 43 10.1007/978-1-4939-1050-2_3 25015141
Fischer T Planz O Stitz L Rziha HJ Novel recombinant parapoxvirus vectors induce protective humoral and cellular immunity against lethal herpesvirus challenge infection in mice J Virol 2003 77 17 9312 9323 10.1128/jvi.77.17.9312-9323.2003 12915547
Fleming SB McCaughan CA Andrews AE Nash AD Mercer AA A homolog of interleukin-10 is encoded by the poxvirus orf virus J Virol 1997 71 6 4857 4861 10.1128/JVI.71.6.4857-4861.1997 9151886
Fleming SB McCaughan C Lateef Z Dunn A Wise LM Real NC Mercer AA Deletion of the chemokine binding protein gene from the parapoxvirus Orf virus reduces virulence and pathogenesis in sheep Front Microbiol 2017 8 46 10.3389/fmicb.2017.00046 28174562
Friebe A Friederichs S Scholz K Janssen U Scholz C Schlapp T Mercer A Siegling A Volk HD Weber O Characterization of immunostimulatory components of orf virus (parapoxvirus ovis) J Gen Virol 2011 92 Pt 7 1571 1584 10.1099/vir.0.028894-0 21346027
Haig DM McInnes CJ Immunity and counter-immunity during infection with the parapoxvirus orf virus Virus Res 2002 88 1–2 3 16 10.1016/s0168-1702(02)00117-x 12297324
Haig DM Mercer AA Ovine diseases. Orf Vet Res 1998 29 3–4 311 326 9689744
Hautaniemi M Ueda N Tuimala J Mercer AA Lahdenpera J McInnes CJ The genome of pseudocowpoxvirus: comparison of a reindeer isolate and a reference strain J Gen Virol 2010 91 Pt 6 1560 1576 10.1099/vir.0.018374-0 20107016
Heidarieh H Hernaez B Alcami A Immune modulation by virus-encoded secreted chemokine binding proteins Virus Res 2015 209 67 75 10.1016/j.virusres.2015.02.028 25791735
Henkel M Planz O Fischer T Stitz L Rziha HJ Prevention of virus persistence and protection against immunopathology after Borna disease virus infection of the brain by a novel Orf virus recombinant J Virol 2005 79 1 314 325 10.1128/JVI.79.1.314-325.2005 15596826
Hosamani M Scagliarini A Bhanuprakash V McInnes CJ Singh RK Orf: an update on current research and future perspectives Expert Rev Anti Infect Ther 2009 7 7 879 893 10.1586/eri.09.64 19735227
Joshi LR Knudsen D Pineyro P Dhakal S Renukaradhya GJ Diel DG Protective efficacy of an Orf virus-vector encoding the hemagglutinin and the nucleoprotein of influenza A virus in swine Front Immunol 2021 12 747574 10.3389/fimmu.2021.747574 34804030
Lateef Z Baird MA Wise LM Young S Mercer AA Fleming SB The chemokine-binding protein encoded by the poxvirus orf virus inhibits recruitment of dendritic cells to sites of skin inflammation and migration to peripheral lymph nodes Cell Microbiol 2010 12 5 665 676 10.1111/j.1462-5822.2009.01425.x 20039877
Lin FY Tseng YY Chan KW Kuo ST Yang CH Wang CY Takasu M Hsu WL Wong ML Suppression of influenza virus infection by the orf virus isolated in Taiwan J Vet Med Sci 2015 77 9 1055 1062 10.1292/jvms.14-0663 25855509
Lye L Wang CC Thymidine kinase as a selectable marker for studying the biogenesis of glycosomes in Trypanosoma brucei Exp Parasitol 1996 82 2 211 217 10.1006/expr.1996.0026 8617348
Lyttle DJ Fraser KM Fleming SB Mercer AA Robinson AJ Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus J Virol 1994 68 1 84 92 10.1128/JVI.68.1.84-92.1994 8254780
Martins M Joshi LR Rodrigues FS Anziliero D Frandoloso R Kutish GF Rock DL Weiblen R Flores EF Diel DG Immunogenicity of ORFV-based vectors expressing the rabies virus glycoprotein in livestock species Virology 2017 511 229 239 10.1016/j.virol.2017.08.027 28898730
Martins M Rodrigues FS Joshi LR Jardim JC Flores MM Weiblen R Flores EF Diel DG Orf virus ORFV112, ORFV117 and ORFV127 contribute to ORFV IA82 virulence in sheep Vet Microbiol 2021 257 109066 10.1016/j.vetmic.2021.109066 33866062
Marzook NB Newsome TP Construction and isolation of recombinant vaccinia virus expressing fluorescent proteins Methods Mol Biol 2019 2023 73 92 10.1007/978-1-4939-9593-6_4 31240671
McGuire MJ Johnston SA Sykes KF Novel immune-modulator identified by a rapid, functional screen of the parapoxvirus ovis (Orf virus) genome Proteome Sci 2012 10 1 4 10.1186/1477-5956-10-4 22243932
Mercer AA Wise LM Scagliarini A McInnes CJ Buttner M Rziha HJ McCaughan CA Fleming SB Ueda N Nettleton PF Vascular endothelial growth factors encoded by Orf virus show surprising sequence variation but have a conserved, functionally relevant structure J Gen Virol 2002 83 Pt 11 2845 2855 10.1099/0022-1317-83-11-2845 12388821
Mercer AA Ueda N Friederichs SM Hofmann K Fraser KM Bateman T Fleming SB Comparative analysis of genome sequences of three isolates of Orf virus reveals unexpected sequence variation Virus Res 2006 116 1–2 146 158 10.1016/j.virusres.2005.09.011 16274827
Nash AD Baca M Wright C Scotney PD The biology of vascular endothelial growth factor-B (VEGF-B) Pulm Pharmacol Ther 2006 19 1 61 69 10.1016/j.pupt.2005.02.007 16286239
Rohde J Schirrmeier H Granzow H Rziha HJ A new recombinant Orf virus (ORFV, Parapoxvirus) protects rabbits against lethal infection with rabbit hemorrhagic disease virus (RHDV) Vaccine 2011 29 49 9256 9264 10.1016/j.vaccine.2011.09.121 22001119
Rohde J Amann R Rziha HJ New Orf virus (Parapoxvirus) recombinant expressing H5 hemagglutinin protects mice against H5N1 and H1N1 influenza A virus Plos One 2013 8 12 e83802 10.1371/journal.pone.0083802 24376753
Rziha H Henkel M Cottone R Bauer B Auge U Gotz F Pfaff E Rottgen M Dehio C Buttner M Generation of recombinant parapoxviruses: non-essential genes suitable for insertion and expression of foreign genes J Biotechnol 2000 83 1–2 137 145 10.1016/s0168-1656(00)00307-2 11000469
Savory LJ Stacker SA Fleming SB Niven BE Mercer AA Viral vascular endothelial growth factor plays a critical role in orf virus infection J Virol 2000 74 22 10699 10706 10.1128/jvi.74.22.10699-10706.2000 11044114
Seet BT McCaughan CA Handel TM Mercer A Brunetti C McFadden G Fleming SB Analysis of an orf virus chemokine-binding protein: shifting ligand specificities among a family of poxvirus viroceptors Proc Natl Acad Sci U S A 2003 100 25 15137 15142 10.1073/pnas.2336648100 14657392
Sharif S Ueda N Nakatani Y Wise LM Clifton S Lateef Z Mercer AA Fleming SB Chemokine-binding proteins encoded by parapoxvirus of red deer of New Zealand display evidence of gene duplication and divergence of ligand specificity Front Microbiol 2019 10 1421 10.3389/fmicb.2019.01421 31293551
Shen Ni L Allaudin ZN Mohd Lila MA Othman AM Othman FB Selective apoptosis induction in MCF-7 cell line by truncated minimal functional region of Apoptin BMC Cancer 2013 13 488 10.1186/1471-2407-13-488 24144306
Tan JL Ueda N Mercer AA Fleming SB Investigation of orf virus structure and morphogenesis using recombinants expressing FLAG-tagged envelope structural proteins: evidence for wrapped virus particles and egress from infected cells J Gen Virol 2009 90 Pt 3 614 625 10.1099/vir.0.005488-0 19218206
Tseng YY Liao GR Sen GC Lin FY Hsu WL Regulation of PACT-mediated protein kinase activation by the OV20.0 protein of Orf virus J Virol 2015 89 22 11619 29 10.1128/JVI.01739-15 26355092
Tseng YY Lin FY Cheng SF Tscharke D Chulakasian S Chou CC Liu YF Chang WS Wong ML Hsu WL Functional analysis of the short isoform of orf virus protein OV20.0 J Virol 2015 89 9 4966 79 10.1128/JVI.03714-14 25694596
Voigt H Merant C Wienhold D Braun A Hutet E Le Potier MF Saalmuller A Pfaff E Buttner M Efficient priming against classical swine fever with a safe glycoprotein E2 expressing Orf virus recombinant (ORFV VrV-E2) Vaccine 2007 25 31 5915 5926 10.1016/j.vaccine.2007.05.035 17600594
Weber O Siegling A Friebe A Limmer A Schlapp T Knolle P Mercer A Schaller H Volk HD Inactivated parapoxvirus ovis (Orf virus) has antiviral activity against hepatitis B virus and herpes simplex virus J Gen Virol 2003 84 Pt 7 1843 1852 10.1099/vir.0.19138-0 12810878
Wise LM Veikkola T Mercer AA Savory LJ Fleming SB Caesar C Vitali A Makinen T Alitalo K Stacker SA Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1 Proc Natl Acad Sci U S A 1999 96 6 3071 3076 10.1073/pnas.96.6.3071 10077638
de Castro DG, Pellizzon ACA, Braun AC, Chen MJ, Silva MLG, Fogaroli RC, Gondim GRM, Ramos H, Neto ES, Abrahao CH, Yu LS, Abdallah EA, Calsavara VF, Chinen LTD (2022) Heterogeneity of HER2 expression in circulating tumor cells of patients with breast cancer brain metastases and impact on brain disease control. Cancers (Basel) 14(13) 10.3390/cancers14133101
Reguzova A, Ghosh M, Muller M, Rziha HJ, Amann R (2020) Orf virus-based vaccine vector D1701-V induces strong CD8+ T cell response against the transgene but not against ORFV-derived epitopes. Vaccines (Basel) 8(2) 10.3390/vaccines8020295
Rintoul JL, Lemay CG, Tai LH, Stanford MM, Falls TJ, de Souza CT, Bridle BW, Daneshmand M, Ohashi PS, Wan Y, Lichty BD, Mercer AA, Auer RC, Atkins HL, Bell JC (2012) ORFV: a novel oncolytic and immune stimulating parapoxvirus therapeutic. Mol Ther 20(6):1148-57 doi:S1525-0016(16)32538-2 [pii] 10.1038/mt.2011.301
Wyatt LS, Earl PL, Moss B (2017) Generation of recombinant vaccinia viruses. Curr Protoc Protein Sci 89:5 13 1–5 13 18 10.1002/cpps.33
| 36484827 | PMC9734686 | NO-CC CODE | 2022-12-14 23:28:30 | no | Appl Microbiol Biotechnol. 2022 Dec 9;:1-17 | utf-8 | Appl Microbiol Biotechnol | 2,022 | 10.1007/s00253-022-12323-0 | oa_other |
==== Front
J Autism Dev Disord
J Autism Dev Disord
Journal of Autism and Developmental Disorders
0162-3257
1573-3432
Springer US New York
36462114
5838
10.1007/s10803-022-05838-y
Original Paper
The Relationship Between Nutrition-Physical Activity Behaviors of Autistic Children with Their Families and Children’s Obesity Levels During Covid Pandemic
GUNER U Umran CEVİK [email protected]
[email protected]
1
İrem BİLKAY [email protected]
2
1 grid.411550.4 0000 0001 0689 906X Pediatric Nursing Department, Faculty of Health Sciences, Tokat Gaziosmanpaşa University, Tasliciftlik Campus, 60250 Tokat, Turkey
2 grid.411550.4 0000 0001 0689 906X Nursing Department, Institute of Graduate Studies, Tokat Gaziosmanpaşa University, Tasliciftlik Campus,60250, Tokat, Turkey
3 12 2022
19
16 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The family has a key role in the obesity management of children with autism. This study examines the relationship between the nutrition-physical activity behaviors of autistic children with their families and children’s obesity levels during covid-19 pandemic. The descriptive and cross-sectional study involved 80 parents of autistic children. A positive correlation was found between children’s mean BMI values before and during the pandemic(p = 0.000). Family Nutrition and Physical Activity Scale(FNPAS) and Brief Autism Mealtime Behavior Inventory(BAMBI) score were 55.18 ± 7.86 and 31.76 ± 8.79, respectively. In addition, it was found that 32.5% of the children ate more than before the pandemic, 50.0% engaged in less physical activity, and 16.3% didn’t do any physical activity. The study results suggesting the risk of obesity.
Keywords
Covid-19
obesity
autism
family
child
==== Body
pmcIntroduction
Obesity is defined as an increase in weight gain due to an increase in body fat (WHO,2020). The prevalence of obesity in children and adolescents is increasing day by day in our country as well as around the world. This increase is accompanied by an increase in the frequency of concomitant obesity-related problems (Yaşar and Karaaslan 2018; Yazar et al. 2019). Children with autism are generally at a greater risk of being obese (i.e., BMI- ≥95th percentile for age) or being overweight (i.e., BMI ≥85th percentile for age) than children experiencing normative development (Dhaliwal et al. 2019; Healy et al. 2019). Because various factors such as low physical activity due to underdeveloped gross motor skills, use of psychiatric drugs, atypical eating patterns, consumption of low-nutrient foods, overeating, stomach and intestinal problems, parents’ body perceptions and the presence of obesity, and food selectivity make overweight and obesity a major problem in children with autism (Dhaliwal et al. 2019 ; Meral and Fidan 2014). Therefore, both personal and familial factors have an effect on the form of nutrition. Therefore, nutrition and physical activity play an important role in preventing this problem (Mccoy et al.2016).
Many negative secondary effects due to the social distancing and curfew imposed due to the COVID 19 pandemic have affected Turkey and the world (Esenturk 2020; Masi et al. 2021). It is important to understand how COVID-19, quarantine, and social distancing affect certain populations (e.g., certain age groups, clinical populations). The pandemic has also affected children with autism and their families mentally and socially, increased their length of time spent at home, limited their activity areas, and affected their nutrition habits (Cahapay, 2020; Shahidi et al. 2020). It is thought that these restrictions caused by the pandemic may trigger the risk of obesity in children with autism. Taking these as a starting point, the present study aimed to investigate the relationship between nutrition habits and physical activity behaviors of children with autism and their parents during the COVID-19 pandemic and the obesity levels of children. In this context, two hypotheses of the study were defined. H1: There is a significant relationship between FNPAS scores and some characteristics of the parents and their children with autism, their views and practices on weight management. H2: There is a significant relationship between the mean FNPAS scores of the parents and the mean BMI values of the children before and during the pandemic.
Methods
Research Design
This is a descriptive and cross-sectional study.
Participants
The questionnaire form prepared by the researchers via Google Forms between 01.02.2021 and 01.08.2021 to parents of children with autism living in Turkey was sent to a social media account with a high rate of comments and appreciation. In the case where the population is 2314, for the α=0.05 significance level and d=0.02 sampling error p=0.01 q=0.99, 85 people should be included in the study with 95% power, 5% margin of error, and an effect size of 0.04. The trial version of the Pass 15 15.0.5 software was used to calculate the sample size. In the literature, it was calculated as 1% and expected to be 5% (the difference between the two is 4% effect size). The inclusion criteria were as follows: having a child diagnosed with autism, using a smartphone, being literate and in the 18-60 age range, not being physically or mentally disabled and consenting to participate in the study. All participant characteristics are presented in Table 1. It was determined that 78.8% of their parents were women, 66.3% were over 35 years old, 37.5% were university graduates, and 60.0% had a medium income. 43.8% of children with autism are 0-6 years old, 56.2% are 7-15 years old, 25.0% are girls, 75.0% are boys, 47.5% were diagnosed with atypical autism, 82.5% did not have any other disease other than autism, and almost half (45.0%) used psychiatric drugs (Table 1).
Table 1 Sociodemographic characteristics of parents and children with autism
n %
Parent gender
Female
Male
63
17
78.8
21.2
Parent age
Under 35
Over 35 years old
27
53
33.7
66.3
Parent educational level
Primary school
Middle School
High school
University
20
10
20
30
25.0
12.5
25.0
37.5
Family income level
Low
Middle
Good
11
48
21
13.8
60.0
26.2
Child age
0–6 years
7–15 years
35
45
43.8
56.2
Child gender
Girl
Boy
20
60
25.0
75.0
Autism diagnosis group
Atypical Autism
Middle
Severe
38
13
29
47.5
16.2
36.3
Conditions comorbid to autism
Yes
No
14
66
17.5
82.5
Psychiatric drug use
Yes
No
36
44
45.0
55.0
Procedure
The data collection forms in this study were filled by the parents. Data collection forms were uploaded to the online system via Google Forms and a link was created. This link has been sent to parents of children with autism via their social media account. The time to fill out the form is approximately 15-20 min in 5 preliminary applications. Written permission of the scale authors and the Social and Human Sciences Ethics Committee, dated 26.02.2021, decision number 04-01-18 and numbered 4-12, was obtained for the feasibility of the research. At the beginning of the questionnaire, it was explained to the parents that the name, surname and the name of the child will not be recorded in the study, only the answers to the questions related to the subject will be recorded, and that participation in the study is completely voluntary, and no compensation will be requested in the face of the negative consequences. Consent form was obtained from the parents, stating the nature of the study, the confidentiality issues, and the voluntary participation.
Measures
Data collection tools were a socio-demographic data form, parents’ views and practices on weight management form, Family Nutrition and Physical Activity Scale (FNPAS), and Brief Autism Mealtime Behavior Inventory (BAMBI).
Sociodemographic Data Form
This form included questions aimed to collect data about the parent’s gender, age, education level, income level, number of children, age of children, gender of children, autism diagnosis group, conditions comorbid to autism, and psychiatric drug use.
Parents’ Views and Practices on Weight Management Form
This form developed by the researchers based on the literature, evaluates many factors such as the child’s physical activity during the pandemic, nutrition behaviors and weight changes, parents’ measurement of their children’s weight and height, and how they perceive their children’s bodies (Gregor et al., 2018; Esenturk and Yarımkaya 2021; Senguzel et al. 2021; Tybor et al., 2019).
Family nutrition and physical activity scale (FNPAS)
This scale was developed by Ihmels et al. (2019) who are researchers at Iowa State University. Ozdemir (2020) conducted the validity and reliability studies of the Turkish version. The questionnaire includes various subheadings such as family meals, family nutrition habits, food preferences, beverage preferences, restriction/reward, screen time and healthy environment, family activity, child activity, family schedule/sleep pattern. The subscales have 4-point Likert-type (never, sometimes, often, always) items. The Cronbach’s alpha value of the scale was calculated as 0.72 previously and as 0.84 in this study. The total score of this scale predicting the risk of overweight and obesity in children varies within the range of 20-80. Since there is no cut-off value when comparing the total score, higher scores indicate less risky family practices and child behaviors for obesity, while low scores indicate high-risk family practices and child behaviors for obesity (Ozdemir, 2020).
Brief Autism Mealtime Behavior Inventory (BAMBI)
It was developed by Lukens and Linscheid (2008) to investigate mealtime behaviors and eating problems of children with autism. Meral and Fidan (2014) conducted the validity and reliability studies of the Turkish version. The inventory has three subscales: “Limited Variety,” “Food Refusal,” and “Features of Autism.” The subscales are evaluated according to 5-point Likert-type items: (never/very rarely (1), rarely (2), a little (3), occasionally (4), and after each mealtime (5)). Higher total scores and subheading scores indicate a higher prevalence of disruptive behaviors (Meral and Fidan 2014).
Data Analysis
The dependent variable of this study was determined as the nutritional and physical activity behavior scale (FNPAS) score averages of children and families. The independent variable is the parent’s gender, age, education level, average BMI, income level, number of children, age, gender, autism diagnosis group, presence of disease accompanying autism, use of psychiatric medication, weight perceptions, height and weight follow-up status of their children and themselves, BMI. mean and BAMBI mean scores.
In the evaluation of the data, descriptive statistics (percentage and frequency measurements, mean and standard deviation), Spearman Correlation Coefficient in case of two continuous variables, and univariate linear regression analysis for each variable were used to determine the factors affecting the FNPAS score averages. SPSS 22 (SPSS Inc., Chicago, Ill, USA) program was used in the analysis of the data. The significance level was determined as p<0.05.
Results
Table 2 shows parents’ views and practices on weight management. It was determined that the mean BMI of the mothers was 25.11±3.69, of the fathers was 27.09±3.77, and of the children before and during the pandemic was 21.69±6.09 and 22.29±5.65, respectively. Moreover, it was found that more than half of the parents (57.5%) did not regularly monitor their children’s height and weight during the pandemic, 53.7% of them perceived their children as normal weight, 46.3% of children gained weight during the pandemic, 56.3% did not change their nutrition habits, 32.5% started to eat more, 50.0% engaged in less physical activity, and 16.2% did not do any physical activity. In addition, it was observed that 41.3% of the parents engaged in less physical activity and 28.7% did not do any physical activity during the pandemic (Table 2).
Table 2 Parents’ views and practices on weight management
n %
Regularly monitor their children’s height and weight
Yes
No
34
46
42.5
57.5
Parental view of the child’s physical appearance
Obese
Fat
Normal
Weak
1
27
43
9
1.3
33.7
53.7
11.3
Parent’s view on weight gain in the covid process
Yes
No
37
43
46.3
53.7
Parent’s view on the child’s nutritional status during the covid process
Started eat more
Never eats
No change
26
9
45
32.5
11.2
56.3
The child’s physical activity level during the covid process (at least half an hour of active activity or games)
Yes, doing more physical activity than before
Yes, doing less physical activity than before
Doesn’t do it at all (Before/Now)
27
40
13
33.8
50.0
16.2
The parent’s physical activity level (at least half an hour of brisk movement) during the covid process
Yes, I do more regular physical activity than before
Yes, I do less regular physical activity than before
I never do (Nor before/Now)
24
33
23
30.0
41.3
28.7
Child/Parent BMI value Mean ± SD
Mother’s BMI value 25.11 ± 3.69
Father’s BMI value 27.09 ± 3.77
Child’s BMI value before covid process 21.69 ± 6.09
Child’s BMI value during the covid process 22.29 ± 5.65
Table 2insert here.
Table 3 shows the sub-dimension and overall total score averages of the parents’ FNPAS and BAMBI scales. FNPAS total score averages were 55.18±7.86, and BAMBI total score averages were 31.76±8.79 (Table 3).
Table 3 Sub-dimensions and overall total mean score of the FNPAS and BAMBI
Scale Mean SD N
FNPAS sub-dimensions mean scores
Family meals 5.60 1.73 80
Family nutrition habits 7.42 1.13 80
Food preferences 5.62 1.22 80
Beverage preferences 5.28 1.11 80
Restriction reward 5.95 1.45 80
Screen time 4.93 1.58 80
Healthy environment 5.57 0.99 80
Family activity 5.11 1.70 80
Child activity 4.27 1.63 80
Family schedule/Sleep pattern 5.40 1.80 80
FNPAS total mean score 55.18 7.86 80
BAMBI sub-dimensions mean scores
Limited variety 19.57 4.62 80
Food refusal 9.17 4.67 80
Features of autism 3.01 1.78 80
BAMBI total mean score 31.76 8.79 80
Table 4 shows the factors affecting the FNPAS scores of children with autism during the COVID-19 pandemic. There was no significant relationship between the mean FNPAS score and the parent’s gender, age, education level, income level, number of children, age and gender of children, psychiatric drug use, parents’ perception of their children’s weight during the pandemic, increase in the child’s weight, changes in the child’s nutrition habits, and changes in the physical activity of the child and parent (p>0.05) (Table 4). In line with this result, hypothesis 1 was rejected. The mean FNPAS score was found to have a significant correlation with the autism diagnosis group and whether the parents regularly monitor their children’s height and weight (p=0.015;0.027). It was determined that the mean FNPAS scores were 2 units lower for the parents of children with severe autism than for the parents of children with atypical autism and 4 units higher for the parents who regularly monitored their children’s height and weight during the pandemic than for those who did not (Table 4).
Table 4 Factors affecting FNPAS levels of children with autism during the covid process
Variables FNPAS
β st hata p değeri
Parent gender 1.808 2.563 0.483
Parent age -0.022 0.110 0.840
Parent educational level
Primary school ref
Middle School 1.700 3.079 0.583
High school 2.800 2.514 0.269
University 2.067 2.295 0.371
Family income level
Low ref
Middle -1.233 2.635 0.641
Good 1.455 2.933 0.621
Child age -0.332 0.207 0.113
Child gender 3.317 2.010 0.103
Autism diagnosis group
Atypical autism ref
Middle -3.731 2.455 0.133
Severe -4.707 1.884 0.015*
Conditions comorbid to autism 1.870 2.760 0.500
Psychiatric drug use 1.242 2.109 0.558
Regularly monitor their children’s height and weight -3.919 1.735 0.027**
Parental view of the child’s physical appearance
Obese ref
Fat 4.222 7.864 0.593
Normal 0.302 7.811 0.969
Weak 5.333 8.120 0.514
Parent’s view on weight gain in the covid process 1,405 1,768 0,429
Parent’s view on the child’s nutritional status during the covid process
Started eat more ref
Never eats 1.081 3.064 0.725
No change -1.319 1.951 0.501
The child’s physical activity level(at least half an hour of active activity or games)
Yes, doing more physical activity than before ref
Yes, doing less physical activity than before -1.668 1.962 0.398
Doesn’t do it at all (Before/Now) -3.516 2.659 0.190
The parent’s physical activity level (at least half an hour of brisk movement)
Yes, I do more regular physical activity than before ref
Yes, I do less regular physical activity than before -3.610 2.088 0.088
I never do (Nor before/Now -0.400 2.271 0.861
BAMBI score 0.022 0.101 0.828
Mother’s BMI value -0.376 0.237 0.117
Father’s BMI value 0.149 0.236 0.531
Child’s BMI value before covid process 0.076 0.146 0.603
Child’s BMI value during the covid process 0.021 0.158 0.895
* There is a 4,707-unit decrease in the FNPAS score of parents of children with severe autism compared to parents of children with atypical autism
** There is a 3,919 unit decrease in the FNPAS score of parents who do not regularly monitor their child’s height and weight compared to the parents who do
Table 5 shows the relationship between parents’ mean FNPAS and BAMBI scores and their children’s obesity levels during the pandemic. There was no significant relationship between the parents’ mean FNPAS and BAMBI scores and the children’s mean BMI values before and during the pandemic (p>0.05). In line with this result, Hypothesis 2 was rejected. Also, no significant correlation was found between mean BAMBI scores and children’s mean BMI values before and during the pandemic (p>0.05). Finally, a very strong positive correlation was found between the BMI value before the pandemic and the BMI value during the pandemic (r=0.857; p=0.000) (Table 5).
Table 5 The relationship between parents’ FNPAS, BAMBI mean scores, and children’s obesity during the covid process
Scale and BMI FNPAS BMI before covid BMI during covid
BAMBI r = 0.008 p = 0.943 r=-0.007 p = 0.950 r=-0.037 p = 0.744
BMI before covid r = 0.011 p = 0.923 r = 1000 r = 0.857 p = 0.000
BMI during covid r = 0.035 p = 0.755 r = 0.857 p = 0.000 r = 1000
Discussion
Considering the studies reporting a higher prevalence of obesity in children with autism than in healthy children (Curtin et al., 2020; Killian et al., 2021; Mccoy et al., 2016) and concluding that parents’ habits and obesity status affect children’s obesity status (Appak et al. 2018; Dhaliwal et al. 2019; Yılmazbas and Gokcay 2018), it was deemed necessary to investigate the correlation between familial nutrition and physical activity habits (obesity risk status) and BMI of children with autism during the pandemic. Few studies have examined the physical activity and educational restrictions of children with autism during the pandemic (Esenturk 2020; Esenturk and Yarımkaya 2021; Shahidi et al. 2020), and these studies did not consider obesity as a variable. The present study is the first study to aim to investigate the relationship between nutrition habits and physical activity behaviors of children with autism and their parents during the COVID-19 pandemic and their obesity levels.
According to the results of the study, when the mean BMI of the children with autism was evaluated it was determined that the children were not obese but gained weight during the pandemic. While those with normal BMI values before the pandemic became overweight during the pandemic, those who were overweight before the pandemic became obese during the pandemic. Similar studies emphasized that school closures during the pandemic caused serious changes in the lives of children with autism, leading to a decrease in physical activity, an increase in the use of psychopharmacological treatment, deterioration of sleep patterns, and a possible increase in the risk of obesity (Esenturk 2020; Masi et al. 2021). Our research confims those findings. Considering the parents’ BMI means, we found that mothers had normal BMI values while fathers had BMI values falling within the obesity range. In the study, no significant correlation was found between the mean BMI of the children with autism before and during the pandemic and the mean BMI of their fathers. Nevertheless, there are studies showing that parental obesity is effective in children’s weight gain (Appak 2018; Dhaliwal et al. 2019). It has also been reported that the father’s obesity increases the probability of the child having autism and being obese (Suren et al. 2014). Therefore, monitoring the BMI values of the parents of children with autism can protect children from obesity and reduce the risk of obesity.
Although nearly half (46.3%) of the children gained weight during the pandemic, more than half of them perceived their children as normal weight (53.7%) and more than half (57.5%) did not regularly monitor their children’s height or weight. This result shows that it is necessary to raise awareness of children in terms of obesity risk, which may be caused by covid restrictions. Previous studies have found that some parents are not sufficiently aware of the diet or nutrition habits that children with autism should have (Girli et al. 2016; Johnson et al. 2015). In addition, some studies have shown that parents’ knowledge, attitudes, and preferences about physical activity are important for their children with autism (Ayvazoglu et al. 2015; Curtin et al., 2020; Gregor et al. 2018). Therefore, the major difficulties experienced by this population in both nutrition habits and physical activity and the stress experienced by their parents require progress and improvement in the current situation to increase family support for both preventive and intervention efforts.
Also, about one-third (32.5%) of the parents reported that their children ate more during the pandemic, and half reported that they engaged in less physical activity than they did before the pandemic. Moreover, it was found that about two out of 10 children (16.3%) did not do any physical activity. Children with autism already face challenges in doing physical activities because their motor development is not at a sufficient level (Ayvazoglu et al. 2015; Yarımkaya and Esenturk 2020). Children with autism cannot perform a more regular physical movement due to the balance posture in their motor development, limitation of movement in fine dexterity or sometimes reluctance, sometimes repetitive movements (Tunç et al., 2020; Kaur et al., 2018). However, it should be noted that physical activity reduces the effects of autism and improves the child’s social skills while minimizing the risk of obesity (Gregor et al. 2018).
A sedentary lifestyle and insufficient physical activity lead to the risk of obesity (Mccoy et al. 2016; Shahidi et al. 2020; Yılmazbaş and Gokcay 2018). Although staying indoors has slowed the spread of COVID-19, it has also created certain challenges, especially for children with special needs and their families. One of these challenges is to have to lead a sedentary lifestyle. It has been determined that necessary support has not been made available for the physical and educational needs of children with ASD (Narzisi 2020; Yarımkaya and Esenturk 2020). In previous studies, parents reported that their children’s physical activity areas were restricted and their nutrition habits changed (Masi et al. 2021; Shurack et al., 2021). A study conducted during the pandemic concluded that WhatsApp-based physical activity interventions aimed at engaging children with autism in more physical activity were found beneficial by parents (Esenturk and Yarımkaya 2021). Similarly, it has been emphasized that distance education-based diet programs are applicable and acceptable in this process (Shurack et al., 2021). In this respect, in the face of the potential to develop adverse health conditions, it is essential to develop effective weight management programs that meet the unique needs of children with ASD (Killian et al., 2021). Nevertheless, all these studies underline the necessity of the participation of parents with their children in order to raise awareness in them (Brown et al. 2020; Shurack et al., 2021). Indeed, 41.3% of the parents in our study reported engaging in less physical activity than they did before the pandemic while 28.7% reported engaging in no physical activity. In a similar study, it was found that the parents of disabled children were inactive and did not have enough awareness about the necessity of physical activity (Tahmaz et al. 2019). The awareness of parents on this issue is extremely important as it can be effective in raising awareness in children.
In this study, the mean FNPAS score of the parents was found to be 55.18±7.86. This score is lower than that reported in previous studies conducted using this scale in different cultures (Herbenick et al., 2018; Ihmels et al. 2019; Peyer and Welk 2017). In addition, the fact that this score is also lower than that reported in the study conducted by Ozdemir (2020) with healthy children in Turkish culture is an important finding in that it implies that the family environment of children with autism is more obesogenic. Studies have shown that there is a relationship between the family environment, shared environment, and family behaviors and the risk of the child becoming obese and that the obesogenic family environment causes obesity in children (Aponte & Romanczyk, 2016; Herbenick et al., 2018; Ihmels et al. 2019; Peyer and Welk 2017). The mean FNPAS score found in our study showed that the overall family environment of the participants was obesogenic and that children with autism had a moderate obesity risk.
In our study, it was determined that the autism diagnosis group and whether the parents monitored their children’s height and weight regularly affected the mean FNPAS score. Based on these results, it can be said that children who are diagnosed with severe autism and whose height and weight are not monitored regularly are at a higher risk of obesity. In children with severe autism, the findings are more pronounced, and, accordingly, parents are more concerned. The fact that the findings are more pronounced may cause challenges in weight management; however, it may also help increase the time the parent spends with the child, providing more opportunities to carefully monitor the child’s weight. One study reported that parents of obese children with autism were more concerned about weight management than parents of obese children with normal development (Tybor et al. 2019). It is very important that parents of children with autism consult with health professionals more frequently, monitor their child’s height and weight regularly, and be informed about how ASD can affect obesogenic behaviors. Therefore, such health services can help parents to monitor their children’s development with a more positive attitude.
In this study, no significant correlation was found between the mean FNPAS score and the mean BAMBI score. The mean BAMBI score found in the study was 31.76±8.79, which is lower than that reported in many similar studies (Aponte & Romanczyk, 2016; Shmaya et al. 2017; Senguzel et al. 2021). This result shows that the children in our study have fewer nutrition problems. In addition, no significant correlation was found between the mean FNPAS and BAMBI scores and the children’s mean BMI values before and during the pandemic. Nutrition disorders, food selectivity, and food refusal is more common in children with autism than in children with normal development (Senguzel et al. 2021; Shmaya et al. 2017). Food selectivity brings with it a single food intake, and, accordingly, a predisposition to obesity (Cutin 2020). While the aforementioned studies argue that food selectivity increases the risk of obesity, there are also studies that advocate that food selectivity does not have a direct effect on the risk of obesity, that it may indirectly increase the risk of obesity, or that it should be evaluated independently of obesity (Cutin 2020; Dhaliwal et al. 2019; Senguzel et al. 2021). Similarly, we can say that the food selectivity of the children in our study does not affect their obesity risk.
Limitations of the Study
The questionnaire form prepared by the researchers via Google Forms was sent to the parents of children with autism living in Turkey via a social media account with a high rate of comments and appreciation, with the participation of parents with autistic children. Therefore, the results cannot be generalized to the population. Another limitation is the low participation rate in the research. In addition, our limitation is the use of FNPASs developed for healthy children, as there is no tool to measure family nutrition and physical activity in children with autism. In order to shed light on future research; social prejudice should be eliminated by increasing awareness and participation should be increased; The height and weight values of the children should be measured by a health professional instead of the parents, and it is recommended that the research be studied with larger groups.
Conclusion
The results of the research revealed that obesity poses a risk for children with autism, as nutrition habits increased during the covid process, sedentary life, mean BMI, and parents’ FNPAS levels are slightly above the mean. In addition, the importance of evaluating the family environment, nutrition and physical activity status in determining obesity risk is emphasized.
Children with ASD may exhibit over-reactive behaviors in situations where changes in their nutrition routines (for example, introducing new foods) and when screen time is limited and physical activity is desired. Parents can often surrender to their children’s behavior because they do not know what to do in the face of these behaviors. In this respect, it is extremely important for parents to get support for their child to cope with these behaviors in preventing obesity.
The covid process has revealed significant changes in family life dynamics, and it is observed that problematic behaviors that may cause obesity have increased. Obesity affects the quality of life and health of children with autism, and it cannot be predicted how long the measures taken in line with the pandemic will last. This uncertainty, future epidemics and the fact that obesity is always a risk factor for children with autism bring to mind the primary health care services. In order to prevent obesity and eliminate all risks, primary health care providers should follow-up children’s height and weight, routine health screenings should be done in cooperation with the family, obesity precautions and management, family/child nutrition and physical activity behaviors should be formed to prevent obesity. An emergency action plan is needed for children with autism, taking into account future epidemics. Parents should be given training on physical activity and nutrition at home. Trainings should be made continuous by providing remote expert resources and support, without interrupting the cooperation with children with autism, by ensuring the participation of parents. It is thought that increasing educational interventions and other support services may be effective in preventing obesity.
Acknowledgements
We would particularly like to thank the parents who participated in the study.
Contributions
UCG has contributions such as Research design, Data analysis, writing the article, presenting the article to the journal. İB has contributions such as Research design, Data analysis, writing the article. All the authors contributed to the article and they reviewed the article from a critical perspective. The final paper was approved by all the authors.
Funding
The authors declare that this study received no funding.
Declarations
Conflict of interest
The authors did not report any conflict of interest for this study.
Ethical Approval statement
Before starting the study, the Social and Human Sciences Ethics Committee approved this study. Ethics committee decision number is 04-01-18 and numbered 4–12. During the study, the provisions of Helsinki Declaration were respected.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Aponte, C. A., & Romanczyk, R. G. (2016). Assessment of feeding problems in children with autism spectrum disorder. Research in Autism Spectrum Disorders, 21, 61–72. https://doi.org/10,1016/2015.09.007.
Appak YC Aksoy B Tınastepe T Emir B Berksoy E Baltalı O Baran M Obez ve fazla kilolu annelerin cocuklarında obezite sıklığı ve iliskili faktorlerin değerlendirilmesi İzmir Kâtip Celebi University Faculty of Health Science Journal 2018 3 3 35 36
Ayvazoglu NR Kozub FM Butera G Murray MJ Determinants and challenges in physical activity participation in families with children with high functioning autism spectrum disorders from a family systems perspective Research in Developmental Disabilities 2015 47 93 105 10.2016/j.ridd.2015.08.015 26368652
Brown DM Arbour-Nicitopoulos KP Ginis M Latimer-Cheung KA Bassett-Gunter RL Examining the relationship between parent physical activity support behaviour and physical activity among children and youth with autism spectrum disorder Autism 2020 24 7 1783 1794 10.1177/1362361320922658 32476438
Cahapay, M. B. (2020). How filipino parents home educate their children with autism during covid – 19 period. International Journal of Developmental Disabilities, 1–4. 10.1080/20473869.2020.1780554.
Curtin C Hyman SL Boas DD Hassink S Broder-Fingert S Ptomey LT Bandini LG Weight management in primary care for children with autism: Expert recommendations Pedıatrıcs 2020 145 1 126 139 10.1542/peds.2019-1895p
Dhaliwal KK Orsso CE Richard C Haqq AM Zwaigenbaum L Risk factors for unhealthy weight gain and obesity among children with autism spectrum disorder International Journal Of Molecular Sciences 2019 20 13 3285 10.3390/ijms20133285 31277383
Esenturk OK Parents’ perceptions on physical activity for their children with autism spectrum disorders during the novel coronavirus outbreak International Journal of Developmental Disabilities 2020 0 0 1 12 10.1080/20473869.2020.1769333
Esenturk OK Yarımkaya E Whatsapp-based physical activity ıntervention for children with autism spectrum disorder during the novel coronavirus (covıd-19) pandemic: a feasibility trial Adapted Physical Activity Quarterly 2021 38 4 569 584 10.1123/apaq.2020-0109 34193630
Girli A Ozgonenel S Sarı HA Ardahan E Otizmi olan cocukların beslenme durumunun değerlendirilmesi Cocuk ve Medeniyet 2016 1 1 87 99
Gregor S Bruni N Grkinic P Schwartz L McDonald A Thille P Jachyra P Parents’ perspectives of physical activity participation among canadian adolescents with autism spectrum disorder Research in Autism Spectrum Disorders 2018 48 53 62 10.1016/j.rasd.2018.01.007
Healy S Aigner CJ Haegele JA Prevalence of overweight and obesity among us youth with autism spectrum disorder Autism 2019 23 4 1046 1050 10.1177/1362361318791817 30101597
Herbenick, S. K., James, K., Milton, J., & Cannon, D. (2018). Effects of family nutrition and physical activity screening for obesity risk in school-age children. Journal For Specialists In Pediatric Nursing : Jspn, 23(4), 10.1111/jspn.12229.
Ihmels MA Welk GJ Eisenmann JC Nusser SM Development and preliminary validation of a family nutrition and physical activity (FNPA) screening tool Int J Behav Nutr Phys Act 2019 6 1 1 10 10.1186/1479-5868-6-14
Johnson CR Foldes E Demand A Brooks MM Behavioral parent training to address feeding problems in children with autism spectrum disorder: a pilot trial Journal Of Developmental and Physical Disabilities 2015 27 5 591 607 10.1007/s10882-015-9437-1
Kaur M Srinivasan SM Bhat AN Comparing motor performance, praxis, coordination, and interpersonal synchrony between children with and without Autism Spectrum disorder (ASD) Research in developmental disabilities 2018 72 79 95 10.1016/j.ridd.2017.10.025 29121516
Killian, H. J., Pallotto, I. K., Sweeney, B. R., & Dreyer Gillette, M. L. (2021). Weight management outcomes of youth with autism spectrum disorder seeking treatment from a multidisciplinary team. Journal of Autism and Developmental Disorders, 1–9. 10.1007/S10803-021-04982-1.
Lukens CT Linscheid TR Development and validation of an inventory to assess mealtime behavior problems in children with autism Journal Of Autism And Developmental Disorders 2008 38 2 342 352 10.1007/s10803-007-0401-5 17578658
Masi A Diaz AM Tully L Azim SI Woolfenden S Efron D Eapen V Impact of the covıd-19 pandemic on the well-being of children with neurodevelopmental disabilities and their parents J Pediatr Cocuk Sağlığı 2021 57 5 631 636 10.1111/jpc.15285
Mccoy SM Jakicic JM Gibbs BB Comparison of obesity, physical activity, and sedentary behaviors between adolescents with autism spectrum disorders and without Journal of Autism and Developmental Disorders 2016 46 7 2317 2326 10.1007/S10803-016-2762-0 26936162
Meral BF Fidan A A study on turkish adaptation, validity and reliability of the brief autism mealtime behavior ınventory (BAMBI) Procedia - Social and Behavioral Sciences 2014 116 403 408 10.1016/j.sbspro.2014.01.230
Narzisi A Handle the autism spectrum condition during coronavirus (COVID-19) stay at home period: ten tips for helping parents and caregivers of young children Brain Sciences 2020 10 4 207 10.3390/brainsci10040207 32244776
Ozdemir, S. (2020). Cocukluk cağı obezitesini değerlendirmede kullanılan ‘aile beslenme ve fiziksel aktivite olceği’nin turkce gecerlilik ve guvenirlik calısması (Specialization Thesis in Medicine). Ondokuz Mayıs University Samsun. Turkey. https://hdl.handle.net/20.500.12712/32049.
Peyer KL Welk G Construct validity of an obesity risk screening tool in two age groups International Journal of Environmental Research and Public Health 2017 14 4 419 10.3390/ijerph14040419 28420116
Senguzel S Cebeci AN Ekici B Gonen İ Tatlı B Impact of eating habits and nutritional status on children with autism spectrum disorder Journal of Taibah University Medical Sciences 2021 16 3 413 421 10.1016/J.Jtumed.2020.11.010 34140869
Shahidi SH Williams S Hassani F Physical activity during covid – 19 quarantine. Acta paediatrica International Journal of Paediatrics 2020 109 1 2147 2148 10.1111/apa.15420
Shmaya Y Eilat-Adar S Leitner Y Reif S Gabis LV Meal time behavior difficulties but not nutritional deficiencies correlate with sensory processing in children with autism spectrum disorder Research in Developmental Disabilities 2017 66 27 33 10.1016/J.ridd.2017.05.004 28578072
Shurack, R. H., Garcia, J. M., Brazendale, K., & Lee, E. (2021). Brief report: feasibility and acceptability of a remote-based nutrition education program for adolescents with autism spectrum disorder: a covıd-19 pilot study. Journal of Autism and Developmental Disorders, 1–7. 10.1007/S10803-021-05301-4.
Suren P Gunnes N Roth C Bresnahan M Hornig M Hirtz D Stoltenberg C Parental obesity and risk of autism spectrum disorder Pediatrics 2014 133 5 1128 1138 10.1542/Peds.2013-3664
Tahmaz T Tarakcı D Tarakcı E Investıgatıon of physical activity levels in disabled individuals with special needs education and their families Journal of Health Sciences and Professions 2019 6 2 275 282
Tunç U Erdoganoglu Y Agce ZB Otizm Spektrum Bozukluğu Olan Çocuklarda Postüral Kontrol, Denge ve İnce Motor Becerilerin İncelenmesi Hacettepe University Faculty of Health Sciences Journal 2020 7 3 271 284
Tybor DJ Eliasziw M Kral T Segal M Sherwood NE Sikich L Must A Parental concern regarding obesity in children with autism spectrum disorder in the United States: National survey of children’s health 2016 Disability and Health Journal 2019 12 1 126 130 10.1016/j.dhjo.2018.09.004 30352729
World Health Organization (2020). Noncommunicable diseases: Childhood overweight and obesity. Date of access:25.06.2022 http://www.who.int/dietphysicalactivity/childhood/en/
Yarımkaya E Esenturk OK Promoting physical activity for children with autism spectrum disorders during coronavirus outbreak: benefits, strategies, and examples International Journal of Developmental Disabilities 2020 12 1 126 130 10.1080/20473869.2020.1756115
Yasar A Karaaslan O Evaluation of the quality of life and depression in obese children in yozgat province Bozok Tıp Dergisi 2018 8 2 42 46 10.16919/bozoktip.339775
Yazar A Kılıcaslan M Akın F Arslan S Obesity frequency of children aged 6–18 years in Konya Bozok Tıp Dergisi 2019 9 1 123 129
Yılmazbas P Gokcay G Cocukluk cağı obezitesi ve onlenmesi Cocuk Dergisi 2018 18 3 103 112 10.5222/j.child.2018.59389
| 36462114 | PMC9734687 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Autism Dev Disord. 2022 Dec 3;:1-9 | utf-8 | J Autism Dev Disord | 2,022 | 10.1007/s10803-022-05838-y | oa_other |
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J Mater Cycles Waste Manag
J Mater Cycles Waste Manag
Journal of Material Cycles and Waste Management
1438-4957
1611-8227
Springer Japan Tokyo
1568
10.1007/s10163-022-01568-6
Review
End-of-life vehicles research development in Malaysia: a comprehensive review with the integrated conceptual model of innovative sustainable manufacturing elements
Chong Jia Yuik 12
http://orcid.org/0000-0001-6077-7370
Mat Saman Muhamad Zameri [email protected]
12
Ngadiman Nor Hasrul Akhmal 12
1 grid.410877.d 0000 0001 2296 1505 Faculty of Mechanical Engineering, Universiti Teknologi Malaysia, Skudai, 81310 Johor, Malaysia
2 Advanced Manufacturing Research Group, Frontier Material Research Alliance, Skudai, 81310 Johor, Malaysia
9 12 2022
119
26 3 2022
29 11 2022
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The end-of-life vehicles (ELV) issue has become an essential topic in the fast-growing automotive industry. This study utilizes comprehensive content analysis to critically review the recent ELV research developments and underpinning issues in Malaysia. Fifty relevant ELV studies in Malaysia from the year 2006 to 2021 are selected and categorized based on three innovative sub-elements (product, process, system) of sustainable manufacturing. The literature review findings show that sustainable product recovery and recyclability issues in ELV treatments are still a major concern. Current studies overlook specific research on sustainable and integrated processes for ELV treatment. There is still lack of detailed ELV implementation framework equipped with the documented procedures and appropriate industrial practices in the ELV ecosystem to optimize the ELV supply chain. ELV policy is yet to be enacted in Malaysia, and public awareness of ELV is still low. There is inadequate alignment in ELV research developments with the current National Automotive Policy 2020 in Malaysia. The proposed integrated conceptual model will provide an extensive overview for scholars, policy-makers, and ELV stakeholders to implement appropriate actions to improve present ELV businesses in line with the public readiness to enact the potential ELV directives or legislation in Malaysia.
Keywords
End-of-life vehicles
Malaysia
National Automotive Policy
Automotive
Sustainable manufacturing
Ministry of Higher Education of MalaysiaUTM vot no. R.J130000.7809.4L943 Mat Saman Muhamad Zameri
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pmcIntroduction
Resource shortages and environmental pollution have become global concerns issues. One of the critical problems the world is presently dealing with is the enormous demand for multiple resources to fulfill the consumer’s needs [1]. It is inevitable that the number of end-of-life vehicles (ELV) in the automotive industry will skyrocket in the coming decades due to the tremendous rise in vehicle ownership [2]. According to European Directive on ELV (2000/53/EC), ELV is defined as “any junk vehicle, whether or not it includes a material or object that the last owner intends to discard or does not wish to keep” [3]. If the ELV issues are not properly addressed, severe social and environmental problems will arise, resulting in huge economic losses. Therefore, the European Union (EU) enacted the ELV Directive (2000/53/EC) in 2000 to encourage the reuse and recycling of ELV components and reduce ELV waste for environmental protection. The ELV guideline mandates a recovery rate at above 95% from 1st January 2015. Europe has already had almost 20 years of experience regulating ELV activities since 2003 [4]. The ELV supply chain system in Europe has been thoroughly comprehended and well adapted to the ELV guideline. Although ELV are treated as substantial cause of environmental pollution, it also possesses high economic value due to its recoverable components and valuable recyclable materials that can be salvaged when appropriately processed in ELV treatment. With the rapid rise of ELV numbers, it was projected that more ELV legislation and policy would be introduced to increase the recovery system efficiency [5]. However, Malaysia has not enacted any ELV-related legislation because most Malaysians are still uncertain about the action taken in the ELV implementation [6]. This showed that the ELV development in Malaysia is still very slow and lags compared with other developed countries.
Automotive has become one of the essential industries in the Fourth Industrial Revolution (4IR), as per Malaysia’s National Policy on Industry 4.0 [7]. The founding of national automotive corporations like Proton in 1985 and, later, Perodua in 1993 served as a stimulus for the rapid growth of the automotive industry in Malaysia. This transforms the country from vehicle assemblers to vehicle manufacturers, thus accelerating the expansion of local automotive component manufacturers and their supply chains. The latest National Automotive Policy (NAP) or NAP 2020 anticipated that the automotive sectors will be generating RM104.2 billion for Gross Domestic Product (GDP) by 2030 [8]. The local vehicle industries are expected to recover from the impact of the Covid-19 pandemic. It is projected that the total number of new passenger and commercial vehicles registered annually in Malaysia will steadily increase from 604,200 in 2022 and hit 662,100 in 2025 [9]. However, the passenger vehicle market in Malaysia is expected to reach saturation in 2030, with 12 million active vehicles and half a million ELV to be produced in that year [10]. The NAP 2020 also aimed to reach RM 10 billion in export for remanufactured automotive parts and components by 2030 [8]. The large quantity of ELV collected is essential to provide sufficient input for secondary raw materials and promote sustainable resource circulation to minimize waste. However, the ELV management system in Malaysia is still at the beginning or infancy level, similar to other emerging nations.
Vehicle manufacturers would prefer their vehicles to last for 15 years; those vehicles which exceed this age limit are classified as ELV [11]. In contrast, most public respondents (38.9%) in Malaysia preferred the vehicle age to be limited to 10 years [12]. However, most Malaysians had driven their vehicles for more than 10 years in the actual situation [13]. The number of vehicles operating on the road between 10 and 15 years is anticipated to exceed five million [14]. This leads to the possible risks of having vehicle breakdown issues and causing safety hazards to drivers and road users. ELV in Malaysia will typically transfer to rural regions after being operated on for lengthy periods. The vehicles are deemed safe on the road if they still meet the required inspection, safety, and environmental standards. Vehicle owners in Malaysia would commonly choose to preserve their vehicles until the end of the product life cycle. Purchasing a new car is costly and not affordable for most low-income families. Many ELV are refurbished and used as “second-hand” cars in rural areas, thus drastically reducing the recycling rate for ELV. The majority of respondents agreed that the automobile industry’s commitment to achieving environmentally sustainable growth would positively impact national economic development [15]. Sadly, many owners still choose to abandon their obsolete or unwanted vehicles improperly and irresponsibly, which has caused considerable challenges in sustainable manufacturing (SM) issues such as negative environmental impact, social issues, and financial loss.
This study of ELV is limited to the Malaysian context as it is one of the fast-emerging industries and plays a critical role in sustainable development. Many studies have focused on Malaysia’s ELV management system and recovery issues. However, there is still a lack of comprehensive research to investigate the ELV progressive research development and sustainability issues to increase the recovery rate. To the best of the authors’ knowledge, no review paper has emphasized assessing the ELV research development in Malaysia. Hence, it would be worthwhile to investigate the key issues of ELV phenomena more holistically and explicitly in Malaysia to narrow the research gaps. Therefore, this study aims to identify several key subjects related to ELV development issues in Malaysia and recommend a future research direction. The review will generate some implications for academicians and practitioners to better understand the underpinning issues of ELV in Malaysia. The proposed ELV model will guide the relevant parties in establishing a strategic plan and regulatory framework to solve the ELV problems in Malaysia. The ELV stakeholders and policy makers can take effective actions to improve current ELV approaches in line with the NAP in preparation for implementing the ELV management system policy.
The entire paper is outlined as follows: Sect. 1 introduces the ELV overview in Malaysia and the problem identification. Section 2 presents the literature review of Malaysia’s NAP and ELV research development issues. This is followed by the critical analysis of the sustainability issues at the product, process, and system levels. Next, the methodological approach employed is described in Sect. 3. Section 4 explains the synthesis and discusses the results derived from the critical literature review. Further categorization of innovative SM sub-elements is developed to obtain insights into sustainable ELV development. The ELV policy and public knowledge of sustainable ELV development are discussed. Next, the integrated conceptual model of innovative SM elements is proposed. Lastly, Sect. 5 concludes the study and suggests future research directions.
Literature review of NAP and ELV research development in Malaysia
The Scopus database was searched within the ‘Article Title, Abstract, and Keywords’ using the exact phrase “end-of-life vehicle” with the selection year ranging from 2006 to 2021. It resulted in a total of 797 articles. Figure 1 depicts the number of documents published for ELV by country or territory (extracted from the Scopus database). China (127) and Japan (84) are the top two countries actively involved in ELV research and development. The Chinese government has implemented several recycling policies that have influenced the practices of the industry players, and effective subsidy policies have improved the recovery rate of ELV [16]. Both Japan and the EU are in the vanguard of ELV management and have implemented several effective policies to promote ELV recycling [17]. The market-based ELV recycling stream had been well developed in Japan before the ELV Recycling Act was enacted in 2005 to govern ELV management [18]. The ELV directive primarily leads the circular economy (CE) of vehicles in the EU with emphasis on the concept of extended producer responsibility (EPR), in which the automobile makers and importers are accountable for recycling expenses [19]. Meanwhile, Malaysia (42) is ranked as one of the top ten countries contributing considerably to ELV-related studies. This clearly showed that ELV issues are becoming a hot topic and receiving great attention from Malaysian researchers. Hence, performing a critical review on ELV, particularly in the Malaysian context, is worthwhile. However, Malaysia still does not have an ELV regulatory structure, unlike the EU or Japan [20]. This indicated most Malaysian are still not yet ready for the ELV implementation. The close collaboration of all the ELV stakeholders and the support from the government are vital to accelerating the potential ELV development in Malaysia. Malaysia should adopt feasible ELV management practices and look into the successful experiences of policy implementation in other countries. Therefore, this review study is essential to provide novel perspectives on ELV issues and serve as a reference guide for ELV players in other developing countries with similar business settings.Fig. 1 Number of ELV published documents by country or territory (extracted from Scopus database)
The NAP was initially launched in 2006 as part of the Third Industrial Masterplan (IMP3), 2006–2020 to make the automotive industry one of the major contributors to the Malaysian economy [8]. It emphasized supply chain integration and planned to equip the local automotive stakeholders to become more efficient and competitive. The second iteration of NAP was launched in 2009 to enhance capabilities and create a favorable investment environment in the local automobile industry. The third version of NAP 2014 was released in 2014, focusing on green initiatives, market expansion, and strengthening the entire automotive ecosystem through technological, human capital, and supply chain growth. The NAP 2014’s objective was to position Malaysia as a regional energy-efficient vehicle hub for energy efficient vehicles (EEV) by 2020 [8]. With the latest technological intrusions and ripples hitting global markets, Malaysia’s automotive industry was struggled and suffered a tough time since the beginning of 2020, especially facing global competitive challenges during the 4IR. Therefore, NAP 2020 (the current fourth edition) seeks to enhance Malaysia’s automotive industry to partake in the digital industrial transformation waves from 2020 to 2030. NAP 2020 is launched to boost the continuous growth of Malaysia’s automotive industry via enhancing “Connected Mobility”. The application of smart automotive, connected mobility, and integrated technology has grown tremendously in vehicle development. The Industry 4.0 elements such as autonomous robots, Big Data Analytics (BDA), Internet of Things (IoT), Artificial Intelligence (AI), and so on have mainly altered the business’s environment setting by introducing smart features to expedite the vehicle’s digital transformation. The fast emergence of Industry 4.0 development can deal with the unpredictability of end-of-life (EOL) product quality by applying smart processing and analyzing complex data to facilitate remanufacturing [14]. Figure 2 shows the evolution of NAP in Malaysia, which began with a policy-driven approach in NAP 2006 to the recent focus on vision drives policy in NAP 2020 to cope with the latest challenges in the digital industrial transformation era.Fig. 2 Evolution of NAP in Malaysia [8]
Remanufacturing is the process of restoring discarded EOL products to a “like-new” functional state with a matching warranty [21]. Remanufacturing would be a valuable recovery strategy for ELV as Malaysia aggressively adopts and embeds advanced Industry 4.0 technologies or tools in the automotive sectors [22]. The automotive industry had included remanufacturing as one of its strategic roadmaps in NAP 2014, and the scope is continually expanding in NAP 2020. The National Roadmap for Automotive Aftermarket (NRAA) has set up detailed criteria to enhance the remanufacturing standards and methodologies for domestic automotive stakeholders to make Malaysia an ASEAN automotive remanufacturing center. NRAA had included recommendations for strengthening component recycling and reuse efficiency using emerging technologies like BDA. This is in line with NAP 2020’s National Automotive Vision, which targeted to improve the local vehicles in auto part manufacturing and promote sustainable remanufacturing. An in-depth discussion on ELV began in Malaysia since 2006 by focusing on the automotive industry’s evolution plan [23]. Table 1 shows an extensive literature study conducted on ELV research development in Malaysia from the latest year (2021) to the oldest year (2006) of publication on identified subgroups: SM elements, scope of study, research method, key findings, and limitations of the study.Table 1 Critical review of ELV research development in Malaysia
No References SM elements Scope of study Research method Key findings Limitations of the study
1 [6] System ELV policy implementation Survey Public awareness and acceptability of ELV applications are relatively poor Lack of suggested solutions to improve the public perception of ELV policy implementation
2 [23] System ELV management ecosystems Observation Recommendations for ELV management ecosystems and implementation were highlighted The sustainable ecosystems for the reverse logistic supply chain in ELV are not emphasized
3 [24] System Supply chain optimization for ELV recycling Literature review The supply chain system for ELV recycling is still in its early stages This study did not evaluate the sustainable supply chain performances
4 [25] System ELV safety issue and policy Literature review ELV initiative must be started to improve the safety features plans to minimize the risk of fatal road accidents Lack of discussion on the safety standard in ELV with regard to SM elements and policy
5 [26] System Awareness and understanding of ELV implementation Survey Most respondents have low knowledge of ELV and agreed about the ELV implementation There is lack of discussion on sustainable ELV development from the other relevant industry players
6 [27] Product The potential of recycled polypropylene in ELV Laboratory testing The rheological test indicated that recycled polypropylene best operates at 190 C The sustainability of the recycled materials is still yet to be verified
7 [14] System Challenges and opportunities in Malaysian remanufacturing industries Literature review Five current challenges with mitigation strategies and two future opportunities have been identified for SM A comprehensive framework is needed to evaluate the current remanufacturing system performances
8 [22] System Supply chain disruption risks in the automotive remanufacturing industry Semi-structured interviews and site visits to 3 companies The most significant disruption element in production planning is obtaining replacement parts The identified disruption factors are not supported by the relevant literature in enhancing the sustainable supply chain management
9 [28] Product ELV waste recycling is used for sandwich panels Laboratory testing ELV waste can be recycled to develop valuable, sustainable thermal insulation The methods used are still required to be qualified to enhance sustainable performances
10 [29] Product Automotive component design for reparation using the additive manufacturing (AM) technology Industrial visit Advanced AM technology offers a great ability to reduce restrictions in manual repair and restoration of EOL cores Lack of discussion on how the design for remanufacturing automotive components can be applied with the AM technology in SM
11 [13] System ELV recovery issues and factors Survey The five factors enhancing ELV recovery are subject to dynamic changes in the aftermarket chain Lack of details discussion on the corresponding sub-factors with the sustainable ELV recovery system
12 [11] System Performance evaluation tool for ELV management system Survey The overall score of the ELV management system implementation in Malaysia is equal to 2.13, indicating an average performance level There is still a lack of critical SM elements incorporated in the performance evaluation tool on ELV management system implementation
13 [30] System ELV recovery factors Interviews The aftermarket cognitive map depicts the interconnections between the ELV recovery factors and recovery effectiveness Lack of investigation of the identified recovery factors in analyzing the significance of their relationships in the proposed model
14 [31] Product Remanufacturing quality-certifying framework for remanufactured components Literature review and survey The key factors of remanufacturing quality control were established The concern on sustainability issues is not considered when establishing the quality factors
15 [32] Process Concept of processing framework for ELV recycling Literature review The construction industry can utilize ELV waste in dismantling and shredding operations The compatibility of raw materials recovery from both industries needs to be evaluated to enhance the sustainable production metrics
16 [33] Process Remanufacturing knowledge support system to facilitate the remanufacturing process of brake callipers Interviews, observations, and documentation review (mixed method) The remanufacturing of brake callipers has been made easier using a Java-based prototype graphical user interface (GUI) assistance system The knowledge is gathered from a local company only, which lacks practical validation on standardizing the process steps
17 [10] System Estimation of the number of ELV generated in Malaysia until 2040 System dynamics modeling The passenger vehicles (PV) market is expected to approach saturation in 2024 while the number of ELV continues to rise Insufficient focus on ELV estimation with regard to the future sustainable development issues
18 [34] System Problems and gaps in the EOL remanufacturing of electronics and automobiles Literature review Addressed the study of remanufacturing in the automobile industry from the system perspective as an integrated approach Lack of focus on the remanufacturing stakeholder's analysis in dealing with the sustainable operations issues
19 [35] Product ELV recovery factors and the connection to product design strategies Literature review The initial recovery model employs a system dynamics method to link product design tools with recovery variables The proposed model is still yet to be validated in the actual scenario, and thus needs further input from the expert
20 [36] Product ELV recovery model in relation to ELV design strategies Interviews EOL design strategies that affect the effectiveness of ELV recovery were developed using system dynamics The model is still incomplete and lacks relevant data to support reflecting the actual situation
21 [37] Product Quality assurance of remanufactured components in ELV Literature review The quality of the remanufactured ELV components in terms of quality assurance and quality after business is vital The essence of quality of the remanufactured ELV components is not shown via its impact on ELV performances
22 [12] System ELV policy and public perception Database review The government still encounters several challenges when implementing the ELV policy in Malaysia The proper ELV plan needs to be accomplished with sustainable practices in the automotive ecosystem
23 [38] System Key success factors for ELV management system Survey The eight success factors and 33 underlying items are identified and discussed The 33 underlying items in these eight key success factors are not explained in this study
24 [39] System Sustainable ELV management Survey A multi-criteria decision-making method can be useful for choosing criteria and evaluating alternatives Future studies can explore the factors that affect the criteria selection and add in more critical criteria from other sources in this field
25 [40] System Sustainable ELV management Survey The eight criteria are consistent with the requirements of selecting sustainable ELV management alternatives Lack of description of the criteria and dimensions for sustainable alternatives evaluation
26 [41] System Public perception of ELV recovery in Japan and Malaysia Survey More than half of respondents in both countries were doubtful about their readiness to engage in ELV endeavors Lack of attention to economic and environmental elements to improve ELV recovery issues
27 [42] Product ELV conceptual design Case study (brake calliper) An evaluation of the product upgradability at the conceptual design stage using Quality Function Deployment (QFD) application The operational performances of the upgraded parts toward SM can be further improved via the continuous product life-cycle assessment
28 [15] System Automotive remanufacturing roadmap and overview of actual implementation Survey The research and development in automotive remanufacturing is still at the very low level The strategic application of remanufacturing concept toward sustainable automotive manufacturing in mitigating the current challenges still needs to be developed
29 [43] System Success factors in ELV management system Literature review A set of preliminary factors were identified and categorized in the survey instrument The survey instrument design is yet to be validated by experts to go for the pilot study
30 [44] System ELV management and future transformation Literature review, discussion with experts and academician Sustainable ELV management is needed to make standard legislation and directive for future transformation Lack of in-depth discussions on the enablers and inhibitors of the sustainable ELV management directive
31 [45] System ELV management system’s practices Literature review ELV are presently handled in three ways: operated on the road, left abandoned, and disposed of in the landfills The study did not discuss the factors that affect the sustainable ELV management system and practices
32 [46] System Public community knowledge on the reuse of ELV Survey The knowledge of ELV in the public community needs to be enhanced Lack of emphasizing the challenges and implications of ELV reuse in sustainable development issues
33 [47] System Framework for ELV recycling system in Malaysia Interviews A comprehensive framework adapted from the ELV management success in other countries The framework focused on the overview of ELV system process flow but did not look into the perspective of the sustainable value chain
34 [48] Product ELV design process and management Literature review Designs for recycling, recycling technology, and ELV management were reviewed Lack of discussion on the relationship between the ELV design process and the management system
35 [49] Product Optimization of the disassembly sequence Case example The genetically optimized disassembly sequence is critical to enhancing the product reusability Lack of discussion on the critical factors that impact the disassembly sequence
36 [50] System Conceptual model of the automotive ecosystem in Malaysia Focus group discussions and literature review A conceptual model of the domestic automotive ecosystem and mapping of the NAP 2009 measures was developed in the study The conceptual model needs to be practically validated by the car users and industry to improve the feasibility of NAP measures
37 [51] Product Design for ELV value framework Case study The presented framework consists of 4 main steps for vehicle design and development The guideline for vehicle design and development process needs to be aligned with the legislation
38 [52] Product A framework of integrated recyclability tools for automobile design Literature review A framework of integrated recyclability tools has been introduced to improve the recyclability The framework focuses on the design environment, the economy and social dimensions that can be explored for further enhancement
39 [53] Process Remanufacturing practices in the automotive industry Survey It is needed to validate the influence of remanufacturing on product quality Lack of discussion on the standard remanufacturing practices in dealing with the sustainable development issues
40 [54] Product Disassemblability of ELV Literature review To identify the optimum stage of ELV disassembly for recovering all commercially viable components The factors that will be affecting the evaluation of disassemblability selection are not discussed in detail
41 [55] Product Optimization of reusability in automotive components Case study Reliability, material, and AI are vital factors in optimizing the vehicle reuse concept The proposed artificial neural network model needs to be tested in a robust environment for SM
42 [56] Product Disassembly for reuse in ELV Survey Optimization of disassembly for reuse in the local industry can improve the recoverability of ELV’s components There are three respondents involved in this survey, which is a lack of generalizations
43 [57] Product Design framework for ELV recovery Survey Optimization of ELV disassembly sequence using genetic algorithm approach The proposed model is still developing; more real-life case validation is needed
44 [58] Product ELV disassemblability and recyclability Software analysis Decision-making software to evaluate the disassemblability of design and examine their recyclability The critical factors that will be affecting the disassembly cost and time need to be thoroughly assessed to improve the economic efficiency
45 [59] Product Automotive component reuse Interviews The identified organizations have never reused the automobile components in newly manufactured vehicles Factors that affect the sustainable development for products recovery can be explored from the supply chain and demand perspectives
46 [60] Product The evaluation methods of disassemblability Literature review The recycling and disassembly elements must be examined thoroughly in the ELV’s product design process Lack of detailed discussion on the integrated design for disassembly with its performance metrics evaluation
47 [61] Product A tool for Design for End-of-Life Value Software prototype (case study) Proposed the two primary methodologies: recycling function deployment and value analysis When performing the value analysis assessment, there is a lack of involvement from the customer’s perspective in value-added creation
48 [62] Product The application of AI to optimize the reuse of automotive components Analysis and modelling The artificial neural networks (ANNs) and genetic algorithms can be adopted to solve the design for reuse components The sustainability assessment needs to be performed to optimize reuse components' durability and reliability
49 [63] Product ELV recovery: process, impact, and research direction Literature review The research framework for the ELV recovery concept was proposed with a conceptual approach The concepts of sustainable development and ELV recovery needs to be enhanced to extend the life cycles of the vehicles
50 [64] Product The key element to the vehicle design process Literature review Four aspects of the vehicle design process had been developed based on the current situation in ELV Directive Other key elements need to be identified to meet the latest industry requirement for SM in ELV development
ELV sustainability issues at the product level
The evaluation of the rheological properties of recycled polypropylene with virgin polypropylene and a product that incorporates recycled polypropylene from ELV are developed [27]; however, the sustainability of the recycled materials is still yet to be verified. A new way to produce thermal insulation sandwich panels is provided using ELV waste from headlamps and seats [28]. The key performances of the thermal insulation sandwich panels in terms of social, economic, and environmental need to be assessed for broader industry application. A framework is proposed as a benchmarking tool to certify the quality assurance of remanufactured components by issuing aftermarket warranties [31]. This framework mainly targeted to certify the remanufactured components with evaluated relevant quality factors; however, the concern on sustainability is still not emphasized.The quality of remanufactured ELV components in emerging nations determined that quality assurance and quality certification aftermarket services are the most notable findings in Malaysia [37]; however, the quality of remanufactured ELV components can be further assessed to meet the customer acceptance to achieve a higher level of assurance in the sustainable remanufacturing industry. The artificial neural network is applied to increase the reliability of the proposed reuse component and material selection as optimization tools to improve the stress analysis of a body-in-white car door [55]; however, the critical performances of the automotive components for reuse need to be assessed to incorporate the SM elements.
An optimization model is developed for disassembly sequences of an engine block using the genetic algorithms method, which can achieve the minimum disassembly time [49]; however, this dissambly process's efficiency was not quantified in terms of actual cost saving or economic benefits. A study of numerous disassemblability approaches for ELV is presented to determine the optimal stage of disassembly to enhance the product recovery [54]; however, the factors that will affect the evaluation of disassemblability selection and its impact on the disassembled product’s quality are not discussed in details. The optimal disassembly stage is vital and rigorous disassembly for reuse to increase product recovery in the Malaysian automobile sector [56]. The results are only obtained from three local automotive component manufacturers in Malaysia, which lacks generalization to other ELV stakeholders in the automotive industry. The design framework using a genetic algorithm method is developed to evaluate EOL product disassembly by adopting the principles and guidelines of design for disasembly into design [57]; however, the proposed model is still in the development stage, and more real-life studies need to perform to verify it’s applicability. A decision-making software is developed to assess the disassemblability of ELV component’s designs, determine their eligibility for recycling, and examine their recyclability [58]. The various critical factors affecting the disassembly cost and time need to be thoroughly assessed to improve economic efficiency. A system dynamics method is proposed to connect the product design approaches with other recovery factors to deal with complicated challenges in the automotive industry [35]; however, the proposed method is still yet to be validated in the actual scenario; thus, this requires further input from industry expert for enhancement.
The disassemblability evaluation methods and functional system requirements are analyzed to assess the impact on various design aspects of automotive components [60]. However, there is still lack of detailed discussion on the integrated product design for disassembly with performance metrics evaluation in the later disassembly stage to enhance the overall design strategy and concept in ELV. The pre-assessment of a chosen automotive component (brake calliper) is conducted to evaluate its conceptual design with the intention of upgradeability using the QFD application [42]. The operational performances of the upgraded parts toward SM can be further improved via the continuous product life-cycle assessment in the actual application stage. An ELV design process and management review were performed to improve the product's recyclability [48]. There is lack of description of the relationship between ELV design protocols and management systems to improve recycling efficiency. The design for the EOL value framework is developed to provide the design evaluation for the vehicle’s recyclability in the early design stage [51]. The design guideline for recycling in ELV and the corresponding development process implementation need to be aligned with the established legislation of the EU Directive on ELV. A framework for an integrated recyclability tool is presented to enhance automotive design and development in product recyclability [52]. The framework focuses on the design environment part; it is suggested to incorporate the social and economic dimensions to improve the recyclability decisions.
A tool for design for the environment is proposed for EOL value and recyclability assessment in the automotive industry [61]. The value analysis highlighted mainly emphasizes the economic parameters but lacks involvement from the customer’s perspective in value-added creation for economic sustainability. The model is developed to assess the design for automotive components' reuse using AI methods at the lowest costs [62]. The sustainability assessment needs to optimize reused components' durability and reliability. The reuse of automotive components is not adopted by original equipment manufacturers (OEM) on new vehicles but is only used for parts replacement [59]. Factors that affect the adoption of automotive component reuse on sustainable development for product recovery can be explored from the supply chain perspective and demand. A research framework is presented for the ELV recovery concept that incorporates recyclability concerns throughout the product design process [63]. The concepts of sustainable development and ELV recovery in the vehicle development process phase need to be further enhanced to facilitate the automotive manufacturing process. Vehicle designers must address four key EOL requirements during vehicle design and development: design aspects, materials factors, cost, and directive requirements [64]. It is important to explore other critical elements to improve the vehicle design process based on the current ELV development in meeting the industry requirement for SM. The design guidelines for repair and restoration utilizing AM technology for product life-cycle extension are highlighted [29]. The utilization of advanced product design approaches to address the common failure modes in automotive components can be further improved to achieve a higher level of sustainable product development. A preliminary model is developed to assess the effectiveness of ELV recovery in reacting to dynamic changes in the automotive industry [36]. The authors highlighted that this model is still incomplete and lacks relevant data to support the effectiveness of EOL product design strategies.
ELV sustainability issues at the process level
A Java-based prototype GUI knowledge-based system is designed to aid the step-by-step remanufacturing process using brake callipers as a case study [33]. However, the knowledge is only gathered from one local company, which still lacks practical validation on standardizing the process steps in enhancing remanufacturing efficiency. The majority of the respondents from the survey indicated that a comprehensive investigation is needed to evaluate the influence of the remanufacturing process on product quality [53]; however, there is lack of discussion on the standard remanufacturing practices in dealing with sustainable development issues. An integrated processing framework for utilizing ELV waste is proposed for the automotive and construction industries [32]. However, the compatibility of raw materials recovery from both industries needs to be evaluated to enhance sustainable production in the ELV processing business.
ELV sustainability issues at the system level
The research and development of the actual implementation of automotive remanufacturing in Malaysia are still in the infancy stage [15]. The strategic application of remanufacturing concept toward sustainable automotive manufacturing in mitigating the current challenges still needs to be developed. The various industry stakeholders' ELV management practices are examined based on their knowledge and involvement in this field [23]. The sustainable ecosystems for the reverse logistic supply chain in ELV were not emphasized as part of this study's proposed ELV Recycling Zone implementation. The factors that improve ELV recovery in the aftermarket chain are studied [13]. However, there is still lack of detail discussion on the corresponding sub-factors with the sustainable ELV recovery system. A comprehensive performance evaluation method is developed based on the analytic hierarchy process (AHP) to determine the eight key critical success factors for continuously improving Malaysian ELV management systems [11]. There is still lack of essential elements of SM incorporated in the performance evaluation tool on ELV management system implementation. The ELV recovery model is developed based on the identified factors that affect the ELV recovery effectiveness in Malaysia from the various perspectives of five key stakeholders [30]. However, there is still lack of investigation of the identified recovery factors in analyzing the significance of their relationships in the proposed model.
An integrated model is developed to assess sustainable alternatives for effective ELV management [40]. However, this model still lacks a detailed description of the criteria and dimensions used for sustainable alternatives evaluation. A model is developed to choose the sustainable dimensions and criteria for assessing the best compromise ELV’s management alternative [39]. Future studies can explore the influential factors affecting criteria selection and add more critical criteria from other sources in this field. A framework containing the factors and items is created for a proper ELV management system in Malaysia [38]; however, this study does not explain the 33 underlying items in these eight key success factors. A survey instrument is designed to assess the success factors in adopting the ELV management system in Malaysia [43]. However, this survey instrument developed is yet to be validated by the experts for the pilot study. The present situation of ELV management is analyzed to promote sustainable growth in ELV for future transformation in Malaysia [44]. However, there is a lack of in-depth discussions on the driving forces and critical inhibitors that can impact the sustainability consideration of the ELV management directive. There is an urgent need for a proper ELV management system to cope with the harmful impacts caused by the ELV issues in Malaysia [45]. However, the study did not discuss the factors affecting the sustainable ELV management system and practices. A framework for the ELV recycling system is developed to highlight the current practices being applied in Malaysia and emphasize the coordination of relevant ELV stakeholders [47]. The proposed framework focused on the overview of ELV system process flow but did not specifically look into a sustainable value chain perspective.
Five main issues are identified in the closed-loop supply chain optimization to address the ELV recycling problems [24]. However, this study did not evaluate these issues' sustainable supply chain performances. The disruptions and sub-factors that affect the supply chain system risks in the automotive remanufacturing industry were analyzed [22]. However, the relevant literature did not support the identified disruption factors in enhancing sustainable supply chain management. There are relatively few models and research focused on automobile remanufacturing operations topics at the system level [34]. Four key issues have been discussed from the findings; however, there is still lack of focus on the remanufacturing stakeholder's analysis in dealing with the sustainable operations issues. The public knowledge and acceptability of ELV adoption in Malaysia are fairly poor [6]. However, there is still lack of focus on suggested solutions to improve the public perception of ELV policy implementation. The public community has a low knowledge of ELV, but the majority have shown positive responses about the ELV implementation in Malaysia [26]. However, there is lack of discussion on sustainable ELV development from the other relevant industry players. ELV initiative must be started to improve the safety features plans to minimize the risk of fatal road accidents [25]; however, there is lack of discussion on the safety standard in ELV with regards to SM elements and policy.
Five challenges with mitigation strategies and two future opportunities have been identified for SM in Malaysia's remanufacturing industries [14]. A comprehensive framework is needed to evaluate the current remanufacturing system performances in terms of SM approach. The government still encounters several challenges when implementing the ELV policy in Malaysia [12]. The proper ELV plan needs to be accomplished with sustainable practices in the automotive ecosystem. More than half of respondents in Japan and Malaysia were doubtful about their readiness to engage in ELV endeavors due to the uncertainty of the ELV concept [41]. However, this study mainly emphasizes the socio-technical perspective but still lacks attention to the economy and environmental elements to improve ELV recovery issues. Public community knowledge of ELV reuse has to be improved to enhance sustainable automotive growth in Malaysia [46]. However, the concept of reuse on ELV can be further explained by emphasizing the challenges and implications of sustainable development issues. A conceptual model of the domestic automotive ecosystem and mapping of the NAP 2009 measures was developed [50]. However, the conceptual model must be practically validated by car users and the industry to improve the feasibility of NAP measures. The PV market in Malaysia is expected to approach saturation in 2024 while the number of ELV continues to rise [10]. However, there is still a lack of discussion for the ELV estimation regarding sustainable development issues and recommendations for future action plans.
Methodology
ELV research development and the implementation of ELV policy are important to develop the strategic roadmap to support the NAP 2020. This study started with the literature review on the overview of the NAP revolution and ELV research development in Malaysia. Since this research aims to study the ELV development issues in Malaysia; Therefore, the search for documents that cover the scopes of ELV and Malaysia was selected as the data collection method. To limit the number of papers selected for review and to identify the most relevant articles, the following search criteria were applied:The keywords used to search the relevant publications for review were the combination of “end-of-life vehicle” OR “ELV” AND “Malaysia” using the “OR” / “AND” boolean operators.
The papers were limited to peer-reviewed English-language publications only.
The data range was chosen from publication years from 2006 to 2021 (excluding the latest year in 2022).
In the first stage of paper collection via the Google Scholar (https://scholar.google.com/) database, 1730 papers appeared in the search results. The identification and screening of the suitable papers were conducted using the steps explained as follows:The document’s ‘title, abstract, and keywords’ were screened to decide whether it is relevant to the ELV research subjects and suits the scope of review during the initial screening.
Papers that are mismatched or not related to the field of study in ELV, duplication and do not fulfill the scope of review criteria were removed.
Subsequently, the suitable papers found were read through the entire content to check whether they had included Malaysia and ELV as key focus studies in fulfiling the research scope for further review.
After the screening process in Google Scholar, 43 papers were finally selected for detailed reading and thoroughly reviewed. Next, the same steps were adopted for documents searched within ‘All fields’ in the Scopus (www.scopus.com) database, generating 374 papers in the search results. After the screening process, another seven pertinent documents were chosen for further review. In addition, literature searched within ‘All fields’ in the Web of Science (https://clarivate.com/webofsciencegroup/solutions/web-of-science/) database was performed by applying the above steps, generating 240 papers. After the screening process, 15 suitable papers were found; however, these papers were duplicated with the previously chosen papers in Google Scholar or Scopus. Finally, altogether 50 papers were selected and reviewed in this study, as listed in Table 1.
Content analysis facilitates observational research by allowing researchers to evaluate the symbolic content of all sorts of recorded documents in a systematic manner [65]. A structured literature review was conducted using the content analysis method on these 50 papers to discover the critical issues and research gaps associated with ELV development in Malaysia. The sustainable topics for these selected papers were further grouped and assessed based on the three innovative SM (product, process, and system) sub-elements. This is followed by a discussion of the ELV policy and public knowledge of ELV development for SM in Malaysia. Lastly, the integrated conceptual model was proposed as guidance to mitigate the ELV development issues in Malaysia.
Results and discussion
The necessity for SM in ELV has been prompted by scarce resource supply and the adverse environmental and socioeconomic repercussions of traditional manufacturing. Integrating SM elements: products, processes, and systems in ELV sustainability are critical for resource conservation. SM would require innovation at all stages of the product, process, and system levels in manufacturing by undergoing multiple life cycles to enhance the sustainable value chain [66]. A shared responsibility framework is proposed to establish a business model with a stakeholder engagement structure to strengthen the sustainability of ELV management and material recovery in India [1]. A sustainable ELV management using a closed-loop supply chain (CLSC) strategy with the CE model is developed to deal with ELV issues and reduce waste in Qatar [67]. A systematic review is presented to identify the factors that will enhance the automotive supply chain’s sustainability and improve the sustainable management performance of the Chinese ELV recycling industry [68]. Turkish automakers are accountable for the free collection of ELV from customers to rehabilitate old components in the industry under ELV regulations; therefore, a CLSC network design is created to handle the material flow of ELV [69].
In Malaysia, the first introduction of the NAP 2006 and the hot debate about ELV have been underway since 2006. However, the sustainable awareness of ELV recycling among Malaysia's public and industrial players is still low. ELV waste management is poorly managed in Malaysia due to the weak regulatory framework [44]. Therefore, there is a need for Malaysian manufacturers and government agencies to focus on design for remanufacturing in automotive and promote the growth of automotive research and technology to achieve policy optimization [15]. Malaysia can review the ELV recycling strategies and adopt the best practices of SM from those countries that have achieved great success in this area prior to developing its framework for enacting the ELV policy. Table 2 shows the literature studies of ELV development in Malaysia that are classified and adapted based on the three innovative SM elements [66]. These innovative SM sub-elements are synthesized based on the nature and aspects of the literature’s content to explore various insights of SM in ELV development. The proper classification of sub-elements in SM is essential for the policy makers and industrial players to work on effective ELV strategy planning and implementation framework to deal with the underlying issues of ELV in Malaysia.Table 2 Classification of innovative SM sub-elements for ELV development in Malaysia (adapted from [66])
SM elements Category of sub-elements in SM References
Product Sustainable materials/components for products [27]; [28]; [31]; [37]
Advanced product design [29]; [55]; [62]
Effective product disassembly [49]; [54]; [56]; [57]; [58]; [60]
Design for reuse/recycling/remanufacturing/recovery [42]; [51]; [48]; [52]; [59]; [61]; [63]; [64]; [35]; [36]
Process Sustainable processes [53]
Integrated processes [32]; [33]
System Sustainable management systems [6]; [23]; [25]; [26]; [14]; [13]; [11]; [30]; [12]; [38]; [39]; [40]; [41]; [15]; [43]; [44]; [45]; [46]; [47]; [50]; [34]; [10]
Supply chain optimization/integration [24]; [22]
Product innovation in sustainable ELV development
ELV recycling companies in emerging and developing countries confront major challenges in the systemic recycling of ELV in enabling the recovery of materials and parts or components to maximize economic advantages according to environmental standards [70]. The major hurdle to optimizing part remanufacturing could be affected if the returning and processing of components or materials cannot be established effectively for SM. Therefore, selecting sustainable materials or components from ELV is vital to producing value-added products. The critical literature review shows that a thorough quality assessment of the sustainable remanufactured or recycled ELV components is still lacking. The product quality of automotive’s components remanufactured product, which fulfill the practical criteria, is a notable indicator of success in remanufacturing [71]. The remanufacturing company must emphasize the essence of quality management in developing ELV remanufactured products. Developing countries like Malaysia would need knowledge-based assistance and strong technical know-how to encourage remanufacturing while ensuring that the components remain in high-quality performance [33]. Therefore, the detailed assessment of the compatible material selection should be well incorporated into the product design and development stage to optimize the automotive vehicle recyclability in the downstream manufacturing processes to fulfill the customer requirements.
The advanced product design by applying the latest Industry 4.0 technological tools is receiving great attention from industry practitioners to improve the product’s efficiency and competency level. The ELV part design for recycling or remanufacturing needs to be integrated with the feasible Industry 4.0 technological elements and tools application in technical data sharing. This can facilitate the effective connection with the downstream processes to improve the product’s quality and circularity. Employing modern and emerging digital technologies to strengthen relationships between product manufacturers, users, and remanufacturers are critical to establishing sustainable remanufacturing development in Industry 4.0 [72]. However, data about remanufacturing and product design-process systems are currently proprietary, and technical know-how is shared sparingly among the industry players in the remanufacturing and aftermarket industry. Therefore, it is critical to highlight how the Industry 4.0 technological enablers and the smart remanufacturing tools can trace the past data of incoming core or EOL products from the sharing system to optimize its remanufacturability.
Effective product disassembly involves adopting feasible disassembly methods and process sequences to deal with the returned product’s complexity challenges. Disassembly techniques are one of the crucial factors in the Chinese ELV recycling business [68]. An appropriate disassembly sequence of ELV that combines the destructive disassembly and non-destructive approach is developed to provide a better guide for ELV recycling economic growth via the cost–benefit analysis [73]. The most significant factors in the development of the recycling industry are regulations on automation factories, disassembly procedures, and value mining [68]. The effective recycling and disassembly elements must be well considered when implementing the ELV concept in the product design stage, especially with proper disassembly evaluation [60]. However, the existing research focusing on effective product disassembly to enhance the ELV recovery rate in Malaysia is still limited to the past 10 years. Product disassembly is still largely dependent on manual labor jobs. The application of human–robot collaboration or human–machine interaction can solve complicated tasks in product disassembly operations. Therefore, there is a strong need to integrate Industry 4.0 technological tools and techniques to improve the efficiency of ELV product disassembly process steps.
The design for reuse/recycling/remanufacturing/recovery concentrates on sustainable techniques application to improve the product life-cycle development in the subsequent manufacturing stage. The challenges that arise during the remanufacturing process could be minimized if good decisions are made during the design phase [74]. The remanufacturing applications could only be advantageous and competitive if the products are intentionally made or designed for remanufacturing in the first place [75]. Therefore, the ELV treatment should focus on product optimization by integrating the design for recovery techniques into the vehicle manufacturing process. The significant external and internal operational factors affecting design for remanufacturing integration are management engagement and relationships between OEM and engineers in the product design phase [76]. From the literature review, the product recovery or recyclability issues for SM in ELV treatments are still a major concern. Design aspects of ELV components should consider the customer perspective in product specification requirements and perform stakeholder analysis to enhance the product life cycle for sustainable value creation. The vehicle design and development guidelines can incorporate green manufacturing elements to meet the latest ELV industry requirements and practices in SM.
Process innovation in sustainable ELV development
Adopting innovative approaches in green product remanufacturing can greatly increase sustainable process performances while raising the manufacturer’s recovery rate in a CLSC [77]. The product cost variations are directly connected to the process uncertainty, particularly in the current dynamic manufacturing environment in cores collection [78]. The essential factors in increasing ELV recovery efficiency are advancing the processing technologies, optimal government subsidies, and public awareness of environmental protection [79]. However, it is noticeable that there is still limited study on implementing standard ELV practices and assessing technical competency for specific ELV treatment processes in Malaysia. The systematic procedures and feasible techniques need to apply to existing ELV remanufacturing or recycling to evaluate the key process performance indicators. The integrated proposing framework developed to recycle the ELV for building products is an innovative approach for ELV waste management across various industries [32]. A feasible approach for decreasing the ELV disposal issues and minimizing the raw material utilization can promote the ELV process development in line with the applicable regulations in Malaysia.
System innovation in sustainable ELV development
ELV management is critical for resource circularity, environmental preservation, and CE development [80]. From the critical literature analysis, Malaysia’s reverse logistic network system still faces difficulties in dealing with sustainable operations issues. There is lack of systematic ELV management in Malaysia, and very few ELV are transported for recycling activities. A shared responsibility-based framework is developed to investigate and create a business concept with the key stakeholder engagement strategy to enhance India’s ELV management sustainability [1]. A dual-cycle ELV recycling and remanufacturing system are created to describe the collaborative relationship among the ELV stakeholders under the extended producer responsibility policy [81]. It is critical to note that any recycling system needs to tailor to each country’s specific needs and environments [82]. Therefore, there is a strong need to develop an implementation framework for enhancing ELV development toward SM in Malaysia. The roles of ELV interested parties involved and influenced in the sustainable management system should be thoroughly assessed via the stakeholder’s analysis to formulate the strategy roadmap and enhance the cooperation to achieve a win–win situation.
A critical assessment of existing literature reveals that several studies have been conducted primarily to address ELV recovery management systems in Malaysia. However, none of these studies presented a practical implementation framework to optimize and streamline the end-to-end solutions of ELV in the supply chain network system. The studies on the supply chain as a whole system in the automotive sector are still in the early stage [83]. Several studies have proposed valuable strategies to deal with ELV management supply chain challenges [84]. However, uncertainties in managing the consistent ELV core return are still the most prominent concern for industry stakeholders in Malaysia. There is no alignment on the standardized procedures established for ELV supply chain optimization to demonstrate the best industrial practices in the automotive sectors. Therefore, it is essential to thoroughly understand Malaysia’s existing ELV recycling supply chain and demand, including its underlying issues and disruption risks. The Malaysian government is presently studying a suitable approach to implement an ELV management policy and is looking at establishing an ELV framework by 2025 [85]. Therefore, the future proposal of a sustainable ELV implementation framework to streamline the reverse ELV value chain network through recycling and remanufacturing is highly required to resolve the ELV issues and optimize the automotive components' reusability.
ELV policy and public knowledge in sustainable ELV development
ELV policy and public awareness are essential in the ELV recovery management system. The public survey results showed that most respondents still lack exposure to ELV laws and are unwilling to pay more on disposal fees [6]. Most survey respondents agreed with the concept of a vehicle age restriction regulation based on their economic stability (income level and car status) and vehicle age factor [12]. The vehicle owners’ attitudes about vehicle maintenance are likely impacted by the financial situation and regional factors (urban or rural) in mapping to the NAP 2009 measure No. 12 [50]. The Malaysian government still confronts some hurdles in adopting the ELV policy in the country. More than half of respondents in Japan and Malaysia communities were doubtful about their desire to engage in ELV activities, indicating a lot of scepticism about the concept of ELV in reuse and remanufacturing [41]. Close cooperation between government and industry is vital in increasing public knowledge and understanding to ensure the compelling implementation journey of ELV recovery. Most public communities had little awareness about ELV; however, most respondents agreed that ELV implementation should be carried out in Malaysia [26]. The sustainable growth of remanufacturing businesses in Malaysia can encourage other emerging economies with similar business prospects to adopt SM practices [14]. However, the ELV policy is still not in place in Malaysia’s automotive environment [86]. The public acceptance of ELV policy enactment from a vehicle safety viewpoint is essential, considering the consumers’ economic implications [25]. Therefore, the implementation of the ELV policy in Malaysia needs to be thoroughly explored to assure that the public can buy-in early and effectively embrace it.
Integrated conceptual model of innovative SM elements
ELV-related laws enacted in other countries were studied, and several recommendations were made to deploy ELV policy in Malaysia based on regulation and public perception [6]. This indicated that the public’s voice and readiness are essential to the government when conducting the study to implement ELV policy and regulations to address the ELV issues. A preliminary review on implementing an efficient CLSC system for ELV recycling suggested that future similar research can focus explicitly on the ELV remanufacturing aspects from different viewpoints in Malaysia in line with the NRP [24]. Manufacturers are permitted to use whichever techniques they like due to the lack of a clearly defined ELV policy [25]. Hence, the standard remanufacturing process as part of ELV recovery practice in Malaysia could not be immediately put into progressive action. The public still perceives that remanufacturing is a type of reuse that does not create value-added operations and has poor profit returns. The government and industry should develop and implement more ELV campaigns related to reuse to increase public knowledge, education, and in-depth understanding of this subject [87].
The sustainable awareness and ELV life-cycle thinking among the public and industrial players are still low. The essential factors to increase the ELV recovery efficiency are advancing processing technologies, optimizing government subsidies, and improving public awareness of environmental protection [79]. The public knowledge and understanding of ELV are critical in implementing the ELV policy for SM in the automotive industry. Therefore, the conceptual model of innovative SM elements with integrated ELV policy and public knowledge was proposed in this study to enhance sustainable ELV implementation in Malaysia, as shown in Fig. 3. From the critical literature analysis, these three SM elements were examined independently rather than as a whole in previous ELV studies and without proper synchronization. Past studies in the automotive industry addressed the sustainable ELV research development issues; however, there is a missing link and lack of proper synchronization with the established NAP in Malaysia. This situation is understandable as the NAP 2020 has no mention of the mandated ELV policy. Therefore, the implementation of relevant ELV regulatory framework and future roadmap should be seriously considered. This conceptual model of integrated SM elements embedded with the ELV policy and public knowledge elements could guide the ELV stakeholders in planning the strategic directions and actions for future industrial applications in line with the latest NAP.Fig. 3 Conceptual model of SM elements with integrated ELV policy and public knowledge
Conclusion
The ELV issue is becoming a hot topic in the Malaysian automotive industry. This study critically assesses ELV research development issues to identify the research gaps. By performing a thorough content analysis based on an extensive literature evaluation of 50 selected papers, this study underlined how Malaysian ELV subjects developed from 2006 to 2021, highlighting the underpinning issues regarding SM. According to the critical review findings, several prospects of key research interests were recommended to improve ELV management in Malaysia as follows:• The product recovery for SM in ELV treatments are still a major concern. Design aspects of ELV components should consider the customer perspective in product specification requirements and perform stakeholder analysis to enhance the product life cycle for sustainable value creation.
• The specific study of sustainable and integrated processes in ELV treatment is mainly overlooked in the current research. Future studies need to improve the performance metric in ELV remanufacturing process steps.
• There is still a lack of a detailed ELV implementation framework equipped with documented procedures and appropriate industrial practices in the ELV ecosystem to optimize the ELV supply chain. A sustainable implementation framework is urgently needed to standardize and create the reverse ELV value chain network.
• ELV policy is yet to be enacted in Malaysia, and public awareness of ELV is still deficient. Future studies can focus on testing the interrelationship of ELV policy and public knowledge by identifying the critical moderating/mediating variables to evaluate their impact on the ELV sustainable management implementation.
• Previous studies in the automobile sector examined the difficulties of sustainable ELV research development; nevertheless, there is a weak connection and a lack of adequate alignment with the current NAP in Malaysia. The implementation of relevant ELV regulatory framework and future roadmap should be seriously considered.
The proposed conceptual model, which integrates the three critical sub-elements of SM (product, process, and system) with effective ELV policy and strong public knowledge, will facilitate ELV implementation in the Malaysian automotive industry in line with NAP. This critical review provides scholars, industry players, or policy makers interested in the ELV field with references and valuable insights into designing a sustainable implementation framework or policy for Malaysia’s automotive ecosystem. Other developing countries can benefit by identifying the current state of ELV management practices and adopting the proposed conceptual model to deploy the right strategy and mitigate the underpinning ELV issues. The key results will support the ELV stakeholders in implementing appropriate actions to improve their present ELV businesses following the latest NAP 2020 in readiness to enact potential ELV directives or legislation in Malaysia. In the early phases of attempting to adopt ELV in Malaysia, firms will benefit from the study’s insights to enhance SM applications and navigate the proper action plan. The present research’s article selection is confined to the Google Scholar, Scopus and Web of Science databases, which is a limitation of this study. This study does not include other related papers beyond these databases. A detailed analysis could be conducted by expanding the large sample size of articles and having documents from various sources to improve the reliability of the findings. An in-depth study is needed to establish a comprehensive SM framework for smooth ELV management system implementation with the integration of Industry 4.0’s technological elements and aligned with the Malaysian government’s policy. Since the global topic of electric vehicle (EV) development is gaining popularity and has been emphasized in the NAP 2020, it is recommended that future EOL management can focus explicitly on this area from the SM perspective. Future real-life case studies can be conducted to verify the feasibility of this proposed integrated conceptual model by including the critical success factors and examining their inter-relationships to sustainable ELV development performances.
Acknowledgements
The research has been carried out under Konsortium Kecemerlangan Penyelidikan (JPT(BKPI)1000/016/018/25(72)) provided by the Ministry of Higher Education of Malaysia (UTM vot no. R.J130000.7809.4L943).
Funding
This study was supported by Ministry of Higher Education of Malaysia, UTM vot no. R.J130000.7809.4L943, Muhamad Zameri Mat Saman.
Data availability
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Arora N Bakshi SK Bhattacharjya S Framework for sustainable management of end-of-life vehicles management in India J Mater Cycles Waste Manag 2019 21 79 97 10.1007/s10163-018-0771-0
2. Wang Z Hao H Gao F Zhang Q Zhang J Zhou Y Multi-attribute decision making on reverse logistics based on DEA-TOPSIS: A study of the Shanghai end-of-life vehicles industry J Clean Prod 2019 214 730 737 10.1016/j.jclepro.2018.12.329
3. European Parliament and Council (2000) Directive 2000/53/EC on end-of-life vehicles. Off J Eur Union L:34–42
4. Li CJ Yang WX Liu XD Wang YM Feng SH He YA Research on vehicle recycling based on ELV Directive IOP Conf Ser Earth Environ Sci 2021 10.1088/1755-1315/687/1/012196
5. Li J Yu K Gao P Recycling and pollution control of the end of life vehicles in China J Mater Cycles Waste Manag 2014 16 31 38 10.1007/s10163-013-0226-6
6. Harun Z Wan Mustafa WMS Abd Wahab D Abu Mansor MR Saibani N Ismail R Mohd Ali H Hashim NA Mohd Paisal SM An analysis of end-of-life vehicle policy implementation in Malaysia from the perspectives of laws and public perception J Kejuruter 2021 33 695 703
7. MITI (2018) Industry 4WRD: National Policy on Industry 4.0. Minist Int Trade Ind. https://www.miti.gov.my/miti/resources/National Policy on Industry 4.0/Industry4WRD_Final.pdf. Accessed 26 July 2021
8. MITI (2020) National Automotive Policy (NAP) 2020. Minist Int Trade Ind. https://www.miti.gov.my/miti/resources/NAP%202020/NAP2020_Booklet.pdf. Accessed 26 July 2021
9. MAA (2021) Vehicle’s sales plunged in June 2021; MAA trims TIV 2021 forecast. Malaysian Automot Assoc. http://www.maa.org.my/news.html. Accessed 25 September 2022
10. Azmi M Tokai A Electric vehicle and end-of-life vehicle estimation in Malaysia 2040 Environ Syst Decis 2017 37 451 464
11. Raja Mamat TNA Mat Saman MZ Sharif S Simic V Abd Wahab D Development of a performance evaluation tool for end-of-life vehicle management system implementation using the analytic hierarchy process Waste Manag Res 2018 36 1210 1222 10.1177/0734242X18790361 30067151
12. Jawi ZM, Isa MHM, Solah MS, Ariffin AH, Shabadin A, Osman MR (2016) The future of end-of-life vehicles (ELV) in Malaysia: A feasibility study among car users in Klang valley. In: MATEC Web Conf. pp 1–8
13. Mohamad-Ali N Raja Ghazilla RA Abdul-Rashid SH Ahmad-Yazid A Aftermarket survey on end-of-life vehicle recovery in Malaysia: Key findings J Clean Prod 2019 211 468 480 10.1016/j.jclepro.2018.11.165
14. Ngu HJ Lee MD Bin Osman MS Review on current challenges and future opportunities in Malaysia sustainable manufacturing: Remanufacturing industries J Clean Prod 2020 273 123071 10.1016/j.jclepro.2020.123071
15. Yusop NM Wahab DA Saibani N Realising the automotive remanufacturing roadmap in Malaysia: Challenges and the way forward J Clean Prod 2016 112 1910 1919 10.1016/j.jclepro.2015.03.072
16. Yu L Chen M Yang B Recycling policy and statistical model of end-of-life vehicles in China Waste Manag Res 2019 37 347 356 10.1177/0734242X19833150 30836861
17. Bhari B Yano J Sakaiichi S Comparison of end-of-life vehicle material flows for reuse, material recycling, and energy recovery between Japan and the European Union J Mater Cycles Waste Manag 2021 23 644 663 10.1007/s10163-020-01154-8
18. Hiratsuka J Sato N Yoshida H Current status and future perspectives in end-of-life vehicle recycling in Japan J Mater Cycles Waste Manag 2014 16 21 30 10.1007/s10163-013-0168-z
19. Saidani M Kendall A Yannou B Leroy Y Cluzel F Management of the end-of-life of light and heavy vehicles in the U.S.: comparison with the European union in a circular economy perspective J Mater Cycles Waste Manag 2019 21 1449 1461 10.1007/s10163-019-00897-3
20. Agamuthu P Mehran SB Circular Economy in Malaysia Circ Econ Glob Perspect 2019 10.1007/978-981-15-1052-6
21. Quist J (2013) Backcasting and scenarios for sustainable technology development. In: Handb. Sustain. Eng. pp 749–771
22. Ropi NM Hishamuddin H Wahab DA Analysis of the supply chain disruption risks in the Malaysian automotive remanufacturing industry-A case study Int J Integr Eng 2020 12 1 11
23. Khan KMA Said MFM Jamaludin KR Amiruddin I Mohd A End of life vehicle (ELV) Management Ecosystems in Malaysia J Soc Automot Eng Malaysia 2021 5 150 163 10.56381/jsaem.v5i1.160
24. Rashid FAA, Hishamuddin H, Radzi M, Mansor A (2021) Supply chain optimization for end-of-life vehicle recycling : A preliminary review. Proc. 11th Annu. Int. Conf. Ind. Eng. Oper. Manag.
25. Kassim KAA Husain NA Ahmad Y Jawi ZM End-of-life vehicles (ELVs) in Malaysia: Time for action to guarantee vehicle safety J Soc Automot Eng Malaysia 2020 4 338 348 10.56381/jsaem.v4i3.27
26. Nawawi NANA Azizul MA Sulaiman S Iskandar ARAM Abdullah A Study of end-of life vehicle (ELV) implementation in Malaysia J Ind Eng Innov 2020 2 1 7
27. Bin Abdul Hamid MHI Mohd Salleh NAB Mohamad Nor NH Bin Ismail MH Bin Yahya MF Bin Saari MI Mohd Pisal SM Study on rheological and dimensional properties of polypropylene on end-of-life vehicles IOP Conf Ser Mater Sci Eng 2020 10.1088/1757-899X/834/1/012003
28. Wong YC Mahyuddin N Aminuddin AMR Development of thermal insulation sandwich panels containing end-of-life vehicle (ELV) headlamp and seat waste Waste Manag 2020 118 402 415 10.1016/j.wasman.2020.08.036 32947219
29. Yusoh SSM Wahab DA Azman AH Analysis of automotive component design for reparation using additive manufacturing technology Int J Integr Eng 2020 12 20 26
30. Mohamad-Ali N Ghazilla RAR Abdul-Rashid SH Sakundarini N Ahmad-Yazid A Stephenie L End-of-life vehicle recovery factors: Malaysian stakeholders’ views and future research needs Sustain Dev 2018 26 713 725 10.1002/sd.1741
31. Mohamed N Mat Saman MZ Sharif S Hamzah HS Strategic factors on interpreting remanufacturing quality-certifying framework to address warranty aftermarket for Malaysian industry IOP Conf Ser Mater Sci Eng 2018 10.1088/1757-899X/328/1/012033
32. Wong YC Al-Obaidi KM Mahyuddin N Recycling of end-of-life vehicles (ELVs) for building products: Concept of processing framework from automotive to construction industries in Malaysia J Clean Prod 2018 190 285 302 10.1016/j.jclepro.2018.04.145
33. Lie LW Aziz NA Wahab DA Rahman MNA Azhari CH Enhancing remanufacturing efficiency in Malaysia through a knowledge support system: A case study of brake calipers Int J Ind Syst Eng 2018 28 451 467
34. Kafuku JM, Mat Saman MZ, Yusof SM (2017) Current and future issues in electronics and automobiles remanufacturing operations. In: FTC 2016 - Proc. Futur. Technol. Conf. pp 415–421
35. Mohamad-Ali N Ghazilla RAR Abdul-Rashid SH Sakundarini N Ahmad-Yazid A Stephenie L A system dynamics approach to develop a recovery model in the Malaysian automotive industry IOP Conf Ser Mater Sci Eng 2017 10.1088/1757-899X/210/1/012068
36. Mohamad-Ali N Ghazilla RAR Abdul-Rashid SH Sakundarini N Ahmad-Yazid A Stephenie L Development of an end-of-life vehicle recovery model using system dynamics and future research needs IOP Conf Ser Mater Sci Eng 2017 10.1088/1757-899X/210/1/012075
37. Mohamed N Mat Saman MZ Safian S Quality assurance of remanufactured components of end-of-life vehicle: A literature review Adv Sci Lett 2017 23 4644 4648 10.1166/asl.2017.8868
38. Raja Mamat TNA Mat Saman MZ Sharif S Simic V Key success factors in establishing end-of-life vehicle management system: A primer for Malaysia J Clean Prod 2016 135 1289 1297 10.1016/j.jclepro.2016.06.183
39. Ahmed S Ahmed S Shumon MRH Quader MA Cho HM Mahmud MI Prioritizing strategies for sustainable end-of-life vehicle management using combinatorial multi-criteria decision making method Int J Fuzzy Syst 2016 18 448 462 10.1007/s40815-015-0061-0
40. Ahmed S Ahmed S Shumon MRH Falatoonitoosi E Quader MA A comparative decision-making model for sustainable end-of-life vehicle management alternative selection using AHP and extent analysis method on fuzzy AHP Int J Sustain Dev World Ecol 2016 23 83 97 10.1080/13504509.2015.1062814
41. Go TF Wahab DA Fadzil ZF Azhari CH Umeda Y Socio-technical perspective on end-of-life vehicle recovery for a sustainable environment Int J Technol 2016 7 889 897 10.14716/ijtech.v7i5.2878
42. Aziz NA Wahab DA Ramli R Evaluating design for upgradability at the conceptual design stage J Teknol 2016 78 37 43
43. Raja Mamat TNA Mat Saman MZ Sharif S A survey instrument design to determine the success factors in implementing the end-of-life vehicles (ELVs) management system in Malaysia Adv Mater Res 2015 1125 620 624 10.4028/www.scientific.net/AMR.1125.620
44. Ahmed S Ahmed S Shumon H Quader MA End-of-life vehicles (ELVs) management and future transformation in Malaysia J Appl Sci Agric 2014 9 227 237
45. Raja Mamat TNA Mat Saman MZ Sharif S The need of end-of-life vehicles management system in Malaysia Adv Mater Res 2014 845 505 509 10.4028/www.scientific.net/AMR.845.505
46. Wahab DA Fadzil ZF Public community knowledge on reuse of end-of-life vehicles: A case study in an automotive industrial city in Malaysia J Appl Sci 2014 14 212 220 10.3923/jas.2014.212.220
47. Azmi M, Mat Saman MZ, Sharif S (2013) Proposed framework for end-of-life vehicle recycling system implementation in Malaysia. In: Proc. 11th Glob. Conf. Sustain. Manuf. - Innov. Solut. Ger. 23–25 Sept. pp 187–193
48. Lashlem AA Wahab DA Abdullah S Che Haron CH A review on end-of-life vehicle design process and management J Appl Sci 2013 13 654 662 10.3923/jas.2013.654.662
49. Go TF Wahab DA Rahman MNA Ramli R Hussain A Genetically optimised disassembly sequence for automotive component reuse Expert Syst Appl 2012 39 5409 5417 10.1016/j.eswa.2011.11.044
50. Jawi ZM Lamin F Manap ARA Abbas F Kassim KAA Voon WS Automotive ecosystem in Malaysia - A conceptual model to explain vehicle ownership and car maintenance issues Appl Mech Mater 2012 165 224 231 10.4028/www.scientific.net/AMM.165.224
51. Mat Saman MZ Zakuan N Blount G Design for end-of-life value framework for vehicles design and development process J Sustain Dev 2012 10.5539/jsd.v5n3p95
52. Sakundarini N Taha Z Ghazilla RAR Rashid SHA Gonzales J A framework of integrated recyclability tools for automobile design Int J Ind Eng Theory Appl Pract 2012 19 401 411
53. Yusop NM Wahab DA Saibani N Analysis of remanufacturing practices in the Malaysian automotive industry J Teknol 2012 59 77 80
54. Go TF Wahab DA Rahman MNA Ramli R Azhari CH Disassemblability of end-of-life vehicle: A critical review of evaluation methods J Clean Prod 2011 19 1536 1546 10.1016/j.jclepro.2011.05.003
55. Mohamed Nazmi MAS Abd Wahab D Abdullah S Mohd Tihth R Development of artificial neural network for optimisation of reusability in automotive components J Appl Sci 2011 11 996 1003 10.3923/jas.2011.996.1003
56. Go TF Wahab DA Ab Rahman MN Ramli R Azhari CH Disassembly for reuse: Implementation in the Malaysian automotive industry Aust J Basic Appl Sci 2010 4 4569 4575
57. Go TF Wahab DA Rahman MNA Ramli R A design framework for end-of-life vehicles recovery: Optimization of disassembly sequence using genetic algorithms Am J Environ Sci 2010 6 350 356 10.3844/ajessp.2010.350.356
58. Afrinaldi F, Mat Saman MZ, Shaharoun AM (2009) A decision making software for end-of-life vehicle disassemblability and recyclability analysis. In: IEEM 2009 - IEEE Int. Conf. Ind. Eng. Eng. Manag. pp 2261–2265
59. Amelia L Wahab DA Che Haron CH Muhamad N Azhari CH Initiating automotive component reuse in Malaysia J Clean Prod 2009 17 1572 1579 10.1016/j.jclepro.2009.06.011
60. Afrinaldi F, Mat Saman MZ, Shaharoun AM (2008) The evaluation methods of disassemblability for automotive components – A review and agenda for future research. J Mek 49–62
61. Mat Saman MZ, Blount G (2008) The DFEL value methodology : A tool for design-for-environment in automotive industry. J Mek 27: 23–41
62. Wahab DA Amelia L Hooi NK Haron CHC Azhari CH The application of artificial intelligence in optimisation of automotive components for reuse J Achiev Mater Manuf Eng 2008 31 595 601
63. Mat Saman MZ, Blount GN (2006) End of life vehicles recovery: Process description, its impact and direction of research. J Mek 40–52
64. Mat Saman MZ, Zakuan N (2006) End-of-life vehicle directive: A key element to the vehicle design process. 1st Reg Conf Veh Eng Technol 1–8
65. Kolbe RH Burnett MS Content-analysis research: An examination of applications with directives for improving research reliability and objectivity J Consum Res 1991 18 243 250 10.1086/209256
66. Jawahir IS, Badurdeen F, Rouch KE (2013) Innovation in Sustainable Manufacturing Education. 11th Glob Conf Sustain Manuf 9–16
67. Al-Quradaghi S Kucukvar M Onat N Towards a sustainable management of end-of-life vehicles in Qatar: A closed-loop circular economy model Proc Int Conf Ind Eng Oper Manag 2018 2018 647 654
68. Zhou F Lim MK He Y Lin Y Chen S End-of-life vehicle (ELV) recycling management: Improving performance using an ISM approach J Clean Prod 2019 228 231 243 10.1016/j.jclepro.2019.04.182
69. Özceylan E Demirel N Çetinkaya C Demirel E A closed-loop supply chain network design for automotive industry in Turkey Comput Ind Eng 2017 113 727 745 10.1016/j.cie.2016.12.022
70. Numfor SA Omosa GB Zhang Z Matsubae K A review of challenges and opportunities for end-of-life vehicle recycling in developing countries and emerging economies : A SWOT analysis Sustainability 2021 13 4918 10.3390/su13094918
71. Tian G Zhang H Feng Y Jia H Zhang C Jiang Z Li Z Li P Operation patterns analysis of automotive components remanufacturing industry development in China J Clean Prod 2017 164 1363 1375 10.1016/j.jclepro.2017.07.028
72. Kerin M Pham DT Smart remanufacturing: a review and research framework J Manuf Technol Manag 2020 10.1108/JMTM-06-2019-0205
73. Xia X Li J Tian H Zhou Z Li H Tian G Chu J The construction and cost-benefit analysis of end-of-life vehicle disassembly plant: A typical case in China Clean Technol Environ Policy 2016 18 2663 2675 10.1007/s10098-016-1185-0
74. Matsumoto M Yang S Martinsen K Kainuma Y Trends and research challenges in remanufacturing Int J Precis Eng Manuf - Green Technol 2016 3 129 142 10.1007/s40684-016-0016-4
75. Singhal D Tripathy S Jena SK Remanufacturing for the circular economy: Study and evaluation of critical factors Resour Conserv Recycl 2020 156 104681 10.1016/j.resconrec.2020.104681
76. Hatcher GD Ijomah WL Windmill JFC A network model to assist “design for remanufacture” integration into the design process J Clean Prod 2014 64 244 253 10.1016/j.jclepro.2013.09.021
77. Chai J, Qian Z, Wang F, Zhu J (2021) Process innovation for green product in a closed loop supply chain with remanufacturing. Ann Oper Res 1–25
78. Kurilova-Palisaitiene J Sundin E Poksinska B Remanufacturing challenges and possible lean improvements J Clean Prod 2018 172 3225 3236 10.1016/j.jclepro.2017.11.023
79. Wan Z Liu J Zhang J Nonlinear optimization to management problems of end-of-life vehicles with environmental protection awareness and damaged/aging degrees J Ind Manag Optim 2020 16 2117 2139 10.3934/jimo.2019046
80. Yang Y Hu J Liu Y Chen X Alternative selection of end-of-life vehicle management in China: A group decision-making approach based on picture hesitant fuzzy measurements J Clean Prod 2019 206 631 645 10.1016/j.jclepro.2018.09.188
81. Khan SAR Godil DI Thomas G Tanveer M Zia-Ul-haq HM Mahmood H The decision-making analysis on end-of-life vehicle recycling and remanufacturing under extended producer responsibility policy Sustain 2021 10.3390/su132011215
82. Petronijević V Ðorđdević A Stefanović M Arsovski S Krivokapić Z Mišić M Energy recovery through end-of-life vehicles recycling in developing countries Sustain 2020 12 1 26
83. Pallaro E Subramanian N Abdulrahman MD Liu C Sustainable production and consumption in the automotive sector: Integrated review framework and research directions Sustain Prod Consum 2015 4 47 61 10.1016/j.spc.2015.07.002
84. Karagoz S Aydin N Simic V End-of-life vehicle management: A comprehensive review J Mater Cycles Waste Manag 2020 22 416 442 10.1007/s10163-019-00945-y
85. Bernama (2022) Malaysia to implement end-of-life vehicle management policy by 2025. New Straits Times. https://www.nst.com.my/news/nation/2022/08/821730/malaysia-implement-end-life-vehicle-management-policy-2025. Accessed 28 Aug 2022
86. Othman N, Razali A, Chelliapan S, Mohammad R, Kamyab H (2021) A Design Framework for an Integrated End-of-Life Vehicle Waste Management System in Malaysia. Soft Comput Tech Solid Waste Wastewater Manag 305–319
87. Aishah N Ahmad N Azizul MA Sulaiman S Rhaodah A Study of End-Of Life Vehicle ( ELV ) Implementation in Malaysia J Ind Eng Innov 2020 2 1 7
| 0 | PMC9734689 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Mater Cycles Waste Manag. 2022 Dec 9;:1-19 | utf-8 | J Mater Cycles Waste Manag | 2,022 | 10.1007/s10163-022-01568-6 | oa_other |
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J Mater Cycles Waste Manag
J Mater Cycles Waste Manag
Journal of Material Cycles and Waste Management
1438-4957
1611-8227
Springer Japan Tokyo
1568
10.1007/s10163-022-01568-6
Review
End-of-life vehicles research development in Malaysia: a comprehensive review with the integrated conceptual model of innovative sustainable manufacturing elements
Chong Jia Yuik 12
http://orcid.org/0000-0001-6077-7370
Mat Saman Muhamad Zameri [email protected]
12
Ngadiman Nor Hasrul Akhmal 12
1 grid.410877.d 0000 0001 2296 1505 Faculty of Mechanical Engineering, Universiti Teknologi Malaysia, Skudai, 81310 Johor, Malaysia
2 Advanced Manufacturing Research Group, Frontier Material Research Alliance, Skudai, 81310 Johor, Malaysia
9 12 2022
119
26 3 2022
29 11 2022
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The end-of-life vehicles (ELV) issue has become an essential topic in the fast-growing automotive industry. This study utilizes comprehensive content analysis to critically review the recent ELV research developments and underpinning issues in Malaysia. Fifty relevant ELV studies in Malaysia from the year 2006 to 2021 are selected and categorized based on three innovative sub-elements (product, process, system) of sustainable manufacturing. The literature review findings show that sustainable product recovery and recyclability issues in ELV treatments are still a major concern. Current studies overlook specific research on sustainable and integrated processes for ELV treatment. There is still lack of detailed ELV implementation framework equipped with the documented procedures and appropriate industrial practices in the ELV ecosystem to optimize the ELV supply chain. ELV policy is yet to be enacted in Malaysia, and public awareness of ELV is still low. There is inadequate alignment in ELV research developments with the current National Automotive Policy 2020 in Malaysia. The proposed integrated conceptual model will provide an extensive overview for scholars, policy-makers, and ELV stakeholders to implement appropriate actions to improve present ELV businesses in line with the public readiness to enact the potential ELV directives or legislation in Malaysia.
Keywords
End-of-life vehicles
Malaysia
National Automotive Policy
Automotive
Sustainable manufacturing
Ministry of Higher Education of MalaysiaUTM vot no. R.J130000.7809.4L943 Mat Saman Muhamad Zameri
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pmcIntroduction
Resource shortages and environmental pollution have become global concerns issues. One of the critical problems the world is presently dealing with is the enormous demand for multiple resources to fulfill the consumer’s needs [1]. It is inevitable that the number of end-of-life vehicles (ELV) in the automotive industry will skyrocket in the coming decades due to the tremendous rise in vehicle ownership [2]. According to European Directive on ELV (2000/53/EC), ELV is defined as “any junk vehicle, whether or not it includes a material or object that the last owner intends to discard or does not wish to keep” [3]. If the ELV issues are not properly addressed, severe social and environmental problems will arise, resulting in huge economic losses. Therefore, the European Union (EU) enacted the ELV Directive (2000/53/EC) in 2000 to encourage the reuse and recycling of ELV components and reduce ELV waste for environmental protection. The ELV guideline mandates a recovery rate at above 95% from 1st January 2015. Europe has already had almost 20 years of experience regulating ELV activities since 2003 [4]. The ELV supply chain system in Europe has been thoroughly comprehended and well adapted to the ELV guideline. Although ELV are treated as substantial cause of environmental pollution, it also possesses high economic value due to its recoverable components and valuable recyclable materials that can be salvaged when appropriately processed in ELV treatment. With the rapid rise of ELV numbers, it was projected that more ELV legislation and policy would be introduced to increase the recovery system efficiency [5]. However, Malaysia has not enacted any ELV-related legislation because most Malaysians are still uncertain about the action taken in the ELV implementation [6]. This showed that the ELV development in Malaysia is still very slow and lags compared with other developed countries.
Automotive has become one of the essential industries in the Fourth Industrial Revolution (4IR), as per Malaysia’s National Policy on Industry 4.0 [7]. The founding of national automotive corporations like Proton in 1985 and, later, Perodua in 1993 served as a stimulus for the rapid growth of the automotive industry in Malaysia. This transforms the country from vehicle assemblers to vehicle manufacturers, thus accelerating the expansion of local automotive component manufacturers and their supply chains. The latest National Automotive Policy (NAP) or NAP 2020 anticipated that the automotive sectors will be generating RM104.2 billion for Gross Domestic Product (GDP) by 2030 [8]. The local vehicle industries are expected to recover from the impact of the Covid-19 pandemic. It is projected that the total number of new passenger and commercial vehicles registered annually in Malaysia will steadily increase from 604,200 in 2022 and hit 662,100 in 2025 [9]. However, the passenger vehicle market in Malaysia is expected to reach saturation in 2030, with 12 million active vehicles and half a million ELV to be produced in that year [10]. The NAP 2020 also aimed to reach RM 10 billion in export for remanufactured automotive parts and components by 2030 [8]. The large quantity of ELV collected is essential to provide sufficient input for secondary raw materials and promote sustainable resource circulation to minimize waste. However, the ELV management system in Malaysia is still at the beginning or infancy level, similar to other emerging nations.
Vehicle manufacturers would prefer their vehicles to last for 15 years; those vehicles which exceed this age limit are classified as ELV [11]. In contrast, most public respondents (38.9%) in Malaysia preferred the vehicle age to be limited to 10 years [12]. However, most Malaysians had driven their vehicles for more than 10 years in the actual situation [13]. The number of vehicles operating on the road between 10 and 15 years is anticipated to exceed five million [14]. This leads to the possible risks of having vehicle breakdown issues and causing safety hazards to drivers and road users. ELV in Malaysia will typically transfer to rural regions after being operated on for lengthy periods. The vehicles are deemed safe on the road if they still meet the required inspection, safety, and environmental standards. Vehicle owners in Malaysia would commonly choose to preserve their vehicles until the end of the product life cycle. Purchasing a new car is costly and not affordable for most low-income families. Many ELV are refurbished and used as “second-hand” cars in rural areas, thus drastically reducing the recycling rate for ELV. The majority of respondents agreed that the automobile industry’s commitment to achieving environmentally sustainable growth would positively impact national economic development [15]. Sadly, many owners still choose to abandon their obsolete or unwanted vehicles improperly and irresponsibly, which has caused considerable challenges in sustainable manufacturing (SM) issues such as negative environmental impact, social issues, and financial loss.
This study of ELV is limited to the Malaysian context as it is one of the fast-emerging industries and plays a critical role in sustainable development. Many studies have focused on Malaysia’s ELV management system and recovery issues. However, there is still a lack of comprehensive research to investigate the ELV progressive research development and sustainability issues to increase the recovery rate. To the best of the authors’ knowledge, no review paper has emphasized assessing the ELV research development in Malaysia. Hence, it would be worthwhile to investigate the key issues of ELV phenomena more holistically and explicitly in Malaysia to narrow the research gaps. Therefore, this study aims to identify several key subjects related to ELV development issues in Malaysia and recommend a future research direction. The review will generate some implications for academicians and practitioners to better understand the underpinning issues of ELV in Malaysia. The proposed ELV model will guide the relevant parties in establishing a strategic plan and regulatory framework to solve the ELV problems in Malaysia. The ELV stakeholders and policy makers can take effective actions to improve current ELV approaches in line with the NAP in preparation for implementing the ELV management system policy.
The entire paper is outlined as follows: Sect. 1 introduces the ELV overview in Malaysia and the problem identification. Section 2 presents the literature review of Malaysia’s NAP and ELV research development issues. This is followed by the critical analysis of the sustainability issues at the product, process, and system levels. Next, the methodological approach employed is described in Sect. 3. Section 4 explains the synthesis and discusses the results derived from the critical literature review. Further categorization of innovative SM sub-elements is developed to obtain insights into sustainable ELV development. The ELV policy and public knowledge of sustainable ELV development are discussed. Next, the integrated conceptual model of innovative SM elements is proposed. Lastly, Sect. 5 concludes the study and suggests future research directions.
Literature review of NAP and ELV research development in Malaysia
The Scopus database was searched within the ‘Article Title, Abstract, and Keywords’ using the exact phrase “end-of-life vehicle” with the selection year ranging from 2006 to 2021. It resulted in a total of 797 articles. Figure 1 depicts the number of documents published for ELV by country or territory (extracted from the Scopus database). China (127) and Japan (84) are the top two countries actively involved in ELV research and development. The Chinese government has implemented several recycling policies that have influenced the practices of the industry players, and effective subsidy policies have improved the recovery rate of ELV [16]. Both Japan and the EU are in the vanguard of ELV management and have implemented several effective policies to promote ELV recycling [17]. The market-based ELV recycling stream had been well developed in Japan before the ELV Recycling Act was enacted in 2005 to govern ELV management [18]. The ELV directive primarily leads the circular economy (CE) of vehicles in the EU with emphasis on the concept of extended producer responsibility (EPR), in which the automobile makers and importers are accountable for recycling expenses [19]. Meanwhile, Malaysia (42) is ranked as one of the top ten countries contributing considerably to ELV-related studies. This clearly showed that ELV issues are becoming a hot topic and receiving great attention from Malaysian researchers. Hence, performing a critical review on ELV, particularly in the Malaysian context, is worthwhile. However, Malaysia still does not have an ELV regulatory structure, unlike the EU or Japan [20]. This indicated most Malaysian are still not yet ready for the ELV implementation. The close collaboration of all the ELV stakeholders and the support from the government are vital to accelerating the potential ELV development in Malaysia. Malaysia should adopt feasible ELV management practices and look into the successful experiences of policy implementation in other countries. Therefore, this review study is essential to provide novel perspectives on ELV issues and serve as a reference guide for ELV players in other developing countries with similar business settings.Fig. 1 Number of ELV published documents by country or territory (extracted from Scopus database)
The NAP was initially launched in 2006 as part of the Third Industrial Masterplan (IMP3), 2006–2020 to make the automotive industry one of the major contributors to the Malaysian economy [8]. It emphasized supply chain integration and planned to equip the local automotive stakeholders to become more efficient and competitive. The second iteration of NAP was launched in 2009 to enhance capabilities and create a favorable investment environment in the local automobile industry. The third version of NAP 2014 was released in 2014, focusing on green initiatives, market expansion, and strengthening the entire automotive ecosystem through technological, human capital, and supply chain growth. The NAP 2014’s objective was to position Malaysia as a regional energy-efficient vehicle hub for energy efficient vehicles (EEV) by 2020 [8]. With the latest technological intrusions and ripples hitting global markets, Malaysia’s automotive industry was struggled and suffered a tough time since the beginning of 2020, especially facing global competitive challenges during the 4IR. Therefore, NAP 2020 (the current fourth edition) seeks to enhance Malaysia’s automotive industry to partake in the digital industrial transformation waves from 2020 to 2030. NAP 2020 is launched to boost the continuous growth of Malaysia’s automotive industry via enhancing “Connected Mobility”. The application of smart automotive, connected mobility, and integrated technology has grown tremendously in vehicle development. The Industry 4.0 elements such as autonomous robots, Big Data Analytics (BDA), Internet of Things (IoT), Artificial Intelligence (AI), and so on have mainly altered the business’s environment setting by introducing smart features to expedite the vehicle’s digital transformation. The fast emergence of Industry 4.0 development can deal with the unpredictability of end-of-life (EOL) product quality by applying smart processing and analyzing complex data to facilitate remanufacturing [14]. Figure 2 shows the evolution of NAP in Malaysia, which began with a policy-driven approach in NAP 2006 to the recent focus on vision drives policy in NAP 2020 to cope with the latest challenges in the digital industrial transformation era.Fig. 2 Evolution of NAP in Malaysia [8]
Remanufacturing is the process of restoring discarded EOL products to a “like-new” functional state with a matching warranty [21]. Remanufacturing would be a valuable recovery strategy for ELV as Malaysia aggressively adopts and embeds advanced Industry 4.0 technologies or tools in the automotive sectors [22]. The automotive industry had included remanufacturing as one of its strategic roadmaps in NAP 2014, and the scope is continually expanding in NAP 2020. The National Roadmap for Automotive Aftermarket (NRAA) has set up detailed criteria to enhance the remanufacturing standards and methodologies for domestic automotive stakeholders to make Malaysia an ASEAN automotive remanufacturing center. NRAA had included recommendations for strengthening component recycling and reuse efficiency using emerging technologies like BDA. This is in line with NAP 2020’s National Automotive Vision, which targeted to improve the local vehicles in auto part manufacturing and promote sustainable remanufacturing. An in-depth discussion on ELV began in Malaysia since 2006 by focusing on the automotive industry’s evolution plan [23]. Table 1 shows an extensive literature study conducted on ELV research development in Malaysia from the latest year (2021) to the oldest year (2006) of publication on identified subgroups: SM elements, scope of study, research method, key findings, and limitations of the study.Table 1 Critical review of ELV research development in Malaysia
No References SM elements Scope of study Research method Key findings Limitations of the study
1 [6] System ELV policy implementation Survey Public awareness and acceptability of ELV applications are relatively poor Lack of suggested solutions to improve the public perception of ELV policy implementation
2 [23] System ELV management ecosystems Observation Recommendations for ELV management ecosystems and implementation were highlighted The sustainable ecosystems for the reverse logistic supply chain in ELV are not emphasized
3 [24] System Supply chain optimization for ELV recycling Literature review The supply chain system for ELV recycling is still in its early stages This study did not evaluate the sustainable supply chain performances
4 [25] System ELV safety issue and policy Literature review ELV initiative must be started to improve the safety features plans to minimize the risk of fatal road accidents Lack of discussion on the safety standard in ELV with regard to SM elements and policy
5 [26] System Awareness and understanding of ELV implementation Survey Most respondents have low knowledge of ELV and agreed about the ELV implementation There is lack of discussion on sustainable ELV development from the other relevant industry players
6 [27] Product The potential of recycled polypropylene in ELV Laboratory testing The rheological test indicated that recycled polypropylene best operates at 190 C The sustainability of the recycled materials is still yet to be verified
7 [14] System Challenges and opportunities in Malaysian remanufacturing industries Literature review Five current challenges with mitigation strategies and two future opportunities have been identified for SM A comprehensive framework is needed to evaluate the current remanufacturing system performances
8 [22] System Supply chain disruption risks in the automotive remanufacturing industry Semi-structured interviews and site visits to 3 companies The most significant disruption element in production planning is obtaining replacement parts The identified disruption factors are not supported by the relevant literature in enhancing the sustainable supply chain management
9 [28] Product ELV waste recycling is used for sandwich panels Laboratory testing ELV waste can be recycled to develop valuable, sustainable thermal insulation The methods used are still required to be qualified to enhance sustainable performances
10 [29] Product Automotive component design for reparation using the additive manufacturing (AM) technology Industrial visit Advanced AM technology offers a great ability to reduce restrictions in manual repair and restoration of EOL cores Lack of discussion on how the design for remanufacturing automotive components can be applied with the AM technology in SM
11 [13] System ELV recovery issues and factors Survey The five factors enhancing ELV recovery are subject to dynamic changes in the aftermarket chain Lack of details discussion on the corresponding sub-factors with the sustainable ELV recovery system
12 [11] System Performance evaluation tool for ELV management system Survey The overall score of the ELV management system implementation in Malaysia is equal to 2.13, indicating an average performance level There is still a lack of critical SM elements incorporated in the performance evaluation tool on ELV management system implementation
13 [30] System ELV recovery factors Interviews The aftermarket cognitive map depicts the interconnections between the ELV recovery factors and recovery effectiveness Lack of investigation of the identified recovery factors in analyzing the significance of their relationships in the proposed model
14 [31] Product Remanufacturing quality-certifying framework for remanufactured components Literature review and survey The key factors of remanufacturing quality control were established The concern on sustainability issues is not considered when establishing the quality factors
15 [32] Process Concept of processing framework for ELV recycling Literature review The construction industry can utilize ELV waste in dismantling and shredding operations The compatibility of raw materials recovery from both industries needs to be evaluated to enhance the sustainable production metrics
16 [33] Process Remanufacturing knowledge support system to facilitate the remanufacturing process of brake callipers Interviews, observations, and documentation review (mixed method) The remanufacturing of brake callipers has been made easier using a Java-based prototype graphical user interface (GUI) assistance system The knowledge is gathered from a local company only, which lacks practical validation on standardizing the process steps
17 [10] System Estimation of the number of ELV generated in Malaysia until 2040 System dynamics modeling The passenger vehicles (PV) market is expected to approach saturation in 2024 while the number of ELV continues to rise Insufficient focus on ELV estimation with regard to the future sustainable development issues
18 [34] System Problems and gaps in the EOL remanufacturing of electronics and automobiles Literature review Addressed the study of remanufacturing in the automobile industry from the system perspective as an integrated approach Lack of focus on the remanufacturing stakeholder's analysis in dealing with the sustainable operations issues
19 [35] Product ELV recovery factors and the connection to product design strategies Literature review The initial recovery model employs a system dynamics method to link product design tools with recovery variables The proposed model is still yet to be validated in the actual scenario, and thus needs further input from the expert
20 [36] Product ELV recovery model in relation to ELV design strategies Interviews EOL design strategies that affect the effectiveness of ELV recovery were developed using system dynamics The model is still incomplete and lacks relevant data to support reflecting the actual situation
21 [37] Product Quality assurance of remanufactured components in ELV Literature review The quality of the remanufactured ELV components in terms of quality assurance and quality after business is vital The essence of quality of the remanufactured ELV components is not shown via its impact on ELV performances
22 [12] System ELV policy and public perception Database review The government still encounters several challenges when implementing the ELV policy in Malaysia The proper ELV plan needs to be accomplished with sustainable practices in the automotive ecosystem
23 [38] System Key success factors for ELV management system Survey The eight success factors and 33 underlying items are identified and discussed The 33 underlying items in these eight key success factors are not explained in this study
24 [39] System Sustainable ELV management Survey A multi-criteria decision-making method can be useful for choosing criteria and evaluating alternatives Future studies can explore the factors that affect the criteria selection and add in more critical criteria from other sources in this field
25 [40] System Sustainable ELV management Survey The eight criteria are consistent with the requirements of selecting sustainable ELV management alternatives Lack of description of the criteria and dimensions for sustainable alternatives evaluation
26 [41] System Public perception of ELV recovery in Japan and Malaysia Survey More than half of respondents in both countries were doubtful about their readiness to engage in ELV endeavors Lack of attention to economic and environmental elements to improve ELV recovery issues
27 [42] Product ELV conceptual design Case study (brake calliper) An evaluation of the product upgradability at the conceptual design stage using Quality Function Deployment (QFD) application The operational performances of the upgraded parts toward SM can be further improved via the continuous product life-cycle assessment
28 [15] System Automotive remanufacturing roadmap and overview of actual implementation Survey The research and development in automotive remanufacturing is still at the very low level The strategic application of remanufacturing concept toward sustainable automotive manufacturing in mitigating the current challenges still needs to be developed
29 [43] System Success factors in ELV management system Literature review A set of preliminary factors were identified and categorized in the survey instrument The survey instrument design is yet to be validated by experts to go for the pilot study
30 [44] System ELV management and future transformation Literature review, discussion with experts and academician Sustainable ELV management is needed to make standard legislation and directive for future transformation Lack of in-depth discussions on the enablers and inhibitors of the sustainable ELV management directive
31 [45] System ELV management system’s practices Literature review ELV are presently handled in three ways: operated on the road, left abandoned, and disposed of in the landfills The study did not discuss the factors that affect the sustainable ELV management system and practices
32 [46] System Public community knowledge on the reuse of ELV Survey The knowledge of ELV in the public community needs to be enhanced Lack of emphasizing the challenges and implications of ELV reuse in sustainable development issues
33 [47] System Framework for ELV recycling system in Malaysia Interviews A comprehensive framework adapted from the ELV management success in other countries The framework focused on the overview of ELV system process flow but did not look into the perspective of the sustainable value chain
34 [48] Product ELV design process and management Literature review Designs for recycling, recycling technology, and ELV management were reviewed Lack of discussion on the relationship between the ELV design process and the management system
35 [49] Product Optimization of the disassembly sequence Case example The genetically optimized disassembly sequence is critical to enhancing the product reusability Lack of discussion on the critical factors that impact the disassembly sequence
36 [50] System Conceptual model of the automotive ecosystem in Malaysia Focus group discussions and literature review A conceptual model of the domestic automotive ecosystem and mapping of the NAP 2009 measures was developed in the study The conceptual model needs to be practically validated by the car users and industry to improve the feasibility of NAP measures
37 [51] Product Design for ELV value framework Case study The presented framework consists of 4 main steps for vehicle design and development The guideline for vehicle design and development process needs to be aligned with the legislation
38 [52] Product A framework of integrated recyclability tools for automobile design Literature review A framework of integrated recyclability tools has been introduced to improve the recyclability The framework focuses on the design environment, the economy and social dimensions that can be explored for further enhancement
39 [53] Process Remanufacturing practices in the automotive industry Survey It is needed to validate the influence of remanufacturing on product quality Lack of discussion on the standard remanufacturing practices in dealing with the sustainable development issues
40 [54] Product Disassemblability of ELV Literature review To identify the optimum stage of ELV disassembly for recovering all commercially viable components The factors that will be affecting the evaluation of disassemblability selection are not discussed in detail
41 [55] Product Optimization of reusability in automotive components Case study Reliability, material, and AI are vital factors in optimizing the vehicle reuse concept The proposed artificial neural network model needs to be tested in a robust environment for SM
42 [56] Product Disassembly for reuse in ELV Survey Optimization of disassembly for reuse in the local industry can improve the recoverability of ELV’s components There are three respondents involved in this survey, which is a lack of generalizations
43 [57] Product Design framework for ELV recovery Survey Optimization of ELV disassembly sequence using genetic algorithm approach The proposed model is still developing; more real-life case validation is needed
44 [58] Product ELV disassemblability and recyclability Software analysis Decision-making software to evaluate the disassemblability of design and examine their recyclability The critical factors that will be affecting the disassembly cost and time need to be thoroughly assessed to improve the economic efficiency
45 [59] Product Automotive component reuse Interviews The identified organizations have never reused the automobile components in newly manufactured vehicles Factors that affect the sustainable development for products recovery can be explored from the supply chain and demand perspectives
46 [60] Product The evaluation methods of disassemblability Literature review The recycling and disassembly elements must be examined thoroughly in the ELV’s product design process Lack of detailed discussion on the integrated design for disassembly with its performance metrics evaluation
47 [61] Product A tool for Design for End-of-Life Value Software prototype (case study) Proposed the two primary methodologies: recycling function deployment and value analysis When performing the value analysis assessment, there is a lack of involvement from the customer’s perspective in value-added creation
48 [62] Product The application of AI to optimize the reuse of automotive components Analysis and modelling The artificial neural networks (ANNs) and genetic algorithms can be adopted to solve the design for reuse components The sustainability assessment needs to be performed to optimize reuse components' durability and reliability
49 [63] Product ELV recovery: process, impact, and research direction Literature review The research framework for the ELV recovery concept was proposed with a conceptual approach The concepts of sustainable development and ELV recovery needs to be enhanced to extend the life cycles of the vehicles
50 [64] Product The key element to the vehicle design process Literature review Four aspects of the vehicle design process had been developed based on the current situation in ELV Directive Other key elements need to be identified to meet the latest industry requirement for SM in ELV development
ELV sustainability issues at the product level
The evaluation of the rheological properties of recycled polypropylene with virgin polypropylene and a product that incorporates recycled polypropylene from ELV are developed [27]; however, the sustainability of the recycled materials is still yet to be verified. A new way to produce thermal insulation sandwich panels is provided using ELV waste from headlamps and seats [28]. The key performances of the thermal insulation sandwich panels in terms of social, economic, and environmental need to be assessed for broader industry application. A framework is proposed as a benchmarking tool to certify the quality assurance of remanufactured components by issuing aftermarket warranties [31]. This framework mainly targeted to certify the remanufactured components with evaluated relevant quality factors; however, the concern on sustainability is still not emphasized.The quality of remanufactured ELV components in emerging nations determined that quality assurance and quality certification aftermarket services are the most notable findings in Malaysia [37]; however, the quality of remanufactured ELV components can be further assessed to meet the customer acceptance to achieve a higher level of assurance in the sustainable remanufacturing industry. The artificial neural network is applied to increase the reliability of the proposed reuse component and material selection as optimization tools to improve the stress analysis of a body-in-white car door [55]; however, the critical performances of the automotive components for reuse need to be assessed to incorporate the SM elements.
An optimization model is developed for disassembly sequences of an engine block using the genetic algorithms method, which can achieve the minimum disassembly time [49]; however, this dissambly process's efficiency was not quantified in terms of actual cost saving or economic benefits. A study of numerous disassemblability approaches for ELV is presented to determine the optimal stage of disassembly to enhance the product recovery [54]; however, the factors that will affect the evaluation of disassemblability selection and its impact on the disassembled product’s quality are not discussed in details. The optimal disassembly stage is vital and rigorous disassembly for reuse to increase product recovery in the Malaysian automobile sector [56]. The results are only obtained from three local automotive component manufacturers in Malaysia, which lacks generalization to other ELV stakeholders in the automotive industry. The design framework using a genetic algorithm method is developed to evaluate EOL product disassembly by adopting the principles and guidelines of design for disasembly into design [57]; however, the proposed model is still in the development stage, and more real-life studies need to perform to verify it’s applicability. A decision-making software is developed to assess the disassemblability of ELV component’s designs, determine their eligibility for recycling, and examine their recyclability [58]. The various critical factors affecting the disassembly cost and time need to be thoroughly assessed to improve economic efficiency. A system dynamics method is proposed to connect the product design approaches with other recovery factors to deal with complicated challenges in the automotive industry [35]; however, the proposed method is still yet to be validated in the actual scenario; thus, this requires further input from industry expert for enhancement.
The disassemblability evaluation methods and functional system requirements are analyzed to assess the impact on various design aspects of automotive components [60]. However, there is still lack of detailed discussion on the integrated product design for disassembly with performance metrics evaluation in the later disassembly stage to enhance the overall design strategy and concept in ELV. The pre-assessment of a chosen automotive component (brake calliper) is conducted to evaluate its conceptual design with the intention of upgradeability using the QFD application [42]. The operational performances of the upgraded parts toward SM can be further improved via the continuous product life-cycle assessment in the actual application stage. An ELV design process and management review were performed to improve the product's recyclability [48]. There is lack of description of the relationship between ELV design protocols and management systems to improve recycling efficiency. The design for the EOL value framework is developed to provide the design evaluation for the vehicle’s recyclability in the early design stage [51]. The design guideline for recycling in ELV and the corresponding development process implementation need to be aligned with the established legislation of the EU Directive on ELV. A framework for an integrated recyclability tool is presented to enhance automotive design and development in product recyclability [52]. The framework focuses on the design environment part; it is suggested to incorporate the social and economic dimensions to improve the recyclability decisions.
A tool for design for the environment is proposed for EOL value and recyclability assessment in the automotive industry [61]. The value analysis highlighted mainly emphasizes the economic parameters but lacks involvement from the customer’s perspective in value-added creation for economic sustainability. The model is developed to assess the design for automotive components' reuse using AI methods at the lowest costs [62]. The sustainability assessment needs to optimize reused components' durability and reliability. The reuse of automotive components is not adopted by original equipment manufacturers (OEM) on new vehicles but is only used for parts replacement [59]. Factors that affect the adoption of automotive component reuse on sustainable development for product recovery can be explored from the supply chain perspective and demand. A research framework is presented for the ELV recovery concept that incorporates recyclability concerns throughout the product design process [63]. The concepts of sustainable development and ELV recovery in the vehicle development process phase need to be further enhanced to facilitate the automotive manufacturing process. Vehicle designers must address four key EOL requirements during vehicle design and development: design aspects, materials factors, cost, and directive requirements [64]. It is important to explore other critical elements to improve the vehicle design process based on the current ELV development in meeting the industry requirement for SM. The design guidelines for repair and restoration utilizing AM technology for product life-cycle extension are highlighted [29]. The utilization of advanced product design approaches to address the common failure modes in automotive components can be further improved to achieve a higher level of sustainable product development. A preliminary model is developed to assess the effectiveness of ELV recovery in reacting to dynamic changes in the automotive industry [36]. The authors highlighted that this model is still incomplete and lacks relevant data to support the effectiveness of EOL product design strategies.
ELV sustainability issues at the process level
A Java-based prototype GUI knowledge-based system is designed to aid the step-by-step remanufacturing process using brake callipers as a case study [33]. However, the knowledge is only gathered from one local company, which still lacks practical validation on standardizing the process steps in enhancing remanufacturing efficiency. The majority of the respondents from the survey indicated that a comprehensive investigation is needed to evaluate the influence of the remanufacturing process on product quality [53]; however, there is lack of discussion on the standard remanufacturing practices in dealing with sustainable development issues. An integrated processing framework for utilizing ELV waste is proposed for the automotive and construction industries [32]. However, the compatibility of raw materials recovery from both industries needs to be evaluated to enhance sustainable production in the ELV processing business.
ELV sustainability issues at the system level
The research and development of the actual implementation of automotive remanufacturing in Malaysia are still in the infancy stage [15]. The strategic application of remanufacturing concept toward sustainable automotive manufacturing in mitigating the current challenges still needs to be developed. The various industry stakeholders' ELV management practices are examined based on their knowledge and involvement in this field [23]. The sustainable ecosystems for the reverse logistic supply chain in ELV were not emphasized as part of this study's proposed ELV Recycling Zone implementation. The factors that improve ELV recovery in the aftermarket chain are studied [13]. However, there is still lack of detail discussion on the corresponding sub-factors with the sustainable ELV recovery system. A comprehensive performance evaluation method is developed based on the analytic hierarchy process (AHP) to determine the eight key critical success factors for continuously improving Malaysian ELV management systems [11]. There is still lack of essential elements of SM incorporated in the performance evaluation tool on ELV management system implementation. The ELV recovery model is developed based on the identified factors that affect the ELV recovery effectiveness in Malaysia from the various perspectives of five key stakeholders [30]. However, there is still lack of investigation of the identified recovery factors in analyzing the significance of their relationships in the proposed model.
An integrated model is developed to assess sustainable alternatives for effective ELV management [40]. However, this model still lacks a detailed description of the criteria and dimensions used for sustainable alternatives evaluation. A model is developed to choose the sustainable dimensions and criteria for assessing the best compromise ELV’s management alternative [39]. Future studies can explore the influential factors affecting criteria selection and add more critical criteria from other sources in this field. A framework containing the factors and items is created for a proper ELV management system in Malaysia [38]; however, this study does not explain the 33 underlying items in these eight key success factors. A survey instrument is designed to assess the success factors in adopting the ELV management system in Malaysia [43]. However, this survey instrument developed is yet to be validated by the experts for the pilot study. The present situation of ELV management is analyzed to promote sustainable growth in ELV for future transformation in Malaysia [44]. However, there is a lack of in-depth discussions on the driving forces and critical inhibitors that can impact the sustainability consideration of the ELV management directive. There is an urgent need for a proper ELV management system to cope with the harmful impacts caused by the ELV issues in Malaysia [45]. However, the study did not discuss the factors affecting the sustainable ELV management system and practices. A framework for the ELV recycling system is developed to highlight the current practices being applied in Malaysia and emphasize the coordination of relevant ELV stakeholders [47]. The proposed framework focused on the overview of ELV system process flow but did not specifically look into a sustainable value chain perspective.
Five main issues are identified in the closed-loop supply chain optimization to address the ELV recycling problems [24]. However, this study did not evaluate these issues' sustainable supply chain performances. The disruptions and sub-factors that affect the supply chain system risks in the automotive remanufacturing industry were analyzed [22]. However, the relevant literature did not support the identified disruption factors in enhancing sustainable supply chain management. There are relatively few models and research focused on automobile remanufacturing operations topics at the system level [34]. Four key issues have been discussed from the findings; however, there is still lack of focus on the remanufacturing stakeholder's analysis in dealing with the sustainable operations issues. The public knowledge and acceptability of ELV adoption in Malaysia are fairly poor [6]. However, there is still lack of focus on suggested solutions to improve the public perception of ELV policy implementation. The public community has a low knowledge of ELV, but the majority have shown positive responses about the ELV implementation in Malaysia [26]. However, there is lack of discussion on sustainable ELV development from the other relevant industry players. ELV initiative must be started to improve the safety features plans to minimize the risk of fatal road accidents [25]; however, there is lack of discussion on the safety standard in ELV with regards to SM elements and policy.
Five challenges with mitigation strategies and two future opportunities have been identified for SM in Malaysia's remanufacturing industries [14]. A comprehensive framework is needed to evaluate the current remanufacturing system performances in terms of SM approach. The government still encounters several challenges when implementing the ELV policy in Malaysia [12]. The proper ELV plan needs to be accomplished with sustainable practices in the automotive ecosystem. More than half of respondents in Japan and Malaysia were doubtful about their readiness to engage in ELV endeavors due to the uncertainty of the ELV concept [41]. However, this study mainly emphasizes the socio-technical perspective but still lacks attention to the economy and environmental elements to improve ELV recovery issues. Public community knowledge of ELV reuse has to be improved to enhance sustainable automotive growth in Malaysia [46]. However, the concept of reuse on ELV can be further explained by emphasizing the challenges and implications of sustainable development issues. A conceptual model of the domestic automotive ecosystem and mapping of the NAP 2009 measures was developed [50]. However, the conceptual model must be practically validated by car users and the industry to improve the feasibility of NAP measures. The PV market in Malaysia is expected to approach saturation in 2024 while the number of ELV continues to rise [10]. However, there is still a lack of discussion for the ELV estimation regarding sustainable development issues and recommendations for future action plans.
Methodology
ELV research development and the implementation of ELV policy are important to develop the strategic roadmap to support the NAP 2020. This study started with the literature review on the overview of the NAP revolution and ELV research development in Malaysia. Since this research aims to study the ELV development issues in Malaysia; Therefore, the search for documents that cover the scopes of ELV and Malaysia was selected as the data collection method. To limit the number of papers selected for review and to identify the most relevant articles, the following search criteria were applied:The keywords used to search the relevant publications for review were the combination of “end-of-life vehicle” OR “ELV” AND “Malaysia” using the “OR” / “AND” boolean operators.
The papers were limited to peer-reviewed English-language publications only.
The data range was chosen from publication years from 2006 to 2021 (excluding the latest year in 2022).
In the first stage of paper collection via the Google Scholar (https://scholar.google.com/) database, 1730 papers appeared in the search results. The identification and screening of the suitable papers were conducted using the steps explained as follows:The document’s ‘title, abstract, and keywords’ were screened to decide whether it is relevant to the ELV research subjects and suits the scope of review during the initial screening.
Papers that are mismatched or not related to the field of study in ELV, duplication and do not fulfill the scope of review criteria were removed.
Subsequently, the suitable papers found were read through the entire content to check whether they had included Malaysia and ELV as key focus studies in fulfiling the research scope for further review.
After the screening process in Google Scholar, 43 papers were finally selected for detailed reading and thoroughly reviewed. Next, the same steps were adopted for documents searched within ‘All fields’ in the Scopus (www.scopus.com) database, generating 374 papers in the search results. After the screening process, another seven pertinent documents were chosen for further review. In addition, literature searched within ‘All fields’ in the Web of Science (https://clarivate.com/webofsciencegroup/solutions/web-of-science/) database was performed by applying the above steps, generating 240 papers. After the screening process, 15 suitable papers were found; however, these papers were duplicated with the previously chosen papers in Google Scholar or Scopus. Finally, altogether 50 papers were selected and reviewed in this study, as listed in Table 1.
Content analysis facilitates observational research by allowing researchers to evaluate the symbolic content of all sorts of recorded documents in a systematic manner [65]. A structured literature review was conducted using the content analysis method on these 50 papers to discover the critical issues and research gaps associated with ELV development in Malaysia. The sustainable topics for these selected papers were further grouped and assessed based on the three innovative SM (product, process, and system) sub-elements. This is followed by a discussion of the ELV policy and public knowledge of ELV development for SM in Malaysia. Lastly, the integrated conceptual model was proposed as guidance to mitigate the ELV development issues in Malaysia.
Results and discussion
The necessity for SM in ELV has been prompted by scarce resource supply and the adverse environmental and socioeconomic repercussions of traditional manufacturing. Integrating SM elements: products, processes, and systems in ELV sustainability are critical for resource conservation. SM would require innovation at all stages of the product, process, and system levels in manufacturing by undergoing multiple life cycles to enhance the sustainable value chain [66]. A shared responsibility framework is proposed to establish a business model with a stakeholder engagement structure to strengthen the sustainability of ELV management and material recovery in India [1]. A sustainable ELV management using a closed-loop supply chain (CLSC) strategy with the CE model is developed to deal with ELV issues and reduce waste in Qatar [67]. A systematic review is presented to identify the factors that will enhance the automotive supply chain’s sustainability and improve the sustainable management performance of the Chinese ELV recycling industry [68]. Turkish automakers are accountable for the free collection of ELV from customers to rehabilitate old components in the industry under ELV regulations; therefore, a CLSC network design is created to handle the material flow of ELV [69].
In Malaysia, the first introduction of the NAP 2006 and the hot debate about ELV have been underway since 2006. However, the sustainable awareness of ELV recycling among Malaysia's public and industrial players is still low. ELV waste management is poorly managed in Malaysia due to the weak regulatory framework [44]. Therefore, there is a need for Malaysian manufacturers and government agencies to focus on design for remanufacturing in automotive and promote the growth of automotive research and technology to achieve policy optimization [15]. Malaysia can review the ELV recycling strategies and adopt the best practices of SM from those countries that have achieved great success in this area prior to developing its framework for enacting the ELV policy. Table 2 shows the literature studies of ELV development in Malaysia that are classified and adapted based on the three innovative SM elements [66]. These innovative SM sub-elements are synthesized based on the nature and aspects of the literature’s content to explore various insights of SM in ELV development. The proper classification of sub-elements in SM is essential for the policy makers and industrial players to work on effective ELV strategy planning and implementation framework to deal with the underlying issues of ELV in Malaysia.Table 2 Classification of innovative SM sub-elements for ELV development in Malaysia (adapted from [66])
SM elements Category of sub-elements in SM References
Product Sustainable materials/components for products [27]; [28]; [31]; [37]
Advanced product design [29]; [55]; [62]
Effective product disassembly [49]; [54]; [56]; [57]; [58]; [60]
Design for reuse/recycling/remanufacturing/recovery [42]; [51]; [48]; [52]; [59]; [61]; [63]; [64]; [35]; [36]
Process Sustainable processes [53]
Integrated processes [32]; [33]
System Sustainable management systems [6]; [23]; [25]; [26]; [14]; [13]; [11]; [30]; [12]; [38]; [39]; [40]; [41]; [15]; [43]; [44]; [45]; [46]; [47]; [50]; [34]; [10]
Supply chain optimization/integration [24]; [22]
Product innovation in sustainable ELV development
ELV recycling companies in emerging and developing countries confront major challenges in the systemic recycling of ELV in enabling the recovery of materials and parts or components to maximize economic advantages according to environmental standards [70]. The major hurdle to optimizing part remanufacturing could be affected if the returning and processing of components or materials cannot be established effectively for SM. Therefore, selecting sustainable materials or components from ELV is vital to producing value-added products. The critical literature review shows that a thorough quality assessment of the sustainable remanufactured or recycled ELV components is still lacking. The product quality of automotive’s components remanufactured product, which fulfill the practical criteria, is a notable indicator of success in remanufacturing [71]. The remanufacturing company must emphasize the essence of quality management in developing ELV remanufactured products. Developing countries like Malaysia would need knowledge-based assistance and strong technical know-how to encourage remanufacturing while ensuring that the components remain in high-quality performance [33]. Therefore, the detailed assessment of the compatible material selection should be well incorporated into the product design and development stage to optimize the automotive vehicle recyclability in the downstream manufacturing processes to fulfill the customer requirements.
The advanced product design by applying the latest Industry 4.0 technological tools is receiving great attention from industry practitioners to improve the product’s efficiency and competency level. The ELV part design for recycling or remanufacturing needs to be integrated with the feasible Industry 4.0 technological elements and tools application in technical data sharing. This can facilitate the effective connection with the downstream processes to improve the product’s quality and circularity. Employing modern and emerging digital technologies to strengthen relationships between product manufacturers, users, and remanufacturers are critical to establishing sustainable remanufacturing development in Industry 4.0 [72]. However, data about remanufacturing and product design-process systems are currently proprietary, and technical know-how is shared sparingly among the industry players in the remanufacturing and aftermarket industry. Therefore, it is critical to highlight how the Industry 4.0 technological enablers and the smart remanufacturing tools can trace the past data of incoming core or EOL products from the sharing system to optimize its remanufacturability.
Effective product disassembly involves adopting feasible disassembly methods and process sequences to deal with the returned product’s complexity challenges. Disassembly techniques are one of the crucial factors in the Chinese ELV recycling business [68]. An appropriate disassembly sequence of ELV that combines the destructive disassembly and non-destructive approach is developed to provide a better guide for ELV recycling economic growth via the cost–benefit analysis [73]. The most significant factors in the development of the recycling industry are regulations on automation factories, disassembly procedures, and value mining [68]. The effective recycling and disassembly elements must be well considered when implementing the ELV concept in the product design stage, especially with proper disassembly evaluation [60]. However, the existing research focusing on effective product disassembly to enhance the ELV recovery rate in Malaysia is still limited to the past 10 years. Product disassembly is still largely dependent on manual labor jobs. The application of human–robot collaboration or human–machine interaction can solve complicated tasks in product disassembly operations. Therefore, there is a strong need to integrate Industry 4.0 technological tools and techniques to improve the efficiency of ELV product disassembly process steps.
The design for reuse/recycling/remanufacturing/recovery concentrates on sustainable techniques application to improve the product life-cycle development in the subsequent manufacturing stage. The challenges that arise during the remanufacturing process could be minimized if good decisions are made during the design phase [74]. The remanufacturing applications could only be advantageous and competitive if the products are intentionally made or designed for remanufacturing in the first place [75]. Therefore, the ELV treatment should focus on product optimization by integrating the design for recovery techniques into the vehicle manufacturing process. The significant external and internal operational factors affecting design for remanufacturing integration are management engagement and relationships between OEM and engineers in the product design phase [76]. From the literature review, the product recovery or recyclability issues for SM in ELV treatments are still a major concern. Design aspects of ELV components should consider the customer perspective in product specification requirements and perform stakeholder analysis to enhance the product life cycle for sustainable value creation. The vehicle design and development guidelines can incorporate green manufacturing elements to meet the latest ELV industry requirements and practices in SM.
Process innovation in sustainable ELV development
Adopting innovative approaches in green product remanufacturing can greatly increase sustainable process performances while raising the manufacturer’s recovery rate in a CLSC [77]. The product cost variations are directly connected to the process uncertainty, particularly in the current dynamic manufacturing environment in cores collection [78]. The essential factors in increasing ELV recovery efficiency are advancing the processing technologies, optimal government subsidies, and public awareness of environmental protection [79]. However, it is noticeable that there is still limited study on implementing standard ELV practices and assessing technical competency for specific ELV treatment processes in Malaysia. The systematic procedures and feasible techniques need to apply to existing ELV remanufacturing or recycling to evaluate the key process performance indicators. The integrated proposing framework developed to recycle the ELV for building products is an innovative approach for ELV waste management across various industries [32]. A feasible approach for decreasing the ELV disposal issues and minimizing the raw material utilization can promote the ELV process development in line with the applicable regulations in Malaysia.
System innovation in sustainable ELV development
ELV management is critical for resource circularity, environmental preservation, and CE development [80]. From the critical literature analysis, Malaysia’s reverse logistic network system still faces difficulties in dealing with sustainable operations issues. There is lack of systematic ELV management in Malaysia, and very few ELV are transported for recycling activities. A shared responsibility-based framework is developed to investigate and create a business concept with the key stakeholder engagement strategy to enhance India’s ELV management sustainability [1]. A dual-cycle ELV recycling and remanufacturing system are created to describe the collaborative relationship among the ELV stakeholders under the extended producer responsibility policy [81]. It is critical to note that any recycling system needs to tailor to each country’s specific needs and environments [82]. Therefore, there is a strong need to develop an implementation framework for enhancing ELV development toward SM in Malaysia. The roles of ELV interested parties involved and influenced in the sustainable management system should be thoroughly assessed via the stakeholder’s analysis to formulate the strategy roadmap and enhance the cooperation to achieve a win–win situation.
A critical assessment of existing literature reveals that several studies have been conducted primarily to address ELV recovery management systems in Malaysia. However, none of these studies presented a practical implementation framework to optimize and streamline the end-to-end solutions of ELV in the supply chain network system. The studies on the supply chain as a whole system in the automotive sector are still in the early stage [83]. Several studies have proposed valuable strategies to deal with ELV management supply chain challenges [84]. However, uncertainties in managing the consistent ELV core return are still the most prominent concern for industry stakeholders in Malaysia. There is no alignment on the standardized procedures established for ELV supply chain optimization to demonstrate the best industrial practices in the automotive sectors. Therefore, it is essential to thoroughly understand Malaysia’s existing ELV recycling supply chain and demand, including its underlying issues and disruption risks. The Malaysian government is presently studying a suitable approach to implement an ELV management policy and is looking at establishing an ELV framework by 2025 [85]. Therefore, the future proposal of a sustainable ELV implementation framework to streamline the reverse ELV value chain network through recycling and remanufacturing is highly required to resolve the ELV issues and optimize the automotive components' reusability.
ELV policy and public knowledge in sustainable ELV development
ELV policy and public awareness are essential in the ELV recovery management system. The public survey results showed that most respondents still lack exposure to ELV laws and are unwilling to pay more on disposal fees [6]. Most survey respondents agreed with the concept of a vehicle age restriction regulation based on their economic stability (income level and car status) and vehicle age factor [12]. The vehicle owners’ attitudes about vehicle maintenance are likely impacted by the financial situation and regional factors (urban or rural) in mapping to the NAP 2009 measure No. 12 [50]. The Malaysian government still confronts some hurdles in adopting the ELV policy in the country. More than half of respondents in Japan and Malaysia communities were doubtful about their desire to engage in ELV activities, indicating a lot of scepticism about the concept of ELV in reuse and remanufacturing [41]. Close cooperation between government and industry is vital in increasing public knowledge and understanding to ensure the compelling implementation journey of ELV recovery. Most public communities had little awareness about ELV; however, most respondents agreed that ELV implementation should be carried out in Malaysia [26]. The sustainable growth of remanufacturing businesses in Malaysia can encourage other emerging economies with similar business prospects to adopt SM practices [14]. However, the ELV policy is still not in place in Malaysia’s automotive environment [86]. The public acceptance of ELV policy enactment from a vehicle safety viewpoint is essential, considering the consumers’ economic implications [25]. Therefore, the implementation of the ELV policy in Malaysia needs to be thoroughly explored to assure that the public can buy-in early and effectively embrace it.
Integrated conceptual model of innovative SM elements
ELV-related laws enacted in other countries were studied, and several recommendations were made to deploy ELV policy in Malaysia based on regulation and public perception [6]. This indicated that the public’s voice and readiness are essential to the government when conducting the study to implement ELV policy and regulations to address the ELV issues. A preliminary review on implementing an efficient CLSC system for ELV recycling suggested that future similar research can focus explicitly on the ELV remanufacturing aspects from different viewpoints in Malaysia in line with the NRP [24]. Manufacturers are permitted to use whichever techniques they like due to the lack of a clearly defined ELV policy [25]. Hence, the standard remanufacturing process as part of ELV recovery practice in Malaysia could not be immediately put into progressive action. The public still perceives that remanufacturing is a type of reuse that does not create value-added operations and has poor profit returns. The government and industry should develop and implement more ELV campaigns related to reuse to increase public knowledge, education, and in-depth understanding of this subject [87].
The sustainable awareness and ELV life-cycle thinking among the public and industrial players are still low. The essential factors to increase the ELV recovery efficiency are advancing processing technologies, optimizing government subsidies, and improving public awareness of environmental protection [79]. The public knowledge and understanding of ELV are critical in implementing the ELV policy for SM in the automotive industry. Therefore, the conceptual model of innovative SM elements with integrated ELV policy and public knowledge was proposed in this study to enhance sustainable ELV implementation in Malaysia, as shown in Fig. 3. From the critical literature analysis, these three SM elements were examined independently rather than as a whole in previous ELV studies and without proper synchronization. Past studies in the automotive industry addressed the sustainable ELV research development issues; however, there is a missing link and lack of proper synchronization with the established NAP in Malaysia. This situation is understandable as the NAP 2020 has no mention of the mandated ELV policy. Therefore, the implementation of relevant ELV regulatory framework and future roadmap should be seriously considered. This conceptual model of integrated SM elements embedded with the ELV policy and public knowledge elements could guide the ELV stakeholders in planning the strategic directions and actions for future industrial applications in line with the latest NAP.Fig. 3 Conceptual model of SM elements with integrated ELV policy and public knowledge
Conclusion
The ELV issue is becoming a hot topic in the Malaysian automotive industry. This study critically assesses ELV research development issues to identify the research gaps. By performing a thorough content analysis based on an extensive literature evaluation of 50 selected papers, this study underlined how Malaysian ELV subjects developed from 2006 to 2021, highlighting the underpinning issues regarding SM. According to the critical review findings, several prospects of key research interests were recommended to improve ELV management in Malaysia as follows:• The product recovery for SM in ELV treatments are still a major concern. Design aspects of ELV components should consider the customer perspective in product specification requirements and perform stakeholder analysis to enhance the product life cycle for sustainable value creation.
• The specific study of sustainable and integrated processes in ELV treatment is mainly overlooked in the current research. Future studies need to improve the performance metric in ELV remanufacturing process steps.
• There is still a lack of a detailed ELV implementation framework equipped with documented procedures and appropriate industrial practices in the ELV ecosystem to optimize the ELV supply chain. A sustainable implementation framework is urgently needed to standardize and create the reverse ELV value chain network.
• ELV policy is yet to be enacted in Malaysia, and public awareness of ELV is still deficient. Future studies can focus on testing the interrelationship of ELV policy and public knowledge by identifying the critical moderating/mediating variables to evaluate their impact on the ELV sustainable management implementation.
• Previous studies in the automobile sector examined the difficulties of sustainable ELV research development; nevertheless, there is a weak connection and a lack of adequate alignment with the current NAP in Malaysia. The implementation of relevant ELV regulatory framework and future roadmap should be seriously considered.
The proposed conceptual model, which integrates the three critical sub-elements of SM (product, process, and system) with effective ELV policy and strong public knowledge, will facilitate ELV implementation in the Malaysian automotive industry in line with NAP. This critical review provides scholars, industry players, or policy makers interested in the ELV field with references and valuable insights into designing a sustainable implementation framework or policy for Malaysia’s automotive ecosystem. Other developing countries can benefit by identifying the current state of ELV management practices and adopting the proposed conceptual model to deploy the right strategy and mitigate the underpinning ELV issues. The key results will support the ELV stakeholders in implementing appropriate actions to improve their present ELV businesses following the latest NAP 2020 in readiness to enact potential ELV directives or legislation in Malaysia. In the early phases of attempting to adopt ELV in Malaysia, firms will benefit from the study’s insights to enhance SM applications and navigate the proper action plan. The present research’s article selection is confined to the Google Scholar, Scopus and Web of Science databases, which is a limitation of this study. This study does not include other related papers beyond these databases. A detailed analysis could be conducted by expanding the large sample size of articles and having documents from various sources to improve the reliability of the findings. An in-depth study is needed to establish a comprehensive SM framework for smooth ELV management system implementation with the integration of Industry 4.0’s technological elements and aligned with the Malaysian government’s policy. Since the global topic of electric vehicle (EV) development is gaining popularity and has been emphasized in the NAP 2020, it is recommended that future EOL management can focus explicitly on this area from the SM perspective. Future real-life case studies can be conducted to verify the feasibility of this proposed integrated conceptual model by including the critical success factors and examining their inter-relationships to sustainable ELV development performances.
Acknowledgements
The research has been carried out under Konsortium Kecemerlangan Penyelidikan (JPT(BKPI)1000/016/018/25(72)) provided by the Ministry of Higher Education of Malaysia (UTM vot no. R.J130000.7809.4L943).
Funding
This study was supported by Ministry of Higher Education of Malaysia, UTM vot no. R.J130000.7809.4L943, Muhamad Zameri Mat Saman.
Data availability
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Arora N Bakshi SK Bhattacharjya S Framework for sustainable management of end-of-life vehicles management in India J Mater Cycles Waste Manag 2019 21 79 97 10.1007/s10163-018-0771-0
2. Wang Z Hao H Gao F Zhang Q Zhang J Zhou Y Multi-attribute decision making on reverse logistics based on DEA-TOPSIS: A study of the Shanghai end-of-life vehicles industry J Clean Prod 2019 214 730 737 10.1016/j.jclepro.2018.12.329
3. European Parliament and Council (2000) Directive 2000/53/EC on end-of-life vehicles. Off J Eur Union L:34–42
4. Li CJ Yang WX Liu XD Wang YM Feng SH He YA Research on vehicle recycling based on ELV Directive IOP Conf Ser Earth Environ Sci 2021 10.1088/1755-1315/687/1/012196
5. Li J Yu K Gao P Recycling and pollution control of the end of life vehicles in China J Mater Cycles Waste Manag 2014 16 31 38 10.1007/s10163-013-0226-6
6. Harun Z Wan Mustafa WMS Abd Wahab D Abu Mansor MR Saibani N Ismail R Mohd Ali H Hashim NA Mohd Paisal SM An analysis of end-of-life vehicle policy implementation in Malaysia from the perspectives of laws and public perception J Kejuruter 2021 33 695 703
7. MITI (2018) Industry 4WRD: National Policy on Industry 4.0. Minist Int Trade Ind. https://www.miti.gov.my/miti/resources/National Policy on Industry 4.0/Industry4WRD_Final.pdf. Accessed 26 July 2021
8. MITI (2020) National Automotive Policy (NAP) 2020. Minist Int Trade Ind. https://www.miti.gov.my/miti/resources/NAP%202020/NAP2020_Booklet.pdf. Accessed 26 July 2021
9. MAA (2021) Vehicle’s sales plunged in June 2021; MAA trims TIV 2021 forecast. Malaysian Automot Assoc. http://www.maa.org.my/news.html. Accessed 25 September 2022
10. Azmi M Tokai A Electric vehicle and end-of-life vehicle estimation in Malaysia 2040 Environ Syst Decis 2017 37 451 464
11. Raja Mamat TNA Mat Saman MZ Sharif S Simic V Abd Wahab D Development of a performance evaluation tool for end-of-life vehicle management system implementation using the analytic hierarchy process Waste Manag Res 2018 36 1210 1222 10.1177/0734242X18790361 30067151
12. Jawi ZM, Isa MHM, Solah MS, Ariffin AH, Shabadin A, Osman MR (2016) The future of end-of-life vehicles (ELV) in Malaysia: A feasibility study among car users in Klang valley. In: MATEC Web Conf. pp 1–8
13. Mohamad-Ali N Raja Ghazilla RA Abdul-Rashid SH Ahmad-Yazid A Aftermarket survey on end-of-life vehicle recovery in Malaysia: Key findings J Clean Prod 2019 211 468 480 10.1016/j.jclepro.2018.11.165
14. Ngu HJ Lee MD Bin Osman MS Review on current challenges and future opportunities in Malaysia sustainable manufacturing: Remanufacturing industries J Clean Prod 2020 273 123071 10.1016/j.jclepro.2020.123071
15. Yusop NM Wahab DA Saibani N Realising the automotive remanufacturing roadmap in Malaysia: Challenges and the way forward J Clean Prod 2016 112 1910 1919 10.1016/j.jclepro.2015.03.072
16. Yu L Chen M Yang B Recycling policy and statistical model of end-of-life vehicles in China Waste Manag Res 2019 37 347 356 10.1177/0734242X19833150 30836861
17. Bhari B Yano J Sakaiichi S Comparison of end-of-life vehicle material flows for reuse, material recycling, and energy recovery between Japan and the European Union J Mater Cycles Waste Manag 2021 23 644 663 10.1007/s10163-020-01154-8
18. Hiratsuka J Sato N Yoshida H Current status and future perspectives in end-of-life vehicle recycling in Japan J Mater Cycles Waste Manag 2014 16 21 30 10.1007/s10163-013-0168-z
19. Saidani M Kendall A Yannou B Leroy Y Cluzel F Management of the end-of-life of light and heavy vehicles in the U.S.: comparison with the European union in a circular economy perspective J Mater Cycles Waste Manag 2019 21 1449 1461 10.1007/s10163-019-00897-3
20. Agamuthu P Mehran SB Circular Economy in Malaysia Circ Econ Glob Perspect 2019 10.1007/978-981-15-1052-6
21. Quist J (2013) Backcasting and scenarios for sustainable technology development. In: Handb. Sustain. Eng. pp 749–771
22. Ropi NM Hishamuddin H Wahab DA Analysis of the supply chain disruption risks in the Malaysian automotive remanufacturing industry-A case study Int J Integr Eng 2020 12 1 11
23. Khan KMA Said MFM Jamaludin KR Amiruddin I Mohd A End of life vehicle (ELV) Management Ecosystems in Malaysia J Soc Automot Eng Malaysia 2021 5 150 163 10.56381/jsaem.v5i1.160
24. Rashid FAA, Hishamuddin H, Radzi M, Mansor A (2021) Supply chain optimization for end-of-life vehicle recycling : A preliminary review. Proc. 11th Annu. Int. Conf. Ind. Eng. Oper. Manag.
25. Kassim KAA Husain NA Ahmad Y Jawi ZM End-of-life vehicles (ELVs) in Malaysia: Time for action to guarantee vehicle safety J Soc Automot Eng Malaysia 2020 4 338 348 10.56381/jsaem.v4i3.27
26. Nawawi NANA Azizul MA Sulaiman S Iskandar ARAM Abdullah A Study of end-of life vehicle (ELV) implementation in Malaysia J Ind Eng Innov 2020 2 1 7
27. Bin Abdul Hamid MHI Mohd Salleh NAB Mohamad Nor NH Bin Ismail MH Bin Yahya MF Bin Saari MI Mohd Pisal SM Study on rheological and dimensional properties of polypropylene on end-of-life vehicles IOP Conf Ser Mater Sci Eng 2020 10.1088/1757-899X/834/1/012003
28. Wong YC Mahyuddin N Aminuddin AMR Development of thermal insulation sandwich panels containing end-of-life vehicle (ELV) headlamp and seat waste Waste Manag 2020 118 402 415 10.1016/j.wasman.2020.08.036 32947219
29. Yusoh SSM Wahab DA Azman AH Analysis of automotive component design for reparation using additive manufacturing technology Int J Integr Eng 2020 12 20 26
30. Mohamad-Ali N Ghazilla RAR Abdul-Rashid SH Sakundarini N Ahmad-Yazid A Stephenie L End-of-life vehicle recovery factors: Malaysian stakeholders’ views and future research needs Sustain Dev 2018 26 713 725 10.1002/sd.1741
31. Mohamed N Mat Saman MZ Sharif S Hamzah HS Strategic factors on interpreting remanufacturing quality-certifying framework to address warranty aftermarket for Malaysian industry IOP Conf Ser Mater Sci Eng 2018 10.1088/1757-899X/328/1/012033
32. Wong YC Al-Obaidi KM Mahyuddin N Recycling of end-of-life vehicles (ELVs) for building products: Concept of processing framework from automotive to construction industries in Malaysia J Clean Prod 2018 190 285 302 10.1016/j.jclepro.2018.04.145
33. Lie LW Aziz NA Wahab DA Rahman MNA Azhari CH Enhancing remanufacturing efficiency in Malaysia through a knowledge support system: A case study of brake calipers Int J Ind Syst Eng 2018 28 451 467
34. Kafuku JM, Mat Saman MZ, Yusof SM (2017) Current and future issues in electronics and automobiles remanufacturing operations. In: FTC 2016 - Proc. Futur. Technol. Conf. pp 415–421
35. Mohamad-Ali N Ghazilla RAR Abdul-Rashid SH Sakundarini N Ahmad-Yazid A Stephenie L A system dynamics approach to develop a recovery model in the Malaysian automotive industry IOP Conf Ser Mater Sci Eng 2017 10.1088/1757-899X/210/1/012068
36. Mohamad-Ali N Ghazilla RAR Abdul-Rashid SH Sakundarini N Ahmad-Yazid A Stephenie L Development of an end-of-life vehicle recovery model using system dynamics and future research needs IOP Conf Ser Mater Sci Eng 2017 10.1088/1757-899X/210/1/012075
37. Mohamed N Mat Saman MZ Safian S Quality assurance of remanufactured components of end-of-life vehicle: A literature review Adv Sci Lett 2017 23 4644 4648 10.1166/asl.2017.8868
38. Raja Mamat TNA Mat Saman MZ Sharif S Simic V Key success factors in establishing end-of-life vehicle management system: A primer for Malaysia J Clean Prod 2016 135 1289 1297 10.1016/j.jclepro.2016.06.183
39. Ahmed S Ahmed S Shumon MRH Quader MA Cho HM Mahmud MI Prioritizing strategies for sustainable end-of-life vehicle management using combinatorial multi-criteria decision making method Int J Fuzzy Syst 2016 18 448 462 10.1007/s40815-015-0061-0
40. Ahmed S Ahmed S Shumon MRH Falatoonitoosi E Quader MA A comparative decision-making model for sustainable end-of-life vehicle management alternative selection using AHP and extent analysis method on fuzzy AHP Int J Sustain Dev World Ecol 2016 23 83 97 10.1080/13504509.2015.1062814
41. Go TF Wahab DA Fadzil ZF Azhari CH Umeda Y Socio-technical perspective on end-of-life vehicle recovery for a sustainable environment Int J Technol 2016 7 889 897 10.14716/ijtech.v7i5.2878
42. Aziz NA Wahab DA Ramli R Evaluating design for upgradability at the conceptual design stage J Teknol 2016 78 37 43
43. Raja Mamat TNA Mat Saman MZ Sharif S A survey instrument design to determine the success factors in implementing the end-of-life vehicles (ELVs) management system in Malaysia Adv Mater Res 2015 1125 620 624 10.4028/www.scientific.net/AMR.1125.620
44. Ahmed S Ahmed S Shumon H Quader MA End-of-life vehicles (ELVs) management and future transformation in Malaysia J Appl Sci Agric 2014 9 227 237
45. Raja Mamat TNA Mat Saman MZ Sharif S The need of end-of-life vehicles management system in Malaysia Adv Mater Res 2014 845 505 509 10.4028/www.scientific.net/AMR.845.505
46. Wahab DA Fadzil ZF Public community knowledge on reuse of end-of-life vehicles: A case study in an automotive industrial city in Malaysia J Appl Sci 2014 14 212 220 10.3923/jas.2014.212.220
47. Azmi M, Mat Saman MZ, Sharif S (2013) Proposed framework for end-of-life vehicle recycling system implementation in Malaysia. In: Proc. 11th Glob. Conf. Sustain. Manuf. - Innov. Solut. Ger. 23–25 Sept. pp 187–193
48. Lashlem AA Wahab DA Abdullah S Che Haron CH A review on end-of-life vehicle design process and management J Appl Sci 2013 13 654 662 10.3923/jas.2013.654.662
49. Go TF Wahab DA Rahman MNA Ramli R Hussain A Genetically optimised disassembly sequence for automotive component reuse Expert Syst Appl 2012 39 5409 5417 10.1016/j.eswa.2011.11.044
50. Jawi ZM Lamin F Manap ARA Abbas F Kassim KAA Voon WS Automotive ecosystem in Malaysia - A conceptual model to explain vehicle ownership and car maintenance issues Appl Mech Mater 2012 165 224 231 10.4028/www.scientific.net/AMM.165.224
51. Mat Saman MZ Zakuan N Blount G Design for end-of-life value framework for vehicles design and development process J Sustain Dev 2012 10.5539/jsd.v5n3p95
52. Sakundarini N Taha Z Ghazilla RAR Rashid SHA Gonzales J A framework of integrated recyclability tools for automobile design Int J Ind Eng Theory Appl Pract 2012 19 401 411
53. Yusop NM Wahab DA Saibani N Analysis of remanufacturing practices in the Malaysian automotive industry J Teknol 2012 59 77 80
54. Go TF Wahab DA Rahman MNA Ramli R Azhari CH Disassemblability of end-of-life vehicle: A critical review of evaluation methods J Clean Prod 2011 19 1536 1546 10.1016/j.jclepro.2011.05.003
55. Mohamed Nazmi MAS Abd Wahab D Abdullah S Mohd Tihth R Development of artificial neural network for optimisation of reusability in automotive components J Appl Sci 2011 11 996 1003 10.3923/jas.2011.996.1003
56. Go TF Wahab DA Ab Rahman MN Ramli R Azhari CH Disassembly for reuse: Implementation in the Malaysian automotive industry Aust J Basic Appl Sci 2010 4 4569 4575
57. Go TF Wahab DA Rahman MNA Ramli R A design framework for end-of-life vehicles recovery: Optimization of disassembly sequence using genetic algorithms Am J Environ Sci 2010 6 350 356 10.3844/ajessp.2010.350.356
58. Afrinaldi F, Mat Saman MZ, Shaharoun AM (2009) A decision making software for end-of-life vehicle disassemblability and recyclability analysis. In: IEEM 2009 - IEEE Int. Conf. Ind. Eng. Eng. Manag. pp 2261–2265
59. Amelia L Wahab DA Che Haron CH Muhamad N Azhari CH Initiating automotive component reuse in Malaysia J Clean Prod 2009 17 1572 1579 10.1016/j.jclepro.2009.06.011
60. Afrinaldi F, Mat Saman MZ, Shaharoun AM (2008) The evaluation methods of disassemblability for automotive components – A review and agenda for future research. J Mek 49–62
61. Mat Saman MZ, Blount G (2008) The DFEL value methodology : A tool for design-for-environment in automotive industry. J Mek 27: 23–41
62. Wahab DA Amelia L Hooi NK Haron CHC Azhari CH The application of artificial intelligence in optimisation of automotive components for reuse J Achiev Mater Manuf Eng 2008 31 595 601
63. Mat Saman MZ, Blount GN (2006) End of life vehicles recovery: Process description, its impact and direction of research. J Mek 40–52
64. Mat Saman MZ, Zakuan N (2006) End-of-life vehicle directive: A key element to the vehicle design process. 1st Reg Conf Veh Eng Technol 1–8
65. Kolbe RH Burnett MS Content-analysis research: An examination of applications with directives for improving research reliability and objectivity J Consum Res 1991 18 243 250 10.1086/209256
66. Jawahir IS, Badurdeen F, Rouch KE (2013) Innovation in Sustainable Manufacturing Education. 11th Glob Conf Sustain Manuf 9–16
67. Al-Quradaghi S Kucukvar M Onat N Towards a sustainable management of end-of-life vehicles in Qatar: A closed-loop circular economy model Proc Int Conf Ind Eng Oper Manag 2018 2018 647 654
68. Zhou F Lim MK He Y Lin Y Chen S End-of-life vehicle (ELV) recycling management: Improving performance using an ISM approach J Clean Prod 2019 228 231 243 10.1016/j.jclepro.2019.04.182
69. Özceylan E Demirel N Çetinkaya C Demirel E A closed-loop supply chain network design for automotive industry in Turkey Comput Ind Eng 2017 113 727 745 10.1016/j.cie.2016.12.022
70. Numfor SA Omosa GB Zhang Z Matsubae K A review of challenges and opportunities for end-of-life vehicle recycling in developing countries and emerging economies : A SWOT analysis Sustainability 2021 13 4918 10.3390/su13094918
71. Tian G Zhang H Feng Y Jia H Zhang C Jiang Z Li Z Li P Operation patterns analysis of automotive components remanufacturing industry development in China J Clean Prod 2017 164 1363 1375 10.1016/j.jclepro.2017.07.028
72. Kerin M Pham DT Smart remanufacturing: a review and research framework J Manuf Technol Manag 2020 10.1108/JMTM-06-2019-0205
73. Xia X Li J Tian H Zhou Z Li H Tian G Chu J The construction and cost-benefit analysis of end-of-life vehicle disassembly plant: A typical case in China Clean Technol Environ Policy 2016 18 2663 2675 10.1007/s10098-016-1185-0
74. Matsumoto M Yang S Martinsen K Kainuma Y Trends and research challenges in remanufacturing Int J Precis Eng Manuf - Green Technol 2016 3 129 142 10.1007/s40684-016-0016-4
75. Singhal D Tripathy S Jena SK Remanufacturing for the circular economy: Study and evaluation of critical factors Resour Conserv Recycl 2020 156 104681 10.1016/j.resconrec.2020.104681
76. Hatcher GD Ijomah WL Windmill JFC A network model to assist “design for remanufacture” integration into the design process J Clean Prod 2014 64 244 253 10.1016/j.jclepro.2013.09.021
77. Chai J, Qian Z, Wang F, Zhu J (2021) Process innovation for green product in a closed loop supply chain with remanufacturing. Ann Oper Res 1–25
78. Kurilova-Palisaitiene J Sundin E Poksinska B Remanufacturing challenges and possible lean improvements J Clean Prod 2018 172 3225 3236 10.1016/j.jclepro.2017.11.023
79. Wan Z Liu J Zhang J Nonlinear optimization to management problems of end-of-life vehicles with environmental protection awareness and damaged/aging degrees J Ind Manag Optim 2020 16 2117 2139 10.3934/jimo.2019046
80. Yang Y Hu J Liu Y Chen X Alternative selection of end-of-life vehicle management in China: A group decision-making approach based on picture hesitant fuzzy measurements J Clean Prod 2019 206 631 645 10.1016/j.jclepro.2018.09.188
81. Khan SAR Godil DI Thomas G Tanveer M Zia-Ul-haq HM Mahmood H The decision-making analysis on end-of-life vehicle recycling and remanufacturing under extended producer responsibility policy Sustain 2021 10.3390/su132011215
82. Petronijević V Ðorđdević A Stefanović M Arsovski S Krivokapić Z Mišić M Energy recovery through end-of-life vehicles recycling in developing countries Sustain 2020 12 1 26
83. Pallaro E Subramanian N Abdulrahman MD Liu C Sustainable production and consumption in the automotive sector: Integrated review framework and research directions Sustain Prod Consum 2015 4 47 61 10.1016/j.spc.2015.07.002
84. Karagoz S Aydin N Simic V End-of-life vehicle management: A comprehensive review J Mater Cycles Waste Manag 2020 22 416 442 10.1007/s10163-019-00945-y
85. Bernama (2022) Malaysia to implement end-of-life vehicle management policy by 2025. New Straits Times. https://www.nst.com.my/news/nation/2022/08/821730/malaysia-implement-end-life-vehicle-management-policy-2025. Accessed 28 Aug 2022
86. Othman N, Razali A, Chelliapan S, Mohammad R, Kamyab H (2021) A Design Framework for an Integrated End-of-Life Vehicle Waste Management System in Malaysia. Soft Comput Tech Solid Waste Wastewater Manag 305–319
87. Aishah N Ahmad N Azizul MA Sulaiman S Rhaodah A Study of End-Of Life Vehicle ( ELV ) Implementation in Malaysia J Ind Eng Innov 2020 2 1 7
| 36472793 | PMC9734691 | NO-CC CODE | 2022-12-14 23:28:30 | no | Obes Surg. 2022 Dec 6; 32(Suppl 4):1115-1176 | latin-1 | Obes Surg | 2,022 | 10.1007/s11695-022-06370-9 | oa_other |
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Research Articles
In-silico docking studies of selected phytochemicals against papain like protease of SARS-Cov-2
http://orcid.org/0000-0002-8559-6776
Saranya Palanisamy [email protected]
1
Karunya Ramesh [email protected]
1
Keerthi Varshini Gopalsamy [email protected]
1
Kowsikan Kalaiselvan [email protected]
1
Prathiksha Ramesh [email protected]
2
1 grid.252262.3 0000 0001 0613 6919 Department of Industrial Biotechnology, Government College of Technology, Thadagam Road, Coimbatore, 641013 India
2 grid.462384.f 0000 0004 1772 7433 Indian Institute of Technology, Gandhinagar, Gujarat 382055 India
6 12 2022
17
15 4 2022
3 11 2022
5 11 2022
© The Author(s) under exclusive licence to Society for Plant Research 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The SARS-Cov-2 virus, which is evolving continuously and causing adverse effects throughout the world, needs an effective drug molecule for its treatment. There are several receptors of SARS Cov-2 which are targeted for its inhibition by many lead molecules both in-vitro and in-vivo. Papain like Protease (PLpro) is one of the two SARS-Cov-2 proteases that can be used as a drug target for SARS Cov-2. It is a coronavirus enzyme that plays a role in the cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex and disruption of host responses. PLpro has also been linked to the cleavage of proteinaceous post translational modifications on host proteins as a means of evading antiviral immune responses. Structure-based drug discovery can be one of the effective methods to screen for various molecules against the target receptors. In this study, PLpro of SARS CoV-2 was chosen as the target for docking. Forty phytochemicals from various plant sources and four synthetic drugs have been screened for their inhibitory potential against PLpro using AutoDock Vina. Phytochemicals such as Tinosponone, Rhoifolin, Rosmanol, Berberin, Nimbin and two other existing drugs Elbasvir and Declatasvir showed higher inhibitory potential in terms of higher binding affinities. ADME and toxicity analysis were also performed to predict the pharmacokinetics and drug likeliness properties. It was concluded from the study that Tinosponone possesss potential inhibitor property of papain-like proteases (PLpro) of SARS CoV-2. Tinosponone from the plant Tinospora cordifolia had a binding affinity of − 9.3 kcal/mol and obeyed the Lipinski rules, making it an effective lead molecule for treating SARS CoV-2. Molecular Dynamics simulation of Tinosponone with PLpro has proved the stability and validity of the binding with RMSD value in range of 0.2 nm when it was run for 50 ns using GROMACS. Therefore, Tinosponone could be considered as a potential inhibitor of PLpro of SARS CoV-2.
Keywords
Papain-like protease (PLpro)
Tinosponone
Docking
SARS CoV-2
MD simulation
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pmcIntroduction
Severe Acute Respiratory Syndrome (SARS) Coronavirus, a novel coronavirus (2019-nCoV), also known as SARS-CoV-2, posed a huge threat to the world since 2019. The Centre for Disease Control and Prevention (CDC) tracked the outbreak of SARS-CoV-2 in Wuhan, China. The virus spread across the globe and leads to a pandemic situation with significant mortality rates that differed from country to country. People with heart disease, diabetes, lung disease, HIV, and pregnant women are at an increased risk of developing a serious illness or contracting COVID-19. The virus does not travel through the air, but rather through the respiratory droplets or aerosols of an infected individual (Dwarka et al. 2020). SARS CoV-2 is a member of the Coronaviridae family of the Nidovirales order. It is classified into four genera and SARS CoV-2 is closely related to the Betacoronavirus genus. Genome sequencing revealed higher similarity with the previous SARS CoV (2003 outbreak). Both viruses share the same membrane-bound exopeptidase Angiotensin converting enzymes (ACE2) as the host receptor to enter the cells (Chakraborty and Member 2020; Silva et al. 2020). Different structural proteins such as spike proteins play the main role in attachment to host receptors. Apart from the structural proteins, different proteases also play a major role in viral replication and immune evasion of the host. Different cysteine proteases: chymotrpsin-like proteases or main proteases (3CLpro), papain-like proteases (PLpro) are important non-structural proteins. The 3CL-like protease (3CLpro) hydrolyzes viral polyproteins to create functional proteins, which are required for coronavirus replication.Papain-like protease is essential for the release of NSP 1–16 from open reading frames ORF1a and ORF 1ab, which forms large polyproteins ppa1a and ppa1ab (Li et al. 2020). Papain-like protease (PLpro) is a SARS CoV-2 enzyme that is required for digesting viral polyproteins to generate a functional replicase complex that allows the virus to spread. It negatively regulates the host immune response by its deubiquitinating and deISGylating effect (Shah et al. 2020; Shin et al. 2020; Mohanraj et al. 2018).
Computer aided drug design tools such as molecular docking and molecular dynamic simulation help us to find the potential inhibitors against various viral targets in lesser time (El-hoshoudy 2020; Shawk et al. 2020; Meng et al. 2020). Plant-based immune modulatory compounds could reduce the effect of inflammatory response and cytokine storm (Abdellatiif et al. 2021; Pall et al. 2020; Vardhan and Sahoo 2020). Several antiviral inhibitors have been found to be more effective against the SARS CoV-2 virus (Alfaroa et al. 2020). Phytochemicals boost immunity and protect against illness (Zhu et al. 2020). This study discusses the results of docking studies of various phytochemicals against SARS CoV-2's papain-like protease (PLpro).
Material and methods
Preparation of protein
The crystal structure of papain-like protease of severe acute respiratory virus -2 (SARS-CoV-2) PDB ID 6W9C was retrieved from PDB database https://doi.org/10.2210/pdb6W9C/pdb and it was used in the present study. It has a resolution of 2.70 Å and molecular weight of 107.81 kDa. It has three chains A, B and C with a total sequence length of 317 amino acids. Energy minimization of the retrieved structure was performed using the SWISS PDB viewer. It helps to repair the distorted geometrics by moving atoms to release internal constraints and is used to minimise the protein energy (Kodchakorn et al. 2020; Tripathi et al. 2011; Trott and Olson 2010).
Preparation of ligand
Antiviral compounds derived from plant resources with variety of traditional applications were screened from a variety of phytochemical databases such as IMPPAT https://cb.imsc.res.in/imppat/ (Indian Medicinal Plants, Phytochemicals and Therapeutics) (Ni et al. 2020; Swain et al. 2020). Compounds with anti-viral properties were screened based on ADME and drug-likeliness properties using SWISS ADME server. (http://www.swissadme.ch/) (Meyer-Almes 2020; Garg et al. 2020). Based on the results, forty phytoligands were chosen for the study. As a control, five commonly recommended synthetic antiviral drugs such as Elbasvir, Cefpiramide, Cefpiramide, Daclatasvir and Delamanid were also docked with PLpro (Sharma et al. 2020; Swain et al. 2020). The structure of phytoligands and drugs was obtained from Pubchem database (https://pubchem.ncbi.nlm.nih.gov/) in SDF format. The phytoligands were then converted from SDF to PDB format using the online SMILES converter. (https://cactus.nci.nih.gov/translate/). ChemSketch was used to convert the 2D structure of certain ligands into a 3D format. (https://www.acdlabs.com/resources/free-chemistry-software-apps/chemsketch-freeware/#chemsketch_modal) (Ferreira et al. 2015). Various phytoligands and synthetic drugs were docked with the target protein, Papain-like protease of SARS CoV-2 using Autodock Vina in blind docking mode (Venkateshana et al. 2020).
Molecular dynamic simulation of Tinosponone
The complex of Tinosponone with Papain-like protease was prepared for Molecular Dynamic simulation and run for 50 ns using GROMACS (version 2022.1) through Google Colab pro (Salsbury 2010; Dutt and Roy 2020). Topology generation and energy minimization of ligand were performed and energy minimization of ligand was performed using the Google colab pro GPU server.
Results and discussion
Molecular docking analysis
The binding energies of forty phytoligands against SARS-CoV-2 papain-like protease (6W9C) ranged from − 9.3 kcal/mol (Tinosponone) to − 2.5 kcal/mol (Methyl Rosmarinate), while synthetic anti-viral drugs ranged from − 9.1 kcal/mol (Bictegravir) to − 13.0 kcal/mol (Elbasvir). Tinosponone and Hespiridin had the highest binding affinity for the PLpro. Because the latter's drug-likeliness had some flaws, Tinosponone from Tinospora cordifolia was further subjected to MD simulation to study its binding stability. The list of various phytochemicals, their sources and their docking score were given in Table 1Table 1 Docking scores of Phytochemicals with source and PUBCHEM ID
S no. Phytochemicals PUBCHEM ID Source Docking score (kcal/mol)
1 Luteolin 5280445 Chrysanthemum indicum − 7.9
2 Thebaine 5324289 Papaversomniferum L − 7.9
3 Rosmanol 13966122 Salvia Rosmarinus − 8.3
4 Tinosponone 15215479 Tinosporacordifolia − 9.3
5 Berberine 2353 Berberis vulgaris − 8.2
6 Chrysin 5281607 Radix scutellariae − 7.6
7 Chrysoeriol 5280666 Artemisia vulgaris − 7.8
8 Chrysophanol 10208 Rheum rhabarbarum − 7.7
9 Cirsimaritin 188323 Coelogynecristata − 7.7
10 Curcumin 969516 Curcuma longa − 7.5
11 Emodin 3220 Polygonum
Cuspidatum
− 7.7
12 Hespiridin 10621 Citrus fruits − 9.1
13 Magnoflorine 73337 Anamirtacocculus − 8.1
14 Nimbin 108058 Azadirachta indica − 8.3
15 Piperine 638024 Piper nigrum − 7.6
16 Quarcetin 5280343 Onions,cherries, Broccoli & citrus fruits − 7.9
17 Allicin 5036 Allium sativum − 4
18 Cinnamaldehyde 637511 Cinnamomumzeylancium − 3.9
19 Scutellarin 185617 Scutellarialateriflora − 7.9
20 Myricetin 5281672 Leaves of Myricarubra − 3.5
21 Amentoflavone 5281600 Ginkgo biloba − 4.1
22 Ramelteon 208902 Sleep-agent medication − 6.4
23 Pectolinarin 168849 Linaria vulgaris − 4.8
24 Licoleafol 11111496 Glycyrrhizauralensis − 3.3
25 Methyl Rosmarinate 6479915 Rosmarinus officinalis L − 2.5
26 Artemisinin 68827 Artemisia annua − 3.1
27 Prulifloxacin 947 Antibacterial fluoroquinolone − 2.9
28 Calceolarioside 5273566 Lepisorous contortus − 4.4
29 Terrestrimine 102335850 Tribulus terrestrias L − 7.1
30 Ellagic acid 5281855 Berries and pomegranate − 5
31 Tryptanthrin 73549 Wrightia tinctoria − 8.4
32 Caffeic acid 689043 Bark of eucalyptus globulus − 2.7
33 Rhoifolin 5282150 Boehmeria nivea(leaf) − 9.2
34 Colistin 5311054 Bacillus colistinus − 6.2
35 Dieckol 3008868 Ecklonia cava − 5.4
36 Glycyrrhizin 3495 Glycyrrhiza glabra L − 4.5
37 Vasicinone 442935 Justicia adhatoda − 6.8
38 Andrographolide 5318517 Andrographi spaniculata − 8
39 Apigenin 5280443 Matricaria chamomilla − 7.7
40 Oxytocin 439302 Fig − 5.1
The pharmacokinetic properties of the selected ligands with preferred docking scores is given in Table 2. Out of five ligands and a drug, Nimbin and Rhoifolin did not meet the required properties as Nimbin’s molecular weight was greater than 500 Da and Rhoifolin’s number of hydrogen acceptors was greater than 10. Tinosponone, Berberine, Rosamanol and Elbasvir satisfied all rules of Lipinski.Table 2 ADME Analysis of selected compounds
S no. Ligand Mol. Wt (g/mol) log pH No of H donors No of H acceptors Drug likeliness
1 Rosmanol 346.42 2.88 3 5 Yes
2 Berberine 336.36 2.53 0 4 Yes
3 Nimbin 540.60 3.23 0 9 No
4 Rhoifolin 578.62 − 0.66 8 14 No
5 Tinosporinine 342.34 2.89 0 6 Yes
6 Elbasvir 880.02 5.50 4 9 Yes
Prediction of the active site of PLpro
The probable active sites or binding pockets of the four viral proteins were identified with PyMOL (Bharadwaj et al. 2020; Yuan et al. 2017). Five phytochemical molecules were analyzed for the identification of the active site of the target molecule which is listed in Table 3. The target protein PLpro contains three chains A, B and C. The binding complex of Tinosponone with the active site of PLpro of SARS CoV-2 is shown in Fig. 1.Table 3 Active site of selected phytochemicals with A, B and C chain of PLpro
Ligands Rosmanol Berberine Nimbin Rhoifolin Tinosponone
Docking Score (kcal/mol) − 8.3 − 8.2 − 8.3 − 9.2 − 9.3
A Chain – Gly 160 Glu 161 – P 247
B Chain Gly 160 – – – –
C Chain Thy 158 Gly 160 – Gly 271 P 248
Fig. 1 Active site predicted using PyMOL for the docked structure of Tinosponone with PLpro of SARS CoV-2
Molecular dynamic simulation of Tinosponone with PLpro
The molecular dynamic simulation was carried out for the docked complex of Tinosponone with papain-like protease using GROMACS (version 2022.1) through Google Colab pro. The conformation of the molecule binding of the compound was found to be stable with a mean RMSD value deviation in the range of 0.2 nm when simulation was done for the period of 50 ns using Google colab pro. RMSD value was plotted as the function of time frame was plotted as shown in Fig. 2. RMSF fluctuation of binding of Tinosponone with PLprowas shown in Fig. 3 (Silva et al. 2020). The number of hydrogen bonds formed during 50 ns Molecular dynamic simulation was shown in Fig. 4Fig. 2 Time dependence RMSD plot of binding of Tinosponone with PLpro using MD simulation
Fig. 3 Time dependence RMS fluctuation plot of binding of Tinosponone with PLpro using MD simulation
Fig. 4 Number of Hydrogen Bonds of Tinosponone binding with PLpro in 50 ns MD simulation
Discussion
In the current study, Tinosponone derived from the plant Tinospora cordifolia showed better binding activity with the binding energy of − 9.6 kcal/mol using Autodock Vina, Similarly in another study by Krupanidhi et al. (2020), Tinosponone showed a better binding affinity with 3CL pro also with binding activity of − 7.7 kcal/mol (Krupanidhi et al. 2020). Results of molecular dynamic simulation with Papain protease of SARS CoV-2 with Tinosponone also indicates the stable binding when the simulation was performed in the 50 ns range (Table 4).Table 4 Affinity of docked Tinosponone with SARS CoV-2 PLpro in different docking modes
Docking mode Affinity (kcal/mol) Distance from best mode
rmsd l.b rmsd u.b
1 − 9.3 0.000 0.000
2 − 9.1 2.767 4.895
3 − 8.9 2.752 4.867
4 − 8.2 3.175 5.338
5 − 8.0 1.798 2.402
Conclusion
Virtual screening of SARS CoV-2 papain-like protease (PDB ID: 6W9C) with various phytoligands demonstrated the five phytoligands, Tinosponone, Rhoifolin, Rosmanol, Berberin, and Nimbin with the best inhibitory potential in terms of higher binding affinities. Tinosponone had a binding affinity of − 9.3 kcal/mol and obeyed all Lipinski rules, making it a potential inhibitor for SARS Cov-2 PLpro. Tinosponone's binding site with the target PLpro was identified as P246 on chain C of SARS CoV-2's papain-like protease (PLpro). Therefore, Tinosponone could be used as a potential inhibitor of papain like protease of SRS CoV-2 based on further in-vitro and in-vivo investigations.
Acknowledgements
The author hasn't received any funds from the funding agencies. The author would like to acknowledge the permission given to access the Bioinformatics facilities of the Department of Industrial Biotechnology, Government College of Technology, Coimbatore.
Declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Publisher's Note
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==== Refs
References
Abdellatiif MH Ali A Ali A Hussien MA Computational studies by molecular docking of some antiviral drugs with COVID-19 receptors are an approach to medication for COVID-19 Open Chem 2021 19 1 245 264 10.1515/chem-2021-0024
Alfaroa M Alfaro I Ange C Identification of potential inhibitors of SARS-CoV-2 papain-like protease from tropane alkaloids from Schizanthusporrigens: a molecular docking study Chem Phys Lett 2020 761 138068 10.1016/j.cplett.2020.138068 33052144
Bharadwaj S Lee KE Dwivedi VD Kanga SG Computational insights into tetracyclines as inhibitors against SARS-CoV-2 Mpro via combinatorial molecular simulation calculations Life Sci 2020 257 118080 10.1016/j.lfs.2020.118080 32653520
Chakraborty K, ERS Member (2020) ACE2 receptor blockers: a novel therapeutic approach for COVID-19
Dutt P Roy P Molecular docking unmasks potent phyto ligands against SARS-CoV-2 Spike glycoprotein, main protease, papain-like protease, and RNA-dependent RNA polymerase J Biomol Struct Dyn 2020 39 236 244 10.1080/07391102.2020.1796808 31948361
Dwarka D Agonib C Mellem JJ Soliman ME Baijnath H Identification of potential SARS-CoV-2 inhibitors from South African medicinal plant extracts using molecular modelling approaches S Afr J Bot 2020 133 273 284 10.1016/j.sajb.2020.07.035 32839635
El-hoshoudy AN Investigating the potential antiviral activity drugs against SARS-CoV-2 by molecular docking simulation J Mol Liquids 2020 318 113968 10.1016/j.molliq.2020.113968
Ferreira LG Ricardo N Oliva G Andricopulo AD Molecular docking and structure-based drug design strategies Molecules 2015 20 7 13384 13421 10.3390/molecules200713384 26205061
Garg S Anand A Roy A Molecular docking analysis of selected phytochemicals against SARS-CoV-2 Mpro receptor Vegetos 2020 10.1007/s42535-020-00162-1
Kodchakorn K Poovorawan Y Suwannakarn K Kongtawelert P Molecular modelling investigation for drugs and nutraceuticals against protease of SARS-CoV-2 J Mol Graph Model 2020 101 107717 10.1016/j.mgm.2020.107717 32861974
Krupanidhi S Abraham Peele KTC Venkateswarulu TC Ayyagari VS Nazneen-Bobby M Babu DJ Venkata-Narayana A Aishwarya G Screening of phytochemical compounds of Tinospora cordifolia for their inhibitory activity on SARS-CoV-2: an in silico study J Biomol Struct Dyn 2020 10.1080/07391102.2020.1787226
Li D Luan J Zhang L Molecular docking of potential SARS-CoV-2 papain-like protease inhibitors Biochem Biophys Res Commun 2020 538 72 79 10.1016/j.bbrc.2020.11.083 33276953
Meng X-Y Zhang H-X Mezei M Cui M Molecular docking: a powerful approach for structure-based drug discovery Curr Comput Aided Drug Des 2020 7 146 157 10.2174/157340911795677602
Meyer-Almes F-J Repurposing approved drugs as potential inhibitors of 3CL-protease of SARS-CoV-2: virtual screening and structure based drug design Comput Biol Chem 2020 88 107351 10.1016/j.combiolchem.2020.10735 32769050
Mohanraj K Karthikeyan BS Vivek-Ananth RP Bharath-Chand RP Aparna SR Mangalapandi P Samal A IMPPAT: a curated database of Indian Medicinal Plants Phytochem Therap Sci Rep 2018 8 4329
Ni W Yang X Yang D Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19 Crit Care 2020 24 1 422 10.1186/s13054-020-03120-0 32660650
Pall S Zhmurov A Baur P Heterogeneous parallelization and acceleration of molecular dynamics simulations in GROMACS J Chem Phys 2020 153 134110 10.1063/5.0018516 33032406
Salsbury FR Molecular dynamics simulations of protein dynamics and their relevance to drug discovery Curr Opin Pharmacol 2010 10 738 744 10.1016/j.coph.2010.09.016 20971684
Shah B Modi P Sagar SR LJ Institute of Pharmacy In silico studies on therapeutic agents for COVID-19: drug repurposing approach Life Sci 2020 252 117652 117652 10.1016/j.ifs.2020.117652 32278693
Sharma K Morla S Goyal A Kumar S Computational guided drug repurposing for targeting 2′-O-ribose methyltransferase of SARS-CoV-2 Life Sci 2020 259 118169 10.1016/j.ifs.2020.118169 32738360
Shawk E Nada AA Ibrahim RS Potential role of medicinal plants and their constituents in the mitigation of SARS-CoV-2: identifying related therapeutic targets using network pharmacology and molecular docking analyses RSC Adv 2020 47 27961 27983 10.1039/dora05126h
Shin D Mukherjee R Grewe D Bojkov D Baek K Bhattacharya A Schulz L Widera M Mehdipour AR Tascher G Geurink PP Wilhelm A van der Heden-van-Noort GJ Schulman B Cinat J Hummer G Ciesek S Dikic I Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity Nature 2020 587 657 662 10.1038/s41586-020-2601-5 32726803
Silva TL Toffano L Fernandes JB das Graças-Fernandes-da-Silva MF de Sousa LRF Vieira PC Mycotoxins from Fusariumproliferatum: new inhibitors of papain-like cysteine proteases Braz J Microbiol 2020 10.1007/s42770-020-00256-7
Swain SS Panda SK Luyten W Phytochemicals against SARS-CoV as potential drug leads Biomed J 2020 44 74 85 10.1016/j.bj.2020.12.002 33736953
Tripathi L Kumar P Haneef J Singh R Molecular docking softwares: an overview Curr Bioact Compd 2011 5 160 168 10.20174/157340709788452019
Trott O Olson AJ AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading J Comput Chem 2010 31 2 455 461 10.1002/jcc.21334 19499576
Vardhan S Sahoo SK In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoid Comput Biol Med 2020 124 103936 10.1016/j.compbiomed.2020.103936 32738628
Venkateshana M Suresha J Muthu M Ranjithkumar R Azaphenantherene derivatives as inhibitor of SARS-CoV-2 Mpro: synthesis, physiochemical, quantum chemical and molecular docking analysis Chem Dtat Collect 2020 10.1016/j.moistruc.2020.128741
Yuan SH Chan S Hu Z Using PyMOL as a platform for computational drug design Comput Mol Sci. 2017 7 2 e1298 10.1002/wcms.1298
Zhu W Xu M Chen CZ Guo H Shen M Hu X Shinn P Klumpp-Thomas C Michael SG Zheng W Identification of SARS-CoV-2 3CL protease inhibitors by a quantitative high-throughput screening ACS Pharmacol Transl Sci 2020 5 1008 1016 10.1021/acsptsci.0c00108
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SN Bus Econ
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Sn Business & Economics
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Springer International Publishing Cham
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10.1007/s43546-022-00387-z
Original Article
Economic analysis through alternative data and big data techniques: what do they tell about Brazil?
http://orcid.org/0000-0003-1411-0553
Libório Matheus Pereira [email protected]
1
http://orcid.org/0000-0001-6372-2316
Ekel Petr Iakovlevitch [email protected]
12
http://orcid.org/0000-0002-9856-2436
da Silva Martins Carlos Augusto Paiva [email protected]
1
1 grid.412520.0 0000 0001 2155 6671 Pontifical Catholic University of Minas Gerais, Belo Horizonte, 30535-012 Brazil
2 grid.8430.f 0000 0001 2181 4888 Federal University of Minas Gerais, Belo Horizonte, 31270-901 Brazil
5 12 2022
2023
3 1 319 1 2022
28 11 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Alternative data are now widely used in economic analyses worldwide but still infrequent in studies on the Brazilian economy. This research demonstrates how alternative data extracted from Google Trends and Google Mobility contribute to innovative economic analysis. First, it demonstrates that the search for the future on the internet is correlated (R = 0.62) with the average household income in Brazilian states. The three Brazilian states with the most people looking for the future on the internet have an average household income 1.6 times higher than people from states that do not have this behavior. The search for the future represents 10.9% of the economic development potential of the states, while the proportion of people with university degrees, scientific publications, and researchers represents another 60.4%. The reduction in mobility in retail/recreation locations averaged 34.28% in Brazil, Ecuador, Paraguay, and Uruguay. This group of countries had COVID-19 infection and death rates 1.25 and 1.74 times higher than in countries that reduced their mobility in retail/recreation locations by 45.03%. The impact of reduced mobility in retail/recreation locations on the unemployment rate, gross domestic product degrowth, and inflation in countries such as Brazil was 1.1, 2.2, and 2.6 times lower than in countries that reduced mobility more of people. The research contributions are associated with identifying new indicators extracted from alternative data and their application to carry out innovative economic analyses.
Keywords
Alternative data
Google Trends
Google Mobility
Big data
Economic analysis
JEL Classification
A12
C00
E01
J1
http://dx.doi.org/10.13039/501100002322 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 0001 Libório Matheus Pereira http://dx.doi.org/10.13039/501100003593 Conselho Nacional de Desenvolvimento Científico e Tecnológico 311032/2016-8 Ekel Petr Iakovlevitch issue-copyright-statement© Springer Nature Switzerland AG 2023
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pmcIntroduction
Big data machine learning techniques that enable the treatment and analysis of large volumes of data have favored diverse economic analyses through the discovery and application of hitherto unknown sets of indicators (Cheng et al. 2021). This new set of indicators of great interest for economic analysis was called alternative data. Although many researchers use the terms big data and alternative data synonymously (Hassani and Silva 2015; Buono et al. 2017; Narita and Yin 2018), alternative data are conceptualized as data not yet fully incorporated into the economic mainstream (Jain 2019).
More and more researchers have taken advantage of big data advances in economic analysis based on alternative data (Garboden 2020; Blazquez and Domenech 2018). The books “Big data and AI strategies: Machine learning and alternative data approach to investing” (Kolanovic and Krishnamachari 2017) and “The Book of Alternative Data: A Guide for Investors, Traders, and Risk Managers” (Denev and Amen 2020) offer useful information for practitioners in this field. Among this information are concepts, types, and alternative data sources, techniques and methods of big data and econometrics, as well as the main risks and challenges faced by practitioners in the field.
Examples of applications of alternative data in economic analysis are easily found in the literature (Varian 2014; Blazquez and Domenech 2018; Charoenwong and Kwan 2021). Among these examples, the work of Choi and Varian (2012) occupies a prominent position. The research entitled “Predicting the Present with Google Trends” developed by Google economists Hyunyoung Choi and Hal Varian exerts enormous influence among researchers in the field.
In particular, economic analysis based on alternative data extracted from Google Trends and Google Mobility are already very popular. Economists worldwide have been presenting several findings from these data, bringing relevant contributions to the field of economics. Although there is sufficient evidence in the literature on the usefulness of data extracted from Google Trends and Google Mobility in economic analyses, little is known about using this type of data in economic analysis in Brazil.
Therefore, the objective of this research is twofold. First, to explain the recent popularity of alternative data in economic analyses, indicating how much this popularity is reflected in studies on the Brazilian economy. Second, to use alternative data from Google Trends and Google Mobility, indicating how these data contribute to understanding the Brazilian economic reality.
The originality of this research is associated with the discovery of indicators extracted from alternative data for carrying out innovative economic analyses, such as the identification of the factors that most impact the potential for the economic development of Brazilian states and the analysis of the impact of COVID-19 on mobility in retail/recreation locations and the relationship of this impact with economic indicators from Brazil and other South American countries.
Alternative data applied to economic analysis
Google Trends data
Until December 17, 2021, 385 articles were indexed in Scopus and Web of Science databases that explicitly mention the use of Google Trends data in the title, abstract, or keywords published in economic journals.
These articles bring quite varied contributions. Choi and Varian (2012) demonstrated how to use data extracted from Google Trends to predict short-term economic indicators such as car sales, unemployment claims, and consumer confidence. Vosen and Schmidt (2011) introduced a new indicator of private consumption from data extracted from Google Trends. The authors show that the new indicator performs better than research-based indicators, suggesting that adding Google Trends data helps significantly to predict private consumption (Vosen and Schmidt 2011). Carrière‐Swallow and Labbé (2013) introduced a car interest index based on data extracted from Google Trends to forecast car sales in Chile. Kearney and Levine (2015) use Google Trends data to analyze the influence of television programs on interest in contraceptives and carrying out abortions.
While Google Trends data provide information for several economic analyses, a significant portion of publications that use this type of alternative data focus on oil and stock market analysis.
Yu et al. (2019) show that using data extracted from Google Trends significantly improves the prediction of the direction and level of oil consumption. Ma et al. (2019) introduce the event-triggered indicator through data extracted from Google Trends to predict oil price volatility. Qadan and Nama (2018) reveal that the greatest interest in the oil topic is related to oil price shocks and that the data extracted from Google Trends is a good predictor of oil price volatility.
Ding and Hou (2015) employed data extracted from Google Trends to capture the active attention that retail investors pay to stocks. The authors show that retail investor attention significantly broadens the shareholder base and improves stock liquidity. Vlastakis and Markellos (2012) study the demand and supply for information on companies with shares traded on stock exchanges. Based on Google Trends data, the authors reveal that risk aversion levels are positively related to the demand for information about stocks by investors.
Five studies that use data extracted from Google Trends in the economic analysis have been done by Brazilian authors. However, three of these studies have been dedicated to economic analyses for other countries and not for Brazil (Perlin et al. 2017; Corbi and Picchetti 2020; Piccoli and Castro 2021). Google Trends data are used by Neto and Candido (2021) to assess and predict loans to households and by Piccoli (2021) to predict currency prices in a speculative attack. This indicates that Google Trends data are still underused in Brazil despite its generally recognized usefulness, including in economic analysis.
Google Mobility data
Until December 17, 2021, 180 articles were indexed in the Scopus and Web of Science databases that explicitly mention the use of Google Mobility or Mobility Reports data in the title, abstract, or keywords.
Two reasons explain this lower number of studies compared to Google Trends. First, mobility data were only made available in 2020 to support studies on the COVID-19 pandemic. Second, the vast majority of articles are associated with the health area. Only 24 articles, or 13% of the total, were published in economic journals.
Studies based on Google Mobility data focus on analyses that relate COVID-19 and the economy (Fernández-Villaverde and Jones 2020). These studies show that population vaccination rates are positively related to country wealth (Auld and Toxvaerd 2021). In the United States, COVID-19 cases would have been 17 to 78% higher in the states without containment measures such as business closures (Chernozhukov et al. 2021). Non-metropolitan indebtedness increased with reduced geographic mobility (Allen and Whitledge 2021). Mobility restriction measures are directly and negatively related to the economic value of green space for the citizens of England (Day 2020). Mobility in workplaces during the coronavirus pandemic is significantly lower in poorer regions than in other regions (Bargain and Aminjonov 2021).
The study by Silva et al. (2021) is the only one to analyze Brazil. The authors rely on Google Mobility data to show that the mobility in European and Canadian cities increased in the second wave compared to the first. In contrast, mobility in the first and second waves remained stable in the Brazilian city of Manaus.
Application examples
Two case studies based on Google Trends and Mobility data were designed to demonstrate the applicability and usefulness of this type of alternative data in economic analysis in Brazil. The case studies bring a brief contextualization, followed by the materials and methods used, ending with the presentation and discussion of the results.
Unveiling the development potential of Brazilian states using Google Trend data
Studies show that economic development is directly or indirectly associated with non-economic indicators. Several studies relate the gross domestic product to the level of education, number of Higher Education Institutions, number of scientific publications, number of scientific journals, number of researchers, and volume of expenditure on Research, Development, and Innovation (Meo et al. 2013; Tümer and Akkuş 2018; Pastor et al. 2018).
In turn, factors associated with Research, Development, and Innovation influence and are influenced by economic and technological factors (Libório et al. 2020a, b). Broadband Internet access positively impacts labor productivity and is strongly associated with economic indicators such as gross domestic product and employment levels in the economy (Holt and Jamison 2009; Gruber et al. 2014; Li and Forzati 2018; Gallardo et al. 2021).
In an innovative approach, researchers show that the economic performance of countries can be explained and predicted through the behavior of people on the internet. How often people search for future years on the internet is correlated with the gross domestic product of countries (Preis et al. 2012). Time orientation refers to individual differences in the relative emphasis one places on the past, present, or future and is related to academic, financial, and health outcomes (Park et al. 2017). In short, these studies suggest that people from developed countries are more future-oriented than people from developing countries.
Development Potential Composite Indicator (DP-CI): data and methods
Composite indicators are one-dimensional measures that facilitate the comprehension of multiple sub-indicators associated with multidimensional economic phenomena. Among these multidimensional economic phenomena, it is possible to mention the uncertainty (Charles et al. 2018), risk (Akin et al. 2016), costs of doing business (Bernardes et al. 2021; Ekel et al. 2022), sustainable development (Salvati and Carlucci 2014; Alaimo and Maggino 2020), competitiveness (Moirangthem and Nag 2022) among others (Mazziotta and Pareto 2016). Composite indicators are constructed by a method that aggregates normalized sub-indicators, weighted or not (El Gibari et al. 2019). Although there is no method exempt from limitations, researchers agree that composite indicators are tools that facilitate the interpretation of complex realities and support decision-makers (Nardo et al. 2005; Kuc-Czarnecka et al. 2020).
This research employs Pearson's (1901) Principal Component Analysis to construct the Development Potential Composite Indicator. Principal Component Analysis is a very popular method in data science because it allows the reduction of a large volume of data in a few components with the least possible loss of the original information (Libório et al. 2018). The original data, that is, the sub-indicators, directly or indirectly related to economic development, which were used in the Principal Component Analysis, are presented in Table 1.Table 1 Sub-indicators of the Development Potential Composite Indicator
ID Subindicator Description Source
BA Broadband access Percentage of households with broadband internet Brazilian National Telecommunications Agencya
FI Future-oriented index The search index for future years on the internet Google Trendsb
UD University degree Percentage of population with a university degree Brazilian institute of geography and statisticsc
AI Average income Average monthly household income Brazilian institute of geography and statisticsd
IC Innovative companies Percentage of companies classified as innovative Ministry of Science, Technology, Innovations, and communicationse
RP Research professionals Percentage of the population employed in the research sector Ministry of labor and social securityf
SP Scientific papers Articles published by a person Web of scienceg
The future-oriented index was generated for each Brazilian state, considering the internet search for the word “2023” between January 2020 and December 2021
ahttps://dados.gov.br/dataset/densidade_banda_larga
bhttps://trends.google.com.br/trends/?geo=BR
chttps://sidra.ibge.gov.br/tabela/5919
dhttps://sidra.ibge.gov.br/tabela/5442
ehttps://antigo.mctic.gov.br/mctic/opencms/tecnologia/Lei_do_bem/Noticia/Resltados.html
fhttp://pdet.mte.gov.br/
ghttps://www.webofscience.com/wos/woscc/basic-search
Following the specialized literature, three parameters were considered to accept the Principal Component Analysis model. First, the variance explained in the first component is greater than 0.50 (Libório et al. 2021). Second, the sampling adequacy measured by the Kaiser–Meyer–Olkin criterion is greater than 0.70 (Kaiser 1974). Third, the degree of deviation between the correlation matrix and an identity matrix measured by Bartlett’s (1937) sphericity test is lesser than 0.05.
Development potential of Brazilian states
In Brazil, future-oriented behavior is more common in the Federal District and states of Minas Gerais and Santa Catarina and less common in the Rio Grande do Norte, Amazonas, and Tocantins states. Figure 1 shows that searching for the future on the internet positively correlates with the average income in Brazilian states.Fig. 1 Correlation between the future-oriented index and average income in Brazilian states. The average household income was due to the absence of gross domestic product per capita data for Brazilian states
These results suggest that the relationship between the search for the future with a higher gross domestic product per capita (Preis et al. 2012) can also occur on a regional scale. Therefore, it is possible to consider the future-oriented index as a relevant sub-indicator for the Development Potential Composite Indicator. Figure 2 shows that the future-oriented index sub-indicator contributes 13% to the Principal Component Analysis model and 10.9% to the Principal Component, that is, to the Development Potential Composite Indicator.Fig. 2 Contribution of the sub-indicators in the Principal Component Analysis model and in the Development Potential Composite Indicator
These results indicate that sub-indicators related to research and teaching have greater weight in the Development Potential Composite Indicator. It also indicates that the sub-indicators representing technology and innovation have the lowest weights. In Fig. 3, it is possible to conclude that these results are statistically consistent. The Principal Component Analysis model validity parameters Variance Explained and Kaiser–Meyer–Olkin exceeded the acceptance threshold of 0.50 and 0.70. The Bartlett test was below the maximum threshold of 0.05.Fig. 3 Acceptance parameters of the Principal Component Analysis and DP-CI model of Brazilian states
Except for the Federal District, the map in Fig. 3 reveals that the south and southeast region concentrates the states with the greatest development potential. Maranhão, Alagoas, and Bahia, all in the country’s northeast region, have the lowest development potential. These results show important regional inequalities between Brazilian states and regions. The development potential of the top five states in the ranking is, on average, 10.9 times greater than the development potential of the five lowest-ranked states. Furthermore, these results suggest that inequality tends to increase due to the states’ development potential.
Therefore, the introduction of public policies aimed at promoting research and education can be a more efficient strategy to reduce regional inequalities with innovative investments or access to the internet. In particular, these policies should seek to increase the proportion of people at the university level engaged in research activities and the production of scientific knowledge.
Measuring the impact of retail and recreation mobility on economic indicators in South American countries through Google Mobility data
Studies that use Google Mobility data reveal how people’s mobility during the COVID-19 pandemic relates to economic indicators. These studies reveal that social distancing leads to declines in the growth rate of coronavirus cases (Milani 2021) and that self-protection, social distancing, and mask use is a behavior directly related to income (Papageorge et al. 2021). Studies also show that the reduction in population mobility was greater in cities with the highest socioeconomic index, in countries with higher sociodemographic indices and universal health coverage (Liu et al. 2021), and in areas where people trust medicine and science more (Brodeur et al. 2021).
From an economic point of view, the correlation of COVID-19 cases with mobility in retail/recreation, grocery/pharmacy, and public transportation locations is greater than mobility in parks/workplaces or homes (Casa Nova et al. 2021). Mobility reduction policies impact the economy, particularly Italian, German, French, and Spanish (Spelta and Pagnottoni 2021). Milani (2021) also shows that the impact of COVID-19 on unemployment is very heterogeneous, being higher in Spain and the United States and lower in countries that have adopted subsidy programs for employers and employees.
Mobility and COVID-19 in South America: data and multivariate analysis
This case study aims to answer two questions. First, what was the impact of mobility in retail/recreation locations on the number of COVID-19 cases and deaths in South American countries? Second, how does this impact relate to economic indicators? Data concerning mobility, COVID-19, economic indicators, and the methods of Cooks distance, k-means cluster analysis, and Two-factor Analysis of Variance (ANOVA) with replication were employed to answer these two questions.
Mobility data at retail/recreation locations were taken from Google COVID-19 Community Mobility Reports.1 Data from the pre-vaccination period, between February 15 and December 31 2020, were retrieved to ensure comparability across countries. Demographic and COVID-19 data were obtained from Our World in Data.2 The economic indicators were obtained from the World Bank from DataBank, the World Development Indicators database.3
Cook’s (1977) distance: is a measure that allows identifying atypical elements in a multivariate set of data, which can distort the result and precision of multivariate analyses. As a general rule, observations with a Cook’s distance greater than three times the mean are possible outliers (Bernardes et al. 2021).
MacQueen’s (1967) k-means clustering: is an algorithm that uses the total variation of Euclidean distances from elements to cluster centroids to separate elements into k-clusters to maximize differences between clusters and minimize differences within each cluster. The average silhouette width of Rousseeuw’s (1987) measures the groups’ cohesion and resolution and guarantees their internal homogeneity and external heterogeneity. Average silhouette width above 0.5 indicates that the clusters have cohesion and resolution. Positive values indicate that the elements are well grouped. Negative coefficients indicate that the elements are poorly placed between the groups (Libório et al. 2021).
Two-factor ANOVA with replication: is an analysis that tests the hypothesis of significant differences between the indicators of countries of different groups (Ekel et al. 2022). In other words, this analysis verifies that the differences between the means of the data sets are significant, allowing several groups to be compared simultaneously (Quirk 2012).
This second case study was developed in four stages. First, the monthly mobility variation in retail/recreation locations in South American countries was calculated. Second, the Cooks Distance multivariate outlier detection method was used to identify and exclude countries that showed atypical variations in monthly mobility. Third, k-means cluster analysis was used to group countries according to their similarity in monthly mobility in retail/recreation locations. Fourth, two-factor ANOVA with replication was used to verify whether the impact of monthly variations in mobility in retail/recreation locations on the number of COVID-19 cases and deaths and economic indicators is significantly different between country groups.
The impact of retail and recreation mobility on economic indicators in South America
Figure 4 shows that Bolivia and Venezuela show atypical variations in monthly mobility in retail/recreation locations. These two countries were excluded from the cluster analysis that separated the countries into two groups.Fig. 4 Exclusion of outliers and definition of groups of countries with similar behavior
Average silhouette width of 0.56, above the acceptance threshold of 0.50, indicates that monthly variations in mobility in retail/recreation locations are similar between countries within the same group and dissimilar between groups. All observations show silhouette width positive, indicating that countries were grouped correctly.
The Cluster 1 countries, Argentina, Chile, Colombia, and Peru, showed monthly mobility variations in similar retail/recreation locations. In ten of the eleven months analyzed, the reduction in mobility in retail/recreation locations in Cluster 1 countries was greater than in Cluster 2 countries, Brazil, Ecuador, Paraguay, and Uruguay.
From the Two-Factor ANOVA with Replication, it is possible to state that the indicators of the two groups are statistically different at a confidence level of 0.05. Figure 5 shows that the reduction in mobility in retail/recreation locations in Cluster 1 countries was 10.75% greater than in Cluster 2 countries. The number of COVID-10 cases and deaths per thousand inhabitants was 1.25 and 1.74 times higher in Cluster 2 countries than Cluster 1 countries. It is noteworthy that countries with populations with higher average age and a higher proportion of older people do not seem to have adopted effective measures to reduce mobility in retail/recreation locations. The absence of these measures significantly increased the number of cases and deaths from COVID-19 in Cluster 2 countries.Fig. 5 Impact of mobility in retail/recreation locations on the number of cases and deaths from COVID-19 and the relationship of this impact with economic indicators
Naturally, reduced mobility in retail/recreation locations has consequences for economic activity. The South American countries that most reduced mobility in retail/recreation locations had higher unemployment and inflation rates and a greater decline in gross domestic product. The most impacted economic indicators were gross domestic product degrowth and inflation. Cluster 1 countries had gross domestic product degrowth and inflation 2.2 and 2.6 times lower than Cluster 2 countries. In turn, the unemployment rate was only 1.1 times higher in the countries that most reduced mobility in retail/recreation locations.
These results are in line with the literature that associates social distancing and mobility in retail/recreation locations with a lower number of coronavirus cases (Milani 2021; Casa Nova et al. 2021). From an economic point of view, the results reinforce the evidence that associates reduced mobility with a worsening of the real economy (Spelta and Pagnottoni 2021). This research also suggests that the impact of COVID-19 on unemployment rates in South American countries is not very different regardless of reduced mobility in retail/recreation locations. Similar to what was observed in Spain and the United (Milani 2021), these results suggest that populations in South American countries suffer from the absence of subsidy programs for employers and permanent employees.
Conclusions
The use of alternative data for economic analysis is becoming a common practice among researchers worldwide. Data extracted from internet searches and mobility can be easily obtained through Google Trend and Google Mobility platforms. Although these data allow for innovative analyses, this research shows that alternative data are still rarely used in Brazil. Only 0.52% of the publications found in the Scopus and Web of Science databases that explicitly mention Google Trends analyze the Brazilian economy. The case of Google Mobility is no different. Only 0.55% of publications analyze Brazil. This research demonstrates through two case studies how alternative data and big data techniques can contribute to the realization of innovative economic analyses in Brazil.
First, we show that searching for the future on the internet is associated with the higher average household income in the Brazilian states. The average household income in the three states where people are most looking for their future on the internet is 1.56 times higher than in the three states where people are least looking for their future. People in the three more forward-looking states have incomes 1.56 times higher than people in the three least forward-looking states. By aggregating this future-oriented index with six other economic and non-economic indicators through Principal Component Analysis, we revealed that the Federal District and the southern and southeastern states of Brazil have greater potential for economic development than the other Brazilian states.
The second case study shows the impact of COVID-19 on mobility in retail/recreation locations in South American countries and the relationship of this impact with economic indicators. The results show that countries like Brazil reduced mobility in retail/recreation locations by 34.28%. This reduction negatively impacted employment levels by 10%, economic growth by − 4%, and inflation by 4%. The rates of infection and deaths by COVID-19 per thousand inhabitants in Brazil were 1.25 and 1.74 higher than in countries that reduced mobility in retail/recreation locations by 45.03%.
The alternative data and the big data techniques used in this research bring two innovative contributions to the Brazilian economic literature. First, the economic development potential of Brazilian states is more associated with knowledge factors than with technology, innovation, or income. Second, the smaller reduction in mobility in retail/recreation locations in Brazil compared to four other South American countries minimized the effects of the coronavirus pandemic on unemployment rates, economic growth, and inflation. However, this lower impact on economic indicators is associated with more infections and deaths from COVID-19 per thousand inhabitants.
Funding
This work was carried out with the support of the Coordination for the Improvement of Higher Education Personnel—Brazil (CAPES)—Financing Code 001 and the National Council for Scientific and Technological Development of Brazil (CNPq) Grant 311032/2016–8.
Data availability
https://doi.org/10.17632/m3y4jncvch.4
Declarations
Conflict of interest
The authors declare they have no potential conflicts of interest.
Research involving human participants
This article does not contain any studies with human participants or animals performed by any of the authors.
1 https://www.google.com/covid19/mobility/
2 https://github.com/owid/covid-19-data/tree/master/public/data
3 https://databank.worldbank.org/source/world-development-indicators#
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References
Akin T Iqbal Z Mirakhor A The composite risk-sharing finance index: implications for Islamic finance Rev Financ Econom 2016 31 18 25 10.1016/j.rfe.2016.06.001
Alaimo LS Maggino F Sustainable development goals indicators at territorial level: Conceptual and methodological issues—the Italian perspective Soc Indic Res 2020 147 2 383 419 10.1007/s11205-019-02162-4
Allen KD Whitledge MD Further evidence on the effectiveness of community banks in the Paycheck Protection program Financ Res Lett 2021 19 102583
Auld C Toxvaerd F The Great COVID-19 vaccine rollout: behavioral and policy responses Natl Inst Econ Rev 2021 257 14 35 10.1017/nie.2021.23
Bargain O Aminjonov U Poverty and COVID-19 in Africa and Latin America World Dev 2021 10.1016/j.worlddev.2021.105422
Bartlett MS Properties of sufficiency and statistical tests. Proceedings of the Royal Society of London Series A-Math Phys Sci 1937 160 901 268 282
Bernardes P Ekel PI Rezende SF Pereira Júnior JG dos Santos AC da Costa MA Carvalhais RL Libório MP Cost of doing business index in Latin America Qual Quant 2021 10.1007/s11135-021-01221-8
Blazquez D Domenech J Big data sources and methods for social and economic analyses Technol Forecast Soc Chang 2018 130 99 113 10.1016/j.techfore.2017.07.027
Brodeur A Grigoryeva I Kattan L Stay-at-home orders, social distancing, and trust J Popul Econ 2021 19 1 34
Buono D Mazzi GL Kapetanios G Marcellino M Papailias F Big data types for macroeconomic nowcasting Eurostat Rev Nat Acc Macroeconom Indicators 2017 1 93 145
Carrière-Swallow Y Labbé F Nowcasting with google trends in an emerging market J Forecast 2013 32 4 289 298 10.1002/for.1252
Casa Nova A Ferreira P Almeida D Dionísio A Quintino D Are Mobility and COVID-19 Related? A dynamic analysis for portuguese districts Entropy 2021 23 6 786 10.3390/e23060786 34205561
Charles A Darné O Tripier F Uncertainty and the macroeconomy: evidence from an uncertainty composite indicator Appl Econ 2018 50 10 1093 1107 10.1080/00036846.2017.1349294
Charoenwong B Kwan A Choi PMS Huang SH Alternative Data, Big Data, and Applications to Finance Fintech with Artificial Intelligence, Big Data, and Blockchain 2021 Springer, Singapore Blockchain Technologies
Cheng P Ferrara L Froidevaux A Huynh TL Consoli S Reforgiato RD Saisana M Massive Data Analytics for Macroeconomic Nowcasting Data Science for Economics and Finance 2021 Cham Springer
Chernozhukov V Kasahara H Schrimpf P Causal impact of masks, policies, behavior on early covid-19 pandemic in the US J Econometrics 2021 220 1 23 62 10.1016/j.jeconom.2020.09.003
Choi H Varian H Predicting the present with Google trends Econom Rec 2012 88 2 9 10.1111/j.1475-4932.2012.00809.x
Cook RD Detection of influential observation in linear regression Technometrics 1977 19 1 15 18 10.1080/00401706.1977.10489493
Corbi R Picchetti P The cost of gendered attitudes on a female candidate: evidence from Google trends Econ Lett 2020 196 109495 10.1016/j.econlet.2020.109495
da Silva GC de Almeida FM Oliveira S Wanner EF Bezerra LC Takahashi RH Lima L Comparing community mobility reduction between first and second COVID-19 waves Transp Policy 2021 112 114 124 10.1016/j.tranpol.2021.08.004
Day BH The value of greenspace under pandemic lockdown Environ Resource Econ 2020 76 4 1161 1185 10.1007/s10640-020-00489-y
Denev A Amen S The Book of Alternative Data: A Guide for Investors 2020 Traders and Risk Managers John Wiley & Sons
Ding R Hou W Retail investor attention and stock liquidity J Int Finan Markets Inst Money 2015 1 37 12 26 10.1016/j.intfin.2015.04.001
Ekel PI Bernardes P Vale GMV Libório MP South American business environment cost index: reforms for Brazil Int J Bus Environ 2022 10.1504/IJBE.2021.10043256
El Gibari S Gómez T Ruiz F Building composite indicators using multicriteria methods: a review J Bus Econ 2019 89 1 1 24
Fernández-Villaverde J Jones CI Macroeconomic outcomes and COVID-19: a progress report National Bureau of Economic Research 2020 10.3386/w28004
Gallardo R Whitacre B Kumar I Upendram S Broadband metrics and job productivity: a look at county-level data Ann Reg Sci 2021 66 1 161 184 10.1007/s00168-020-01015-0
Garboden PM Fuleky P Sources and types of big data for macroeconomic forecasting Macroeconomic Forecasting in the Era of Big Data Advanced Studies in Theoretical and Applied Econometrics 2020 Cham Springer
Gruber H Hätönen J Koutroumpis P Broadband access in the EU: an assessment of future economic benefits Telecommun Policy 2014 38 11 1046 1058 10.1016/j.telpol.2014.06.007
Hassani H Silva ES Forecasting with big data: a review Ann Data Sci 2015 2 1 5 19 10.1007/s40745-015-0029-9
Holt L Jamison M Broadband and contributions to economic growth: lessons from the US experience Telecommun Policy 2009 33 10–11 575 581 10.1016/j.telpol.2009.08.008
Jain A Macro forecasting using alternative data Handbook of US Consumer Economics Jan 1 2019 Elseiver Academic Press 273 327
Kaiser HF An index of factorial simplicity Psychometrika 1974 39 1 31 36 10.1007/BF02291575
Kearney MS Levine PB Media influences on social outcomes: the impact of MTV's 16 and pregnant on teen childbearing Am Econom Rev 2015 105 12 3597 3632 10.1257/aer.20140012
Kolanovic M, Krishnamachari RT (2017) Big data and AI strategies: machine learning and alternative data approach to investing. JP Morgan Global Quantitative & Derivatives Strategy Report. https://www.casociety.org/cleveland/lists/events%20calendar/attachments/1045/big-data_ai-jpmmay2017.pdf. Accessed 4 Dec 2022
Kuc-Czarnecka M Piano SL Saltelli A Quantitative storytelling in the making of a composite indicator Soc Indic Res 2020 23 1 28 10.1007/s11205-020-02276-0
Li J, Forzati M (2018)The Social-Economic Impact of Fiber Broadband: A Hype or a Reality?. In2018 20th International Conference on Transparent Optical Networks (ICTON) (pp. 1–7). IEEE.
Libório MP Machado-Coelho TM Bernardes P Machado AM Ekel PY Soares GL Forecasting Internet demand using public data: a case study in brazil IEEE Access 2018 6 65974 65980 10.1109/ACCESS.2018.2878130
Libório MP da Silva MO Machado AM Machado-Coelho TM Laudares S Bernardes P Principal component analysis applied to multidimensional social indicators longitudinal studies: limitations and possibilities GeoJournal 2020 21 1 6 10.1007/s10708-020-10322-0
Libório MP Ekel PY Lyrio RD Bernardes P Soares GL Machado-Coelho TM Structural Equation Modeling Applied to internet consumption forecast in Brazil IEEE Access 2020 8 161816 161824 10.1109/ACCESS.2020.3016286
Libório MP Martinuci OD Machado AM Lyrio RD Bernardes P Time-space analysis of multidimensional phenomena: a composite indicator of social exclusion through k-means Soc Indic Res 2021 25 1 23 10.1007/s11205-021-02763-y
Liu Y Wang Z Rader B Li B Wu CH Whittington JD Zheng P Stenseth NC Bjornstad ON Brownstein JS Tian H Associations between changes in population mobility in response to the COVID-19 pandemic and socioeconomic factors at the city level in China and country level worldwide: a retrospective, observational study Lancet Dig Health 2021 3 6 e349 e359 10.1016/S2589-7500(21)00059-5
Ma YR Ji Q Pan J Oil financialization and volatility forecast: evidence from multidimensional predictors J Forecast 2019 38 6 564 581
MacQueen J (1967) Some methods for classification and analysis of multivariate observations. InProceedings of the fifth Berkeley symposium on mathematical statistics and probability 1: 281–297).
Mazziotta M Pareto A On a generalized non-compensatory composite index for measuring socio-economic phenomena Soc Indic Res 2016 127 3 983 1003 10.1007/s11205-015-0998-2
Meo SA Al Masri AA Usmani AM Memon AN Zaidi SZ Impact of GDP, spending on R&D, number of universities and scientific journals on research publications among Asian countries PLoS ONE 2013 20 6 e66449 10.1371/journal.pone.0066449
Milani F COVID-19 outbreak, social response, and early economic effects: a global VAR analysis of cross-country interdependencies J Popul Econ 2021 34 1 223 252 10.1007/s00148-020-00792-4 32839640
Moirangthem NS Nag B Developing a competitiveness index at sub-national level for India: an economic growth measure Int J Emerg Mark 2022 10.1108/IJOEM-02-2021-0209
Nardo M Saisana M Saltelli A Tarantola S Tools for composite indicators building Europ Comiss, Ispra 2005 15 1 19 20
Narita MF Yin R In search of information: use of google trends’ data to narrow information gaps for low-income developing countries Int Monet Fund 2018 10.2139/ssrn.3333732
Neto AR Candido O What does Google say about credit developments in Brazil? Stud Nonlinear Dyn Econom 2021 10.1515/snde-2019-0122
Papageorge NW Zahn MV Belot M Van den Broek-Altenburg E Choi S Jamison JC Tripodi E Socio-demographic factors associated with self-protecting behavior during the Covid-19 pandemic J Popul Econ 2021 34 2 691 738 10.1007/s00148-020-00818-x 33462529
Park G Schwartz HA Sap M Kern ML Weingarten E Eichstaedt JC Berger J Stillwell DJ Kosinski M Ungar LH Seligman ME Living in the past, present, and future: Measuring temporal orientation with language J Pers 2017 85 2 270 280 10.1111/jopy.12239 26710321
Pastor JM Peraita C Serrano L Soler Á Higher education institutions, economic growth and GDP per capita in European Union countries Eur Plan Stud 2018 26 8 1616 1637 10.1080/09654313.2018.1480707
Pearson KLIII On lines and planes of closest fit to systems of points in space London, Edinburgh Dublin Philosophical Mag J Sci 1901 2 11 559 572 10.1080/14786440109462720
Perlin MS Caldeira JF Santos AA Pontuschka M Can we predict the financial markets based on Google's search queries? J Forecast 2017 36 4 454 467 10.1002/for.2446
Piccoli P Speculative attacks and investor attention Available at SSRN 2019 10.1111/twec.13207
Piccoli P de Castro J Attention-return relation in the gold market and market states Resour Policy 2021 74 102333 10.1016/j.resourpol.2021.102333
Preis T Moat HS Stanley HE Bishop SR Quantifying the advantage of looking forward Sci Rep 2012 2 1 1 2 10.1038/srep00350
Qadan M Nama H Investor sentiment and the price of oil Energ Econom 2018 69 42 58 10.1016/j.eneco.2017.10.035
Quirk TJ (2012) One-way analysis of variance (ANOVA). In: Excel 2007 for Educational and Psychological Statistics. Springer New York, New York, NY
Rousseeuw PJ Silhouettes: a graphical aid to the interpretation and validation of cluster analysis J Comput Appl Math 1987 20 53 65 10.1016/0377-0427(87)90125-7
Salvati L Carlucci M A composite index of sustainable development at the local scale: Italy as a case study Ecol Ind 2014 43 162 171 10.1016/j.ecolind.2014.02.021
Spelta A Pagnottoni P Mobility-based real-time economic monitoring amid the COVID-19 pandemic Sci Rep 2021 11 1 1 5 10.1038/s41598-021-92134-x 33414495
Tümer AE Akkuş A Forecasting gross domestic product per capita using artificial neural networks with non-economical parameters Physica A 2018 512 468 473 10.1016/j.physa.2018.08.047
Varian HR Big data: new tricks for econometrics J Econom Perspect 2014 28 2 3 28 10.1257/jep.28.2.3
Vlastakis N Markellos RN Information demand and stock market volatility J Bank Finance 2012 36 6 1808 1821 10.1016/j.jbankfin.2012.02.007
Vosen S Schmidt T Forecasting private consumption: survey-based indicators vs. Google trends J Forecast 2011 30 6 565 578 10.1002/for.1213
Yu L Zhao Y Tang L Yang Z Online big data-driven oil consumption forecasting with Google trends Int J Forecast 2019 35 1 213 223 10.1016/j.ijforecast.2017.11.005
| 0 | PMC9734695 | NO-CC CODE | 2022-12-14 23:28:30 | no | SN Bus Econ. 2023 Dec 5; 3(1):3 | utf-8 | SN Bus Econ | 2,022 | 10.1007/s43546-022-00387-z | oa_other |
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High Educ (Dordr)
High Educ (Dordr)
Higher Education
0018-1560
1573-174X
Springer Netherlands Dordrecht
979
10.1007/s10734-022-00979-6
Article
Global pathways: new evidence on the international graduate school choice of Chinese outbound students
Yang Suhong [email protected]
1
Ye Xiaoyang [email protected]
2
He Dean [email protected]
3
1 grid.411054.5 0000 0000 9894 8211 School of Government, Central University of Finance and Economics, Beijing, China
2 grid.40263.33 0000 0004 1936 9094 Annenberg Institute for School Reform, Brown University, Providence, RI 02906 USA
3 grid.21729.3f 0000000419368729 Teachers College, Columbia University, New York, NY 10027 USA
5 12 2022
140
28 11 2022
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China serves as an indispensable recruitment market for higher education institutions across the globe. Using large-scale administrative and survey data from one of China’s pipeline provinces for sending students abroad, we provide new evidence on the factors influencing Chinese students’ graduate school choices internationally. We model international student mobility as a function of schooling-constrained, international migration, and consumption values. Descriptive results from nested logit model and multinomial logit model support the model predictions. We also construct counterfactual policy simulations by examining what would have happened under different potential scenarios in both China and destination countries. The simulation results show that the changes in Chinese college quality and family income are likely to affect the number of Chinese students studying abroad but not their distribution patterns among destination countries. In the meanwhile, factors including scholarship opportunities, work visa policies, and recruitment efforts in the destination countries would substantially shift Chinese students’ choice of destination country and therefore the specific graduate school location.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10734-022-00979-6.
JEL Classification
I20
I23
Keywords
Chinese outbound students
Graduate education
College choice
Counterfactual simulation
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 71704076 Yang Suhong
==== Body
pmcIntroduction
The globalization of higher education has made graduate study opportunities in developed countries abundantly available to bachelor’s degree recipients from other developing countries. Consequently, international graduate students have contributed positively to university finance and transformed the ways that highly sought-after global universities recruit and educate their international students. In the USA, Cantwell (2015) observed that US universities were able to generate positive revenue by simply enrolling additional international students. Bound et al. (2020) acknowledged that the revenue stream from international students would indeed help counteract the diminishing state support for public higher education.
Governments and higher education institutions are encouraged to specifically recruit and enroll students from outside their national borders (Altbach & Knight, 2007; Knight, 2008). While the USA remains the top destination country for international students, new international student enrollment in the USA has been declining since the fall of 2016 due to rising competition from other destination countries. Of course, the occurrence of the global COVID-19 pandemic has worsened the situation. As a result, proactive competition for international students becomes paramount, particularly in the post-pandemic world and with the restoration of political stability.
Over the past decades, Chinese students have been favored by nearly all developed countries at both the undergraduate and graduate levels, particularly in the USA and UK. According to data from the Higher Education Statistics Agency in the UK, Chinese students make up the largest cohort with 139,130 studying in the UK in 2019–2020 academic year. China is followed with a large gap by 52,545 students from India and 19,940 from the USA. Students from Italy and France are the two largest cohorts from the European Union, with 13,605 and 13,430 students, respectively, studying in the UK in the same academic year. In the USA, the situation is even more intensified because higher education institutions rely largely on full-paying international students, particularly Chinese students, to compensate for budget shortfalls caused by the decline in both domestic enrollment and state government funding (Curs & Jaquette, 2017; Krupnick, 2016; Li, 2017). In the 2019–2020 academic year alone, the number of international students studying in the USA from China totaled approximately 36% of all international students studying in the USA at all levels. Khanna et al. (2020) emphasized that the US higher education system had been transformed by the increasing number of international students since 2005, driven largely by Chinese students.
Beyond observational statistics, education policy researchers have closely examined international student mobility empirically (Barnett et al., 2016; Brooks & Waters, 2011; Kondakci et al., 2018; Levatino, 2017), especially that of Chinese students (Xiang & Shen, 2009; Cebolla-Boado et al., 2017; Lin, 2020; Yang, 2020). A growing body of literature has examined various determinants of international student mobility in the past decade. However, one obvious commonality and disadvantage of the published datasets is that they are country-level observations. Rosenzweig et al., 2006, 2008) demonstrated that variations in skill price and country-level GDP significantly impacted the number and quality of migrants to the USA. Using data from 13 OECD countries. Bird and Turner (2014) demonstrated statistically significant correlations between foreign undergraduate enrollment in the USA and a variety of (student-side) factors, including exchange rate fluctuations, home country income, and home county population of potential undergraduates, all of which were largely driven by China. Beine et al. (2014) analyzed the determinants of international students’ college choices and concluded that international students were responsive to college-side factors, such as the wage and quality of higher education, cost of living in host countries, and tuition expenses. Moreover, Stuen and Ramirez (2019) revealed a clear pattern of international student flow between pair countries (origin and host) and showed how factors such as earnings potential, educational opportunities, and cost affected the number of international students.
On the student supply side in China, existing studies have examined the overall trend and policy changes relevant to the rapid growth in the number of Chinese students who study abroad in a range of leading destination countries (Cheng & Miao, 2010; Wang, 2012). However, most of these studies remain descriptive and do not empirically examine students’ decision-making rationales. With respect to supply–demand interactions, some studies focus on the push–pull factors behind students’ decisions to study abroad (Bodycott, 2009; Li & Bray, 2007). Khanna et al. (2020) clarified that growth in housing and personal wealth was one of the key factors pushing Chinese students from families in the top tier of income distribution to study abroad. In contrast, the changing returns to education or information flows did not play a pivotal role as expected. Chen (2019) argued that US education at the undergraduate level did not necessarily boost job prospects for Chinese students returning to their home country. Furthermore, Chen et al. (2020) reported that one of the factors that forced Chinese students to return home after graduation was tightening work visa policies (H-1B program). As a result, the US education export service market is deteriorating, together with the worsened but recovering political situation.
In this paper, we examine the decisions of Chinese outbound graduate students at the individual level. Using a combination of large-scale administrative and survey data, we are among the first to provide empirical evidence on the graduate school choices of Chinese outbound students. In addition, by modeling students’ choices of graduate studies on the framework of schooling-constrained, international migration, and consumption motive, we conduct policy simulations to investigate counterfactuals: what would have happened if potential socioeconomic or policy changes were to take place in either China or destination countries under different scenarios?
Our work extends the classic college choice theories originating from the seminal work of Manski and Wise (1983) that discussed students’ preferences for different college attributes such as academic quality, job opportunities, and consumption amenities. In addition, migration has been recognized as the investment in human capital (Sjaastad, 1962). Therefore, we model international student mobility as a function of factors with respect to schooling-constrained, international migration, and consumption motive. To test the theoretical predictions, we use unique administrative and survey data on bachelor’s degree recipients from Jiangsu Province, China. With the second largest provincial GDP in China, Jiangsu Province also has the third largest number of college graduates who pursue postgraduate studies abroad,1 serving as one of the primary recruitment pipelines for US and UK universities and colleges, as well as supplying a considerable number of college graduates who pursue graduate schools in many other countries or regions.
We present several important empirical findings. We find that Chinese bachelor’s degree recipients are incentivized to pursue graduate studies abroad when their perceived domestic education opportunities are limited (schooling-constrained model). Therefore, students with stronger preferences for better teaching and research environments are more likely to choose the USA. We also find that Chinese outbound graduate students are more likely to choose destination countries with promising job prospects, such as Australia and New Zealand, and/or jobs providing competitive salaries, such as the USA (international migration model). Finally, we find that college graduates who are motivated to study abroad for reasons of cultural enrichment or other noneconomic motivations have diverse preferences for destinations such as Germany, France, and South Korea that have casual vocational lifestyles (consumption motive model). Our empirical findings are consistent with the theoretical predictions that are positioned to explain the rationales of graduate school choices of Chinese college graduates.
Using the estimated parameters from the choice models and following the standard approach of counterfactual policy simulations widely used in the economics of higher education (Arcidiacono et al., 2012; Bordón et al., 2020; DesJardins & McCall, 2010; DesJardins et al., 2002; Groen et al., 2008), we simulate counterfactuals of a set of policy shocks under different scenarios, i.e., to examine what would have happened if the policy become effect or not based on certain simulation assumptions. We focus on changes from both the student side (Chinese higher education quality and family income) and the college side in the destination countries (scholarship opportunities, work visa policies, and recruitment strategies). The results show that home country factors affect the number of Chinese bachelor’s degree recipients pursuing graduate studies abroad but are unlikely to shift their distributions in destination countries. In contrast, the market factors in destination countries, including the availability of scholarship opportunities, work visa policies, and recruitment efforts, significantly affect Chinese students’ choice of destination country.
We make three major contributions to the college choice literature as well as the practice of international graduate education. We start by providing a detailed, micro-level descriptive analysis of Chinese outbound graduates. The question of who among Chinese bachelor’s degree recipients are pursuing graduate studies abroad is answered descriptively. Second, we extend the classic college choice model by further considering the values of international education and exploring underlying factors that impact the supply of Chinese outbound students. Third, we provide counterfactual simulations based on student preferences to promote the understanding of policy impact on Chinese outbound graduate students. The findings facilitate discussions on policies and practices pertinent to university finance and international student recruitment and enrollment in the destination countries. Identifying the key characteristics of Chinese outbound students and their motives is critical for higher education institutions in the USA, the UK, and other destination countries to continue benefiting from the enrollment of international students.
The rest of the study is organized as follows. The “Background” section introduces the background. The “Theoretical framework” section establishes the theoretical framework, and the “Survey and data” section describes the data. The “Examining the graduate school choices of Chinese bachelor’s degree recipients” section presents the model and estimation results. The “Counterfactual policy simulations” section presents the counterfactual policy simulations. The “Conclusion” section concludes.
Background
This study focuses on international graduate students from China who would consider choosing to enroll at graduate schools overseas rather than in China. Empirical evidence on international graduate students is limited, although a large proportion of international students tend to enroll at advanced levels of tertiary institutions overseas. According to the Organization for Economic Co-operation and Development (OECD, 2019), while only 4% of the total university enrollment at the bachelor’s level are international students, master’s degree-seeking students account for 13% of these students, while international doctoral students constitute 22% of the total. Several factors contribute to the enrollment pattern of international students, including capacity constraints in the origin countries and the monetary and cultural return to educational investments from studying abroad, particularly when studying at prestigious institutions or earning advanced professional degrees (OECD, 2017, 2019).
China has been the source of the largest number of international students studying in OECD countries since 2008 (OECD, 2010). Reportedly, Chinese students have accounted for approximately 22% of all international students enrolled in OECD countries since 2016; this share is the highest among all reporting countries. Among Chinese students enrolled in OECD areas, almost 40% are studying in the USA (OECD, 2018). Figure 1 illustrates the enrollment trend of postgraduate students from China in the USA, indicating a sharp increase from the 2006–2007 academic year. From 2006 to 2018, the total enrollment of Chinese postgraduate students in the USA grew significantly from 47,968 to 133,396.2 In the past decade, Chinese students alone accounted for more than 30% of all international graduate students enrolled in the USA, peaking at 35.1% in 2013, followed by a two-year decline and then a rise to 35.3% in 2018. Other major countries hosting Chinese graduate students have experienced a similar growth trend. For instance, the number of Chinese postgraduate students has been rising in the UK for more than a decade to 69,305 in the 2018–2019 academic year, accounting for nearly 40% of non-UK domiciled graduate students.3Fig. 1 Trends in the number and percentage of international postgraduates enrolled from China at US higher education institutions, 2000–2018. Notes: Data are obtained from Open Doors, Institute for International Education, various years. Enrollment in the figure includes international postgraduates from China, Mainland
The increase in demand for graduate studies in China relates to its dramatic expansion in higher education access since 1998 (Ding et al., 2021). Figure 2 documents the increasing number of associate degree and bachelor’s degree recipients in China since the expansion. This higher education expansion policy creates a uniquely large candidate pool of Chinese students who seek to pursue graduate studies somewhere, either domestically or abroad. Similarly, the number of master’s degree graduates has also grown rapidly in China during the same period, as indicated in Appendix Figure A.2. However, opportunities for graduate education at the master’s and doctoral levels in China are scarce relative to the number of bachelor’s degree recipients. According to the Report on National Postgraduate Enrollment Survey in China (2020), approximately 805,000 students enrolled in postgraduate study in 2019, while the total number of students applying for the postgraduate entrance examination was nearly four times larger at approximately 2,900,000 applicants.4 This indicates the extremely limited availability of graduate education in China and shows that only one in four applicants can earn the opportunity to pursue graduate studies.5 Student demand itself creates a market for international graduate education.Fig. 2 Trends in the number of Chinese undergraduates, 1998–2018. Notes: Data are obtained from the Educational Statistics Yearbook of China, published by the Ministry of Education in China. Number of students is in thousands
Theoretical framework
Extension of college choice model
We build on and extend the classic college choice model originated from Manski and Wise (1983) to analyze the graduate school decision-making process of Chinese bachelor’s degree recipients. Since the pioneering work of Manski and Wise (1983), this college choice model, with a focus on domestic undergraduate college choice, assumes that a student college choice is affected by academic quality, college price, distance from home, and education consumption values. For example, Long (2004) applied a conditional logistic model to analyze how high school graduates in the USA chose their colleges in 1972, 1982, and 1992. The research results indicated that college quality and price were key factors for college choices, particularly for low-income students. Skinner (2019) updated Long’s findings with a new cohort of students and showed that students in the 2000s remained sensitive to both cost and distance when deciding among colleges, particularly during the college application stage. Other scholars also have extended Perna’s (2004, 2006) conceptual framework to domestic graduate school choice (Chen & Bahr, 2020; English & Umbach, 2016; Kallio, 1995; Zhang, 2005).
Extending from the college choice model, our study models international student mobility (graduate school choice) as a function of schooling-constrained, international migration, and consumption motive. Those three factors are not included in the previous literature on domestic college choice, which we use to capture different motivating factors that drive students’ international graduate school decisions and thus can have different theoretical predictions from the previous studies. Our empirical descriptions, guided by this three-factor framework, aim to describe the diversification of student demand and to explore different policy counterfactuals, i.e., to examine what would have happened if the policy become effect or not based on certain simulation assumptions.
The first model, schooling-constrained model, explains the cost‒benefit tradeoff for international students who choose to study abroad, mediated by the constrained domestic schooling model (Rosenzweig et al., 2006). This model indicates that international students typically come from countries with high rewards for skills but fewer opportunities to obtain advanced schooling. These students are most likely to be incentivized to study abroad with the goal of returning to their home country and reaping the rewards of the high return on educational investment.
In contrast, the second model of international migration model, explains that students may regard studying abroad as an initial springboard for establishing their lives in the host countries (Rosenzweig, 2008). The migration option values are particularly high when the domestic returns to education are low, for example, in the form of college graduates’ earnings. In fact, Kennan and Walker (2011) emphasized the association between income and migration being driven by both geographic differences in mean wages and a tendency to move in search of a better locational match, especially when the income realization in the current location is unfavorable. Both abovementioned motivational factors supplement the international migration model framework in explaining the considerations involved in the decision-making of Chinese outbound graduate students.
Different from the previous two models that focus on labor market benefits, the third model, consumption motive model, explains the decision-making of graduate school choices differently by shifting focus on the nonmonetary rewards of studying abroad, such as access to the culture of host countries and cultural heritage. Student preferences in colleges, graduate programs, and destination countries are heterogeneous, given their individual characteristics and living circumstances. High-achieving students tend to be more willing to pay for high-quality academic programs/institutions, while some low-achieving students from wealthier families may be more inclined to pay for consumption goods such as location, school brand names, and campus amenities.
Model predictions
The schooling-constrained and international migration frameworks differ in model predictions, although they both explain the underlying cost‒benefit mechanisms that guide the decision-making progress of prospective international students. Under the schooling-constrained model, increasing the quantity and quality of domestic education programs will reduce the probability of students seeking to study abroad. Bound et al. (2009) explored the enrollment trend of foreign doctoral students from different countries studying in the USA and concluded that countries with fewer domestic high-quality doctoral program options, such as China, sent greater numbers of students to US doctoral programs. Bird and Turner (2014) showed that the college-aged population of the sending countries positively and significantly impacted graduate enrollment in the receiving countries, but this positive relationship grew weaker as the number of universities in the sending countries increased. Consequently, our first testable hypothesis based on the schooling-constrained model is that Chinese students respond positively to education quality in the host countries but negatively to the lack of high-quality graduate education programs in China.6
Under the international migration model, decreasing job opportunities and prospects in host countries would create an adverse effect, while increasing the quality and quantity of the home countries’ graduate education programs may not stop students from going abroad. International students would find even the most advanced education opportunities less appealing if labor market conditions deteriorate and visa policies tighten. Kato and Sparber (2013) and Shih (2016) validated this model by demonstrating that, first, H-1B visa restrictions decreased the average quality of international applicants who were eventually enrolled in degree programs in the USA and second, education visa restrictions discouraged students from choosing to study abroad. Chen et al. (2020) stated that greater anticipation of student visa refusal in the USA would reduce the submission of SAT scores to and the subsequent enrollment at US universities. Our second testable hypothesis based on the international migration model hypothesizes that, incentivized by the option value of working in the host countries, Chinese students would be discouraged from studying abroad or in specific countries if job opportunities decrease in the host countries.7
To date, only a handful of studies have quantitatively explored the consumption motive aspects of college choice. Alter and Reback (2014) found that changes in both academic and quality-of-life features listed in two credible college guidebooks could affect the number of applications received by different colleges. Furthermore, Jacob et al. (2018) showed that most students appeared to value consumption elements such as high expenditure on student activities, sports, and dormitories, while the preferential taste for academic quality was confined only to high-achieving, academically driven students. A sizable portion of Chinese outbound graduate students do not reveal any rational and/or economic motivations behind their graduate school choice decision-making process. Instead, they exhibit more hedonistic incentives such as individual enjoyment, external amenities, and cultural enrichment. Their goals are to acquire foreign experience rather than to improve job competitiveness or enhance skills training. As some students tend not to respond to factors such as the educational quality, opportunities, and labor market conditions of either the sending or destination country, our third testable hypothesis is that a potential decrease in family wealth might negatively affect the likelihood of students who choose to study abroad.
In the next sections, we will use those college choice model extensions to empirically investigate the factors impact the study abroad (graduate school) choice of Chinese bachelor’s degree recipients and explore what could have happened using respective policy simulations. As students are probably motivated by various reasons to study abroad in different host countries and their motivations could change constantly based on personal and circumstantial contexts, the college choice theories are not mutually exclusive of each other. We will show that results are robust to whether we include the three factors—schooling-constrained, international migration, and consumption motive—separately or jointly (i.e., assuming a student has multiple motivations for studying abroad and those factors have interaction impacts on graduate school decisions).
Survey and data
Sampling and survey details
The Survey on Bachelor’s Degree Recipients was conducted among four graduation cohorts from 2015 to 20188 and was designed and administered under the direction and management of the College Enrollment and Employment Service Center in Jiangsu Province, an official government organization and subsidiary of the Jiangsu Province Department of Education. The surveys were conducted to inform higher education policymaking in Jiangsu, including college curriculum innovation, teaching method improvement, and student affairs. The survey was designed by a group of accomplished academic scholars and public policy practitioners in Jiangsu Province, including one of our authors. Questions on international studies were particularly based on the theoretical framework presented in the “Theoretical framework” Sect. 3.9 We replicated the same survey questions with four graduation cohorts to confirm the validity of the survey design.
We take advantage of this unique dataset because of its detailed responses from a sizable number of graduates and because Jiangsu Province is the third largest demographic region having the most college graduates who choose to study abroad. Specifically, the survey respondents were invited to participate six months after their graduation each year, just shortly after all the students had gone through the decision-making process of postgraduate planning.10 As a result, we have confidence in the validity of the survey response. Six months was a reasonable amount of time in which students had not yet forgotten their graduate school decision-making process. In fact, given that they had graduated from college and had moved onto the next phase of life, they were reporting life events as facts instead of imaginary outcomes. Therefore, data validity is worth being examined. The specific survey items (motivational, planning, and execution types) also allowed us to conveniently group them under our analytical frameworks of schooling-constrained, international migration, and consumption motive. Thus, we could further examine the costs and benefits under each mechanism to explore the deterministic factors.
Jiangsu, located in the eastern-central coastal area of China, is one of the most economically developed provinces. In 2018, Jiangsu had the second largest total GDP in China; the annual per capita disposable (after tax) income of urban residents was approximately $6,666, compared to a national average of $5,544, and the average for rural residents was $2,944, compared to a national average of $2,064.11 Jiangsu also has one of the nation’s most extensive higher education systems. In 2018, there were 271,607 graduates with bachelor’s degrees from all 78 universities in Jiangsu (the national scale was 3,868,358). This included 48 public universities, four private universities, two Sino-foreign universities, and 24 independent colleges.12 Since 2014, the gross enrollment rate for higher education in Jiangsu has exceeded 50%.13
The surveys covered 73 universities in Jiangsu Province.14 Among them, only three nonelite universities did not take part in all four surveys (two participated only in 2018, and one missed the 2015 survey).15 Thanks to the administrative efforts organized by the provincial education department and the collaboration of these universities,16 completed questionnaires were collected from 59,065 graduates with bachelor’s degrees in 2015, 58,055 graduates in 2016, 75,100 graduates in 2017, and 83,339 graduates in 2018.17
The overall response rate remained consistently stable over the four consecutive years when the surveys took place in Jiangsu Province. Detailed data were obtained from approximately 25% of all graduate cohorts annually and the subgroups who chose to pursue graduate studies abroad (see Table 1 and Table A.2 for detailed data). One important advantage of this dataset is that the survey data could be matched with the administrative data of the overall graduate population from the same year in Jiangsu Province. This feature allowed us to calculate the poststratification or nonresponse weight of the survey data due to the precise identification of who was in the survey cohort and who was not, hence facilitating weighted samples to reveal the study abroad trends of Chinese outbound graduate students. The weighted proportional distribution of the survey sample in Table A.3 and its spread is consistent with the population’s proportional distribution in Table 1.Table 1 Summary statistics on student characteristics based on overall bachelor’s degree recipients studying abroad for graduate education
2015 2016 2017 2018
Frequency % within group Frequency % within group Frequency % within group Frequency % within group
College type
Project-985 universities 1392 15.5 1363 13.2 1376 12.2 1284 10.0
Project-211 universities 2237 24.9 3100 30.1 3172 28.1 3923 30.7
Other universities 5343 59.6 5847 56.7 6741 59.7 7579 59.3
Total 8972 100 10,310 100 11,289 100 12,786 100
Majors
Engineering 3211 35.8 3603 35.0 4093 36.3 4918 38.5
Science 839 9.4 900 8.7 1120 9.9 1216 9.5
Social science 3311 36.9 3957 38.4 4020 35.6 4371 34.2
Humanities 1366 15.2 1556 15.1 1744 15.5 1921 15.0
Agriculture 82 0.9 95 0.9 108 1.0 110 0.9
Medicine 163 1.8 199 1.9 204 1.8 250 2.0
Female 5157 57.5 6142 59.6 6691 59.3 7331 57.3
Male 3815 42.5 4168 40.4 4598 40.7 5455 42.7
This table is based on the Administrative Data of College Graduates from Jiangsu, China. Project 985 is a constructive project for funding world-class universities in the twenty-first century conducted by the government of China, which includes the 39 most selective universities. Project 211 is the Chinese government’s new endeavor aimed at strengthening approximately 100 institutions of higher education and key disciplinary areas as a national priority for the twenty-first century. There are 112 universities in Project 211
The collected survey results revealed comprehensive information on the college graduates, including but not limited to individual and parental characteristics and options after graduation (work, continue to study domestically, or study abroad). For bachelor’s degree recipients who had commenced studies abroad, the survey responses also included information on their specific choices of destination countries, detailed reasoning for studying abroad, planning after graduate schools abroad, primary funding source, intended majors, and resource channels where college graduates obtained study abroad information. To the best of our knowledge, this is the only available student-level dataset that includes such comprehensive information. The rich nature of the dataset, both quantity and quality, makes our empirical analysis possible.
Summary statistics
Table A.1 describes the student characteristics of all college graduates (bachelor’s degree recipients) in Jiangsu Province from 2015 to 2018. Among them, approximately 20% chose to pursue graduate studies each year, either domestically or abroad. The percentage of graduates who chose to study abroad for graduate schools was roughly one-fourth of the total graduates who chose to pursue graduate studies each year, with an upward increasing trend, ranging from 20.7% in 2015 to 23.7% in 2016, 22.9% in 2017, and 24.2% in 2018. The absolute change in the total number of students who chose to study abroad was not insignificant, and we observed an increase of nearly 4000 students over four years from one province in China.
It is worth exploring the types of institutions from which students who chose to study abroad graduated. In China, universities have been broadly classified with or without the labeling of Project 985 University and Project 211 University in recent decades,18 which resembles the tier system of university rankings in the Western world in general. Note, however, that the Project 985 University and Project 211 University ranking systems no longer exist in China. They have been replaced by a new tertiary education development initiative called the Double First Class, a combination of World First Class University and World First Class Academic Discipline Construction movement in China. The new development initiative released university rankings in 2017, so the new list did not apply to our sample. We observed that college graduates who chose to study abroad were disproportionately from different types of higher education institutions, as indicated by the Project 985 University and Project 211 University rankings. Table 1 demonstrates that although nearly 60% of all bachelor’s degree recipients who chose to study abroad came from nonelite universities in China, the relative ratio19 of peers who came from elite Chinese universities (namely, institutions in the Project 985 and Project 211 categories) was much higher. For every 100 bachelor’s degree recipients from the Project 985 universities in 2018, approximately 18 graduates chose to study abroad. This number was smaller among Project 211 universities (10) and even smaller in nonelite colleges (4).
Table 1 also shows that the college graduates who majored in engineering and social science constituted most of the group choosing to study abroad for graduate school, both accounting for more than one-third. The rest were students who majored in humanities (15%), science (approximately 10%), and other majors. The proportion of major occupancy was consistent across years on average. Most of the graduates with bachelor’s degrees who chose to pursue graduate studies outside China were from higher-income families (see Table A.3). Their parents were college-educated professionals (close to three-quarters) who worked as public servants (more than one-third) or corporate employees (approximately one-third) or were self-employed (almost one quarter).
Table 2 describes the destinations of college graduates who chose to study abroad. The USA and UK were the top 2 destination countries, attracting nearly half of all college graduates from Jiangsu who chose to pursue graduate school abroad. Analyzing the reasons and motivations of students who chose to study abroad for graduate school, we observed that their responses corresponded to our proposed theoretical models: schooling-constrained model, international migration model, and consumption motive model.Table 2 Descriptive analysis of the bachelor’s degree recipients studying abroad for graduate education (weighted)
2015 2016 2017 2018
Destination countries/regions
UK 24.6 29.5 30.8 32.1
USA 22.1 17.1 18.3 16.6
Australia and New Zealand 17.9 17.9 18.4 15.3
Korea, Japan, and Singapore 10.3 12.6 11.7 11.9
Germany and France 8.6 7.5 6.4 6.5
EU countries 4.1 3.1 3.5 3.1
Canada 2.3 2.0 2.9 2.0
Others 10.3 10.2 8.0 12.6
Reasons for studying abroad
Pursuing better teaching and research environment 75.1 77.9 81.0 82.1
Improving employability 60.2 54.7 57.6 59.6
Enhancing foreign language capacity 40.5 38.4 40.2 41.4
Obtaining development opportunity abroad 39.6 34.1 31.1 32.1
Getting knowledge of different customs and culture 28.0 29.1 29.9 26.7
Keeping away from intense competition in mainland’s graduate entrance examination 7.3 8.2 10.4 11.2
Accepting the arrangement of family members and relatives 3.8 3.9 3.1 2.7
Following the craze in studying abroad 1.3 1.3 1.3 1.0
Plans after graduation
Getting back after working in the destination county 35.6 31.5 31.3 30.5
Working in the destination county 11.1 7.0 5.4 5.4
Getting back to the origin country 27.2 31.6 37.0 35.6
Uncertain 26.0 29.9 26.2 28.6
Main funding sources
Funded by parents, relatives, and friends 91.4 92.7 93.5 93.7
Funded by higher education institution applied to 5.1 4.6 3.7 3.6
Funded by domestic government or universities 1.2 0.9 0.9 1.0
Income from working abroad 1.5 0.8 1.1 0.8
Bank loans 0.5 0.4 0.2 0.2
Others 0.4 0.5 0.5 0.7
Major Switching
Attending a major related to the BA major 49.5 46.0 49.3 50.2
Attending the same BA major 38.5 40.2 38.5 37.5
Attending a major unrelated to the BA major 12.0 13.8 12.2 12.3
Information channels for studying abroad
Studying abroad consulting agencies 56.8 57.4 59.8 63.7
websites of target universities 51.8 49.8 54.0 53.8
Recommendations from other people 32.8 33.7 34.5 37.0
University cross-border education partnerships 22.4 18.2 18.8 15.8
Field trip abroad 6.4 9.2 10.8 11.0
Percent share within each question is reported. This table is based on the Survey on Bachelor’s Degree Recipients data from Jiangsu, China, weighted by the overall population from the administrative data
We found that the primary reason for studying abroad was the preference for quality education and research opportunities. In each survey year, more than three-quarters of all degree-seeking students reported that they were studying abroad for a better teaching and research environment. The second most prevalent reason for studying abroad was to improve employability; on average each year, 60% of the survey respondents reported this reasoning. Other common rationales included enhancing foreign language capacity, obtaining development opportunities abroad, acquiring knowledge of different customs and cultures, and avoiding the intense competition of mainland China’s postgraduate entrance examination. One interesting discovery was that graduates from different cohorts were very consistent in their reasoning regarding each question.
Additionally, Table 2 shows that Chinese students who chose to study abroad for graduate school were also diverse in their funding sources, major switching, information channels, and work plans after graduation. An overwhelming majority of international graduate students from Jiangsu were funded by their parents, relatives, friends, bank loans, and/or themselves. More than 86% of this group chose graduate majors that were consistent with or related to their undergraduate majors. To obtain information on studying abroad, students relied heavily on consulting agencies (from 56.8% in 2015 to 63.7% in 2018), the websites of prospective universities (from 51.8% in 2015 to 53.8% in 2018), recommendations from friends and other acquaintances (approximately one-third), and official university cross-border education partnerships (from 22.4% in 2015 to 15.8% in 2018). College graduates also differed in their postgraduate plans, with 46.7% preferring to look for a job in the destination countries or working temporarily in those countries before returning to China in 2015. However, the proportion decreased to 35.9% in 2018, implying that an increasing number of Chinese graduates preferred to return to China after completing their graduate studies (from 27.2% in 2015 to 35.6% in 2018).
Examining the graduate school choices of Chinese bachelor’s degree recipients
Discrete choice model
We adopt the discrete choice model to examine the graduate school choices of Chinese outbound college graduates. According to the data structure in the survey in which students reported their postgraduate status, they selected among three different options: pursuing graduate degrees in China, pursuing graduate degrees abroad, and entering the labor market directly. For those students who chose to study abroad, they further selected among a list of host countries. The ideal approach is to model after a three-step nested decision-making structure in which in the first stage a student decides between working and graduate schools, in the second stage between Chinese and foreign graduate schools, and in the third stage between different host counties. However, we cannot combine these three stages together, as we do not observe host country preference data of students who did not study abroad by the time of the survey. This limitation is unlikely to alter our main conclusions, as most Chinese students decide whether to study abroad much earlier than contemplating destination countries. Therefore, we adopt a two-level nested logit model to explore students’ choices between pursuing graduate studies abroad and domestically, and then a multinomial logit model to analyze their decisions on host countries.
The two-stage nested logit model assumes that students choose between working and graduate studies first and then make choices between Chinese and foreign graduate schools.
The graduate education choice could be represented by a random utility model introduced by McFadden (1973), which assumes that one student selects an option from among all the alternatives to maximize their expected utility (perceived level of satisfaction measure either monetarily or spiritually). In this study, students’ postgraduate choices are modeled in Eq. (1.1):1.1 Uijb=xijb′βjb+zib′γb+wjb′δ+εijb(i=1,⋯,n;j=1,2,3;b=1,2)
Uijb is a random utility if individual i chooses alternative j from the three choices (employment, domestic graduate studies, or study abroad) which can be grouped into branch b (working or graduate studies), and εijb is the error term.20 All the explanatory variables xijb are case specific or alternative invariant. The coefficient βjb identifies the impact of xijb on Uijb depending on alternative jand branch b. The coefficient γb represents the effect of the branch-level variable zib on Uijb, while the coefficient δ indicates the influence of the alternative-level variable wjb on Uijb. Obviously, individual i will choose alternative j only if its expected utility is larger than any of the other alternatives. The probability of individual i choosing alternative j from branch b can be written as Eq. (1.2):1.2 Pijb=Pij|bPb=exp(xij|b′βjb+wjb′δ)∑j=1Jbexp(xij|b′βjb+wjb′δ)×exp[τbzib′γb+IVib]∑b=1Bexp[τbzib′γb+IVib]
Define the inclusion value for branch b as:1.3 IVib=ln(∑j=1Jbexp(xij|b′βjb+wjb′δ))
The new parameter τb=1-Corr(εijb,εikb) must equal 1 to satisfy the independence from irrelevant alternatives (IIA) to produce the multinomial logit model. As the IIA assumption may not be satisfied in post-graduation decision making, we adopt the above nested logit model where the IIA restriction continues to hold within each branch. The more efficient way to estimate the parameters of the nested logit model is full information maximum likelihood approach.
When studying host country choices among students who have already studied abroad, we use a multinomial logit model as Eq. (1.4):1.4 Uij=xi′βj+εij(i=1,⋯,n;j=1,⋯,6)
Uij is a random utility if individual i chooses alternative j from one of the host country options, and εij is the error term. All the explanatory variables xi are case specific or alternative invariant. The coefficients βj identify the impacts of xi on Uij depending on alternative j. Obviously, individual i will choose alternative j only if its expected utility is larger than any of the other alternatives. As a result, the probability of individual i choosing alternative j can be written as Eq. (1.5):1.5 Pyi=j|xi=PUij≥Uik,∀k≠j=Pεik-εij≤xi′βj-xi′βk,∀k≠j
Assuming that εij satisfies the IIA assumption, the probability of individual i choosing alternative j can be written as Eq. (1.6):1.6 P(yi=jxi)=11+∑k=2Jexp(xi′βk)(j=1)exp(xi′βj)1+∑k=2Jexp(xi′βk)(j=2,...,J)
Given the data on realized choices for host countries, the logarithmic form of the likelihood function for an individual i is given by the following (the base category is j=1):1.7 lnLi(β1,...,βJ)=∑j=1JIyi=jlnP(yi=jxi)
In this equation, I is an indicator function. If yi=j, I=1; otherwise, I=0. Eventually, we obtain the estimated coefficients β1^,...,βJ^ by maximizing the sum of the total samples’ logarithmic likelihood functions.
In both the nested logit model and multinomial logit model, the primary explanatory variables xi are based on our theoretical framework. We examine the correlations between individual preferences and students’ respective study abroad decisions. In the empirical models, we control student characteristics, including demographics, family background, college and major information, and peer effects in college. Importantly, when studying host country choices among students who have already studied abroad, xi include a rich set of subjective measures of graduate school preferences, including reasons and motivations, graduation plans, funding sources, information channels, and major preferences. These measures are likely to sufficiently capture individual preferences in their study-abroad decisions. Although the results could not help us identify a causal relationship between the proposed deterministic factors and final graduate school choice due to potential omitted variable bias, the results are informative enough to suggest clear associations between influencing factors and school choices. Our argument is that we have controlled for most, if not all, confounding factors in the model. It is expected that the model minimizes the potential bias from omitted variables and can be used for further counterfactual simulations.
A remaining limitation, however, is that we do not observe the branch-level variables zib and the alternative-level variables wjb in the two-stage nested logit model. This limitation is unlikely to alter our main conclusions, as the features of the above specific alternation and branch are difficult to accurately measure. Future work can track students’ preferences and decision-making over time and deepen this line of inquiry.
The choice between pursuing graduate studies abroad and domestically
To predict the association of each covariate on the probability of one specific choice (international graduate studies, domestic graduate studies, or domestic employment), we construct the two-level nested logit model in two different ways, as shown in Table 3. One approach is to group Chinese and foreign graduate schools into one category of graduate study and working into another one, while the other approach is to partition pursuing graduate studies in China and seeking domestic employment into one category of staying in China and pursuing foreign graduate schools into a separate category. The IIA assumption tests are rejected in the above two models, which supports that the nested logit model is much more appropriate than the multinomial logit model, while the coefficients of each covariate in different models in Table 3 are very similar. As there is no well-defined testing procedure for discriminating among tree structures (Greene, 2020) , we explain the results according to the first structure.21Table 3 Multiple choice model results: postgraduation plans of bachelor’s degree recipients
Nested logit model Multinomial logit model
Branches: working vs. graduate studies Branches: study abroad vs. staying in China
International graduate studies Domestic employment International graduate studies Domestic employment International graduate studies Domestic employment
Domestic graduate studies [base outcome] [base outcome] [base outcome]
Male − 0.022* (0.010) 0.189*** (0.012) − 0.166*** (0.032) 0.077*** (0.019) − 0.091** (0.031) 0.182*** (0.012)
Reference: other universities
Project-211 universities 0.082*** (0.017) 0.067*** (0.016) 0.342*** (0.038) 0.027** (0.010) 0.349*** (0.039) 0.071*** (0.017)
Project-985 universities − 0.012 (0.025) 0.302*** (0.040) 0.025 (0.078) 0.099** (0.031) 0.179* (0.078) 0.268*** (0.042)
Reference: Social science
Engineering − 0.024 (0.013) − 0.174*** (0.015) − 0.049 (0.041) − 0.082*** (0.020) − 0.153*** (0.038) − 0.192*** (0.016)
Science − 0.059** (0.021) − 0.103*** (0.021) − 0.188** (0.060) − 0.051*** (0.015) − 0.251*** (0.060) − 0.119*** (0.022)
Humanities 0.019 (0.014) − 0.022 (0.019) 0.098* (0.039) − 0.005 (0.009) 0.088* (0.041) − 0.010 (0.020)
Agriculture − 0.033 (0.038) − 0.058 (0.041) − 0.188 (0.121) − 0.034 (0.019) − 0.225 (0.123) − 0.078 (0.042)
Medicine − 0.167*** (0.036) − 0.029 (0.026) − 0.568*** (0.091) − 0.022 (0.012) − 0.618*** (0.092) − 0.052 (0.027)
Parents: college education 0.379*** (0.049) − 0.386*** (0.017) 1.375*** (0.043) − 0.111*** (0.027) 1.262*** (0.040) − 0.261*** (0.017)
Reference: Parental job: unemployed
Parent’s job: farmer − 0.246*** (0.051) − 0.085*** (0.023) − 0.811*** (0.132) − 0.037** (0.013) − 0.851*** (0.133) − 0.089*** (0.024)
Parent’s job: self- employment 0.168*** (0.033) 0.023 (0.022) 0.524*** (0.083) 0.016 (0.010) 0.547*** (0.084) 0.038 (0.022)
Parent’s job: public servant 0.136*** (0.032) − 0.141*** (0.025) 0.538*** (0.084) − 0.056** (0.017) 0.491*** (0.086) − 0.132*** (0.026)
Parent’s job: corporate employee 0.212*** (0.037) 0.023 (0.023) 0.700*** (0.083) 0.024* (0.011) 0.731*** (0.084) 0.059* (0.023)
Reference: Family economic conditions: lowest
Family’s economic conditions: low 0.186*** (0.030) 0.273*** (0.015) 0.517*** (0.064) 0.120*** (0.029) 0.636*** (0.061) 0.286*** (0.015)
Family’s economic conditions: middle 0.480*** (0.064) 0.318*** (0.027) 1.387*** (0.075) 0.206*** (0.050) 1.588*** (0.070) 0.487*** (0.028)
Family’s economic conditions: high 0.611*** (0.082) 0.205*** (0.053) 1.792*** (0.096) 0.206*** (0.054) 1.998*** (0.098) 0.490*** (0.059)
Family’s economic conditions: highest 0.583*** (0.085) 0.337*** (0.077) 1.640*** (0.133) 0.241*** (0.067) 1.878*** (0.142) 0.563*** (0.089)
Reference: Very dissatisfied
Dissatisfied with the university graduated from − 0.019 (0.068) − 0.182 (0.105) 0.023 (0.188) − 0.092 (0.054) − 0.073 (0.206) − 0.219 (0.116)
Satisfied with the university graduated from − 0.187** (0.068) − 0.189 (0.100) − 0.485** (0.177) − 0.119* (0.055) − 0.617*** (0.194) − 0.284* (0.111)
Very Satisfied with the university graduated from − 0.256*** (0.072) − 0.173 (0.100) − 0.716*** (0.179) − 0.120* (0.055) − 0.851*** (0.196) − 0.287** (0.111)
Monthly income of peers (1000 yuan) 0.005 (0.007) − 0.032*** (0.010) 0.032 (0.020) − 0.015** (0.005) 0.013 (0.021) − 0.035*** (0.010)
The peers’ domestic employment possibility (%) 0.002 (0.001) 0.023*** (0.001) − 0.009** (0.003) 0.010*** (0.002) 0.003 (0.003) 0.024*** (0.001)
The peers’ international 0.038*** − 0.025** 0.104** − 0.002 0.102*** − 0.0
graduate studies possibility (%) (0.005) * (0.002) * (0.004) (0.001) (0.004) 06** (0.002)
The peers’ domestic graduate studies possibility (%) − 0.011*** (0.002) − 0.038*** (0.001) − 0.022*** (0.004) − 0.016*** (0.004) − 0.034*** (0.003) − 0.039*** (0.001)
Year 2016 dummy 0.041** (0.014) 0.025 (0.015) 0.152*** (0.039) 0.016* (0.007) 0.172*** (0.040) 0.037* (0.015)
Year 2017 dummy 0.034* (0.014) 0.007 (0.015) 0.128*** (0.038) 0.007 (0.007) 0.141*** (0.039) 0.016 (0.015)
Constant − 1.003*** (0.166) 0.740*** (0.150) − 3.746*** (0.342) 0.340** (0.105) − 3.427*** (0.431) 1.069*** (0.183)
Number of observations 741,933 741,933
Number of cases 247,311 247,311 247,311
Pseudo R2
0.177
Wald chi2 34,428.79
Prob > chi2 = 0.000
10,857.08
Prob > chi2 = 0.000
LR test for IIA chi2 = 248.25
Prob > chi2 = 0.000
chi2 = 32.68
Prob > chi2 = 0.000
Dissimilarity Parameters Graduate_study_tau = 0.296
Employment_tau = 1
Staying_in_China_tau = 0.419
Study_abroad_tau = 1
This table is based on the Survey on Bachelor’s Degree Recipients data from Jiangsu, China. Raw coefficients of the nested logit model are reported. Standard errors in parentheses. Some observations have missing data on university satisfaction, monthly income of peers, parent education level and job. The model therefore also includes dummy variables for missing data on these variables. “Peers” means graduates from the same university, education level and major to samples. The peers’ monthly income variable is deflated by the consumer price index for all urban consumers and is in 2015 RMB. * p < 0.05, ** p < 0.01, *** p < 0.001
Table 3 indicates that students with different characteristics have varied postgraduation plans.22 All else being equal, male graduates are less likely to pursue international graduate studies than female graduates. Males, however, are more likely to enter the labor market immediately after college. Compared with nonelite university graduates, Chinese college graduates from Project 211 universities have a higher probability of choosing graduate studies abroad, while the corresponding figure for students from Project 985 universities is insignificant. Similarly, compared with Chinese college graduates who major in social sciences, those majoring in science and medicine are less likely to pursue graduate studies abroad. Last, compared with students whose parents are less educated and unemployed, those from culturally and economically advantaged families are more likely to study abroad.
Consistent with the domestic schooling-constrained model, the empirical results also state that the more satisfied Chinese students are with the universities they graduated from, the lower their probability of wanting to pursue graduate studies abroad. We also study peer effects to understand how peers perform on domestic graduate studies and how progress toward the study abroad option affects recent outbound college graduates’ decision-making. Peer effects indicate the “average condition” in the same college and graduation cohort. Ceteris paribus, college graduates are less likely to pursue graduate studies abroad if their peers secure more domestic graduate study opportunities. In contrast, students are more likely to study abroad if they observe that it is relatively easy for their peers to do the same.
Our findings contributed to the classic college choice model in two major ways. First, by exploring how underlying factors such as domestic higher education quality and opportunities would impact the decision-making process of graduate school choice for the Chinese bachelor’s degree recipients, we extended the classic college choice model that focused on domestic college choice only to include the consideration of the value of international education, which could be explained from the perspective of domestic schooling-constrained. Second, by using a combination of detailed, micro-level and large-scale administrative and survey data, we were able to examine the question of who chose to study abroad empirically.
The choice between studying in the USA, the UK, and other countries
To clearly interpret the multinomial logit model results, following Nguyen and Taylor (2003), we predict the marginal effect of each covariate on the probability of one specific choice. Assuming that destination country decisions are independent of studying abroad, we adopt model 1.4 using the subsample that includes graduates who have already studied abroad. Therefore, for Chinese outbound graduate students who pursue graduate studies from J total countries, the expected utility Uij for individual i from studying in country j is a function of individual-level variables. Alongside the variables included in the previous estimation, we include explanatory variables such as goals and reasons for studying abroad, whether to pursue rigorous academic training, enhancing employability, enjoying cultural enrichment, or seeking job opportunities in host countries. We also include variables that identify the channels from which students obtain their study-abroad information, funding sources, and other relevant miscellaneous factors.23
Marginal effects are estimated on each covariate to explore the association between the covariate and the corresponding probability of pursuing graduate studies in one specific destination country. Table 4 shows that students’ preferences are substantially and significantly heterogeneous regarding choosing the destination country of study.24 Our observations lead to four main findings. First, students choose destination countries for a variety of reasons. Students who emphasize the teaching and research environment and/or the opportunity to improve foreign language proficiency are more likely (by 3.6 and 2.1 percentage points, respectively) to study in the USA. In contrast, students whose goals of pursuing graduate studies abroad are to obtain career advancement opportunities abroad and/or strengthen cultural awareness are less likely (by 4.1 and 4.8 percentage points, respectively) to choose the USA.Table 4 Marginal effects of multinomial logit model: destination country choices of Chinese outbound graduate students
USA UK Australia and New Zealand Germany and France Korea, Japan, and Singapore Others
Reasons for studying abroad
Pursuing better teaching and research environment 0.036** 0.019 0.01 − 0.005 − 0.025** − 0.036***
Improving employability 0.013 0.025* − 0.015 0.014* − 0.023** − 0.012
Obtaining development opportunity abroad − 0.041*** 0.015 0.057*** 0.017* 0.001 − 0.048***
Enhancing foreign language capacity 0.021* − 0.061*** 0.036*** 0.014 0.020* − 0.030**
Getting knowledge of different customs and culture − 0.048*** 0.015 − 0.015 0.036*** 0.033*** − 0.021*
Mainly funded by personal sources − 0.101*** 0.086** 0.129*** 0.019 − 0.025 − 0.109***
Plans after graduation
Working in the destination county 0.083*** − 0.281*** 0.080*** − 0.017 0.079*** 0.056***
Getting back after working in the destination county 0.097*** − 0.177*** 0.066*** 0.019* 0.043*** − 0.048***
Uncertain 0.062*** − 0.146*** 0.081*** − 0.002 0.026* − 0.021
Information channels for studying abroad
Studying abroad consulting agencies 0.018 0.088*** 0.080*** − 0.050*** − 0.059*** − 0.077***
Websites of target universities 0.032*** 0.032** − 0.031*** 0.004 − 0.038*** 0.001
Recommendations from other people 0.011 − 0.030** 0.013 0.001 − 0.027** 0.032***
Field trip abroad 0.024 0.003 − 0.030 − 0.036** 0.004 0.034*
University cross-border education partnerships − 0.036** − 0.014 − 0.008 0.060*** − 0.002 0.000
Other control variables Omitted (see full results in Table 5)
This table is based on the Survey on Bachelor’s Degree Recipients data from Jiangsu, China. The sample includes 2015–2017 cohorts. Some marginal effect results of the multinomial logit model are reported in this table and the raw coefficients are reported in Table 5. Some observations have missing data on university satisfaction, monthly income of peers, parent education level and job, and plans after graduation. The multinomial logit model therefore also includes dummy variables for missing data on these variables. “Peers” means graduates from the same university, education level and major to samples. The peers’ monthly income variable is deflated by the consumer price index for all urban consumers and is in 2015 RMB. Taking sample size into account, we merge HMT regions of China, EU countries, Canada, and Others into one group as “others” in the dependent variable of this multinomial logit model. * p < 0.05, ** p < 0.01, *** p < 0.001
Table 5 Multinomial logit model results: destination country choices of Chinese outbound graduate students
UK Australia and New Zealand Germany and France Korea, Japan, and Singapore Others
USA (base outcome)
Male − 0.425*** (0.089) − 0.162 (0.094) − 0.093 (0.116) 0.029 (0.100) − 0.281** (0.093)
Reference: other universities
Project-211 universities 0.067 (0.109) − 0.183 (0.118) 0.564*** (0.150) 0.076 (0.126) 0.314** (0.115)
Project-985 universities − 0.851*** (0.187) − 0.877*** (0.206) 1.100*** (0.247) 0.184 (0.204) 0.055 (0.187)
Reference: Social science
Engineering 0.062 (0.110) − 0.026 (0.116) 1.028*** (0.157) 0.190 (0.132) 0.189 (0.118)
Science − 0.080 (0.166) − 0.609** (0.195) 0.194 (0.245) − 0.042 (0.192) − 0.461* (0.182)
Humanities 0.176 (0.131) − 0.117 (0.143) 1.089*** (0.178) 1.441*** (0.141) 0.859*** (0.134)
Agriculture − 0.530 (0.411) − 0.224 (0.392) − 0.693 (0.656) 0.431 (0.396) 0.459 (0.342)
Medicine − 0.435 (0.274) − 0.292 (0.277) − 0.854 (0.505) − 0.393 (0.333) − 0.430 (0.281)
Reference: Very dissatisfied
Dissatisfied with the university graduated from − 0.123 (0.610) − 0.878 (0.556) − 1.819** (0.620) − 0.805 (0.584) 0.023 (0.635)
Satisfied with the university graduated from − 0.017 (0.582) − 0.648 (0.521) − 1.362* (0.558) − 0.530 (0.549) 0.305 (0.607)
Very Satisfied with the university graduated from − 0.057 (0.586) − 0.688 (0.527) − 1.492** (0.566) − 0.895 (0.555) 0.238 (0.611)
Monthly income of peers (1000 yuan) − 0.257*** (0.054) − 0.226*** (0.059) − 0.554*** (0.076) − 0.231*** (0.061) − 0.229*** (0.055)
The peers’ domestic employment possibility (%) − 0.007 (0.009) − 0.016 (0.010) 0.012 (0.013) − 0.018 (0.010) − 0.005 (0.009)
The peers’ international graduate studies possibility (%) 0.011 (0.009) − 0.004 (0.010) − 0.010 (0.014) − 0.026* (0.011) − 0.011 (0.010)
The peers’ domestic graduate studies possibility (%) − 0.026** (0.009) − 0.032** (0.010) 0.000 (0.013) − 0.029** (0.010) − 0.015 (0.010)
Parents: college education − 0.306* (0.127) − 0.122 (0.137) − 0.363* (0.160) − 0.910*** (0.133) − 0.368** (0.129)
Reference: Family economic conditions: lowest
Family’s economic conditions: low 0.241 (0.211) − 0.238 (0.208) − 0.166 (0.241) 0.168 (0.210) − 0.018 (0.194)
Family’s economic conditions: middle 0.452* (0.224) − 0.106 (0.223) 0.094 (0.262) − 0.007 (0.230) − 0.015 (0.210)
Family’s economic conditions: high 0.344 (0.264) − 0.327 (0.272) − 0.513 (0.358) − 0.680 (0.306) * − 0.259 (0.262)
Family’s economic conditions: highest 0.189 (0.357) − 0.459 (0.371) − 0.474 (0.473) − 0.359 (0.386) − 0.849* (0.394)
Reference: Parental job: unemployed
Parent’s job: farmer − 0.152 (0.504) − 0.711 (0.613) 0.417 (0.547) 0.078 (0.448) − 0.334 (0.427)
Parent’s job: self-employment 0.309 (0.298) 0.142 (0.314) 0.334 (0.370) 0.026 (0.295) − 0.342 (0.268)
Parent’s job: public servant 0.307 (0.295) 0.079 (0.311) 0.166 (0.370) − 0.040 (0.296) − 0.481 (0.267)
Parent’s job: corporate employee 0.089 (0.293) 0.059 (0.308) 0.098 (0.367) − 0.132 (0.292) − 0.622* (0.264)
Reasons for studying abroad
Pursuing better teaching and research environment − 0.136 (0.108) − 0.148 (0.114) − 0.309* (0.134) − 0.439*** (0.114) − 0.447*** (0.108)
Improving employability 0.036
(0.086)
− 0.171 (0.092) 0.091 (0.114) − 0.259** (0.096) − 0.148 (0.089)
Obtaining development opportunity abroad − 0.422*** (0.099) 0.088 (0.101) 0.051 (0.126) 0.023 (0.104) − 0.310** (0.099)
Enhancing foreign language capacity 0.349*** (0.089) 0.643*** (0.095) 0.461*** (0.117) 0.258* (0.100) − 0.028 (0.094)
Getting knowledge of different customs and culture 0.372*** (0.096) 0.209* (0.105) 0.794*** (0.122) 0.577*** (0.105) 0.197* (0.100)
Mainly funded by personal sources 1.094*** (0.211) 1.529*** (0.286) 0.840*** (0.226) 0.408* (0.175) − 0.020 (0.148)
Plans after graduation
Working in the destination county − 1.877*** (0.202) − 0.098 (0.182) − 0.716** (0.248) 0.094 (0.180) − 0.220 (0.164)
Getting back after working in the destination county − 1.470*** (0.110) − 0.235 (0.123) − 0.359* (0.144) − 0.294* (0.128) − 0.910*** (0.117)
Uncertain − 1.090*** (0.113) 0.092 (0.126) − 0.432** (0.154) − 0.209 (0.133) − 0.536*** (0.120)
Information channels for studying abroad
Studying abroad consulting agencies 0.338*** (0.093) 0.467*** (0.102) − 0.816*** (0.120) − 0.618*** (0.102) − 0.592*** (0.094)
Websites of target universities − 0.059 (0.087) − 0.391*** (0.092) − 0.154 (0.117) − 0.497*** (0.099) − 0.200* (0.091)
Recommendations from other people − 0.216* (0.087) − 0.003 (0.092) − 0.071 (0.114) − 0.274** (0.098) 0.105 (0.089)
Field trip abroad − 0.141 (0.132 − 0.344* (0.147) − 0.607** (0.187) − 0.123 (0.140) 0.047 (0.130)
University cross-border education partnerships 0.154 (0.130) 0.163 (0.140) 1.013*** (0.147) 0.236 (0.136) 0.238 (0.129)
Year 2016 dummy 0.297* (0.123) 0.155 (0.130) 0.241 (0.157) 0.308* (0.136) 0.148 (0.126)
Year 2017 dummy 0.255* (0.118) 0.185 (0.126) 0.323* (0.155) 0.349** (0.132) 0.223 (0.121)
Constant 1.456 (1.794) 0.274 (2.077) − 0.529 (2.112) 1.516 (1.975) 3.219 (2.022)
N 6983
Pseudo R2 0.121
This table is based on the Survey on Bachelor’s Degree Recipients data from Jiangsu, China. The raw coefficients of the multinomial logit model are reported. Standard errors in parentheses. Some observations have missing data on university satisfaction, monthly income of peers, parent education level and job, and plans after graduation. The model therefore also includes dummy variables for missing data on these variables. “Peers” means graduates from the same university, education level, and major to samples. The peers’ monthly income variable is deflated by the consumer price index for all urban consumers and is in 2015 RMB. Taking sample size into account, we merge HMT regions of China, EU countries, Canada, and Others into one group as “others” in the dependent variable of this multinomial logit model. * p < 0.05, ** p < 0.01, *** p < 0.001
Second, the funding sources to support Chinese outbound graduate students are found to be associated with choosing a host country in which to study. Students who mainly use personal funds are 10.1 percentage points less likely to choose the USA, ceteris paribus. Instead, they seem to favor the UK by 8.6 percentage points and Australia and New Zealand by 12.9 percentage points.
Third, we find that students’ plans after graduate schools overseas are strong predictors of their choices of host countries. Students who want to seek job opportunities in the destination countries temporarily or permanently are 9.7 and 8.3 percentage points more likely to choose the USA, respectively. Students are 17.7 and 28.1 percentage points less likely to choose the UK if their goal is to settle down either temporarily or permanently, respectively.
Finally, we discover that channels to obtain information about pursuing graduate studies abroad are also important predictors of destination country choices. Students who use publicly available websites to guide them in where to attend graduate school are 3.2 percentage points more likely to be enrolled at schools in the USA and UK. In contrast, students who depend on university cross-border education partnerships to obtain information for studying abroad are 3.6 percentage points less likely to choose to study in the USA. Unsurprisingly, with the assistance of study-abroad consulting agencies incentivized by institutional enrollment commissions, destinations such as the UK, Australia, and New Zealand are prioritized in educational marketing campaigns. It is important to keep in mind that the abovementioned channels can at the best inform us where students would acquire information to guide them for study abroad decision makings, but they will not ensure the accuracy of the information obtained. Information validity from various channels is worth being examined further as they could easily be biased or simply inaccurate. One data caveat is that we also do not have the specific information students obtained. As a result, the limitation of our prediction based on information channels can be informative but would not lead to anything precise or directional.
Therefore, our findings made additional contributions to the classic college choice model by first exploring the underlying factors such as why study abroad, the specific plans after postgraduation, funding sources, and information channels that would impact the Chinese bachelor’s degree recipients. The additional discussion towards the value of international graduate schools now can be explained from the perspective of international migration model and consumption motive model. Secondly, the nature of our datasets proved to be extremely valuable for us to examine graduate school choice empirically, once again.
Counterfactual policy simulations
Simulation algorithm
Using the parameter estimates of the nested logit model (see Table 3) and multinomial logit model (see Table 5), we simulate how potential policy variations in China (origin country) and in destination countries might impact the study-abroad decision-making of Chinese outbound graduate students. The series of “what if” questions in different contexts enables us to understand the magnitudes of such potential changes and to further explore strategies that can help both the supply and demand parties to maximize their benefits. For example, how can higher education institutions in the destination countries advance their recruitment and enrollment agenda by exploiting and understanding Chinese outbound graduate students’ specific needs for improving job market skills, seeking advanced educational opportunities or job/immigration opportunities, or even simply satisfying their hunger for foreign cultural appreciations and exposures? The highlights of the various policy differences inevitably facilitate the positioning strategy of different institutions in the USA, the UK, Canada, or elsewhere.
Krupnick (2016) stated that the decline in economic growth in China, domestic and foreign competition for international students, and rising scrutiny of nonimmigrant student visas all contribute to the challenging circumstances faced by US higher education institutions regarding recruiting Chinese students for master’s programs. Additionally, other China-related factors, such as improved education quality and increased education opportunities with affordable tuition, stronger job prospects, safe environments, and political stability, all make the USA a less preferable and less attractive destination to study abroad. In contrast, this loss of the USA is a gain for other popular countries, such as the UK and Canada.25
Based on the theoretical decision-making framework of Chinese outbound graduate students, as well as the available parameters of interest from the empirical models in the previous section, we conduct seven pairs of counterfactual simulations that are policy relevant. Specifically, we set out to examine the impact of the change in student satisfaction with Chinese higher education and the impact of financial stocks that are closely associated with college affordability in the USA, the UK, and other countries on the student demand side (schooling-constrained model). On the college supply side, the simulations examine the impact of financial aid policy change in destination countries and the impact of work visa policy change (international migration model). For example, the USA is the best-known and most reputable country that uses its generous, merit-based, and need-based financial aid policies to compete for the best minds in the world. The H-1B work program, although controversial, is regarded as a direct and convenient path to permanent residency in the USA. Our final three pairs of simulations examine specific recruitment efforts that are rooted in and can explain the consumption motive model. The scenarios include recruitment collaborations and partnerships with consulting agencies in China, the building and maintenance of user-friendly recruitment/college websites, and the establishment of bilateral partnerships with Chinese universities and colleges.
The standard counterfactual simulation approach considers different scenarios and compares the outcomes between an actual scenario and the counterfactual scenario. For simplicity, our assumption is that policy changes are exogeneous and that there are no confounding general equilibrium effects that would reverse the results, at least in a short period. This approach has been widely adopted to simulate counterfactual changes in the effects of financial aid on student departure from college (DesJardins & McCall, 2010; DesJardins et al., 2002), the effects of graduate program quality on student attrition (Groen et al., 2008), the effects of expected earnings on college major choice (Arcidiacono et al., 2012), and the effects of preferences on the gender gap in college major choice (Bordón et al., 2020).
The algorithmic construction of the counterfactual policy simulations is presented in Algorithm 1 in the Appendix. We consider both the choice of whether to study abroad and the choice of which country to study in, resulting in the nested logit model and multinomial logit model as reported in the previous sections.
Counterfactual scenario #1: changes in higher education satisfaction in China
The first counterfactual simulation examines the impact of hypothetical changes in higher education satisfaction on Chinese outbound graduate students’ decision-making. The schooling-constrained model predicts that there exists a substitutional effect between studying abroad and staying to attend graduate studies or work locally. China has invested significant efforts to build world-class universities (Song, 2018), and we have witnessed the rapid development of growing US university enterprises such as the New York University Shanghai campus and the Duke Kunshan campus. Even so, development efforts will take a considerable amount of time, and access to high-quality higher education opportunities in China is ultra-selective. The concerns that higher education quality in China is generally low will not disappear overnight (Loyalka et al., 2019). In this simulation, we assume that Chinese outbound graduate students’ choices are only affected by the change in higher education quality to ensure the exogeneity of the policy variation. To measure and account for university quality, we use students’ satisfaction (subjective evaluation) as a proxy. The probabilities of choosing to study abroad in the baseline model are compared with two scenarios that include Chinese outbound graduate students who reported increased or decreased satisfaction with the domestic institution for one unit level.
Based on the simulation results of the nested logit model, Fig. 3 depicts the predicted study abroad probability of Chinese bachelor’s degree recipients, in which the probability is higher if there are more values farther to the right, while the probability becomes lower if there are more values farther to the left. Noticeable changes in the probability of studying abroad can be seen when Chinese bachelor’s degree recipients experienced the change in graduates’ level of satisfaction with domestic university education.26 Note that the scale of probability changes when higher education satisfaction increased/decreased is not symmetric. The implication is that additional factors exist that impact the decision-making of Chinese bachelor’s degree recipients.Fig. 3 Changes in university satisfaction and predicted study abroad probability of Chinese bachelor’s degree recipients. Notes: The sample mean of predicated study abroad probability is 2.8%. If the university satisfaction of Chinese bachelor’s degree recipients had increased for one level, the predicted probability would be 2.6%, while the predicted probability would be 3.7% if their university satisfaction had decreased for one level
This result is consistent with the predictions of schooling-constrained model and nested logit model estimation: dissatisfaction with domestic higher education (particularly due to a lower level of higher education quality) would increase the probability of studying abroad for Chinese bachelor’s degree recipients. In contrast, the probability of studying abroad would decrease if student satisfaction with domestic higher education became greater (particularly due to increasing higher education quality).
We also discover that among students who have already chosen to study abroad, the impact of a change in higher education satisfaction on their selection of destination countries is relatively small (see Figure A.3 for details). Table 6 reports the percentage of all students by destination country under each policy scenario. Under the scenario of lower domestic institutional satisfaction, the probabilities of choosing to study in the USA and UK are 19.2% and 26.3% (8% and 3% increase from the status quo estimates from the model), respectively. The corresponding predicted probabilities under higher domestic institutional satisfaction are 18.5% and 26.0% (4% and 2% increases from the status quo estimates) for the USA and UK, respectively.Table 6 Simulation of destination country choices: adjusted probability of assuming all Chinese outbound graduate students had…
Baseline model estimates Decrease/no in factors of panels A–G Increase/yes in factors of panels A–G
Adjusted probabilities Differences in adjusted probabilities Percent change in adjusted probabilities Adjusted probabilities Differences in adjusted probabilities Percent change in adjusted probabilities
Panel A: satisfaction on university graduated from
USA 0.178 0.192 0.014 7.87% 0.185 0.007 3.93%
UK 0.255 0.263 0.008 3.14% 0.260 0.005 1.96%
Australia and New Zealand 0.164 0.159 − 0.005 − 3.05% 0.167 0.003 1.83%
Germany and France 0.083 0.074 − 0.009 − 10.84% 0.082 − 0.001 − 1.20%
Korea, Japan, and Singapore 0.140 0.142 0.002 1.43% 0.123 − 0.017 − 12.14%
Others 0.180 0.171 − 0.009 − 5.00% 0.184 0.004 2.22%
Panel B: family income
USA 0.178 0.180 0.002 1.12% 0.182 0.004 2.25%
UK 0.255 0.230 − 0.025 − 9.80% 0.276 0.021 8.24%
Australia and New Zealand 0.164 0.180 0.016 9.76% 0.166 0.002 1.22%
Germany and France 0.083 0.085 0.002 2.41% 0.081 − 0.002 − 2.41%
Korea, Japan, and Singapore 0.140 0.139 − 0.001 − 0.71% 0.120 − 0.02 − 14.29%
Others 0.180 0.186 0.006 3.33% 0.176 − 0.004 − 2.22%
Panel C: scholarship for studying abroad
USA 0.178 0.173 − 0.005 − 2.81% 0.274 0.096 53.93%
UK 0.255 0.260 0.005 1.96% 0.162 − 0.093 − 36.47%
Australia and New Zealand 0.164 0.168 0.004 2.44% 0.066 − 0.098 − 59.76%
Germany and France 0.083 0.086 0.003 3.61% 0.060 − 0.023 − 27.71%
Korea, Japan, and Singapore 0.140 0.140 0.000 0.00% 0.151 0.011 7.86%
Others 0.180 0.174 − 0.006 − 3.33% 0.287 0.107 59.44%
Panel D: working permit in destination country
USA 0.178 0.121 − 0.057 − 32.02% 0.195 0.017 9.55%
UK 0.255 0.381 0.126 49.41% 0.110 − 0.145 − 56.86%
Australia and New Zealand 0.164 0.115 − 0.049 − 29.88% 0.187 0.023 14.02%
Germany and France 0.083 0.077 − 0.006 − 7.23% 0.060 − 0.023 − 27.71%
Korea, Japan, and Singapore 0.140 0.111 − 0.029 − 20.71% 0.194 0.054 38.57%
Others 0.180 0.195 0.015 8.33% 0.254 0.074 41.11%
Panel E: consulting agencies for studying abroad
USA 0.178 0.190 0.012 6.74% 0.195 0.017 9.55%
UK 0.255 0.293 0.038 14.90% 0.110 − 0.145 − 56.86%
Australia and New Zealand 0.164 0.197 0.033 20.12% 0.187 0.023 14.02%
Germany and France 0.083 0.060 − 0.023 − 27.71% 0.060 − 0.023 − 27.71%
Korea, Japan, and Singapore 0.140 0.114 − 0.026 − 18.57% 0.194 0.054 38.57%
Others 0.180 0.146 − 0.034 − 18.89% 0.254 0.074 41.11%
Panel F: websites of target universities
USA 0.178 0.192 0.014 7.87% 0.195 0.017 9.55%
UK 0.255 0.271 0.016 6.27% 0.110 − 0.145 − 56.86%
Australia and New Zealand 0.164 0.149 − 0.015 − 9.15% 0.187 0.023 14.02%
Germany and France 0.083 0.086 0.003 3.61% 0.060 − 0.023 − 27.71%
Korea, Japan, and Singapore 0.140 0.122 − 0.018 − 12.86% 0.194 0.054 38.57%
Others 0.180 0.180 0.000 0.00% 0.254 0.074 41.11%
Panel G: university cross-border education partnerships
USA 0.178 0.147 − 0.031 − 17.42% 0.195 0.017 9.55%
UK 0.255 0.241 − 0.014 − 5.49% 0.110 − 0.145 − 56.86%
Australia and New Zealand 0.164 0.155 − 0.009 − 5.49% 0.187 0.023 14.02%
Germany and France 0.083 0.140 0.057 68.67% 0.060 − 0.023 − 27.71%
Korea, Japan, and Singapore 0.140 0.138 − 0.002 − 1.43% 0.194 0.054 38.57%
Others 0.180 0.179 − 0.001 − 0.56% 0.254 0.074 41.11%
This table is based on simulation results of the multinomial logit model which explores Chinese students’ destination country choices for international graduate studies, using the Survey on Bachelor’s Degree Recipients data from Jiangsu, China. The sample includes 2015–2017 cohorts. Baseline displays the predicted international study probabilities of the sample. Adjusted probabilities simulate how the predicted international study probabilities of Chinese students would change if their university satisfaction or families’ economic affordability decreased or increased, whether scholarships or working opportunities were provided by their destination countries or not, and whether studying abroad consulting agencies, friendly websites, or partner universities were used to attract Chinese students with bachelor’s degrees by their target universities or no
The implication that comes out of this policy simulation is that although skills training and access to quality education are core elements under the schooling-constrained model, many other influencing factors equally impact where Chinese outbound graduate students choose to study abroad. Although lower satisfaction with domestic higher education incentivizes Chinese bachelor’s degree recipients to study abroad, a more important message for US institutions is that the quality of higher education of US universities is seen as a given for Chinese outbound graduate students. Therefore, US higher education institutions should focus on emerging factors under the international migration model framework and consumption motive model framework, such as relaxed work visa policies and additional cultural enrichment programs, which we will discuss in the following simulations, to compete with other countries, such as the UK, for the best graduate students from China. The predictions of the probabilities imply that the UK is a competitive destination for Chinese outbound graduate students.
Counterfactual scenario #2: changes in financial affordability of Chinese students
In 2019, approximately 400,000 Chinese students enrolled at US colleges and universities, contributing approximately $15 billion in tuition and fees to the US economy.27 In US graduate schools, particularly at the master’s level (our focus of the survey study), most programs are tuition driven, and international graduate students pay out of their own pocket. Other countries, such as the UK, Canada, and especially Australia, are similar in this regard. As a result, international graduate students from China, who have the financial capacity to pay independently, are particularly welcomed in the global education market.
The second counterfactual simulation examines what would happen to the probability of enrollment in graduate schools abroad if there were positive or negative changes in Chinese students’ financial situations. Unlike in the USA or other industrialized countries such as the UK and Canada, many students are financially dependent on their parents in China regarding educational investment. Chinese parents are also more than willing to spend money on education, which they regard as a path to a better life. The schooling-constrained model predicts that the impact of financial stocks is closely associated with college affordability in the USA, the UK, and other countries. Our assumption is that financial capacity is a standalone, exogenous factor. Consequently, provided that China’s economy has entered a “new normal” in which China’s economic growth has shifted significantly from high speed to medium to high speed since 2014, the individual wealth level of Chinese families will be negatively impacted, and their willingness to pay to study abroad will also decrease significantly in the coming years.
Figure 4 presents evidence that family income is an indispensable factor that influences the probability of studying abroad for Chinese bachelor’s degree recipients, in which the probability is higher if there are more values farther to the right, while the probability becomes lower if there are more values farther to the left. When families could not pay more, there would be a lower probability of choosing (and lower affordability) to study abroad.28 Table 6 presents detailed results of the second policy simulation. Whether students choose to study in the USA does not seem to be very affected by changes in family financial circumstances. This result could arise because an absolute change of one unit of family income is not financially significant enough or because the USA is a solid choice for Chinese outbound graduate students despite their financial situations. Nevertheless, the UK might be most negatively affected by the decreasing affordability of Chinese students for an overseas education. The alternative destination country options include Australia, New Zealand, Germany, and France. When family income in China increased, students would be redirected from Asia and Europe to pursue graduate studies in the USA and UK.Fig. 4 Changes in family income and predicted study abroad probabilities of Chinese bachelor’s degree recipients. Notes: The sample mean of predicated study abroad probability is 2.8%. If the family income of Chinese bachelor’s degree recipients had increased for one level, the predicted probability would be 4.3%, while the predicted probability would be 2.2% if their family income had decreased for one level
Overall, our finding demonstrates that family income plays an indispensable role in influencing the probability of studying abroad for Chinese bachelor’s degree recipients. The finding is consistent with the predictions of schooling-constrained model and nested logit model estimation: higher family income would increase the probability of studying abroad while the probability of studying abroad would decrease if the family income became lower. However, family income has mixed effects on students’ host country choices. The implication is that although financial affordability is important under the schooling-constrained model, many other influencing factors equally and concurrently impact where Chinese outbound graduate students choose to study abroad.
Counterfactual scenario #3: changes in scholarship policies in host countries
While most Chinese students who study abroad pay for their own education, there are a reasonable number of students who rely primarily on merit-based scholarships, particularly at the doctorate level. The third counterfactual simulation examines the impact of financial aid policy change in destination countries. The international migration model predicts that the impact of financial aid policy change in destination countries is closely related to destination choice of Chinese bachelor’s degree recipients.
The results from panel C in Table 6 suggest that the USA would experience a loss of a small number of Chinese outbound graduate students if all destination countries would not provide scholarships. In contrast, almost all Chinese outbound graduate students would choose to study in the USA if scholarships were available. Statistically, the probability of Chinese students going to the USA for graduate studies would rise dramatically by 54%. Under the same scenario, the probability of Chinese outbound graduate students going to the UK, Australia, New Zealand, Germany, and France would suffer a large decrease.
The finding is consistent with predictions from the international migration model and multinomial logit model estimation that said providing financial aid in one country (leading to lower cost for international student mobility) would increase the probability of being selected as destination for international graduate study while the probability of being selected as destination for studying abroad would decrease if the country could not provide financial aid (leading to higher cost for international student mobility on the contrary).
Another important discovery is that result from the impact of merit-based scholarship on the enrollment of Chinese outbound graduate students contradicts findings from the domestic context in the USA. For example, Fitzpatrick and Jones (2016) documented a moderate to no impact of merit-based scholarships on college enrollment and degree completion and an unknown impact on economic prosperity when combining datasets from across multiple states. We cautiously note, however, that our target student population is different. Moreover, our simulation incorporated a sample of students who had already started to study abroad, and we focused on the distributional changes (intensive margin). We are unable to answer the question regarding potentially new entrants to the international graduate education market (extensive margin) due to data limitations. Nonetheless, the extensive margin effect would be minimal in the short term, as we have shown that students make the two-step decisions sequentially and separately.
Counterfactual scenario #4: changes in work visa policy in host countries
Given that job prospects after graduation are obviously critical considerations for students deciding to study abroad, it is anticipated that tightening or loosening the work visa approval rate will affect international students’ choices of host countries (Chen et al., 2020). The fourth counterfactual simulation examines the impact of work visa policy change in destination countries. The international migration model predicts that the impact of work visa policy change in destination countries is closely related to destination choice of Chinese bachelor’s degree recipients.
Figure 5 virtualizes the changes in working opportunities and predicts the enrollment probabilities of going to the USA and UK, while the probability is higher if there are more values farther to the right and the probability becomes lower if there are more values farther to the left. The USA and UK are the two largest destination countries and competitors that recruit Chinese outbound graduate students. In both countries, changes in work visa policies would greatly impact the graduate school enrollment decisions of Chinese students.29Fig. 5 Changes in working opportunities and predicted enrollment probability of Chinese outbound graduate students. Notes: The figures are based on the simulation results of the multinomial logit model which explores Chinese students’ destination country choices for graduate studies abroad. The raw model displays the predicted enrollment probability of the sample; All Stay and All Return simulate how the predicted enrollment probability of Chinese students would change if their destination countries had provided enough or no working opportunities, respectively
Panel D in Table 6 presents the detailed findings. If none of the destination countries provided work permits for international graduate students, the probability of Chinese students choosing to study in the USA would decrease rapidly by 32%. Meanwhile, students would be more likely to choose the UK alternatively (the probability increases by 49.4%). Under the same scenario, Chinese students would also become less likely to study in Australia, New Zealand, Germany, France, and other Asian countries.
In contrast, the probability of Chinese students choosing to pursue graduate studies in the USA as a destination country would be obviously higher than the baseline probability of 9.6% when host countries could provide work permits for international students. It is surprising that the probability of Chinese outbound graduate students choosing the UK as the destination would decrease by 56.9% in this scenario. A direct implication is that the UK is not a priority place to work if students are given options. Note that the probabilities of studying in other countries indicated in the survey also increase under this scenario, except for France and Germany.
The findings are consistent with the predictions from the international migration model and multinomial logit model estimation that loosening work visa policy in one country (mainly leading to more working opportunities for international students) would increase the probability of being selected as destination for international graduate study while the probability of being selected as destination for studying abroad would decrease if the country tightened work visa policy (mainly leading to fewer working opportunities for international students).
Counterfactual scenario #5: changes in recruitment strategies
The final set of simulations examines changing recruitment approaches (see panel E, panel F, and panel G in Table 6). Established recruitment measures include setting up study-abroad consulting agencies in China, designing user-friendly college websites, and developing cross-border education partnerships with Chinese higher education institutions. The consumption motive model predicts that recruitment strategies of destination countries are closely related to destination choice of Chinese bachelor’s degree recipients.
Under the scenario in which all destination countries adopted the abovementioned recruitment strategies, the probability of Chinese students pursuing graduate studies in the USA would increase by 9.6%, while the corresponding probability of choosing the UK would decline significantly by 56.9%. Under the scenario in which none of the destination countries would set up study-abroad consulting agencies in China or design user-friendly college websites, the probabilities of Chinese students going to the USA would appear to increase by 6.7% and 7.9%, respectively, and the probabilities would increase by 14.9% and 6.3%, respectively, for the UK. Similarly, if no host countries developed cross-border education partnerships with Chinese higher education institutions, the probabilities of Chinese students choosing to study in the USA and UK would decrease by 17.4% and 5.5%, respectively. Therefore, the efforts invested in building cross-border higher education partnerships make strategic sense.
We find that both active and passive recruitment strategies have mixed effects on students’ host country choices. The implication is that although recruitment strategies play an important role under the consumption motive model, many other influencing factors impact where Chinese outbound graduate students choose to study abroad equally and concurrently.
Conclusion
Using a uniquely large-scale administrative and survey dataset from Jiangsu Province, China, we study the decision-making of Chinese outbound graduate students from the region. Our findings provide novel evidence on the characteristics of Chinese outbound graduate students. From a descriptive perspective, we present and discuss the characteristics and patterns of Chinese outbound graduate students. Taking advantage of the estimation results from the nested logit model and multinomial logit model, we conduct a series of counterfactual policy simulations to examine how different policy change scenarios would impact the decision-making of Chinese outbound graduate students, such as where they would choose to attend a graduate program. To the best of our knowledge, our paper is one of the first studies to provide such comprehensive simulations of Chinese outbound graduate students’ destination country choice.
Our findings have important implications at both the state (government policymaking) and institutional levels (universities and colleges) of the destination countries, given the diplomatic and financial interests of participating stakeholders. In terms of policy implications for individual institutions in the USA or elsewhere, we believe that the framework that we propose and empirically examine in this paper will help institutions better understand how Chinese students make their international graduation education choices. Particularly, students have diverse preferences for international studies that lead to varying responses to different potential scenarios. Our simulations are at the extensive margin for between-country comparisons that can provide alerts for the overall flows of Chinese students. One of our simulations also target institutional policies (recruitment strategies), which can be informative institutions about how Chinese students respond to different recruitment efforts. With more detailed data among a specific institution’s recruiting pool, our framework and simulation methodology (as we provide open-source algorithms and codes) can be readily applied to institution’s own analysis.
Our findings can help universities adapt to the academic, cultural, and professional needs of prospective Chinese outbound graduate students by designing a graduate curriculum that addresses the driving factors discussed in the schooling-constrained, international migration, and consumption motive frameworks. The ultimate educational goal is to equip graduates with adequate market competencies to satisfy career requirements as well as connecting students with personal development opportunities such as internships. We observe that some US universities that emphasize the career training aspect of graduate education, which falls under the international migration option framework, achieve great success in international graduate student recruitment. By doing so, US universities occupy the pivotal position in leading in the global graduate education market and remain ultracompetitive in terms of academic training, research development, institutional strategy, the maintenance of US job market prosperity, and global talent attraction.
Finally, our research contributes to the growing college choice literature by presenting solid empirical evidence and we have associated our findings with an integrated framework that incorporates the schooling-constrained model, international migration model, and consumption motive model with a focus on international graduate education. We uncover the underlying mechanisms that shed light on why Chinese college graduates would choose to study abroad, supporting the schooling-constrained model and international migration model with empirical results. We demonstrate that increasing the satisfaction of Chinese higher education will reduce the probability of Chinese bachelor’s degree recipients seeking to study abroad for graduate education, and we show that decreasing job opportunities in destination countries such as the USA will lower the appeal for Chinese students to study there. Consistent with the consumption motive model, our findings also emphasize the importance of incorporating cultural enrichment and other nonmonetary efforts into formal graduate school education to attract international graduate students in sustainable ways. However, we would like to acknowledge that characteristics (quality factors for example) of the destination institution should be included for future research analysis. The specific measures of institution quality, for example, would add value to the discussion of students’ decision-making process for study abroad, as the quality factor makes more sense for high caliber students, rather than the destination country factor alone. This would be something to be hopeful for in the coming years as we are currently making efforts on it.
We conclude by pointing out that although our descriptive findings are very consistent with theoretical models, the results in this paper are still limited and not able to examine long-run general equilibrium effects. Future work can provide quasi-experimental and experimental evidence to demonstrate factors that would causally impact Chinese outbound graduate students’ decision-making, particularly their informational and behavioral barriers (Ye, 2021). Consequently, the work can also be helpful for evaluating relevant and critical higher education policy changes in the context of China, the USA, the UK, and other interested destination countries.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 890 KB)
Acknowledgements
We are particularly grateful to Brendan Cantwell and Judith Scott-Clayton for their suggestions that shaped this paper constructively. We wish to thank the reviewers, William Dickens, Alex Eble, Jeongeun Kim, Xiaojie Li, Joydeep Roy, Sarah Cohodes, Xiaohao Ding, Wei Ha, Lei Zheng, Xue Gong, Ying Zhai, and participants at 2017 ASHE and 2021 AEFP conferences and various seminars for their insightful comments. We also thank the College Enrollment and Employment Service Center of the Department of Education in Jiangsu Province for making this project possible and providing data, and the financial support from the National Natural Science Foundation of China (71704076). The comments, findings, and conclusions expressed in this paper are those of the authors. All authors contributed equally to this paper and all errors and omissions are our own.
Data Availability
The data is a restrictive admistrative data owned by the College Enrollment and Employment Service Center, a subsidiary of the Jiangsu Province Department of Education, and is not accessible by the public.
1 According to the national administrative data on Chinese bachelor’s degree recipients in 2011 provided by the Ministry of Education, there were 50,237 college graduates seeking graduate studies abroad throughout China, Jiangsu Province, accounting for 8.2%, which was just below that of Beijing (20.5%) and Shanghai (15.4%).
2 On a similar scale, it is evident from Appendix Figure A.1 that the trend of both undergraduate and postgraduate students from China enrolled at the US higher education institutions also increased for about four times, from 57,956 in 2006 to 282,276 in 2018.
3 Data are obtained from Higher Education Student Statistics: UK, 2018/19 statistical bulletin.
https://www.hesa.ac.uk/data-and-analysis/students/where-from
4 The graduate school admissions and enrollment policy further stipulates that those Chinese students applying to postgraduate entrance examination can only apply to one school and one major at a time for that academic year, according to the official website of the National Postgraduate Registration and Transfer in China. In case of failing in meeting the admission standards of the school applying for, students can only be considered to transfer his application to a different school (same major) if and when there are additional spaces become available with approval from university officials and that they meet the basic admission standard.
5 Data are obtained from The Report on National Postgraduate Enrollment Survey in China (2020). https://www.eol.cn/e_ky/zt/report/2020/catalog.html
6 The rationale is that, conditional on improvements in the quality of domestic graduate education, more Chinese bachelor’s degree recipients would opt to stay in China and fewer would opt to pursue graduate education abroad. College quality is not necessarily unidimensional but may also involve some matching of students to institutions. It could be that the home country institutions are excellent but that studying abroad offers access to a wider variety of different models of education. This means that the push–pull factors for international graduate study choices are not always necessarily higher in quality per se, but host countries could provide different and, in some cases, potentially better matches for students’ learning style, interests, and goals.
7 For example, the political instability emerging in the USA under the current administration (events such as the visa tightening policy/visa administration check/suspension of the H-1B work visa program) greatly reduced Chinese graduate students’ motivation to study abroad since 2017. The total number of international (Chinese) students studying in the USA decreased in three consecutive years (Open Door Report, 2019).
8 Because family background information for college graduates in 2018 is unavailable, we use only the 2018 data to conduct descriptive analysis.
9 Due to confidentiality restrictions, we were not given access to the survey administration roster. We present the relevant survey items in the Online Appendix.
10 According to the administrative data of college graduates from Jiangsu, China, from 2015 to 2018, approximately 88% of all bachelor’s degree recipients had chosen to study abroad or domestically or enter the labor market when the surveys were conducted.
11 See “China Statistical Yearbook (2019), complied by National Bureau of Statistics of China, China Statistics Press, p188,196.”.
12 See “Jiangsusheng Putong Gaodeng Xuexiao Mingdan (List of the Regular Institutions of Higher Education in Jiangsu Province)”. http://jyt.jiangsu.gov.cn/art/2020/4/21/art_58319_6929344.html
13 See “2014 Nian Jiangsusheng Guomin Jingji he Shehui Fazhan Tongji Gongbao (Statistical Communiqué of Jiangsu Province on the 2014 National Economic and Social Development).”.
http://district.ce.cn/newarea/roll/201502/25/t20150225_46457212.shtml
14 There were 78 undergraduate institutions in Jiangsu Province. Among them, four public nonelite and one Sino-foreign undergraduate institutions did not take part in the survey.
15 As we focus on the group who choose to study abroad and as the probabilities of going abroad in these three nonelite undergraduate institutions were very low, the influence of missing data was negligible.
16 The Ministry of Education of the People’s Republic of China called on every university to release an annual report on the employment of their graduates, so most of these undergraduate institutions had strong motivations to collect a sample that was large enough for them to conduct analysis on their own.
17 In addition to bachelor’s degree recipients, we also collected data on graduates with associate, master’s or doctoral degrees. As our primary concern is the supply of international graduates from China in this study, we consider only the bachelor’s degree samples for analysis.
18 The Project 985 and Project 211 categorization can be interpreted as China’s version of elite universities comparable with Ivy Leagues in the USA’ Ivy League, albeit with a much smaller absolute number. In Jiangsu, only Nanjing University and Southeast University are Project 985 Universities. There are 9 other Project 211 Universities, which are China University of Mining and Technology, China Pharmaceutical University, Nanjing Agricultural University, Nanjing Normal University, Nanjing University of Science and Technology, Nanjing University of Aeronautics and Astronautics, Jiangnan University, Hohai University, and Soochow University. In this study, Project 211 universities strictly refer to these 9 universities.
19 The relative ratio of college graduates who chose to study abroad in Project 985 universities equals the proportion of college graduates who chose to study abroad from Project 985 universities divided by the proportion of overall college graduates from Project 985 universities. The calculation of the relative ratio of Project 211 universities and nonelite universities are similar to this.
20 This basic model setup has been widely used in the college choice literature (e.g., Jacob et al., 2018; Long, 2004).
21 The values of dissimilarity parameters equal to 0 implies that the alternatives in the relative nest are perfectly correlated, whereas 1 implies independence.
22 Our main results are from the surveys in 2015–2017, as parental information was missing in 2018. The results are similar when including the 2018 cohort or omitting parental information in the model.
23 Note that we constructed an additional multinomial logit model to include the interaction terms of factors (motivations and information channels) that would impact study abroad, as these are not mutually exclusive. The results of marginal effects and raw coefficients are presented in Table A.5 and Table A.6, respectively. The simulation results in Table A.7 are similar to those in Table 6 without interaction terms. To clearly explain the estimation results, we present the results without interactions in the main text. There are data limitations to be considered in future studies, such as that the students’ motivations may change over time, different students can be motivated by different reasons at various degrees, and the content of information obtained from different channels are dissimilar.
24 The raw coefficients of the multinomial logit model are presented in Table 5.
25 https://www.bangkokpost.com/world/1953984/chinese-students-turn-away-from-us-universities
26 The simulation results based on the nested logit model and multinomial logit model presented in Table A.4 are very close.
27 https://theconversation.com/5-reasons-chinese-students-may-stop-studying-in-the-us-141966
28 The simulation results based on the nested logit model and multinomial logit model presented in Table A.4 are very close.
29 The simulation results based on the multinomial logit model with interaction terms presented in Table A.7 are very similar to those without interaction terms.
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References
Altbach PG Knight J The internationalization of higher education: Motivations and realities Journal of Studies in International Education 2007 11 3–4 290 305 10.1177/1028315307303542
Alter M Reback R True for your school? How changing reputations alter demand for selective US colleges Educational Evaluation and Policy Analysis 2014 36 3 346 370 10.3102/0162373713517934
Arcidiacono P Hotz VJ Kang S Modeling college major choices using elicited measures of expectations and counterfactuals Journal of Econometrics 2012 166 1 3 16 10.1016/j.jeconom.2011.06.002
Barnett GA Lee M Jiang K Park HW The flow of international students from a macro perspective: A network analysis Compare: A Journal of Comparative and International Education 2016 46 4 533 559 10.1080/03057925.2015.1015965
Beine M Noël R Ragot L Determinants of the international mobility of students Economics of Education Review 2014 41 40 54 10.1016/j.econedurev.2014.03.003
Bird, K., & Turner, S. (2014). College in the states: Foreign student demand and higher education supply in the US. Working Paper. Curry School of Education, University of Virginia.
Bodycott P Choosing a higher education study abroad destination: What mainland Chinese parents and students rate as important Journal of Research in International Education 2009 8 3 349 373 10.1177/1475240909345818
Bordón P Canals C Mizala A The gender gap in college major choice in Chile Economics of Education Review 2020 77 102011 10.1016/j.econedurev.2020.102011
Bound J Turner S Walsh P Freeman RB Goroff DL Internationalization of US doctorate education Science and engineering careers in the United States: Analysis of markets and employment 2009 Chicago University of Chicago Press.
Bound J Braga B Khanna G Turner S A passage to America: University funding and international students American Economic Journal: Economic Policy 2020 12 1 97 126
Brooks R Waters J Student mobilities, migration and the internationalization of higher education 2011 Springer
Cantwell B Are international students cash cows? Examining the relationship between new international undergraduate enrollments and institutional revenue at public colleges and universities in the US Journal of International Students 2015 5 4 512 525 10.32674/jis.v5i4.412
Cebolla-Boado H Hu Y Soysal YN Why study abroad? Sorting of Chinese students across British universities British Journal of Sociology of Education 2017 39 3 365 380 10.1080/01425692.2017.1349649
Chen R Bahr PR How does undergraduate debt affect graduate school application and enrollment? Research in Higher Education 2020 62 4 528 555 10.1007/s11162-020-09610-y
Chen, M., Howell, J., & Smith, J. (2020). Best and brightest? The impact of student visa restrictiveness on who attends college in the US. Ed Working Paper: 20–225.
Chen, M. (2019). The value of U.S. college education in global labor markets: Experimental evidence from China. Working Paper.
Cheng X Miao DG Reviews on the sixty-year history of Chinese studying abroad (1949–2009) Southeast Asian Studies 2010 1 79 87
Curs BR Jaquette O Crowded out? The effect of nonresident enrollment on resident access to public research universities Educational Evaluation and Policy Analysis 2017 39 4 644 669 10.3102/0162373717704719
DesJardins SL McCall BP Simulating the effects of financial aid packages on college student stopout, reenrollment spells, and graduation chances The Review of Higher Education 2010 33 4 513 541 10.1353/rhe.0.0169
DesJardins SL Ahlburg DA McCall BP Simulating the longitudinal effects of changes in financial aid on student departure from college Journal of Human Resources 2002 37 3 653 679 10.2307/3069685
Ding Y Wu Y Yang J Ye X The elite exclusion: Stratified access and production during the Chinese higher education expansion Higher Education 2021 82 2 323 347 10.1007/s10734-021-00682-y 33840818
English D Umbach PD Graduate school choice: An examination of individual and institutional effects The Review of Higher Education 2016 39 2 173 211 10.1353/rhe.2016.0001
Fitzpatrick MD Jones D Post-baccalaureate migration and merit-based scholarships Economics of Education Review 2016 54 155 172 10.1016/j.econedurev.2016.07.002 28220052
Greene WH Econometric Analysis: Global Edition 2020 8 China Renmin University Press 839
Groen JA Jakubson GH Ehrenberg RG Condie S Liu AY Program design and student outcomes in graduate education Economics of Education Review 2008 27 2 111 124 10.1016/j.econedurev.2006.09.010
IIE. (2019). Open Doors 2019: Economic Impact of International Students. https://www.iie.org/Research-and-Insights/Open-Doors/Data/Economic-Impact-of-International-Students
International student recruitment data. (n.d.). Retrieved from https://www.universitiesuk.ac.uk/universities-uk-international/explore-uuki/international-student-recruitment/international-student-recruitment-data
Jacob B McCall B Stange K College as country club: Do colleges cater to students’ preferences for consumption? Journal of Labor Economics 2018 36 2 309 348 10.1086/694654
Kallio RE Factors influencing the college choice decisions of graduate students Research in Higher Education 1995 36 1 109 124 10.1007/BF02207769
Kato T Sparber C Quotas and quality: The effect of H-1B visa restrictions on the pool of prospective undergraduate students from abroad Review of Economics and Statistics 2013 95 1 109 126 10.1162/REST_a_00245
Kennan J Walker JR The effect of expected income on individual migration decisions Econometrica 2011 79 1 211 251 10.3982/ECTA4657
Khanna G Shih K Weinberger A Xu M Yu M Trade liberalization and Chinese students in US higher education 2020 SSRN Electronic Journal
Knight J Higher education in turmoil: The changing world of global perspectives on higher education 2008 Brill Sense
Kondakci Y Bedenlier S Zawacki-Richter O Social network analysis of international student mobility: Uncovering the rise of regional hubs Higher Education 2018 75 3 517 535 10.1007/s10734-017-0154-9
Krupnick, M. (2016). China downturn, increased competition could affect supply of foreign students: Problems loom as U.S. universities increasingly rely on internationals for cash. The Hechinger Report: http://hechingerreport.org/china-downturn-increased-competition-could-affect-supply-of-foreign-students/.
Levatino, A. (2017). Transnational higher education and international student mobility: Determinants and linkage. Higher Education: The International Journal of Higher Education Research, 637–653.
Li X College admissions policy of international students: Theory and evidence Available at SSRN 2017 10.2139/ssrn.2889858
Li M Bray M Cross-border flows of students for higher education: Push–pull factors and motivations of mainland Chinese students in Hong Kong and Macau Higher Education 2007 53 6 791 818 10.1007/s10734-005-5423-3
Lin L The visible hand behind study-abroad waves: Cram schools, organizational framing and the international mobility of Chinese students Higher Education 2020 79 2 259 274 10.1007/s10734-019-00408-1
Long BT How have college decisions changed over time? An application of the conditional logistic choice model Journal of Econometrics 2004 121 1 271 296 10.1016/j.jeconom.2003.10.004
Loyalka P Liu OL Li G Chirikov I Kardanova E Gu L Hu S Computer science skills across China, India, Russia, and the United States Proceedings of the National Academy of Sciences 2019 116 14 6732 6736 10.1073/pnas.1814646116
Manski CF Wise DA College choice in America 1983 Harvard University Press 1983
McFadden, D. (1973). Conditional logit analysis of qualitative choice behavior. In Zaremka, P., Frontiers in Econometrics. New York: Academic Press, 105–142.
Nguyen AN Taylor J Post-high school choices: New evidence from a multinomial logit model Journal of Population Economics 2003 16 2 287 306 10.1007/s001480300149
OECD (2010), Education at a Glance 2010: OECD Indicators, OECD Publishing, Paris, https://www.oecd-ilibrary.org/education/education-at-a-glance-2010_eag-2010-en
OECD (2017), Education at a Glance 2017: OECD Indicators, OECD Publishing, Paris, https://www.oecd-ilibrary.org/education/education-at-a-glance-2017_eag-2017-en
OECD (2018), Education at a Glance 2018: OECD Indicators, OECD Publishing, Paris, https://www.oecd-ilibrary.org/education/education-at-a-glance-2018_eag-2018-en
OECD (2019), Education at a Glance 2019: OECD Indicators, OECD Publishing, Paris, https://www.oecd-ilibrary.org/education/education-at-a-glance-2019_f8d7880d-e
Perna LW Understanding the decision to enroll in graduate school: Sex and racial/Ethnic group differences The Journal of Higher Education 2004 75 5 487 527 10.1353/jhe.2004.0032
Perna, L. W. (2006). Studying college access and choice: A proposed conceptual model. In Higher Education: Handbook of Theory and Research (99–157). Springer, Dordrecht.
Rosenzweig, M., Irwin, D., & Williamson, J. (2006). Global wage differences and international student flows [with comments and discussion]. Brookings Trade Forum,57–96.
Rosenzweig, M. (2008). Higher education and international migration in Asia: Brain circulation. Annual World Bank Conference on Development Economics (pp. 59–100).
Shih K Labor market openness, h-1b visa policy, and the scale of international student enrollment in the United States Economic Inquiry 2016 54 1 121 138 10.1111/ecin.12250
Sjaastad, L. A. (1962). The costs and returns of human migration. Journal of Political Economy, 70(5, Part 2), 80–93. 10.1086/258726
Skinner BT Choosing college in the 2000s: An updated analysis using the conditional logistic choice model Research in Higher Education 2019 60 2 153 183 10.1007/s11162-018-9507-1
Song J Creating world-class universities in China: Strategies and impacts at a renowned research university Higher Education 2018 75 4 729 742 10.1007/s10734-017-0167-4
Stuen ET Ramirez S The effects of social networks on the flow of international students The World Economy 2019 42 2 509 529 10.1111/twec.12728
Wang Q. (2012). China’s Elite Sector and National Projects in “China: Emerging Opportunities and Challenges in Higher Education Cooperation” by Center for International Higher Education (CIHE) at Boston College and American Council on Education. International Briefs for Higher Education Leaders Series No. 1. Retrieved May 6, 2014
Xiang B Shen W International student migration and social stratification in China International Journal of Educational Development 2009 29 5 513 522 10.1016/j.ijedudev.2009.04.006
Yang, P. (2020). China in the global field of international student mobility: An analysis of economic, human and symbolic capitals. Compare: A Journal of Comparative and International Education, 1–19. 10.1080/03057925.2020.1764334
Ye, X. (2021). Personalized advising for college math: Experimental evidence on the use of human expertise and machine learning to improve college choice. Working Paper.
Zhang L Advance to graduate education: The effect of college quality and undergraduate majors The Review of Higher Education 2005 28 3 313 338 10.1353/rhe.2005.0030
| 0 | PMC9734696 | NO-CC CODE | 2022-12-14 23:28:30 | no | High Educ (Dordr). 2022 Dec 5;:1-40 | utf-8 | High Educ (Dordr) | 2,022 | 10.1007/s10734-022-00979-6 | oa_other |
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Build Simul
Build Simul
Building Simulation
1996-3599
1996-8744
Tsinghua University Press Beijing
950
10.1007/s12273-022-0950-8
Research Article
Occupancy of rooms in urban residential buildings by users in cold areas of China
Dong Qi 12
Ma Zikai 12
Sun Cheng [email protected]
12
1 grid.19373.3f 0000 0001 0193 3564 School of Architecture, Harbin Institute of Technology, Harbin, 150006 China
2 grid.424018.b 0000 0004 0605 0826 Key Laboratory of Cold Region Urban and Rural Human Settlement Environment Science and Technology, Ministry of Industry and Information Technology, Harbin, 150006 China
7 12 2022
115
6 6 2022
1 9 2022
5 10 2022
© Tsinghua University Press 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Occupancy is used to represent the movements and locations of users among various zones of buildings, and it is the basis of all other daily energy consumption behaviors. This study investigated eight families in cold areas of China based on occupancy measurements obtained in four main rooms, i.e., living room, bedroom, kitchen, and bathroom. In particular, we analyzed the duration of user occupancy and hourly mean occupancy, and characterized their regular and random features. According to the results, we developed an event-based occupancy model using an inhomogeneous Markov chain, where the rooms were modeled and daily events were divided into three categories according to their randomness. We established a new method for conversion between event characteristic parameters and a transition probability matrix, as well as an overlap avoidance method for active events. The model was then validated using real data. The results showed that the model performed well in terms of two evaluation criteria. The model should improve the accuracy of simulations of occupancy.
Keywords
event
occupancy
urban residential building
simulation
cold areas of China
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pmcAcknowledgements
The authors gratefully acknowledge the funding support from the National Natural Science Foundation of China (No. 52008129), the Postdoctoral Science Foundation of China (No. 2019M651289), and the National Natural Science Foundation of Heilongjiang Province (No. LH2020E051, No. GZ20210211).
Declaration of competing interest
The authors have no competing interests to declare that are relevant to the content of this article.
Author contribution statement
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Qi Dong and Zikai Ma. The first draft of the manuscript was written by Zikai Ma and all authors commented on previous versions of the manuscript. Cheng Sun guided and revised the manuscript. All authors read and approved the final manuscript.
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References
Aerts D Minnen J Glorieux I A method for the identification and modelling of realistic domestic occupancy sequences for building energy demand simulations and peer comparison Building and Environment 2014 75 67 78 10.1016/j.buildenv.2014.01.021
Blight TS Coley DA Sensitivity analysis of the effect of occupant behaviour on the energy consumption of passive house dwellings Energy and Buildings 2013 66 183 192 10.1016/j.enbuild.2013.06.030
Chang WK Hong T Statistical analysis and modeling of occupancy patterns in open-plan offices using measured lighting-switch data Building Simulation 2013 6 23 32 10.1007/s12273-013-0106-y
Chen Z Xu J Soh YC Modeling regular occupancy in commercial buildings using stochastic models Energy and Buildings 2015 103 216 223 10.1016/j.enbuild.2015.06.009
Cover TM Thomas JA Elements of information theory 2006 2nd edn. New York John Wiley & Sons
Crawley DB Lawrie LK Winkelmann FC EnergyPlus: Creating a new-generation building energy simulation program Energy and Buildings 2001 33 319 331 10.1016/S0378-7788(00)00114-6
Diao L Sun Y Chen Z Modeling energy consumption in residential buildings: A bottom-up analysis based on occupant behavior pattern clustering and stochastic simulation Energy and Buildings 2017 147 47 66 10.1016/j.enbuild.2017.04.072
Dong B, Lam KP, Neuman CP (2011). Integrated building control based on occupant behavior pattern detection and local weather forecasting. In: Proceedings of the 12th International IBPSA Building Simulation Conference, Sydney, Australia.
Fajilla G Austin MC Mora D Assessment of probabilistic models to estimate the occupancy state in office buildings using indoor parameters and user-related variables Energy and Buildings 2021 246 111105 10.1016/j.enbuild.2021.111105
Flett G Kelly N An occupant-differentiated, higher-order Markov Chain method for prediction of domestic occupancy Energy and Buildings 2016 125 219 230 10.1016/j.enbuild.2016.05.015
Flett G Kelly N Modelling of individual domestic occupancy and energy demand behaviours using existing datasets and probabilistic modelling methods Energy and Buildings 2021 252 111373 10.1016/j.enbuild.2021.111373
Hong T Taylor-Lange SC D’Oca S Advances in research and applications of energy-related occupant behavior in buildings Energy and Buildings 2016 116 694 702 10.1016/j.enbuild.2015.11.052
Jeong B Kim J de Dear R Creating household occupancy and energy behavioural profiles using national time use survey data Energy and Buildings 2021 252 111440 10.1016/j.enbuild.2021.111440
Jiang Y Hu S Paths to carbon neutrality in China’s building sector Journal of HV&AC 2021 51 5 1 13
Li Y Yamaguchi Y Shimoda Y Impact of the pre-simulation process of occupant behaviour modelling for residential energy demand simulations Journal of Building Performance Simulation 2022 15 287 306 10.1080/19401493.2021.2022759
Liao C Lin Y Barooah P Agent-based and graphical modelling of building occupancy Journal of Building Performance Simulation 2012 5 5 25 10.1080/19401493.2010.531143
Malekpour Koupaei DM Cetin KS Passe U Stochastic residential occupancy schedules based on the American Time-Use Survey Science and Technology for the Built Environment 2022 28 776 790 10.1080/23744731.2022.2087536
McKenna E Krawczynski M Thomson M Four-state domestic building occupancy model for energy demand simulations Energy and Buildings 2015 96 30 39 10.1016/j.enbuild.2015.03.013
Mitra D Chu Y Cetin K Cluster analysis of occupancy schedules in residential buildings in the United States Energy and Buildings 2021 236 110791 10.1016/j.enbuild.2021.110791
Page J Robinson D Morel N A generalised stochastic model for the simulation of occupant presence Energy and Buildings 2008 40 83 98 10.1016/j.enbuild.2007.01.018
Ren XX Yan D A study of lighting energy consumption model for office buildings based on occupant behavior Building Science 2014 30 6 1 9
Richardson I Thomson M Infield D A high-resolution domestic building occupancy model for energy demand simulations Energy and Buildings 2008 40 1560 1566 10.1016/j.enbuild.2008.02.006
Rueda L Sansregret S Le Lostec B A probabilistic model to predict household occupancy profiles for home energy management applications IEEE Access 2021 9 38187 38201 10.1109/ACCESS.2021.3063502
Salimi S Liu Z Hammad A Occupancy prediction model for open-plan offices using real-time location system and inhomogeneous Markov chain Building and Environment 2019 152 1 16 10.1016/j.buildenv.2019.01.052
Serfozo R Basics of Applied Stochastic Processes 2009 Heidelberg, Germany Springer
Sun K Yan D Hong T Stochastic modeling of overtime occupancy and its application in building energy simulation and calibration Building and Environment 2014 79 1 12 10.1016/j.buildenv.2014.04.030
Wang D Federspiel CC Rubinstein F Modeling occupancy in single person offices Energy and Buildings 2005 37 121 126 10.1016/j.enbuild.2004.06.015
Wang C Yan D Jiang Y A novel approach for building occupancy simulation Building Simulation 2011 4 149 167 10.1007/s12273-011-0044-5
Wang C Simulation research on occupant energy-related behaviors in building 2014 China Tsinghua University
Wang C Yan D Feng X A Markov chain and event based model for building occupant movement process Building Science 2015 31 10 188 198
Wang Y Gu BH New process of China’s sustainable development: Exploring the road towards carbon neutrality China Sustainability Tribune 2021 2021 6 15 20
Wilke U Haldi F Scartezzini JL A bottom-up stochastic model to predict building occupants’ time-dependent activities Building and Environment 2013 60 254 264 10.1016/j.buildenv.2012.10.021
Yamaguchi Y Shimoda Y A stochastic model to predict occupants’ activities at home for community-/urban-scale energy demand modelling Journal of Building Performance Simulation 2017 10 565 581 10.1080/19401493.2017.1336255
Yan D O’Brien W Hong T Occupant behavior modeling for building performance simulation: Current state and future challenges Energy and Buildings 2015 107 264 278 10.1016/j.enbuild.2015.08.032
Yao R Steemers K A method of formulating energy load profile for domestic buildings in the UK Energy and Buildings 2005 37 663 671 10.1016/j.enbuild.2004.09.007
Zhang Y Bai X Mills FP Rethinking the role of occupant behavior in building energy performance: A review Energy and Buildings 2018 172 279 294 10.1016/j.enbuild.2018.05.017
Zhang L Huang X Chen YY Literature review on residential energy behavior Urbanism and Architecture 2019 16 2 160 164
| 0 | PMC9734699 | NO-CC CODE | 2022-12-14 23:28:30 | no | Build Simul. 2022 Dec 7;:1-15 | utf-8 | Build Simul | 2,022 | 10.1007/s12273-022-0950-8 | oa_other |
==== Front
Build Simul
Build Simul
Building Simulation
1996-3599
1996-8744
Tsinghua University Press Beijing
950
10.1007/s12273-022-0950-8
Research Article
Occupancy of rooms in urban residential buildings by users in cold areas of China
Dong Qi 12
Ma Zikai 12
Sun Cheng [email protected]
12
1 grid.19373.3f 0000 0001 0193 3564 School of Architecture, Harbin Institute of Technology, Harbin, 150006 China
2 grid.424018.b 0000 0004 0605 0826 Key Laboratory of Cold Region Urban and Rural Human Settlement Environment Science and Technology, Ministry of Industry and Information Technology, Harbin, 150006 China
7 12 2022
115
6 6 2022
1 9 2022
5 10 2022
© Tsinghua University Press 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Occupancy is used to represent the movements and locations of users among various zones of buildings, and it is the basis of all other daily energy consumption behaviors. This study investigated eight families in cold areas of China based on occupancy measurements obtained in four main rooms, i.e., living room, bedroom, kitchen, and bathroom. In particular, we analyzed the duration of user occupancy and hourly mean occupancy, and characterized their regular and random features. According to the results, we developed an event-based occupancy model using an inhomogeneous Markov chain, where the rooms were modeled and daily events were divided into three categories according to their randomness. We established a new method for conversion between event characteristic parameters and a transition probability matrix, as well as an overlap avoidance method for active events. The model was then validated using real data. The results showed that the model performed well in terms of two evaluation criteria. The model should improve the accuracy of simulations of occupancy.
Keywords
event
occupancy
urban residential building
simulation
cold areas of China
==== Body
pmcAcknowledgements
The authors gratefully acknowledge the funding support from the National Natural Science Foundation of China (No. 52008129), the Postdoctoral Science Foundation of China (No. 2019M651289), and the National Natural Science Foundation of Heilongjiang Province (No. LH2020E051, No. GZ20210211).
Declaration of competing interest
The authors have no competing interests to declare that are relevant to the content of this article.
Author contribution statement
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Qi Dong and Zikai Ma. The first draft of the manuscript was written by Zikai Ma and all authors commented on previous versions of the manuscript. Cheng Sun guided and revised the manuscript. All authors read and approved the final manuscript.
==== Refs
References
Aerts D Minnen J Glorieux I A method for the identification and modelling of realistic domestic occupancy sequences for building energy demand simulations and peer comparison Building and Environment 2014 75 67 78 10.1016/j.buildenv.2014.01.021
Blight TS Coley DA Sensitivity analysis of the effect of occupant behaviour on the energy consumption of passive house dwellings Energy and Buildings 2013 66 183 192 10.1016/j.enbuild.2013.06.030
Chang WK Hong T Statistical analysis and modeling of occupancy patterns in open-plan offices using measured lighting-switch data Building Simulation 2013 6 23 32 10.1007/s12273-013-0106-y
Chen Z Xu J Soh YC Modeling regular occupancy in commercial buildings using stochastic models Energy and Buildings 2015 103 216 223 10.1016/j.enbuild.2015.06.009
Cover TM Thomas JA Elements of information theory 2006 2nd edn. New York John Wiley & Sons
Crawley DB Lawrie LK Winkelmann FC EnergyPlus: Creating a new-generation building energy simulation program Energy and Buildings 2001 33 319 331 10.1016/S0378-7788(00)00114-6
Diao L Sun Y Chen Z Modeling energy consumption in residential buildings: A bottom-up analysis based on occupant behavior pattern clustering and stochastic simulation Energy and Buildings 2017 147 47 66 10.1016/j.enbuild.2017.04.072
Dong B, Lam KP, Neuman CP (2011). Integrated building control based on occupant behavior pattern detection and local weather forecasting. In: Proceedings of the 12th International IBPSA Building Simulation Conference, Sydney, Australia.
Fajilla G Austin MC Mora D Assessment of probabilistic models to estimate the occupancy state in office buildings using indoor parameters and user-related variables Energy and Buildings 2021 246 111105 10.1016/j.enbuild.2021.111105
Flett G Kelly N An occupant-differentiated, higher-order Markov Chain method for prediction of domestic occupancy Energy and Buildings 2016 125 219 230 10.1016/j.enbuild.2016.05.015
Flett G Kelly N Modelling of individual domestic occupancy and energy demand behaviours using existing datasets and probabilistic modelling methods Energy and Buildings 2021 252 111373 10.1016/j.enbuild.2021.111373
Hong T Taylor-Lange SC D’Oca S Advances in research and applications of energy-related occupant behavior in buildings Energy and Buildings 2016 116 694 702 10.1016/j.enbuild.2015.11.052
Jeong B Kim J de Dear R Creating household occupancy and energy behavioural profiles using national time use survey data Energy and Buildings 2021 252 111440 10.1016/j.enbuild.2021.111440
Jiang Y Hu S Paths to carbon neutrality in China’s building sector Journal of HV&AC 2021 51 5 1 13
Li Y Yamaguchi Y Shimoda Y Impact of the pre-simulation process of occupant behaviour modelling for residential energy demand simulations Journal of Building Performance Simulation 2022 15 287 306 10.1080/19401493.2021.2022759
Liao C Lin Y Barooah P Agent-based and graphical modelling of building occupancy Journal of Building Performance Simulation 2012 5 5 25 10.1080/19401493.2010.531143
Malekpour Koupaei DM Cetin KS Passe U Stochastic residential occupancy schedules based on the American Time-Use Survey Science and Technology for the Built Environment 2022 28 776 790 10.1080/23744731.2022.2087536
McKenna E Krawczynski M Thomson M Four-state domestic building occupancy model for energy demand simulations Energy and Buildings 2015 96 30 39 10.1016/j.enbuild.2015.03.013
Mitra D Chu Y Cetin K Cluster analysis of occupancy schedules in residential buildings in the United States Energy and Buildings 2021 236 110791 10.1016/j.enbuild.2021.110791
Page J Robinson D Morel N A generalised stochastic model for the simulation of occupant presence Energy and Buildings 2008 40 83 98 10.1016/j.enbuild.2007.01.018
Ren XX Yan D A study of lighting energy consumption model for office buildings based on occupant behavior Building Science 2014 30 6 1 9
Richardson I Thomson M Infield D A high-resolution domestic building occupancy model for energy demand simulations Energy and Buildings 2008 40 1560 1566 10.1016/j.enbuild.2008.02.006
Rueda L Sansregret S Le Lostec B A probabilistic model to predict household occupancy profiles for home energy management applications IEEE Access 2021 9 38187 38201 10.1109/ACCESS.2021.3063502
Salimi S Liu Z Hammad A Occupancy prediction model for open-plan offices using real-time location system and inhomogeneous Markov chain Building and Environment 2019 152 1 16 10.1016/j.buildenv.2019.01.052
Serfozo R Basics of Applied Stochastic Processes 2009 Heidelberg, Germany Springer
Sun K Yan D Hong T Stochastic modeling of overtime occupancy and its application in building energy simulation and calibration Building and Environment 2014 79 1 12 10.1016/j.buildenv.2014.04.030
Wang D Federspiel CC Rubinstein F Modeling occupancy in single person offices Energy and Buildings 2005 37 121 126 10.1016/j.enbuild.2004.06.015
Wang C Yan D Jiang Y A novel approach for building occupancy simulation Building Simulation 2011 4 149 167 10.1007/s12273-011-0044-5
Wang C Simulation research on occupant energy-related behaviors in building 2014 China Tsinghua University
Wang C Yan D Feng X A Markov chain and event based model for building occupant movement process Building Science 2015 31 10 188 198
Wang Y Gu BH New process of China’s sustainable development: Exploring the road towards carbon neutrality China Sustainability Tribune 2021 2021 6 15 20
Wilke U Haldi F Scartezzini JL A bottom-up stochastic model to predict building occupants’ time-dependent activities Building and Environment 2013 60 254 264 10.1016/j.buildenv.2012.10.021
Yamaguchi Y Shimoda Y A stochastic model to predict occupants’ activities at home for community-/urban-scale energy demand modelling Journal of Building Performance Simulation 2017 10 565 581 10.1080/19401493.2017.1336255
Yan D O’Brien W Hong T Occupant behavior modeling for building performance simulation: Current state and future challenges Energy and Buildings 2015 107 264 278 10.1016/j.enbuild.2015.08.032
Yao R Steemers K A method of formulating energy load profile for domestic buildings in the UK Energy and Buildings 2005 37 663 671 10.1016/j.enbuild.2004.09.007
Zhang Y Bai X Mills FP Rethinking the role of occupant behavior in building energy performance: A review Energy and Buildings 2018 172 279 294 10.1016/j.enbuild.2018.05.017
Zhang L Huang X Chen YY Literature review on residential energy behavior Urbanism and Architecture 2019 16 2 160 164
| 0 | PMC9734701 | NO-CC CODE | 2022-12-14 23:28:30 | no | Dtsch Dermatolog. 2022 Dec 9; 70(12):960-967 | latin-1 | null | null | null | oa_other |
==== Front
Ann Oper Res
Ann Oper Res
Annals of Operations Research
0254-5330
1572-9338
Springer US New York
5098
10.1007/s10479-022-05098-0
Original Research
Developing an evidence-based TISM: an application for the success of COVID-19 Vaccination Drive
Singh Shiwangi [email protected]
[email protected]
2
Dhir Sanjay [email protected]
1
http://orcid.org/0000-0002-3118-5461
Sushil Sushil [email protected]
1
1 grid.417967.a 0000 0004 0558 8755 Indian Institute of Technology Delhi, New Delhi, India
2 grid.512371.3 0000 0004 1767 583X Indian Institute of Management Ranchi, Ranchi, Jharkhand, India
5 12 2022
119
4 8 2022
10 10 2022
18 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The study illustrates an application of evidence data for performing Total Interpretive Structural Modeling (TISM). TISM is widely used to analyze the critical success factors or inhibitors and their interlinkages. This study uses learning from evidence data, specifically social media analytics, to identify the relationship between the elements. Thus, it leads to the advancement of the TISM-P methodology with evidence-based TISM (TISM-E). This study uses Twitter as a source of evidence data. Further, 2,60,297 tweets were used to illustrate the process of TISM-E. The paper demonstrates the application of TISM-E for the success of the COVID-19 vaccination drive. The pandemic effects are long-term; therefore, the hierarchical model developed shows a sustainable approach for vaccinating maximum population. Further, the framework developed will ensure the distribution efficacy of vaccines. In addition, it will aid practitioners in developing future vaccination policies. The enhanced model provides evidence for polarity (positive/negative) of relationships and can help to build propositions for theory development. The study contributes to healthcare, modeling research, and graph-theoretic literature.
Keywords
Critical success factors
TISM-E
Social media analytics
Evidence data
Graph-theoretic literature
Twitter
==== Body
pmcIntroduction
Modeling research in the COVID-19 vaccination drive requires mapping the hypothesized relationship between different identified elements (Romate et al., 2022). In the past, modeling research has been aided by various methodologies, including structural equation modeling (Hair et al., 2019; Singh, Sharma, & Dhir, 2021; Dixit et al., 2021; Singh et al., 2022), interpretive structural modeling (Warfield, 1974) (ISM), system dynamics (Sterman, 2000), and total interpretive structural modeling (Sushil, 2012; Sushil, 2017a; Sushil, 2018a; Sushil & Dinesh, 2022) (TISM). TISM and ISM transform ill-structured factors into well-structured mental models and offer explanations of what and how. Furthermore, TISM also explains why components and defines the reason for the relationship between two identified elements. Previously, a few advancements in the TISM modeling process were suggested, including m-TISM (Sushil, 2017a), argumentation-based TISM (Sushil & Dinesh, 2022), and TISM-P (Sushil, 2018b). m-TISM is the modified TISM, where a simultaneous transitivity check was performed. Thus, it eliminated various steps for performing transitivity. In TISM-P, polarity in the relationships was identified. It provided the nature of the relationship (positive/negative) between two elements. Earlier, these relationships were identified based on interviews or defined relationships in the existing literature. However, there is another dimension to building an understanding of TISM, i.e., through evidence data (Sushil, 2017b). This dimension explains the relationship and nature of elements based on available evidence data. Therefore, the relationships are simultaneously validated. Numerous evidence data points can also lead to the generalization of results as compared to other methods with limited sample sizes.
The researchers have suggested using evidence data for developing hierarchical models that can aid the decision-making process in organizations (Sushil, 2017b; Chan & Moses, 2016; Nyawa et al., 2022; Rathore & Ilavarasan, 2020). Furthermore, acquiring data from end-users can facilitate the success of new product development (Piller & Walcher, 2006). Social media platforms can enable sharing views and opinions from end-users (Luo et al., 2022; Zhang et al., 2022a; Alkouz et al., 2022; Alwabel & Zeng, 2021; Ullah et al., 2021). Various researchers have studied evidence data for improving the existing process or developing a new product (Rathore & Ilavarasan, 2020; Singh et al., 2020; Zhang et al., 2022b). Further, scholars have studied the effect of the COVID-19 pandemic on the global operations disruptions (Dubey et al., 2022; Masudin et al., 2021; Meier & Pinto, 20222022; Momeni et al., 2022; Sarker et al., 2021) and communication (Tam et al., 2021; Paramita et al., 2021; Warrier et al., 2021). In addition, previous studies have used TISM to develop a hierarchical framework to address various issues. For instance, Sushil and Anbarasan (2021) developed a framework for sustainable operational complexity in organizations. Dwivedi et al. (2021) suggested a framework in value chain flexibility to address the issue of sustainable initiatives. However, very limited studies are conducted to understand the end-users’ views about the “COVID-19 vaccination drive success”. Therefore, this illustrates the applicability of evidence data to understand the “COVID-19 vaccination drive success”.
This study aims to propose an enhanced methodology of TISM-P based on evidence data (TISM-E) to aid the modeling for the COVID-19 vaccination drive success. Further, the study interprets the results based on the evidence data and contributes to the existing literature on TISM, social media analytics, and the COVID-19 vaccination literature.
The study first presents a selective review of the TISM methodology. In Sect. 3, the study enhances the TISM-P method based on evidence data (TISM-E). Section 4 discusses the steps of TISM-E in the context of modeling the elements for the success of the COVID-19 vaccination drive. At last, the study presents discussions, limitations, conclusions, and offers future research directions.
Overview of TISM: review and application
Sushil (2012) highlighted the unclear articulated model of ISM and suggested a way of interpreting the directed link of ISM through a more evolved methodology, i.e., TISM. It provided a step-by-step direction for understanding and building a TISM framework. Sushil (2018a) provided detailed guidelines to check the correctness of the TISM model. In TISM, “large number of pair-comparisons are to be made by experts and cumbersome multi-order transitivity checks are to be carried out” (Sushil, 2018b, p. 39). Therefore, this work was enhanced by m-TISM (Sushil, 2017a), which led to simultaneously checking the transitivity among the elements. This enhancement added more efficiency to the TISM methodology. However, a missing dimension in the hierarchical model was polarity of relationships. Sushil (2018b) introduced the concept of polarity in the m-TISM methodology (TISM-P). Polarity helps to identify the nature of the relationships. Sushil & Dinesh (2022) highlighted the importance of argumentation-based discussion to enrich the interpretation of links.
TISM is widely used in supply chain management and sustainability research (Sushil & Anbarasan, 2021; Dwivedi et al., 2021; Yadav et al., 2021; Dohale et al., 2022). For instance, Dubey et al. (2017) studied sustainable supply chain management and analyzed the drivers and their interlinkages. Balaji and Arshinder (2016) reviewed the food supply chain and modeled the causes of food wastage. Mangla et al. (2014) studied the performance variables under the uncertainty and risk of a sustainable supply chain. Further, the application of TISM can also be seen in the area of industry 4.0 (Ajmera & Jain, 2019; Jain & Ajmera, 2020), lean manufacturing (Chaple et al., 2021; Singh et al., 2018; Virmani et al., 2018), flexibility (Yadav & Sagar, 2021; Jain & Raj, 2015; Mangla et al., 2014), higher education (Sravat & Pathranarakul, 2022; Menon et al., 2021), implementation (Chaple et al., 2021; Singh & Dhir, 2022), start-up ecosystem (Sindhwani et al., 2022; Singh et al., 2020; Singh et al., 2019), and information systems (Dwivedi & Madaan, 2020; Singh & Singla, 2021). With the advancement of technologies and fields, TISM is also applied in the area of blockchain (Shardeo et al., 2020; Mathivathanan et al., 2021; Dwivedi et al., 2022), internet of things (Patil & Suresh, 2019; Singh et al., 2020), artificial intelligence (Mir et al., 2020; Jain et al., 2021), and health care research (Logesh & Vinodh, 2022; Priyadarsini et al., 2020; Patri & Suresh, 2017).
Methodology
Enhanced TISM Methodology with evidence-based on Semantic Network
The evidence-based TISM (TISM-E) is a methodological extension of TISM (Sushil, 2012), m-TISM (Sushil, 2017a), argumentation-based TISM (Sushil & Dinesh, 2022), and TISM-P (Sushil, 2018b). The modified TISM is the methodological extension of TISM and ISM with a simultaneous transitivity check. TISM with polarity was introduced to study the nature of the relationships. It helps to interpret the results with clarity in polarity of the relationship. However, these studies were performed using interview data. It required a greater involvement of experts to define polarity of the relationships. The application of evidence data (such as data available on social media) was majorly ignored to identify linkages between the elements. Further, the application of evidence data can enhance generalizability of the findings. In this study, TISM with polarity (Sushil, 2018b) is taken as a basis to describe the steps of this evidence-based TISM. The steps of this enhanced evidence-based TISM methodology are presented in Fig. 1.
Figure 1 highlights that steps I, II, III, and VII are different from the defined steps of TISM-P. These steps introduce the basic guidelines for building evidence-based TISM. Steps VIII and IX are additional steps in the enhanced process. Steps IV, V, and VI are similar to the existing methodology of TISM. The steps of evidence-based TISM are discussed below:
Step I: Collect the evidence data from any Social Media platform and perform texts cleaning, tokenization, word stemming, and lemmatization.
The user-generated texts are collected from Twitter using various hashtags. After data collection, text cleaning was performed. It helps to convert all words to small letters and removes punctuations, stop words, and other noise data. Further, tokenization was performed to split the sentence into meaningful parts and identify individual entities in a sentence. In addition, word stemming and lemmatization were also executed. Word stemming helps to convert various forms of one word to its root form. Lemmatization groups together the inflected forms of a word to its base or dictionary form of a word.
Step II. Define elements based on the evidence data.
Based on the evidence data, the elements are identified. These elements can be used to study the hierarchical relationships using the evidence-based TISM.
Step III: Define contextual relationships based on node-link and semantic network as association methods.
The semantic network relationship is formed with the help of node-link data. Further, the contextual relationships can be visualized based on word matrices based on the semantic network graph. UCINET (Borgatti et al., 2002; Yoo & Lim, 2021) or other similar software can be used to visualize the network graph.
Step IV: Prepare digraph for simultaneous transitivity check and prepare transitive reachability matrix.
Sushil (2017a) describes the process of successive comparison of elements. The author(s) need to compare the first two sets of elements (i,j) and (j,k); further, the comparison between (i,k) is checked based on rule of transitivity. The identified relationship among the identified elements can be forward, backward, transitive, or no relationship. Based on the digraph, a binary transitive matrix is prepared, as elaborated by Sushil (2017a).
Step V: Perform hierarchical partitioning of reachability matrix.
Hierarchical partitioning is performed based on the reachability set, antecedent set, and intersection set (Sushil, 2018; Sushil, 2017a). The elements with same reachability set and intersection set are labeled as level I and are placed at the highest level in hierarchy. Further, this element is removed from the set. This process is repeated iteratively till all the elements are categorized into different hierarchical levels.
Step VI: Prepare hierarchical digraph with selected transitive links.
All the elements are arranged in hierarchical levels. The direct and important transitive links are shown in the digraph as per the transitive binary matrix.
Step VII: Interpret the nodes and links along with polarity of links and obtain TISM based on evidence data.
The interpretation of nodes and links are interpreted with + ve or -ve orientation based on evidence data. In the process, the excerpts from the evidence data can be used for interpretation of the relationship and identification of polarity of relationships. Final TISM model based on evidence data is obtained.
Step VIII: Obtain dependence and driving power of all elements.
Based on driving and dependence power with + ve or -ve orientation, autonomous, driver, linkage, and dependent elements are identified.
Step IX: Identify the paths from driving variable to dependent variable via different linkage or intermediate variable with polarity of relationships based on evidence data.
The paths from the dependent elements to driving elements with linkage / intermediate elements are identified along with their polarity.
In the next section, the above-mentioned steps are illustrated with the help of an illustration in the context of the COVID-19 vaccination program success.
Results
Illustration: COVID-19 vaccination program success model
The present evidence-based TISM is illustrated with an example of successful modeling of COVID-19 vaccination program.
Step I: The data from Twitter platform was collected using hashtags including covid19vaccine, coronavaccine, coronavirusvaccine, and covidvaccine. Scholars have used Twitter analysis to understand the existing processes or to analyze perception of new product (Rathore & Ilavarasan, 2020; Singh et al., 2020; Zhang et al., 2022b). The tweets were collected between 11 November 2020 and 20 February 2021. The tweets collected demonstrate pre- and post-vaccination launch period. The period demonstrates launch of vaccination campaigns all over the world. A total of 11,09,367 tweets were collected. After removing duplications, the data cleaning was performed on 2,60,297 tweets. At first, the unnecessary characters, including punctuations, URLs, hashtags, and special characters were removed. Next, the stop words were removed. Further, tokenization was performed. At last, word stemming was done based on the snowball algorithm (Porter, 2001).
Fig. 1 Indicative steps of total interpretive structural modeling with polarity based on evidence data (TISM-E)
Step II: The keywords are selected after analyzing the word frequency. The keywords are chosen based on their overall relationship with the overall success of the COVID-19 vaccination program. Therefore, six keywords are identified. Thus, belief, communication, distribution, frontline, policies, and rollout are identified. Further, these keywords were interpreted based on the Tweets. Therefore, the identified keywords are further interpreted and defined as the population’s belief, communication effectiveness, distribution efficacy, role of frontline workers, role of government policies, vaccine rollout implementation, and success of the COVID-19 vaccination program. Further, the factors are defined based on the extant literature and tweets.
Belief of the population
The belief of the population can predict health-promoting behavior by addressing the association between health behaviors and health services utilization. The beliefs of the population were related to the risk of getting infected by the COVID-19 and benefits of getting vaccinated.
Communication effectiveness
The tweets on communication were related to clarity on vaccine safety and efficacy, the COVID-19 vaccine challenges, national vaccine communication, and education campaign, etc., to name a few. Majority of the communications were aimed to make the population confident about taking the COVID-19 vaccination. It is believed that honest, open, and transparent communication is essential for vaccination uptake by the population.
Distribution efficacy
The government aimed to optimize the distribution of vaccines to vaccination sites to minimize the period needed to vaccinate individual populations. In places where the vaccine distribution is not utilized properly, communication can play a vital role.
Role of frontline workers
Frontline health workers are the pillar of health ecosystems, especially in delivering healthcare services in rural areas. The frontline healthcare workers play a vital role in responding to and managing the COVID-19 vaccination process. They have worked in extreme conditions and are responsible for managing the population’s fear, anxieties, and hesitancy.
Role of government policies
The government’s goals, decisions, and actions have played an important role in the COVID-19 vaccination process. The policy of vaccine allocation to states and vaccination policy related to different age groups has a major impact on the success of the COVID-19 vaccination program. Other policies such as wearing masks, maintaining proper social distancing, and closing schools are crucial for success.
Vaccine roll-out implementation
The vaccine roll-out implementation focuses on the key aspects such as preparation of a central vaccination system, training of healthcare workers, strategy for distribution, managing supply chains, and preparing communication plans for vaccine uptake and acceptance. The implementation exercises can be done at the central and regional levels. The main purpose of these exercises is that the vaccines are delivered correctly and disseminated as planned.
Success of COVID-19 vaccination program
The success of the COVID-19 vaccination program can be seen in short term and long term. In the short term, the success can be seen via interrupting disease transmission, including fewer hospitalizations, reduced deaths, and fewer cases. In the long run, the success can be measured by institutional capabilities to foster vaccine confidence among diverse communities, enhanced public understanding regarding vaccination’s value to society, and heightened public trust in government.
Step III: The relationship between the factors is based on node-link data. The interrelationships between the factors are analyzed by studying and comparing the data. Figure 2 shows the semantic network relationship between the identified factors. Table 1 presents the interrelationship between the factors. UCINET software is used to visualize the semantic network based on the interrelationship between the factors.
Fig. 2 Semantic network of key factors
Table 1 Binary matrix
F1 F2 F3 F4 F5 F6 F7
Belief of the population F1 1 1 0 0 0 0 1
Communication effectiveness F2 1 1 1 0 0 0 1
Distribution efficacy F3 1 1 1 0 0 0 1
Role of frontline workers F4 1 1 1 1 0 0 0
Role of government policies F5 0 0 0 1 1 1 0
Vaccine rollout implementation F6 1 1 1 0 0 1 0
Success of COVID-19 vaccination program F7 0 0 0 0 0 0 1
Step IV: Digraph for simultaneous transitivity check is prepared (Fig. 3) based on the evidence data as mentioned in Fig. 2; Table 1. The diagraph shows direct and transitive linkages. Based on the digraph (Fig. 3), binary matrix with transitivity is prepared (Table 2). The relationships are entered as 1, 1*, and 0. 1 denotes a direct relationship, 1* denotes a transitive relationship, and 0 denotes no relationship.
Step V: Level partitioning is performed based on the transitive reachability matrix. The iterations for level partitioning are highlighted in Appendix Table A1. The level-wise summarization of factors for success of the COVID-19 vaccination program is presented in Table 3. It is seen that the ‘success of the COVID-19 vaccination program’ is at level I in the hierarchy (highest level), and ‘role of government policies’ is at level IV (lowest level).
Table 2 Transitive reachability matrix
F1 F2 F3 F4 F5 F6 F7
Belief of the population F1 1 1 1* 0 0 0 1
Communication effectiveness F2 1 1 1 0 0 0 1
Distribution efficacy F3 1 1 1 0 0 0 1
Role of frontline workers F4 1 1 1 1 0 0 1*
Role of government policies F5 1* 1* 1* 1 1 1 1*
Vaccine rollout implementation F6 1 1 1 0 0 1 1*
Success of COVID-19 vaccination program F7 0 0 0 0 0 0 1
Table 3 List of elements and their levels in TISM
Factor Number Factors Level in TISM
F1 Belief of the population II
F2 Communication effectiveness II
F3 Distribution efficacy II
F4 Role of frontline workers III
F5 Role of government policies IV
F6 Vaccine rollout implementation III
F7 Success of COVID-19 vaccination program I
Fig. 3 Digraph for transitivity check
Step VI: All the elements F1, F2, F3, F4, F5, F6, and F7 are arranged in the hierarchical levels. All the direct links and selected transitive links are shown in the digraph as per the transitive reachability matrix (Fig. 4).
Step VII: Based on data collected from Twitter, the nodes and links, along with the polarity of links, are interpreted. Table 4 lists the direct links, the excerpts from Twitter, and the interpretation of the linkages. Further, the final TISM model based on evidence data is drawn, showing the polarity of the relationships (Fig. 5).
Table 4 Links, sample excerpts, polarity, and their interpretations
Links Sample Excerpts Polarity Interpretations
F5-F4 “..COVID19vaccine rollout is planned vaccinations will start with healthcare workers..”
“..phased introduction of the vaccine to health-care workers..”
+ve Can ensure planning for the requirement of vaccination for frontline workers and subsequently other people
F5-F6 “..Narendra Modi To Launch Pan India Rollout of COVID-19 Vaccination Drive..”
“..comprehensive breakdown of state-level policies regarding COVID19 vaccination rollout..”
“..coordination between mass vaccination centres..”
“..clear coordination among federal, state, tribal and other local levels..”
+ve Can ensure coordination across various stakeholders for the successful rollout
F6-F1 “..rollout will only succeed with the biggest community engagement and trust-building campaigns..”
“..skepticism and mistrust from minority communities..”
“..population lags behind due to distrust of the government..”
+ve/-ve Flexible vaccine rollout plan allows adaptation according to the local context and thus build belief among its population
F6-F2 “..to share the latest information about the COVID19 vaccine rollout..”
“..a communication strategy. to disseminate accurate..”
“..botched Vaccination Rollout: Fragmented Communication..”
+ve Clarity about the vaccine rollout plan can ensure effective communication
F6-F3 “..rollout across the UK by distributing the vaccine storage freezer..”
“..issues with CovidVaccine rollout… are logistical and coordination..”
“..to receive and distribute..”
+ve Helps to plan for logistical requirements for vaccine distribution and storage
F4-F1 “..trust Indian doctors..”
“..trust the physicians you work with each day..”
“..information from trusted community health workers..”
+ve/-ve Direct involvement of frontline workers with local population can increase the belief about COVID-19 vaccine
F4-F2 “..best explain the safety and efficacy of the COVID vaccine..”
“..Covid Vaccine information from trusted community health workers..”
+ve Frontline worker can provide accurate information about the vaccine efficacy and safety
F3-F2 “..vaccine distribution plans…communicated this more..”
“..Glad to attend VC….delivery distribution..”
+ve Vaccine distribution can ensure effective communication
F2-F3 “..Fragmented Communication, Misallocated Supply..”
“..need for better patient communication and outreach about vaccine distribution..”
“..communication on the efficacy of the COVID19Vaccine..”
+ve Provide feedback for effective communication
F2-F1 “..Covid Vaccine safety messages tailored to reach communities working with trusted messengers..”
“..tailored messages and communication that are equally important for breaking barrier..”
“..Culturally Tailored Messaging Is Pivotal..”
+ve Tailored for diverse audiences and sharing the information by trusted people can build belief
F1-F2 “..personal beliefs about vaccines. I always try to be guided by facts, science, faith..”
“..Hearing really good feedback from constituents about CovidVaccine..”
“..trust in your COVID19Vaccine strategy? Get the resident feedback..”
+ve Provide feedback for effective communication
F1-F7 “..population lags behind due to distrust..”
“..mistrust behind low Vaccine uptake by some communities..”
“..CovidVaccine uptake depends on. COVID-19 vaccine as a brand and trust..”
+ve/-ve Proper belief can increase the vaccine uptake by the population
F2-F7 “..communicating with individuals about vaccinations..”
“..communication required for addressing vaccine hesitancy..”
“..Inclusive communications is vital to ensuring successful CovidVaccine uptake..”
+ve It helps to provide information related to COVID-19 in a clear way and can reduce the vaccine hesitancy
F3-F7 “..successful distribution of 2.9 million Pfizer COVID19Vaccine across the nation..”
“..CovidVaccine distribution. some states and localities so much more successful..”
“..success of the rollout of COVID-19 vaccines.depends on their availability and distribution..”
+ve Proper distribution can ensure the success of COVID-19 vaccination program by vaccinating maximum eligible population
Fig. 4 Digraph after hierarchical partitioning
Step VIII: Based on the TISM model, transitive reachability matrix with the polarity of the relationship is drawn. Further, dependence and driving power with + ve or -ve orientation is calculated (Table 5). Additionally, the elements are categorized into autonomous, driver, linkage, and dependent factors. Figure 6 shows the graphical classification for the identified elements of ‘success of COVID-19 vaccination program’. Further, the role of frontline workers (F4), role of government policies (F5), and vaccine rollout implementation (F6) are classified as driving factors. The elements belief of the population (F1), communication effectiveness (F2), and distribution efficacy (F3) are linkage factors. The success of the COVID-19 vaccination program (F7) is a dependent factor. The orientation of the elements is presented in Table 5 as + ve/-ve driving power and + ve/-ve dependence. The elements have more + ve dependence and driving power, so the identified elements can be treated as + ve. For instance, element F5, i.e., role of frontline workers (driving factor), has more + ve driving power than -ve. Therefore, it can be treated as + ve driving factor.
Table 5 Modified binary transitive matrix based on evidence data with dependence and driving power
F1 F2 F3 F4 F5 F6 F7 Driving
+ve Power
-ve
Belief of the population F1 + 1 + 1 + 1* 0 0 0 ± 1 4 1
Communication effectiveness F2 + 1 + 1 + 1 0 0 0 + 1 4 0
Distribution efficacy F3 + 1 + 1 + 1 0 0 0 + 1 4 0
Role of frontline workers F4 ± 1 + 1 + 1 + 1 0 0 ± 1* 5 2
Role of government policies F5 ± 1* + 1* + 1* + 1 + 1 + 1 ± 1* 7 1
Vaccine rollout implementation F6 ± 1 + 1 + 1 0 0 + 1 ± 1* 5 2
Success of COVID-19 vaccination program F7 0 0 0 0 0 0 + 1 1 0
Dependence +ve 6 6 6 2 1 2 7
-ve 3 0 0 0 0 0 4
Fig. 5 Total interpretive structural modell based on evidence data for COVID-19 vaccination program success
Fig. 6 Classification of elements for COVID-19 vaccination program success
Step IX: Thirteen key paths are identified that can lead towards success of the COVID-19 vaccination program based on driving, linkage, and dependent factors. Further, three factors are categorized as driving factors. Therefore, the driving factors are taken as the starting point to trace the paths and their influence on final dependent variable (Table 6). It can be observed from Table 6 that 8 paths are + ve and 5 paths can have both + ve and -ve impact on the dependent factor. This kind of analysis describes the success of COVID-19 vaccination program adopted in any country or region.
Table 6 Nature of paths
Driving factors Path through the variable Path
Role of frontline workers Belief of the population +ve/-ve
Communication effectiveness +ve
Role of government policies Vaccine rollout implementation-Belief of the population +ve/-ve
Vaccine rollout implementation- Communication effectiveness +ve
Vaccine rollout implementation-Distribution efficacy +ve
Role of frontline workers- Belief of the population +ve/-ve
Role of frontline workers-Communication effectiveness +ve
Communication effectiveness +ve
Belief of the population +ve/-ve
Distribution efficacy +ve
Vaccine rollout implementation Distribution efficacy +ve
Belief of the population +ve/-ve
Communication effectiveness +ve
Discussion
This study provides an enhanced version of TISM as evidence-based TISM or TISM-E (applicable to ISM also as ISM-E) based on evidence data generated from social media platforms. The proposed methodology (as presented in Fig. 1) is different from the existing process of TISM or ISM in collecting data from social media platforms, identification of elements, defining the relationship between the elements, and interpreting the relationship with polarity. Further, it can be noted that a few steps related to preparing digraph for transitivity check, hierarchical partitioning, and hierarchal digraph are similar to the existing methodology of TISM. The enhanced version of TISM-E is primarily based on collecting, analyzing, and interpreting evidence data to identify and define the relationship between the elements. The additional insights by incorporating the evidence data will integrate this TISM method with social media analytics to understand the interrelationships between the identified elements. Further, this method will have practical applications to information management, change management, success model development, and operations management.
In the mentioned context of COVID-19 vaccination program success, the study identifies six elements by collecting and analyzing data from Twitter. Further, based on the node-link data semantic network was drawn, and the relationships between the elements were identified. In addition, the links were interpreted, and the polarity of the relationships were also identified based on tweets. Additionally, in this study, most of the relationships were positive, and a few were both positive and negative. For instance, the relationship between belief of the population and the success of the COVID-19 vaccination program is both positive and negative. The belief and trust in vaccination can increase the chances of success of the COVID-19 vaccination program. In contrast, any disbelief or mistrust in vaccination can decrease the chances of success for the COVID-19 vaccination program. The identified relationships conceptualize a model for the success of the COVID-19 vaccination program and can be validated using empirical measures.
Implications for research
The advanced version of TISM, i.e., TISM-E will be useful for various research fronts, including developing the research based on practical insights where the scant literature is available and hypothesizing the relationship between the elements based on semantic network.
The TISM-E will also facilitate the validation of relationships by capturing insights from tweets. It can act as an alternate pathway for validating relationships from experts. The positive and negative relationship can also be captured from tweets. Therefore, it can help in identifying the facilitators or barriers of the research topic. Further, the evidence data can also help in building propositions for theory development and testing. The TISM-E also contributes to graph-theoretic literature. The hierarchical digraph developed can be used as an input to a mathematical model. Based on the relationships and interdependencies, the matrix can be formed for further calculations. In addition, the measures of nodes can be quantified for simulation purposes or assessment of relationships.
Implications for practice
For practitioners, the evidence-based TISM (TISM-E) can be useful in the identification of various elements along with polarity that can contribute to the success of the project/policy under study. This study will also enable the practitioners to identify the facilitators and inhibitors. Therefore, the practitioners can plan a proper course of action for minimizing the effects of inhibitors. In practice, the enhanced version of TISM can be applied to different areas including supply chain, sustainability, new product launches, policy implications, strategic thinking, etc., to name a few. In the mentioned areas, the evidence data will play a major role in understanding and generalizing the role of facilitators or inhibitors. The COVID-19 effects are long-term. Therefore, by developing a model for successful COVID-19 vaccination program will enable policy makers to vaccinate maximum population and overcome the challenges related to vaccination processes. In addition, the model will lead to distribution efficacy. The distribution efficacy can be achieved through role of government policies, vaccine rollout implementation, and proper communication. Further, in the developed hierarchal model more positive linkages are seen, and there are a few both positive and negative relationships. Therefore, the model also highlights that how an element’s negative impact should be minimized to promote the positive desired outcome. The model developed can also be applied to other vaccination programs for better outreach.
Conclusion
This research provides the enhanced version of ISM and TISM based on evidence data from social media platforms. The enhanced version of TISM-E is based on social media analytics. The method provides a mix of quantitative and qualitative analysis along with the identification of polarity. The identification of elements and relationships are based on social media analytics, i.e., node-link data and semantic network. The interpretations are based on social media data gathered through different platforms.
Polarity identification is based on the tweets that depict the relationship between two elements. The proposed method contributes to the existing literature on TISM, graph-theoretic, and modeling literature, in addition with social media analytics literature. Further, the research has important implications for research and practice. In addition, the study also extends the literature on the COVID-19 vaccination and provides a path for success of the COVID-19 vaccination program. The elements such as role of frontline workers, role of government policies, and vaccine rollout implementation are driving factors. In contrast, the elements including communication effectiveness, belief of the population, and distribution efficacy are categorized as linkage factors. The independent and linkage factors lead to the success of COVID-19 vaccination program.
The limitations of this study are twofold. First, the study captures and defines the relationship using social media platform data. Therefore, some factors important for the study could be ignored or missed. In this case of the COVID-19 vaccination program, wastage is an important factor for the success of the overall program. But overall, the relationships and elements were not identified using Twitter analytics. Therefore, to overcome such limitation Twitter data can be combined with existing literature. Second, the linkages and polarity are defined using tweets excerpts. Therefore, subjectivity can be a problem during interpretation. It is important to validate such interpretation and linkages with the help of experts or based on previous literature. The TISM-E is a methodological extension of TISM and ISM with polarity. It can be examined across different research intersections using TISM and social media analytics. Further, the interrelationship of the elements can be tested using the structural equation modeling technique.
Appendix
Table A1 Level-partitioning matrix
Iteration 1
Factors Reachability Set Antecedent Set Intersection set Level
F1 1, 2, 3, 7 1, 2, 3, 4, 6 1, 2, 3
F2 1, 2, 3, 7 1, 2, 3, 4, 5, 6 1, 2, 3
F3 1, 2, 3, 7 1, 2, 3, 4, 5, 6 1, 2, 3
F4 1, 2, 3, 4, 7 4, 5 4
F5 1, 2, 3, 4, 5, 6, 7 5 5
F6 1, 2, 3, 6, 7 5, 6 6
F7 7 1, 2, 3, 4, 5, 6, 7 7 I
Iteration 2
Factors Reachability Set Antecedent Set Intersection set Level
F1 1, 2, 3 1, 2, 3, 4, 6 1, 2, 3 II
F2 1, 2, 3 1, 2, 3, 4, 5, 6 1, 2, 3 II
F3 1, 2, 3 1, 2, 3, 4, 5, 6 1, 2, 3 II
F4 1, 2, 3, 4 4, 5 4
F5 1, 2, 3, 4, 5, 6 5 5
F6 1, 2, 3, 6 5, 6 6
Iteration 3
Factors Reachability Set Antecedent Set Intersection set Level
F4 4 4, 5 4 III
F5 4, 5, 6 5 5
F6 6 5, 6 6 III
Iteration 4
Factors Reachability Set Antecedent Set Intersection set Level
F5 5 5 5 IV
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Ajmera P Jain V Modelling the barriers of Health 4.0–the fourth healthcare industrial revolution in India by TISM Operations Management Research 2019 12 3 129 145 10.1007/s12063-019-00143-x
Alkouz, B., Al Aghbari, Z., Al-Garadi, M. A., & Sarker, A. (2022). Deepluenza: Deep Learning for Influenza Detection from Twitter. Expert Systems with Applications, 198, 116845.
Alwabel ASA Zeng XJ Data-driven modeling of technology acceptance: a machine learning perspective Expert Systems with Applications 2021 185 115584 10.1016/j.eswa.2021.115584
Balaji M Arshinder K Modeling the causes of food wastage in indian perishable food supply chain Resources Conservation and Recycling 2016 114 153 167 10.1016/j.resconrec.2016.07.016
Borgatti, S. P., Everett, M. G., & Freeman, L. C. 2002 Ucinet for Windows: software for social network analysis. Harvard:Analytic Technologies
Chan J Moses LB Is big data challenging criminology? Theoretical criminology 2016 20 1 21 39 10.1177/1362480615586614
Chaple AP Narkhede BE Akarte MM Raut R Modeling the lean barriers for successful lean implementation: TISM approach International Journal of Lean Six Sigma 2021 12 1 98 119 10.1108/IJLSS-10-2016-0063
Dixit S Singh S Dhir S Dhir S Antecedents of strategic thinking and its impact on competitive advantage Journal of Indian Business Research 2021 13 4 437 458 10.1108/JIBR-08-2020-0262
Dohale, V., Ambilkar, P., Gunasekaran, A., & Bilolikar, V. (2022). Examining the barriers to operationalization of humanitarian supply chains: lessons learned from COVID-19 crisis. Annals of Operations Research, 1-40, https://doi.org/10.1007/s10479-022-04752-x.
Dubey R Bryde DJ Foropon C Tiwari M Gunasekaran A How frugal innovation shape global sustainable supply chains during the pandemic crisis: lessons from the COVID-19 Supply Chain Management: An International Journal 2022 27 2 295 311 10.1108/SCM-02-2021-0071
Dubey R Gunasekaran A Papadopoulos T Childe SJ Shibin KT Wamba SF Sustainable supply chain management: framework and further research directions Journal of cleaner production 2017 142 1119 1130 10.1016/j.jclepro.2016.03.117
Dwivedi, A., & Madaan, J. (2020). A hybrid approach for modeling the key performance indicators of information facilitated product recovery system. Journal of Modelling in Management, 15(3), 933-965.
Dwivedi A Agrawal D Jha A Gastaldi M Paul SK D’Adamo I Addressing the challenges to sustainable initiatives in value chain flexibility: implications for Sustainable Development Goals Global Journal of Flexible Systems Management 2021 22 2 179 197 10.1007/s40171-021-00288-4
Dwivedi, A., Agrawal, D., Paul, S. K., & Pratap, S. (2022). Modeling the blockchain readiness challenges for product recovery system. Annals of Operations Research, 1–45, https://doi.org/10.1007/s10479-021-04468-4.
Hair JF Risher JJ Sarstedt M Ringle CM When to use and how to report the results of PLS-SEM European business review 2019 31 1 2 24 10.1108/EBR-11-2018-0203
Jain, M., Goel, A., Sinha, S., & Dhir, S. (2021). Employability implications of artificial intelligence in healthcare ecosystem: responding with readiness. Foresight, 23(1), 73-94.
Jain, V., & Ajmera, P. (2020). Modelling the enablers of industry 4.0 in the Indian manufacturing industry. International Journal of Productivity and Performance Management, 70(6), 1233-1262.
Jain V Raj T Modeling and analysis of FMS flexibility factors by TISM and fuzzy MICMAC International Journal of System Assurance Engineering and Management 2015 6 3 350 371
Logesh, S., & Vinodh, S. (2022). TISM-based analysis of important factors for additive manufacturing in healthcare: a case study. Rapid Prototyping Journal, 28(2), 268-284.
Luo, L., Wang, Y., & Liu, H. (2022). COVID-19 Personal Health Mention Detection from Tweets Using Dual Convolutional Neural Network. Expert Systems with Applications, 200, 117139.
Mangla SK Kumar P Barua MK Flexible decision approach for analysing performance of sustainable supply chains under risks/uncertainty Global Journal of Flexible Systems Management 2014 15 2 113 130 10.1007/s40171-014-0059-8
Masudin I Ramadhani A Restuputri DP Amallynda I The effect of traceability system and managerial initiative on indonesian food cold chain performance: a Covid-19 pandemic perspective Global Journal of Flexible Systems Management 2021 22 4 331 356 10.1007/s40171-021-00281-x
Mathivathanan D Mathiyazhagan K Rana NP Khorana S Dwivedi YK Barriers to the adoption of blockchain technology in business supply chains: a total interpretive structural modelling (TISM) approach International Journal of Production Research 2021 59 11 3338 3359 10.1080/00207543.2020.1868597
Meier M Pinto E Covid-19 supply chain disruptions Covid Economics 2022 48 139 170
Menon, S., Suresh, M., & Raman, R. R. (2021). Enablers facilitating industry-academia, transnational education and university-community partnering agility in higher education. Higher Education, Skills and Work-Based Learning, 12(3), 604-626.
Mir, U. B., Sharma, S., Kar, A. K., & Gupta, M. P. (2020). Critical success factors for integrating artificial intelligence and robotics. Digital Policy, Regulation and Governance, 22(4), 307-331.
Momeni, M. A., Mostofi, A., Jain, V., & Soni, G. (2022). COVID19 epidemic outbreak: operating rooms scheduling, specialty teams timetabling and emergency patients’ assignment using the robust optimization approach. Annals of Operations Research, 1–31, https://doi.org/10.1007/s10479-022-04667-7.
Nyawa, S., Tchuente, D., & Fosso-Wamba, S. (2022). COVID-19 vaccine hesitancy: a social media analysis using deep learning. Annals of Operations Research,1–39, https://doi.org/10.1007/s10479-022-04792-3.
Paramita W Rostiani R Winahjoe S Wibowo A Virgosita R Audita H Explaining the voluntary compliance to COVID-19 measures: an extrapolation on the gender perspective Global Journal of Flexible Systems Management 2021 22 1 1 18 10.1007/s40171-021-00261-1
Patil M Suresh M Modelling the enablers of workforce agility in IoT projects: a TISM approach Global Journal of Flexible Systems Management 2019 20 2 157 175 10.1007/s40171-019-00208-7
Patri R Suresh M Modelling the enablers of agile performance in healthcare organization: a TISM approach Global Journal of Flexible Systems Management 2017 18 3 251 272 10.1007/s40171-017-0160-x
Piller FT Walcher D Toolkits for idea competitions: a novel method to integrate users in new product development R&d Management 2006 36 3 307 318 10.1111/j.1467-9310.2006.00432.x
Porter, M. F. (2001). Snowball: A language for stemming algorithms, http://snowball.tartarus.org/texts/introduction.html.
Priyadarsini SL Suresh M Huisingh D What can we learn from previous pandemics to reduce the frequency of emerging infectious diseases like COVID-19? Global transitions 2020 2 202 220 10.1016/j.glt.2020.09.003 32984800
Rathore AK Ilavarasan PV Pre-and post-launch emotions in new product development: insights from twitter analytics of three products International Journal of Information Management 2020 50 111 127 10.1016/j.ijinfomgt.2019.05.015
Romate J Rajkumar E Greeshma R Using the integrative model of behavioural prediction to understand COVID-19 vaccine hesitancy behaviour Scientific Reports 2022 12 1 1 13 10.1038/s41598-022-12466-0 34992227
Sarker M Moktadir M Santibanez-Gonzalez ED Social sustainability challenges towards flexible supply chain management: post-COVID-19 perspective Global Journal of Flexible Systems Management 2021 22 2 199 218 10.1007/s40171-021-00289-3
Shardeo V Patil A Madaan J Critical success factors for blockchain technology adoption in freight transportation using fuzzy ANP–modified TISM approach International Journal of Information Technology & Decision Making 2020 19 06 1549 1580 10.1142/S0219622020500376
Sindhwani, R., Hasteer, N., Behl, A., Varshney, A., & Sharma, A. (2022). Exploring “what,”“why” and “how” of resilience in MSME sector: a m-TISM approach. Benchmarking: An International Journal, https://doi.org/10.1108/BIJ-11-2021-0682.
Singh, A., & Singla, A. R. (2021). Modelling and analysis of factors for implementation of smart cities: TISM approach. Journal of Modelling in Management, 17(4), 1587-1622.
Singh MK Kumar H Gupta MP Madaan J Analyzing the determinants affecting the industrial competitiveness of electronics manufacturing in India by using TISM and AHP Global Journal of Flexible Systems Management 2018 19 3 191 207 10.1007/s40171-018-0182-z
Singh S Dhir S Modified total interpretive structural modelling of innovation implementation antecedents International Journal of Productivity and Performance Management 2022 71 4 1515 1536 10.1108/IJPPM-05-2020-0239
Singh S Chauhan A Dhir S Analyzing the startup ecosystem of India: a Twitter analytics perspective Journal of Advances in Management Research 2020 17 2 262 281 10.1108/JAMR-08-2019-0164
Singh S Haneef F Kumar S Ongsakul V A framework for successful IoT adoption in agriculture sector: a total interpretive structural modelling approach Journal for Global Business Advancement 2020 13 3 382 403 10.1504/JGBA.2020.111013
Singh S Sharma M Dhir S Modeling the effects of digital transformation in indian manufacturing industry Technology in Society 2021 67 101763 10.1016/j.techsoc.2021.101763
Singh, S., Singh, G., & Dhir, S. (2022). Impact of digital marketing on the competitiveness of the restaurant industry. Journal of Foodservice Business Research, 1–29, DOI: 10.1080/15378020.2022.2077088.
Singh S Sinha S Das VM Sharma A A framework for linking entrepreneurial ecosystem with institutional factors: a modified total interpretive structural modelling approach Journal for Global Business Advancement 2019 12 3 382 404 10.1504/JGBA.2020.111013
Sravat N Pathranarakul P Flipped learning pedagogy: modelling the challenges for higher education in India International Journal of Learning and Change 2022 14 2 221 240 10.1504/IJLC.2022.121137
Sterman, J. (2000). Business dynamics. McGraw-Hill, Inc.
Sushil Interpreting the interpretive structural model Global Journal of Flexible Systems Management 2012 13 2 87 106 10.1007/s40171-012-0008-3
Sushil Modified ISM/TISM process with simultaneous transitivity checks for reduced direct pair comparisons Global Journal of Flexible Systems Management 2017 18 4 331 351 10.1007/s40171-017-0167-3
Sushil Multi-criteria valuation of flexibility initiatives using integrated TISM–IRP with a big data framework Production Planning & Control 2017 28 11–12 999 1010 10.1080/09537287.2017.1336794
Sushil How to check correctness of total interpretive structural models? Annals of Operations Research 2018 270 1–2 473 487 10.1007/s10479-016-2312-3
Sushil Incorporating polarity of relationships in ISM and TISM for theory building in information and organization management International Journal of Information Management 2018 43 38 51 10.1016/j.ijinfomgt.2018.06.003
Anbarasan P Organization’s sustainable operational complexity and strategic overview: TISM Approach and Asian Case Studies Sustainability 2021 13 17 9790 10.3390/su13179790
Sushil Dinesh KK Structured literature review with TISM leading to an argumentation based conceptual model Global Journal of Flexible Systems Management 2022 23 387 407 10.1007/s40171-022-00309-w
Tam LT Ho HX Nguyen DP Elias A Le ANH Receptivity of governmental communication and its effectiveness during COVID-19 pandemic emergency in Vietnam: a qualitative study Global Journal of Flexible Systems Management 2021 22 1 45 64 10.1007/s40171-021-00269-7
Ullah I Khan S Imran M Lee YK Rweetminer: automatic identification and categorization of help requests on twitter during disasters Expert Systems with Applications 2021 176 114787 10.1016/j.eswa.2021.114787
Virmani N Saha R Sahai R Social implications of leagile manufacturing system: TISM approach International Journal of Productivity and Quality Management 2018 23 4 423 445 10.1504/IJPQM.2018.090265
Warfield, J. N. (1974). Toward interpretation of complex structural models. IEEE Transactions on Systems, Man, and Cybernetics, (5), 405–417.
Warrier, U., Shankar, A., & Belal, H. M. (2021). Examining the role of emotional intelligence as a moderator for virtual communication and decision making effectiveness during the COVID-19 crisis: revisiting task technology fit theory. Annals of Operations research, 1–17, https://doi.org/10.1007/s10479-021-04216-8.
Yadav A Sagar M Modified total interpretive structural modeling of marketing flexibility factors for indian telecommunications service providers Global Journal of Flexible Systems Management 2021 22 4 307 330 10.1007/s40171-021-00278-6
Yadav, V. S., Singh, A. R., Raut, R. D., & Cheikhrouhou, N. (2021). Blockchain drivers to achieve sustainable food security in the Indian context (pp. 1–39). Annals of Operations Research, https://doi.org/10.1007/s10479-021-04308-5.
Yoo SY Lim GG Analysis of news agenda using text mining and semantic network analysis: focused on COVID-19 emotions Journal of Intelligence and Information Systems 2021 27 1 47 64
Zhang X Xu J Soh C Chen L LA-HCN: label-based attention for hierarchical multi-label text classification neural network Expert Systems with Applications 2022 187 115922 10.1016/j.eswa.2021.115922
Zhang, Y., Chen, K., Weng, Y., Chen, Z., Zhang, J., & Hubbard, R. (2022b). An Intelligent Early Warning System of Analyzing Twitter Data Using Machine Learning on COVID-19 Surveillance in the US. Expert Systems with Applications,198, 116882.
| 0 | PMC9734704 | NO-CC CODE | 2022-12-14 23:28:30 | no | Ann Oper Res. 2022 Dec 5;:1-19 | utf-8 | Ann Oper Res | 2,022 | 10.1007/s10479-022-05098-0 | oa_other |
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http://orcid.org/0000-0003-0609-9083
Liu Jianli [email protected]
1
Liu Qiang 2
An Lihui 3
Wang Ming 4
Yang Qingbo 4
Zhu Bo 1
Ding Jiannan 5
Ye Chuanyu 6
Xu Yuyao 78
1 grid.258151.a 0000 0001 0708 1323 School of Textile Science and Engineering, Jiangnan University, Wuxi, 214021 China
2 grid.13402.34 0000 0004 1759 700X MOE Key Laboratory of Environment Remediation and Ecological Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058 China
3 grid.418569.7 0000 0001 2166 1076 State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing, 100012 China
4 grid.497867.3 Wuxi Little Swan Electric Appliance Co., Ltd, Wuxi, 214122 China
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6 grid.452666.5 0000 0004 1762 8363 The Second Affiliated Hospital of Soochow University, Suzhou, 215123 China
7 grid.50971.3a 0000 0000 8947 0594 School of Geographical Sciences, Faculty of Sciences and Engineering, University of Nottingham, Ningbo, 315100 China
8 grid.9227.e 0000000119573309 Institute of Urban Environment, Chinese Academy of Sciences, Ningbo Station, Ningbo, 315800 China
6 12 2022
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Microfibers, as emerging contaminants, pose a growing threat to the global environment. Microfiber pollution has been one of the hot research topics in environmental science. However, there is no consensus on microfiber definition from ecological and environmental perspectives. The underestimated sources, the distribution in the ocean and the atmosphere, the transport pathway, the potential human exposure, and mitigation strategies of microfibers from a global perspective have not been systemically discussed. So, we aim to discuss and analyze these concerns in this review. Firstly, the definition of microfiber pollutants from the ecological and environmental perspectives is proposed. Secondly, the largest source and some emerging sources of microfibers on the Earth have been explored. Thirdly, the distribution and transmission path of microfibers in the ocean and the atmosphere are discussed. Fourthly, the exposure path of microfibers to the human body is analyzed. Lastly, some applicable measures to control microfiber pollution are proposed from global environmental sustainable development perspectives.
Keywords
Microfiber pollution
Potential sources
Textiles and apparel
Domestic washing
Fiber loss
Mitigation strategy
http://dx.doi.org/10.13039/501100017684 Foundation Research Project of Jiangsu Province BK20200608 Zhu Bo http://dx.doi.org/10.13039/501100010031 Postdoctoral Research Foundation of China 2019M651704 Ding Jiannan issue-copyright-statement© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
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pmcIntroduction
Since the first thread of wild flax fibers was used to create strings about 30,000 years ago, the demand for fibers has driven and enriched human civilization as time moves on (Dyer 2021; Kvavadze et al. 2009). In 2020, the total volume of global fiber production accounted for 120 million tonnes or almost 16 kg per capita on average for consumption (Engelhardt 2020). Synthetic fibers amounted to 74 million tonnes, accounting for 61.77% of the total global fibre production, with an annual growth of up to 5% (Liu et al. 2021). However, the production and consumption of textiles and apparel for decades also resulted in multiple environmental problems, including the discharge of industrial wastes, including toxic chemicals, wastewater, greenhouse gases as well as microfibre pollutants (Muthu 2017).
Microfiber has been strictly defined as a staple fiber or a filament with a linear density ranging from 0.3 dtex to 1 dtex (Song 2011), where 1 dtex means one gram per 10000 m. The diameter of microfiber is usually less than 10 μm, and the lengthto-diameter ratio is on the order of 103 (Liu et al. 2019c). Polyester (PET) and polyamide (PA or Nylon) are the two main types of microfiber widely used as raw materials in the textile and apparel industry. Although acrylic, viscose, and polypropylene (PP) are also widely produced and applied in the textiles and apparel industry, they only account for a proportion of no more than five percent (Acharya et al. 2021). Microfibers have excellent properties contributing to human comfort. Clothes made of microfibers are usually strong and durable, lightweight, resist wrinkling and pilling, and have luxurious and various colors (Song 2011). As an emerging contaminant, microfiber has been gradually raising concerns because of the systematic research and mitigation measures for microplastic pollution (Rathinamoorthy and Balasaraswathi 2021). Microfiber is also called microplastic fiber, synthetic fiber, or even chemical fiber with a length of less than 5 mm when referred to as an environmental pollutant.
Microplastic fibers or plastic microfibers are a prevalent type of microplastics, where their potential ecological and toxicological impacts have been systematically discussed (Il Kwak et al. 2022; Woods et al. 2018). However, there is still no clear consensus on a definition that is extensive enough to encompass all necessary parameters to describe microfiber when studied as a global environmental pollutant, although microfiber only refers to synthetic fiber in the textile industry. Natural and regenerated cellulosic fibers have dominated microfibers in the atmosphere and freshwater (Finnegan et al. 2022; Stanton et al. 2019). So, we need to redefine microfiber from ecological and environmental science perspectives. In addition, microfibers are always subcategorized as microplastics and called microplastic fibers or fibrous microplastics despite their differences in shape, size, production mechanism, spatial distribution, transport pathway, and human effect. An extensive and critical review of the sources of microfiber, especially the textile and clothes chain, and some new emerging sources, such as clothes dryers, face masks, wet wipes, and cigarette butts, are not symmetrically performed. The review of the potential human exposures, including textile mill workers and infants, is limited. Furthermore, very few potential strategies have been widely adopted to control and mitigate microfiber release from textiles during the production, usage, caring, and disposal stages (Ramasamy and Subramanian 2021).
We propose a general definition of microfiber as an environmental pollutant and review the potential sources and distribution of microfibers in the ocean and the atmosphere, human exposure to microfibers, and applicable measures to mitigate microfiber pollution globally. Firstly, the definition of microfiber pollutants from the ecological and environmental perspectives is proposed. Secondly, the loss rate of fibers in spinning, weaving, finishing, and garment processing, some essential and indispensable processes of the cotton textile industry, is used as an index to analyze and clarify that the largest source of microfibers should be the textile and garment processing industry chain, not home laundering. Thirdly, we point out that the longer-range or global transport of microfiber through the atmosphere is another important transmission path that is not limited to rivers. The specific characteristics of microfibers, such as small fineness, low density, large surface area, and natural or artificial curling shape, make them more susceptible to airborne transport. Fourthly, we propose that the harmful path of microfibers to the human body is not only through the food chain but also through inhalation of respiratory diseases. Lastly, some applicable measures to control microfiber pollution, combined with the United Nations Environment and Development Programme UNEA 5.2 resolution and the United Nations Sustainable Development Goals (SDGs) are proposed from the perspective of global environmental sustainable development.
Definition of Microfiber Pollutant
The term ‘microfiber’ in the textile industry is usually confused with the term ‘microplastic fiber’ in the area of microplastic pollution (Xu et al. 2021). The concept of microfiber was initially proposed by the Japanese fiber manufacturing company, Toray, to represent micro-denier products during the 1970s, followed by mass production in Europe and America during the 1980s and 1990s (Song 2011). In textile engineering, microfibers are formally defined as staple fibers or filaments of linear density with no more than one denier and above 0.3 deniers (Liu et al. 2019b). Denier (abbreviated D), a unit to describe the linear mass density of fibers, is the mass of grams per 9000 m of the fiber. The natural reference of a denier is a 9000-m strand of silk that weighs about one gram (Amutha 2016). The definition of microfiber in textile engineering is a clear consensus that has been widely accepted from a professional textile engineering point of view. However, there is still no clear consensus on a definition that is extensive enough to encompass all necessary parameters to describe microfiber when studied as a global environmental pollutant with a ubiquitous distribution. In 2019, we proposed a general and extensive definition of microfiber pollutants as “Microfibers are any natural or artificial fibrous materials of threadlike structure with a diameter less than 50 μm, length ranging from 1 μm to 5 mm, and length to diameter ratio greater than 100” (Liu et al. 2019c). Since microfiber is one type of emerging pollutants and their related research is at the beginning, the definition of microfiber is a methodological challenge and an on-going debate, although we all attempt to reach a consensus on a definition for microfiber from the ecological and environmental perspectives.
Review Methods
A mini literature review was conducted on microfiber pollution in the earth system from 1995 (the earliest research about the effect of cotton dust pollution on textile worker health) through October 2022. The literature search included title search and abstract search using Web of Science, and title searches and keyword search using SCOPUS with the given terms as: “microfiber pollution”; “microplastic fiber” OR “microplastic fibre”; “ microplastic textiles”; “ microplastic” AND “synthetic fibers” OR “textile fibers”; “plastic microfibers”; “microplastic” AND “natural fiber” or “natural fibre”; “ textile pollution”. For all 4017 retrieved references, the title was identified first before abstract and keyword screening to exclude those deemed irrelevant articles. After the abstract screening, eligibility assessment, and relevant analysis, 194 related articles are selected and included in this review. The review framework is demonstrated in Fig. 1.Fig. 1 The review framework of microfiber pollution
Potential Sources of Microfiber Pollution
Domestic Washing was Initially Identified as the Primary Source
Initially, microfibers were more likely described as synthetic fibers shed from clothing during laundry (Napper and Thompson 2016). It was reported that approximately 700,000 microfibers (about 0.5 g in weight) could be discharged with laundry sewage every cycle the washing machine drum rotates (Karkkainen and Sillanpaa 2021; Napper and Thompson 2016). So, domestic and commercial washing was primarily identified as a leading potential source of microfibers (Cai et al. 2020a). As many as 700,000 can be released into the wastewater each cycle, weighing approximately 0.5 g in total. Globally, it is estimated that 500,000 tonnes of microfibers are released into the ocean because of domestic washing annually (Boucher and Friot 2017). Textiles contribute about 14% of plastic waste production by sector, the second source of plastic pollution following packaging (Smith and Vignieri 2021). Therefore, domestic washing was regarded as a leading potential source of microfibers at the beginning (Cai et al. 2020a).
Fiber Losses in the Textiles and Apparel Industry have been Underestimated
The fiber losses in the production process of the textile and apparel industry are inevitable but usually ignored and rarely reported, which may lead to the relevant research underestimating the emission capacity of this part of microfibres towards the environment. From raw materials to the end-product, fiber losses occur at each step of the textile production processes, including spinning, weaving, dyeing, finishing, cutting, trimming, and sewing, especially through the wet-processing dyeing and finishing mills (Chan et al. 2021). For example, in different manufacturing processes, cotton fiber loss rates for different end-products are listed in Table 1, released by Better Cotton Initiative (2022) through member survey responses in 2020 (Initiative 2020). 6% to 43% of fibers were lost during each process (Table 1). If the fiber loss rate is simply set at 30% from fiber to end-product, about 70,000,000 tonnes of cotton were globally wasted in 2020 (James Johnson, 2021). Assuming that the microfiber loss rate is 1% from fiber to end-production during the home textiles and apparel production, nearly 1.1 million metric tons of microfiber, which is 2.2 × 106 times the weight of the estimated ones being released from domestic washing. Although the detailed loss rate of synthetic fiber during production is so far unclear, the mismanagement of the fiber losses at spinning mills, fabric mills, and manufacturing factories of home textiles and apparel, as well as a sale and usage stages, should not be ignored (Cai et al. 2020b). Incineration and landfills have been the main measures to prevent microfiber from being directly released into the environment for those who originated from dry processes such as spinning, weaving, and sewing (Periyasamy and Tehrani-Bagha 2022). Therefore, compared to domestic washing, the microfibres s of microfiber are the spinning mills, fabric mills, and manufacturing factories of home textiles and apparel compared with domestic washing.Table 1 Cotton fiber loss rates for different intermediary products and end-products (Initiative 2020)
Loss rate (%) Home
textiles Apparel:
denim Apparel:
wovens Apparel:
flat knits Apparel:
circular knits
Fiber-to-yarn (open-end) 10% – – – –
Fiber-to-yarn (carded) – 12% 12% – –
Fiber-to-yarn (combed) – – – 21% 21%
Fiber-to-fabric 20% 17% 21% – 31%
Yarn-to-fabric 11% 6% 10% 13% 18%
Fiber-to-end-product 24% 30% 35% 31% 43%
Fabric-to-end-product 5% 15% 18% 13% 18%
In Table 1, a considerable amount of fiber loss is reported, although a remarkable difference exists between intermediary products, i.e. yarn, fabric, and end-products, including home textiles and four types of apparel. The fiber loss during spinning, weaving, dyeing, finishing, cutting, trimming and sewing processes is the major microfiber source in the textile and clothes industry. If the expected fiber loss is set at 30% from fiber to end-product and the weight of a cotton bale is 200 kg, more than 35.0 million bales of cotton, about 7,000 million kilograms of cotton was globally wasted in 2020 (James Johnson, 2021). The mismanagement of the fiber loss at spinning mills, fabric mills, and manufacturing factories of home textiles and apparel will generate an enormous amount of microfiber in solid wastes and contaminants in wastewater. Additionally, the origin of microfibers within the production, sale, and usage stages of chemical fibers and industrial textiles should not be ignored (Cai et al. 2020b).
The wastewater discharged from the wet-processing stages, including dyeing, sizing, post-processing, and finishing, is another direct and significant route for the fiber losses entering the environment. Microfiber released from textile wastewater is considerably higher than from municipal sewage treatment plants, heavily contributing to microfiber pollution. The microfiber concentration was up to 54,100 microfibers/L in textile printing and dyeing wastewater sampled in three typical textile mills in Keqiao textile industrial park in southeast China (Zhou et al. 2020). Correspondingly, the effluents from the centralized wastewater treatment plants (WWTPs) of the same park reached as high as 537 microfibers/L, which means that 430 billion microfibers were discharged daily by WWTPs (Zhou et al. 2020). Microfiber released from textile wastewater is considerably higher than municipal sewage treatment plants, significantly contributing to microfiber pollution (Liu et al. 2021). Azizi et al. reported that the microfibres took average 57% of the microplastics in the wastewater sampled after each treatment step in conventional WWTPs according to the results of the meta-analysis (Azizi et al. 2022). Bao et al 2022. sampled the wastewater after each treatment process of a tropical urban WWTP and pointed out that 79.7% and 82.9% of microplastics detected in the wastewater are fibers during dry and wet seasons, respectively (Bao et al. 2022). Hu et al. analyzed the physical characteristics of microplastics in 48 WWTPs in China and concluded that the maximum percentage of fibers was higher than 70% in both influent and effluent samples (Hu et al. 2022a). Other microfiber research indicates that fibers contribute up to 50% of the total microplastic mass in WWTPs (Roscher et al. 2022; Shan et al. 2022; Sun et al. 2019). Additionally, the sewage sludges used by WWTPs could also act as another important route for microfiber to enter the environment when the sludges were piled or buried in the terrestrial environment (Liu et al. 2021; Takdastan et al. 2021).
Clothes Dryers, Face Masks, Wet Wipes, and Cigarette Butts are Emerging Sources
An electric clothes dryer is one of the important emerging sources of discharging microfibers toward the environment but is also easily underestimated (Yousef, 2021). In 2021, the global clothes dryers market grew steadily and will gradually become a common household appliance for the middle class in the next five years (Ahmadi, 2021). However, it was reported that 35 and 70 mg of microfibers could be released by 100% polyester fleece blankets when dried by two different types of domestic dryer (Kapp and Miller 2020). It is imperative to install a novel filter for the clothes dryer to capture microfiber to significantly reduce the amount of microfiber directly entering the environment (Karkkainen and Sillanpaa 2021).
The tools that human beings used for controlling the COVID-19 epidemic, may also become emerging sources of microfiber pollutants. Wearing a face mask is considered to be one of the effective ways to reduce the spread of COVID-19. Surgical masks, made of polymeric nonwoven materials consisting of polypropylene-based and polyethylene-based microfiber, were widely used worldwide. The daily face mask production and consumption have been up to 110 million, with growth at 450% in China since February 2020 (Wu et al. 2022). Worldwide, approximately 129 billion face masks have been demanded each month to effectively deal with the COVID-19 pandemic since 2020, with a 40% monthly increase (Fadare and Okoffo 2020; Prata et al. 2020). The demand for face masks is expected to be substantial during the post-pandemic period, with an estimated annual growth of 20%, from 2020 to 2025 (Singh et al. 2020). A dramatic increase in face mask production and consumption leads to a rapid accumulation of used PPEs in domestic solid waste streams. If only 1% of face masks are inappropriately disposed of, about 10 million masks, nearly 30–40,000 kg of microfibers, will be globally released into the environment every month (De-la-Torre et al. 2022; Fadare and Okoffo 2020; Torres-Agullo et al. 2021). Thus, microfiber and nanofiber from face masks will sharply increase in the Earth system in the future (Akhbarizadeh et al. 2021a).
Wet wipes with alcohol-based sanitizers for disinfection and sterilization during the COVID-19 pandemic have also been identified as a potential source of microfibers (Shruti et al. 2021). The Discarded wet wipes and disposable face masks will degrade into microfibers with the help of solar radiation, mechanical friction, and microbial corrosion (Hu et al. 2022b). Although wet wipes are not widely used as face masks for the public in the COVID-19 era, the risk of microfiber pollution caused by discarded wet wipes and other personal protective equipment cannot be neglected (Briain et al. 2020; Haque and Fan 2022).
Cigarette butts are also an emerging microfiber source. Cigarette butts are made of cellulose acetate fibers. A cigarette butt comprises more than 15,000 cellulose acetate microfibers (Shen et al. 2021). Cigarette butts will release about 300,000 tonnes of potential microfibers annually into global aquatic environments (Belzagui et al. 2021). Although the amount of microfibers released from smoked cigarette butts is relatively smaller than other discussed microfiber sources, the joint ecotoxicity of microfibers and toxic pollutants (i.e. nicotine, carcinogenic tar, and polycyclic aromatic hydrocarbons) to the environment cannot be ignored. The leachate of five smoked cigarettes dissolved in 1L of water will cause 60% to 100% mortality of four types of freshwater invertebrates within five days (Green et al. 2020). A few butts in the soil could cause decreased activity in soil-dwelling invertebrates (Gill et al. 2018) (see Fig. 2). A summary of the potential sources and the release volume of microfibers each year is demonstrated in Table 2.Fig. 2 The potential sources of microfibers
Table 2 Microfibers from various sources
Source Amount of release per year Potential harm
Domestic washing 500,000 tonnes The harmful effects on the ocean and freshwater system
Fiber losses 1,100,000 tonnes The harmful effects on the ocean, air, soil, and human
Clothes dryer / The harmful effects on the air
Face masks 360–480 tonnes The harmful effects on the ocean, freshwater, and soil
Wet wipes / The harmful effects on the ocean, freshwater, and soil
Cigarette butts 300,000 tonnes The harmful effects on the freshwater system and soil
Degradation offers a strategy for microfibers to mitigate microfiber pollution. Four degradation methods include photodegradation, electrochemical oxidation, thermodegradation, and biodegradation. The products of PET, PA, polyacrylonitrile (PAN), and wool include Bisphenol A, bisphenol S, benzophenone-3, and some volatile organic compounds through photocatalytic oxidation in seawater and freshwater media over ten months (Sait et al. 2021). The thermodegradation and biodegradation of the synthetic and cellulosic microfibers, especially biodegradation using functional microbial and multiple enzymes, can provide sustainable concurrent routes to producing biofuel and mitigating environmental pollution (Arpia et al. 2021; Du et al. 2021).
Microfibers in the Ocean
Microfibers are the most common types of microplastics identified in the ocean (Belzagui et al. 2019; Mishra et al. 2019; Salvador Cesa et al. 2017; Suaria et al. 2020). Microfibers in the ocean, including polyester, acrylic, polypropylene, polyethylene, and polyamide, are widely and mainly used in the textiles and apparel industry(Garlapati 2019; Mishra et al. 2019). Especially polyester fibers account for more than 50% of the collected microplastic samples (Mishra et al. 2019). Fibrous microplastics, 0.1—1.5 mm in length, are predominantly 91% of microplastics in a global marine microfiber contamination study of surface water samples (Barrows et al. 2018). Synthetic fibers released from domestic washing have ever been considered the major microfiber source in the marine environment (Belzagui et al. 2019; Salvador Cesa et al. 2017). However, fibrous materials, including various textiles and apparel, are the main sources of microfibers in the ocean, which are released during the whole life cycle of fiber production, use, care, and waste disposal (Liu et al. 2021).
Microfibers are dispersed and accumulated throughout the global ocean and are recorded in the samples from surface and subsurface seawater to deep-sea sediments and organisms. Microfibers ingestion is ubiquitous in marine organisms and biota because of their high bioavailability in benthic and pelagic habitats. Microfibers are susceptible to ingestion by a wide range of marine organisms, from zooplankton (Botterell et al. 2020, 2019; Sun et al. 2018, 2017), fish (Akhbarizadeh et al. 2020a; Neves et al. 2015), shellfish (Ding et al. 2020), reptiles (Duncan et al., 2019), and seabirds (Provencher et al. 2018) to mammals (Zantis et al. 2021). The microfiber abundance in the various tissues of marine organisms was significantly correlated with those of the surrounding seawater (Sui et al. 2020). Thus, some marine organisms, such as zooplankton species, can be used as indicators of microfiber pollution in marine ecosystems (Kvale et al. 2021). The ingestion, trophic transfer, accumulation, and potentially toxic effects of microfibers in the marine ecosystem are still poorly understood (Athey and Erdle 2022). However, microfibers have properties similar to those of microplastics, which makes them have potentially negative effects on the organisms that ingest them. The surfaces of microfibers have high adsorption capacities for organic, inorganic, and mixed pollutants (Zhao et al. 2022), such as the adsorption of sulfonamides on virgin PA (Jiang et al. 2022), carcinogenic polycyclic aromatic hydrocarbons on polyester fiber (Wisniowska and Wlodarczyk-Makula 2022), and Pb, Cd, Cs, and Zn onto PE (Besson et al. 2020; Li et al. 2022b). Additionally, more than 100,000 chemical additives, such as natural and synthetic dyes, softening, ultraviolet protective, and antimicrobial and antiviral agents, have been widely used during fiber, yarn, and fabric manufacturing or finishing processes to endow some special functional properties to textiles, for example, dope additives, including but not limited to plasticizers, dyes, pigments, fire retardants, and UV absorbers, which might be ecotoxic. Considering that microfibers in the marine environment are the reservoirs for antibiotic, metal-resistance genes (Akhbarizadeh et al. 2020a) and microbial communities (Mishra et al. 2022; Yang et al. 2019), the toxic substances adhering on or released from microfibers may threaten the survival, feeding, and fecundity of marine organisms, and represent a great risk for marine biodiversity (Guzzetti et al. 2018; Vroom et al. 2017).
Although rivers and urban runoff are implicated as major pathways of microplastics and microfibers transporting to marine environments (Gago et al. 2018; Hajiouni et al. 2022; Wang et al. 2022), the transportation of fibrous materials from land to coastal areas and deep ocean is still poorly understood. Atmospheric transport, that is, wind entrainment, has been proposed to be a novel pathway for microfiber movement, although only a handful of related studies have been carried out. Microfibers are preferentially transported to a longer-range or global scale by wind entrainment and erosion because of its smaller size and lighter density compared to plastic microbeads and fragments (Bullard et al. 2021). Microfibers were found in most samples, accounting for 92%, through atmospheric deposition in central London with higher deposition rates of up to 1008 fibers/m2/d (Wright et al. 2020). Atmospheric microfiber transport has been considered a significant pathway for microfiber to the ocean from the indoor origin in times of favorable wind speeds and trajectories (Brahney et al. 2020; Kash et al. 2022). It was estimated that 7.64–33.76 tonnes of microfibers were globally generated in 2018, constituting a great proportion of ingestible solid pollutants in the ocean air and marine ecosystem (Il Kwak et al. 2022; Li et al. 2022a; Liu et al. 2020). Furthermore, sea ice is also considered an important temporal transport for microfiber in the Polar regions, which is transported by oceanic currents in different seasons (Peeken et al. 2018).
Mathematical modeling provides an effective means to explore the transport mechanism of microfiber in the aquatic environment. Liedermann et al. proposed to measure microplastic transport in large or medium rivers using a net-based device with different net sizes exposed in three different depths (Liedermann et al. 2018). Sheerman and Sebile proposed a model based on satellite-tracked buoy observations to simulate the transport of plastic floating on the ocean surface from 2015 to 2025 (Sherman and van Sebille 2016). Choi et al. proposed an orientation-dependent drag model, considering the secondary motion, toward realistic predictions of microfiber transport in aquatic environments (Choi et al. 2022). Mathematical modeling provides an effective means to explore the transport mechanism of microfiber in the aquatic environment. Through a systematic review, Uzun et al. deduced that more reliable results are obtained using hybrid methods, especially the coupling of hydrodynamic and process-based models and hydrodynamics and statistical models (Uzun et al. 2022). The research on the microfiber transport mechanism is limited. In the future, more data in longer periods and a variety of properties of microfibers are required to increase the robustness and accuracy of mathematical modeling of microfiber transport in the aquatic environment.
Microfibers in the Atmosphere
Microfiber released from the various textiles and garments production, including spinning, weaving, dyeing, cutting and sewing, shedding from clothing during normal wear and laundry drying, emissions from outdoor textile sports equipment, and discarded textiles, are the principal sources of microfibers in the atmosphere. Though synthetic microfibers have been widely reported as the majority of microplastic pollution in the air, natural fibers also constitute a more significant proportion of the atmospheric pollutants transported by wind and rain (Rochman and Hoellein 2020; Stanton et al. 2019). Furthermore, some research indicated that atmospheric microfibers are dominated by natural and regenerated cellulosic fibers instead of synthetic fibers (Finnegan et al. 2022; Li et al. 2020). Microfibers in the atmosphere will lead to direct respiratory exposure to human health, especially for textile and clothing factory workers. Recent research indicated that at least 13,000 to 68,000 household dust microfibers have been inhaled from textiles per year (Catarino et al. 2018). Additionally, several additives, such as inorganic salts, metal nanoparticles, and natural and synthetic macromolecular substances, will release from microfiber into the atmospheric and aquatic environment as environmental hormones (Lin et al. 2018). The desorption of fiber additives in the atmosphere, such as disperse dyes, UV stabilizers, and degradation products, is the most important contact allergen in textile dermatitis (Malinauskiene et al. 2013; Sait et al. 2021). Exposure to mixed airborne microcontaminants, including fine particulate matter (PM2.5) microfibers and polycyclic aromatic hydrocarbons, will increase the cancer risk in winter (Akhbarizadeh et al. 2021b).
The low density, moderate length, natural or artificial crimp, and greater surface-area-to-volume ratios of microfibers compared with plastic microbeads and fragments facilitate their wind entrainment and regional transport from 10 to 1000 km (Brahney et al. 2020), which means the atmospheric environment is also an important pathway to spread microfiber pollution. Especially dry microfibers are susceptible to atmospheric conditions, mainly contributing to the longer-ranger or global transport rather than regional areas through several suspension-deposition cycles for years (Brahney et al. 2020). Though high-altitude winds and rainstorms have been considered the main forces that transport and circulate atmospheric microfibers globally, the route of microfibers to the atmosphere and the transport pathway with air have not been clarified. Applying concepts and methods from geosciences will accelerate our understanding of the mechanism of atmospheric pollution of microfiber, the fate of microfibers in the atmosphere, and how microfibers affect air quality (Stubbins et al. 2021).
The Potential Human Exposures
Indoor and outdoor dust ingestion has been reported as human exposure pathways to microfibers of great magnitude (Dris et al. 2017). The highly concentrated microfibers have been detected in indoor dust, accounting for 88.0% of microplastics ranging from 1550 to 120,000 mg/kg (Liu et al. 2019a). The daily exposure for adults was 64.1 fibers/kg-bw/day, while a daily exposure risk of 889 fibers/kg-bw/day for infants and indoor dust accounted for 97% of the total exposure (Liu et al. 2019a). The daily exposure risk of microfibers for infants was more than ten times that of adults, likely due to increased dust ingestion caused by crawling behavior and the higher frequency of nibbling behavior of hands, feeding bottle, plush toys, and clothes (Liu, 2022). The potential pathways of microfiber exposure for infants are demonstrated in Fig. 3. The quantitatively instrumental analysis of polyethylene terephthalate (PET) and polycarbonate (PC) microplastics in infant and adult feces also supports the daily exposures from the diet of an infant are significantly higher than those of adults (Zhang et al. 2021). Common microfibers or microplastics, such as PET, PE, and PP have also been detected in human stool, placenta, and meconium in some clinical cases (Braun et al. 2021; Nor et al. 2021; Schwabl et al. 2019). The latest research indicated that common polymers applied in fibrous materials, such as PET and PE are bioavailable in the human bloodstream within nano-size, and the sum quantifiable concentration in blood was 1.6 µg/ml (Leslie et al. 2022). The microplastic beads ranging from 1 to 10 μm lead to significant mechanical stretching of the lipid membranes without inflammatory reactions and serious dysfunction of the cell machinery (Fleury and Baulin 2021). Correspondingly, the negative effect of microfiber on the micro-nanometers size of cell membranes and their physiological toxicity of additive chemical content on the human digestive system should be experimentally and theoretically studied.Fig. 3 The potential pathways of microfiber exposure for infants
Inhalation and ingestion are the two main pathways for daily human exposure to microfibers. For inhalation, the significant correlation between microfiber exposure and the occupational health of textile workers has been confirmed in massive clinical cases (Hussain et al. 2019; Karanikas and Hasan 2022; Lai and Christiani 2013; Too et al. 2016). Long-term and high exposure to organic dust containing hemp and cotton microfiber through inhalation and skin contact has negative effects on textile workers' byssinosis, respiratory diseases, allergies, and epithelial growth (van Dijk et al. 2020; Zele et al. 2021). A cross-sectional study in Pakistan has indicated that 35.6% of textile workers suffer from byssinosis, especially those in spinning and weaving mills exposed to a higher density of microfiber (Memon et al. 2008). The worldwide prevalence of byssinosis among textile workers is up to 40% (Murlidhar et al. 1995). Particularly in low/middle countries, byssinosis has been a basic occupational disease for textile workers. Respiratory diseases, including reversible or irreversible obstructive lung diseases (i.e., asthma or chronic obstructive pulmonary disease), and restrictive lung diseases, are prevalent in textile workers (Lai and Christiani 2013). Polypropylene and polyethylene terephthalate fibers (≤ 3 μm) were most abundantly identified using μFTIR spectroscopy in all regions of 13 human lungs collected from thoracic surgical procedures at Castle Hill Hospital in the United Kingdom (Jenner et al. 2022). Microfibers are reservoirs for additive chemical content (Sait et al. 2021), volatile and semivolatile organic compounds, bacteria, and fungi in indoor and outdoor environments, acting as selective pressure within developing respiratory and gut microbiomes (Gardner et al. 2020) (see Fig. 4).Fig. 4 Implications of microfibers inhalation and possible consequences in the human respiratory system
Microfibers have been documented in the digestive tract, gills, and the select internal organs of commercial marine species such as bivalves, crabs, and fish (Dawson et al. 2021). Therefore, seafood has been regarded as the main transfer pathway of microfibers to humans by the public. However, the tissues are always discarded instead of eaten by seafood consumers. Drinking water (Akhbarizadeh et al. 2020b; Gouin et al. 2021; Zhang et al. 2020), and salt (Peixoto et al. 2019; Zhang et al. 2020) are other ingestion ways for microfibers to enter human bodies. The exposure data, adsorption model, and health risk evaluation of microfiber in humans are inadequate. The adverse health effects on humans at different levels, including cytotoxicity, immune response, oxidative stress, and barrier attributes of microfibers of human cells, are still unknown (Danopoulos et al. 2022).
The Way Forward
At present, the abundance, distribution, and mechanism of environmental microfiber pollution are still unclear, which makes it difficult for stakeholders and the public to pay attention to the management of microfiber. In recent years, with the increasing exposure to microplastic pollution in mass media, relevant practitioners began to focus on the problem of microplastic fiber pollution. However, it should be clarified that microfiber is not directly equivalent to microplastic fiber. Microfiber sometimes refers to a wider group of materials than microplastic fiber. Therefore, it is necessary to study and understand the short-term, medium-term, and long-term mechanisms of microfiber pollution, and gradually realize the management of microfiber pollution in industry and daily life.
A Binding Global Agreement
In February 2021, an international agreement to combat plastic pollution has been proposed by many governments at the fifth summit of the United Nations Environment Assembly (UNEA) (Simon et al. 2021). A draft resolution on a global binding to reduce the discharge of plastics throughout the plastic life cycle has been negotiated at the UNEA5.2 on March 2, 2022. An internationally legally binding agreement to effectively curb increasingly serious plastic pollution will be a historic initiative and advance for humans. However, the plastic pollution problem mentioned in the agreement has not specifically included microfiber pollution, although more than 35% of microplastics are fibers coming from textiles. If the microplastics from textile sources are included in the draft resolution to be further negotiated at the UNEA5.2 framework in 2024, urgent actions on plastic and microplastic pollution will be strengthened within a more comprehensive scope through more holistic and prospective responses.
Legislation on Microfiber Pollution
Since February 2020, all newly sold washing machines are mandated to be equipped with a microfiber filter by 2025, which has already been adopted under a France law (Sánchez 2020). France is the first country in the world to reduce and control microfiber pollution from laundry through regulations. The experience of France shows that it is feasible to manage microfiber pollution by legislation. While controversially, France's legislation in the field of microfiber pollution is a viable response to the severe environmental and ecological problem. It is foreseeable that microfiber pollution will be legislated on a much broader level. As discussed in previous sections, the most important source of microfibers in the environment is not domestic laundry but the waste and wastewater produced in the relevant industrial production processes. Therefore, future legislation must focus on microfiber emission events in industrial production. It requires a quantitative evaluation and a lamination of the microfiber discharge from a technical point of view.
Development of Technical Standards on Microfiber Pollution
Some voluntary, consensus-based, or mandatory standards related to microplastics from textile sources will be developed to provide solutions to microfiber pollution. In 2022, the ISO/TC 38 subcommittees dealing with the sampling and measuring material loss for microfibers from textile end-products by domestic washing method, and the qualitative and quantitative evaluation of microfiber from domestic washing, approved the development of three technical standards on microplastic from end textile products (ISO 2021a, b, c). The implementation of measurement and quantitative evaluation standards on microplastic from textile sources will accelerate the innovation of fiber and yarn production, and the design evolution of fabric and clothes. A broad range of stakeholders of the textile and clothes chain including, but not limited to, the textile and fashion industry, and washing machine manufacturers, look for and promote solutions using strategic and tactical interventions throughout the full fibrous material lifecycle. In the future, a series of technical standards and guidelines will be amended and issued at multilevel in a bid to regulate the design and production, reuse, recycling, disposal, and retrieval of textiles and clothing (Simon et al. 2021).
Addressing Microfiber Pollution Through Circular Economy
The global annual textile consumption has reached up to 100 million tonnes, while only 15% was recycled in the last two decades (Shirvanimoghaddam et al. 2020). The disposal nature of fast fashion and “throwaway culture” in a linear economy has directly contributed to a large amount of textiles wastes (Bucknall 2020). However, this leads to not only a huge loss of valuable resources but an ever-increasing environmental problem. A circular textile economy provides a new approach to reducing textile waste and mitigating microfiber pollution. In general, reuse and recycling can maintain fibrous materials at their highest value and reduce environmental impact compared to traditional ways, such as landfills and incineration. The reuse of aged but wearable clothes, such as cotton clothes and synthetic fiber fashion without aging, through the sale of secondhand goods, is more beneficial than recycling (Cao et al. 2022; Sandin and Peters 2018). A circular textile economy, especially for some major textile and clothing production countries in Asia and Africa, will trigger and promote the adjustment of the textile value chain from a sustainable development perspective. Meanwhile, the circular textiles economy will drive advances in next-generation fibrous materials design from the environmental and ecological dimensions, increasing their end-of-life value in the long-term.
Conclusions
As an emerging pollutant, microfibers are now generally categorized as a dominant type of microplastics. In the future, microfibers will be systematically studied as an independent type of pollutant instead of a subgroup of microplastics. The knowledge gaps remain about the potential source, transport pathway, spatial distribution, environmental toxicity and fate, and risk of microfiber to ecosystems on the Earth. Microfiber, a suite of synthetic polymers intentionally created for the benefit of humans, is still being explored through holistic approaches to the extent that they are harming organisms and ecosystems on the Earth. However, we must urgently address the full lifecycle of microfiber, given the scale of microfiber pollution and our increasing levels of microfiber consumption.
In this review, microfiber as an environmental pollutant is defined. Some underestimated sources of microfiber are discussed. The potential human exposure to microfiber is summarized. Moreover, some feasible measures to migrate microfiber pollution are proposed.An extensive definition of microfiber as an emerging contaminant was proposed, including both natural and synthetic fibers. Considering that microfibers and microplastic fibers have many various commonalities, thus, it is necessary to further recognize the microfibres in the textile area from ecological and environmental perspectives.
The potential sources of microfiber have been explored in different scenarios. Although domestic washing was always identified as the primary source, fiber losses in the textiles and apparel production processes have been identified as the main source that cannot be neglected and underestimated. We have also pointed out that clothes dryers, face masks, wet wipes, and cigarette butts are emerging sources.
Atmospheric microfiber transportation is also identified as a significant pathway for microfiber to the ocean from its indoor origins, although rivers are implicated as major pathways of microfibers transport to marine.
The research on the environmental impact of microfiber on organisms and ecosystems is just beginning. Inhalation and ingestion are the two main pathways for daily human exposure to microfibers. Textile workers’ exposure to microfiber at high doses and for long periods can cause respiratory disease.
Some feasible measures to mitigate microfiber pollution from the global perspective are also suggested, including global management of plastic pollution from textile sources, technical standards for microfiber pollution, and a circular economy pattern to reduce textile waste and mitigate microfiber pollution.
Future Outlook
It will be a difficult and long way to eliminate microfiber pollution. The research about the systematic source, patterns, and processes of microfiber transport around the globe could last for years, let alone the medium to long-term effects of microfiber pollution on environments and humans. However, despite the growing research on microfiber pollution, this field still has some limitations. The future directions included but were not limited to the followings,Collaborative research on the mixed micro-nano pollutants, including microplastic, microfiber, suspended fine particulate matter (PM2.5), polycyclic aromatic hydrocarbons (PAHs), heavy metals, and other emerging contaminants will reveal the real environmental risk and effects on human.
The realistic and theoretical modeling of microfiber abundance, distribution, transport, and accumulation in aquatic, atmospheric, and marine-atmosphere environments will assess the feasibility and efficiency of migration methods.
The industrial application of microfiber in energy and architecture will provide a sustainable concurrent approach to producing biofuel and fibrous composites and mitigating microfiber pollution.
Funding
This project was supported by the Natural Science Foundation of Jiangsu Province (Grant No. BK20200608) and the Postdoctoral Science Foundation of China (Grant No. 2019M651704).
Declarations
Conflict of interest
The authors declare that there is no conflicts of interest.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Acharya S Rumi SS Hu Y Abidi N Microfibers from synthetic textiles as a major source of microplastics in the environment: a review Text Res J 2021 91 2136 2156 10.1177/0040517521991244
Akhbarizadeh R Dobaradaran S Nabipour I Tajbakhsh S Darabi AH Spitz J Abundance, composition, and potential intake of microplastics in canned fish Mar Pollut Bull 2020 10.1016/j.marpolbul.2020.111633
Akhbarizadeh R Dobaradaran S Schmidt TC Nabipour I Spitz J Worldwide bottled water occurrence of emerging contaminants: a review of the recent scientific literature J Hazard Mater 2020 10.1016/j.jhazmat.2020.122271
Akhbarizadeh R Dobaradaran S Nabipour I Tangestani M Abedi D Javanfekr F Jeddi F Zendehboodi A Abandoned Covid-19 personal protective equipment along the Bushehr shores, the Persian Gulf: an emerging source of secondary microplastics in coastlines Mar Pollut Bull 2021 10.1016/j.marpolbul.2021.112386
Akhbarizadeh R Dobaradaran S Torkmahalleh MA Saeedi R Aibaghi R Ghasemi FF Suspended fine particulate matter (PM2.5), microplastics (MPs), and polycyclic aromatic hydrocarbons (PAHs) in air: their possible relationships and health implications Environ Res 2021 10.1016/j.envres.2020.110339
Amutha K A practical guide to textile testing 2016 Woodhead Publishing India Pvt Ltd
Arpia AA Chen WH Ubando AT Naqvi SR Culaba AB Microplastic degradation as a sustainable concurrent approach for producing biofuel and obliterating hazardous environmental effects: a state-of-the-art review J Hazard Mater 2021 418 126381 10.1016/j.jhazmat.2021.126381 34329008
Athey SN Erdle LM Are we underestimating anthropogenic microfiber pollution? A critical review of occurrence, methods, and reporting Environ Toxicol Chem 2022 41 822 837 10.1002/etc.5173 34289522
Azizi N Nasseri S Nodehi RN Jaafarzadeh N Pirsaheb M Evaluation of conventional wastewater treatment plants efficiency to remove microplastics in terms of abundance, size, shape, and type: a systematic review and Meta-analysis Mar Pollut Bull 2022 10.1016/j.marpolbul.2022.113462
Bao RQ Wang ZZ Qi HY Mehmood T Cai MG Zhang YM Yang RL Peng LC Liu FJ Occurrence and distribution of microplastics in wastewater treatment plant in a tropical region of China J Clean Prod 2022 10.1016/j.jclepro.2022.131454
Barrows APW Cathey SE Petersen CW Marine environment microfiber contamination: global patterns and the diversity of microparticle origins Environ Pollut 2018 237 275 284 10.1016/j.envpol.2018.02.062 29494921
Belzagui F Buscio V Gutierrez-Bouzan C Vilaseca M Cigarette butts as a microfiber source with a microplastic level of concern Sci Total Environ 2021 10.1016/j.scitotenv.2020.144165
Belzagui F Crespi M Alvarez A Gutierrez-Bouzan C Vilaseca M Microplastics' emissions: microfibers' detachment from textile garments Environ Pollut 2019 248 1028 1035 10.1016/j.envpol.2019.02.059 31091635
Besson M Jacob H Oberhaensli F Taylor A Swarzenski PW Metian M Preferential adsorption of Cd, Cs and Zn onto virgin polyethylene microplastic versus sediment particles Mar Pollut Bull 2020 10.1016/j.marpolbul.2020.111223
Better Cotton Initiative (2022). Measuring Cotton Consumption: Better Cotton Conversion Factors and Multipliers. Geneva, Switzerland: 23. https://bettercotton.org/wpcontent/uploads/2022/05/Measuring-Cotton-Consumption_Better-Cotton-Conversion-Factors-and-Multipliers_v2.pdf. Accessed 3 December 2022
Botterell ZLR Beaumont N Cole M Hopkins FE Steinke M Thompson RC Lindeque PK Bioavailability of microplastics to marine zooplankton: effect of shape and infochemicals Environ Sci Technol 2020 54 12024 12033 10.1021/acs.est.0c02715 32927944
Botterell ZLR Beaumont N Dorrington T Steinke M Thompson RC Lindeque PK Bioavailability and effects of microplastics on marine zooplankton: a review Environ Pollut 2019 245 98 110 10.1016/j.envpol.2018.10.065 30415037
Boucher, J. and Friot D. (2017). Primary Microplastics in the Oceans: A Global Evaluation of Sources. Gland,Switzerland: IUCN. 43pp. 10.2305/IUCN.CH.2017.01.en
Brahney J Hallerud M Heim E Hahnenberger M Sukumaran S Plastic rain in protected areas of the United States Science 2020 368 1257 1260 10.1126/science.aaz5819 32527833
Braun T Ehrlich L Henrich W Koeppel S Lomako I Schwabl P Liebmann B Detection of microplastic in human placenta and meconium in a clinical setting Pharmaceutics 2021 13 7 921 10.3390/pharmaceutics13070921 34206212
Briain OO Marques Mendes AR McCarron S Healy MG Morrison L The role of wet wipes and sanitary towels as a source of white microplastic fibres in the marine environment Water Res 2020 182 116021 10.1016/j.watres.2020.116021 32591164
Bucknall DG Plastics as a materials system in a circular economy Philos Trans A Math Phys Eng Sci 2020 378 20190268 10.1098/rsta.2019.0268 32623994
Bullard JE Ockelford A O'Brien P McKenna Neuman C Preferential transport of microplastics by wind Atmos Environ 2021 10.1016/j.atmosenv.2020.118038
Cai Y Yang T Mitrano DM Heuberger M Hufenus R Nowack B Systematic study of microplastic fiber release from 12 different polyester textiles during washing Environ Sci Technol 2020 54 4847 4855 10.1021/acs.est.9b07395 32250104
Cai YP Mitrano DM Heuberger M Hufenus R Nowack B The origin of microplastic fiber in polyester textiles: The textile production process matters J Clean Prod 2020 10.1016/j.jclepro.2020.121970
Cao Y Qu Y Guo LL Identifying critical eco-innovation practices in circular supply chain management: evidence from the textile and clothing industry Int J Logist-Res App 2022 10.1080/13675567.2022.2076817
Catarino AI Macchia V Sanderson WG Thompson RC Henry TB Low levels of microplastics (MP) in wild mussels indicate that MP ingestion by humans is minimal compared to exposure via household fibres fallout during a meal Environ Pollut 2018 237 675 684 10.1016/j.envpol.2018.02.069 29604577
Chan CKM Park C Chan KM Mak DCW Fang JKH Mitrano DM Microplastic fibre releases from industrial wastewater effluent: a textile wet-processing mill in China Environ Chem 2021 18 93 100 10.1071/En20143
Choi CE Zhang J Liang Z Towards realistic predictions of microplastic fiber transport in aquatic environments: Secondary motions Water Res 2022 218 118476 10.1016/j.watres.2022.118476 35483208
Danopoulos E Twiddy M West R Rotchell JM A rapid review and meta-regression analyses of the toxicological impacts of microplastic exposure in human cells J Hazard Mater 2022 427 127861 10.1016/j.jhazmat.2021.127861 34863566
Dawson AL Santana MFM Miller ME Kroon FJ Relevance and reliability of evidence for microplastic contamination in seafood: a critical review using Australian consumption patterns as a case study Environ Pollut 2021 276 116684 10.1016/j.envpol.2021.116684 33618116
De-la-Torre GE Dioses-Salinas DC Dobaradaran S Spitz J Keshtkar M Akhbarizadeh R Abedi D Tavakolian A Physical and chemical degradation of littered personal protective equipment (PPE) under simulated environmental conditions Marine Pollution Bulletin 2022 178 113587 10.1016/j.marpolbul.2022.113587 35397345
Ding J Li J Sun C Jiang F He C Zhang M Ju P Ding NX An examination of the occurrence and potential risks of microplastics across various shellfish Sci Total Environ 2020 739 139887 10.1016/j.scitotenv.2020.139887 32758939
Dris R Gasperi J Mirande C Mandin C Guerrouache M Langlois V Tassin B A first overview of textile fibers, including microplastics, in indoor and outdoor environments Environ Pollut 2017 221 453 458 10.1016/j.envpol.2016.12.013 27989388
Du H Xie Y Wang J Microplastic degradation methods and corresponding degradation mechanism: research status and future perspectives J Hazard Mater 2021 418 126377 10.1016/j.jhazmat.2021.126377 34130168
Duncan EM Broderick AC Fuller WJ Galloway TS Godfrey MH Hamann M Limpus CJ Lindeque PK Mayes AG Omeyer LCM Santillo D Snape RTE Godley BJ Microplastic ingestion ubiquitous in marine turtles Glob Chang Biol 2019 25 744 752 10.1111/gcb.14519 30513551
Dyer S The fabric of civilization: how textiles made the world Hist Today 2021 71 97 99
Engelhardt AW (2020) The Fiber Year 2020 – Deceleration along the textile chain. https://fiberjournal.com/the-fiber-year-2020-deceleration-along-the-textile-chain/
Fadare OO Okoffo ED Covid-19 face masks: a potential source of microplastic fibers in the environment Sci Total Environ 2020 737 140279 10.1016/j.scitotenv.2020.140279 32563114
Finnegan AMD Susserott R Gabbott SE Gouramanis C Man-made natural and regenerated cellulosic fibres greatly outnumber microplastic fibres in the atmosphere Environ Pollut 2022 310 119808 10.1016/j.envpol.2022.119808 35926740
Fleury JB Baulin VA Microplastics destabilize lipid membranes by mechanical stretching Proc Natl Acad Sci U S A 2021 10.1073/pnas.2104610118
Gago J Carretero O Filgueiras AV Vinas L Synthetic microfibers in the marine environment: a review on their occurrence in seawater and sediments Mar Pollut Bull 2018 127 365 376 10.1016/j.marpolbul.2017.11.070 29475673
Gardner CM Hoffman K Stapleton HM Gunsch CK Exposures to semivolatile organic compounds in indoor environments and associations with the gut microbiomes of children Environ Sci Technol Lett 2020 8 73 79 10.1021/acs.estlett.0c00776
Garlapati D Comments on the paper "Marine microfiber pollution: a review on present status and future challenges" Mar Pollut Bull 2019 141 187 187 10.1016/j.marpolbul.2019.02.043 30955724
Gill H Rogers K Rehman B Moynihan J Bergey EA Cigarette butts may have low toxicity to soil-dwelling invertebrates: evidence from a land snail Sci Total Environ 2018 628–629 556 561 10.1016/j.scitotenv.2018.02.080
Gouin T Cunliffe D De France J Fawell J Jarvis P Koelmans AA Marsden P Testai EE Asami M Bevan R Carrier R Cotruvo J Eckhardt A Ong CN Clarifying the absence of evidence regarding human health risks to microplastic particles in drinking-water: high quality robust data wanted Environ Int 2021 150 106141 10.1016/j.envint.2020.106141 33039157
Green DS Kregting L Boots B Smoked cigarette butt leachate impacts survival and behaviour of freshwater invertebrates Environ Pollut 2020 10.1016/j.envpol.2020.115286
Guzzetti E Sureda A Tejada S Faggio C Microplastic in marine organism: environmental and toxicological effects Environ Toxicol Pharmacol 2018 64 164 171 10.1016/j.etap.2018.10.009 30412862
Hajiouni S Mohammadi A Ramavandi B Arfaeinia H De-la-Torre GE Tekle-Rottering A Dobaradaran S Occurrence of microplastics and phthalate esters in urban runoff: a focus on the Persian Gulf coastline Sci Total Environ 2022 10.1016/j.scitotenv.2021.150559
Haque F Fan C Prospect of microplastic pollution control under the "New normal" concept beyond COVID-19 pandemic J Clean Prod 2022 367 133027 10.1016/j.jclepro.2022.133027 35821718
Hu E Sun CS Yang F Wang YP Hu LG Wang LX Li M Gao L Microplastics in 48 wastewater treatment plants reveal regional differences in physical characteristics and shape-dependent removal in the transition zone between North and South China Sci Total Environ 2022 10.1016/j.scitotenv.2022.155320
Hu T Shen M Tang W Wet wipes and disposable surgical masks are becoming new sources of fiber microplastic pollution during global COVID-19 Environ Sci Pollut Res Int 2022 29 284 292 10.1007/s11356-021-17408-3 34757558
Hussain N Kadir MM Nafees AA Karmaliani R Jamali T Needs assessment regarding occupational health and safety interventions among textile workers: a qualitative case study in Karachi, Pakistan J Pak Med Assoc 2019 69 87 93 30623919
Il Kwak J Liu HL Wang DY Lee YH Lee JS An YJ Critical review of environmental impacts of microfibers in different environmental matrices Comp Biochem Phys C 2022 10.1016/j.cbpc.2021.109196
Initiative BC (2020) Measuring cotton consumption: bci conversion factors and multipliers. Geneva, Switzerland: Better Cotton Initiative. 23pp. https://bettercotton.org/wp-content/uploads/2022/05/Measuring-Cotton-Consumption_Better-Cotton-Conversion-Factors-and-Multipliers_v2.pdf. Accessed 3 December 2022
ISO (2021a) Textiles and textile products — Microplastics from textile sources — Part 1: Determination of material loss from fabrics during washing. https://www.iso.org/standard/82238.html. Accessed 3 December 2022
ISO (2021b) Textiles and textile products — Microplastics from textile sources — Part 2: Qualitative and quantitative evaluation of microplastics. https://www.iso.org/standard/80011.html. Accessed 3 December 2022
ISO (2021c) Textiles and textile products — Microplastics from textile sources — Part 3: Measurement of collected material mass released from textile end products by domestic washing method. https://www.iso.org/standard/81035.html. Accessed 3 December 2022
James Johnson SM (2021) The world and united states cotton outlook. pp 1–21 https://www.usda.gov/sites/default/files/documents/S21_MacDonald_Cotton_Outlook_02.pdf. Accessed 3 December 2022
Jenner LC Rotchell JM Bennett RT Cowen M Tentzeris V Sadofsky LR Detection of microplastics in human lung tissue using μFTIR spectroscopy Sci Total Environ 2022 10.1016/j.scitotenv.2022.154907
Jiang ZS Huang LL Fan YX Zhou SF Zou XM Contrasting effects of microplastic aging upon the adsorption of sulfonamides and its mechanism Chem Eng J 2022 10.1016/j.cej.2021.132939
Kapp KJ Miller RZ Electric clothes dryers: an underestimated source of microfiber pollution PLoS ONE 2020 15 e0239165 10.1371/journal.pone.0239165 33027292
Karanikas N Hasan SMT Occupational Health & Safety and other worker wellbeing areas: Results from labour inspections in the Bangladesh textile industry Safety Sci 2022 146 105533 10.1016/j.ssci.2021.105533
Karkkainen N Sillanpaa M Quantification of different microplastic fibres discharged from textiles in machine wash and tumble drying Environ Sci Pollut R 2021 28 16253 16263 10.1007/s11356-020-11988-2
Kash FS Ramavandi B Arfaeinia H Mohammadi A Saeedi R De-la-Torre GE Dobaradaran S Occurrence and exposure assessment of microplastics in indoor dusts of buildings with different applications in Bushehr and Shiraz cities, Iran Sci Total Environ 2022 829 154651 10.1016/j.scitotenv.2022.154651 35314230
Kvale K Prowe AEF Chien CT Landolfi A Oschlies A Zooplankton grazing of microplastic can accelerate global loss of ocean oxygen Nat Commun 2021 12 2358 10.1038/s41467-021-22554-w 33883554
Kvavadze E Bar-Yosef O Belfer-Cohen A Boaretto E Jakeli N Matskevich Z Meshveliani T 30,000-Year-old wild flax fibers Science 2009 325 1359 1359 10.1126/science.1175404 19745144
Lai PS Christiani DC Long-term respiratory health effects in textile workers Curr Opin Pulm Med 2013 19 152 157 10.1097/MCP.0b013e32835cee9a 23361196
Leslie HA van Velzen MJM Brandsma SH Vethaak AD Garcia-Vallejo JJ Lamoree MH Discovery and quantification of plastic particle pollution in human blood Environ Int 2022 163 107199 10.1016/j.envint.2022.107199 35367073
Li Y Shao L Wang W Zhang M Feng X Li W Zhang D Airborne fiber particles: Types, size and concentration observed in Beijing Sci Total Environ 2020 705 135967 10.1016/j.scitotenv.2019.135967 31841913
Li Y Lu Q Xing Y Liu K Ling W Yang J Yang Q Wu T Zhang J Pei Z Gao Z Li X Yang F Ma H Liu K Zhao D Review of research on migration, distribution, biological effects, and analytical methods of microfibers in the environment Sci Total Environ 2022 10.1016/j.scitotenv.2022a.158922
Li Y Wang XJ Wang Y Sun Y Xia SQ Zhao JF Effect of biofilm colonization on Pb(II) adsorption onto poly(butylene succinate) microplastic during its biodegradation Sci Total Environ 2022 10.1016/j.scitotenv.2022.155251
Liedermann M Gmeiner P Pessenlehner S Haimann M Hohenblum P Habersack H A methodology for measuring microplastic transport in large or medium rivers Water 2018 10.3390/w10040414
Lin K-S Lin Y-G Cheng H-W Haung Y-H Preparation and characterization of V-Loaded titania nanotubes for adsorption/photocatalysis of basic dye and environmental hormone contaminated wastewaters Catal Today 2018 307 119 130 10.1016/j.cattod.2017.05.075
Liu C Li J Zhang Y Wang L Deng J Gao Y Yu L Zhang J Sun H Widespread distribution of PET and PC microplastics in dust in urban China and their estimated human exposure Environ Int 2019 128 116 124 10.1016/j.envint.2019.04.024 31039519
Liu J Liang J Ding J Zhang G Zeng X Yang Q Zhu B Gao W Microfiber pollution: an ongoing major environmental issue related to the sustainable development of textile and clothing industry Environ Dev Sustain 2021 23 11240 11256 10.1007/s10668-020-01173-3
Liu J Zhao X Yang Y Yang Q Zhu B Gao W Wang S Li Z Beyond the definition of microfiber pollution is more research AATCC Review 2019 19 49 52 10.14504/ar.19.4.3
Liu JL Yang YF Ding JN Zhu B Gao WD Microfibers: a preliminary discussion on their definition and sources Environ Sci Pollut R 2019 26 29497 29501 10.1007/s11356-019-06265-w
Liu K Wang X Song Z Wei N Ye H Cong X Zhao L Li Y Qu L Zhu L Zhang F Zong C Jiang C Li D Global inventory of atmospheric fibrous microplastics input into the ocean: an implication from the indoor origin J Hazard Mater 2020 400 123223 10.1016/j.jhazmat.2020.123223 32947683
Malinauskiene L Bruze M Ryberg K Zimerson E Isaksson M Contact allergy from disperse dyes in textiles: a review Contact Dermatitis 2013 68 65 75 10.1111/cod.12001 23289879
Memon I Panhwar A Rohra DK Azam SI Khan N Prevalence of byssinosis in spinning and textile workers of Karachi, Pakistan Arch Environ Occup Health 2008 63 137 142 10.3200/AEOH.63.3.137-142 18980877
Mishra S Dash D Al-Tawaha ARMS Das AP A review on heavy metal ion adsorption on synthetic microfiber surface in aquatic environments Appl Biochem Biotech 2022 10.1007/s12010-022-04029-w
Mishra S Rath CC Das AP Marine microfiber pollution: a review on present status and future challenges Mar Pollut Bull 2019 140 188 197 10.1016/j.marpolbul.2019.01.039 30803634
Murlidhar V Murlidhar VJ Kanhere V Byssinosis in a Bombay textile mill Natl Med J India 1995 8 204 207 7549849
Muthu SS Sustainnable fibres and textiles 2017 Cambridge, MA Woodhead Publishing
Napper IE Thompson RC Release of synthetic microplastic plastic fibres from domestic washing machines: Effects of fabric type and washing conditions Mar Pollut Bull 2016 112 39 45 10.1016/j.marpolbul.2016.09.025 27686821
Neves D Sobral P Ferreira JL Pereira T Ingestion of microplastics by commercial fish off the Portuguese coast Mar Pollut Bull 2015 101 119 126 10.1016/j.marpolbul.2015.11.008 26608506
Nor NHM Kooi M Diepens NJ Koelmans AA Lifetime accumulation of microplastic in children and adults Environ Sci Technol 2021 55 5084 5096 10.1021/acs.est.0c07384 33724830
Peeken I Primpke S Beyer B Gutermann J Katlein C Krumpen T Bergmann M Hehemann L Gerdts G Arctic sea ice is an important temporal sink and means of transport for microplastic Nat Commun 2018 9 1505 10.1038/s41467-018-03825-5 29692405
Peixoto D Pinheiro C Amorim J Oliva-Teles L Guilhermino L Vieira MN Microplastic pollution in commercial salt for human consumption: a review Estuar Coast Shelf Sci 2019 219 161 168 10.1016/j.ecss.2019.02.018
Periyasamy AP Tehrani-Bagha A A review on microplastic emission from textile materials and its reduction techniques Polym Degrad Stabil 2022 10.1016/j.polymdegradstab.2022.109901
Prata JC Silva ALP Walker TR Duarte AC Rocha-Santos T COVID-19 Pandemic Repercussions on the Use and Management of Plastics Environ Sci Technol 2020 54 7760 7765 10.1021/acs.est.0c02178 32531154
Provencher JF Vermaire JC Avery-Gomm S Braune BM Mallory ML Garbage in guano? Microplastic debris found in faecal precursors of seabirds known to ingest plastics Sci Total Environ 2018 644 1477 1484 10.1016/j.scitotenv.2018.07.101 30743860
Ramasamy R Subramanian RB Synthetic textile and microfiber pollution: a review on mitigation strategies Environ Sci Pollut Res Int 2021 28 41596 41611 10.1007/s11356-021-14763-z 34100210
Rathinamoorthy R Balasaraswathi SR A review of the current status of microfiber pollution research in textiles Int J Cloth Sci Tech 2021 33 364 387 10.1108/Ijcst-04-2020-0051
Rochman CM Hoellein T The global odyssey of plastic pollution Science 2020 368 1184 1185 10.1126/science.abc4428 32527817
Roscher L Halbach M Nguyen MT Hebeler M Luschtinetz F Scholz-Bottcher BM Primpke S Gerdts G Microplastics in two German wastewater treatment plants: Year-long effluent analysis with FTIR and Py-GC/MS Sci Total Environ 2022 10.1016/j.scitotenv.2021.152619
Sait STL Sorensen L Kubowicz S Vike-Jonas K Gonzalez SV Asimakopoulos AG Booth AM Microplastic fibres from synthetic textiles: Environmental degradation and additive chemical content Environ Pollut 2021 268 115745 10.1016/j.envpol.2020.115745 33065478
Salvador Cesa F Turra A Baruque-Ramos J Synthetic fibers as microplastics in the marine environment: A review from textile perspective with a focus on domestic washings Sci Total Environ 2017 598 1116 1129 10.1016/j.scitotenv.2017.04.172 28482459
Sánchez LD (2020) France is leading the fight against plastic microfibers - Ocean clean wash. https://www.oceancleanwash.org/2020/02/france-is-leading-the-fight-against-plastic-microfibers/ 2020
Sandin G Peters GM Environmental impact of textile reuse and recycling - a review J Clean Prod 2018 184 353 365 10.1016/j.jclepro.2018.02.266
Schwabl P Koppel S Konigshofer P Bucsics T Trauner M Reiberger T Liebmann B Detection of various microplastics in human stool: a prospective case series Ann Intern Med 2019 171 453 457 10.7326/M19-0618 31476765
Shan W Li BB Zhang HC Zhang ZH Wang Y Gao ZY Li J Distribution, characteristics and daily fluctuations of microplastics throughout wastewater treatment plants with mixed domestic-industrial influents in Wuxi City China Front Env Sci Eng 2022 10.1007/s11783-021-1440-4
Shen M Li Y Song B Zhou C Gong J Zeng G Smoked cigarette butts: Unignorable source for environmental microplastic fibers Sci Total Environ 2021 791 148384 10.1016/j.scitotenv.2021.148384 34139503
Sherman P van Sebille E Modeling marine surface microplastic transport to assess optimal removal locations Environ Res Lett 2016 10.1088/1748-9326/11/1/014006
Shirvanimoghaddam K Motamed B Ramakrishna S Naebe M Death by waste: fashion and textile circular economy case Sci Total Environ 2020 718 137317 10.1016/j.scitotenv.2020.137317 32088483
Shruti VC Pérez-Guevara F Kutralam-Muniasamy G Wet wipes contribution to microfiber contamination under COVID-19 era: an important but overlooked problem Environmental Challenges 2021 10.1016/j.envc.2021.100267
Simon N Raubenheimer K Urho N Unger S Azoulay D Farrelly T Sousa J van Asselt H Carlini G Sekomo C Schulte ML Busch PO Wienrich N Weiand L A binding global agreement to address the life cycle of plastics Science 2021 373 43 47 10.1126/science.abi9010 34210873
Singh N Tang YY Ogunseitan OA Environmentally sustainable management of used personal protective equipment Environ Sci Technol 2020 54 8500 8502 10.1021/acs.est.0c03022 32597663
Smith J Vignieri S A devil's bargain Science 2021 373 34 35 10.1126/science.abj9099 34210870
Song G Improving comfort in clothing 2011 Oxford, Philadelphia. Woodhead Publishing Limited
Stanton T Johnson M Nathanail P MacNaughtan W Gomes RL Freshwater and airborne textile fibre populations are dominated by 'natural', not microplastic, fibres Sci Total Environ 2019 666 377 389 10.1016/j.scitotenv.2019.02.278 30798244
Stubbins A Law KL Munosz SE Bianchi TS Zhu L Plastics in the Earth system Science 2021 373 51 55 10.1126/science.abb0354 34210876
Suaria G Achtypi A Perold V Lee JR Pierucci A Bornman TG Aliani S Ryan PG Microfibers in oceanic surface waters: a global characterization Sci Adv 2020 10.1126/sciadv.aay8493
Sui M Lu Y Wang Q Hu L Huang X Liu X Distribution patterns of microplastics in various tissues of the Zhikong scallop (Chlamys farreri) and in the surrounding culture seawater Mar Pollut Bull 2020 160 111595 10.1016/j.marpolbul.2020.111595 32866685
Sun J Dai XH Wang QL van Loosdrecht MCM Ni BJ Microplastics in wastewater treatment plants: detection, occurrence and removal Water Res 2019 152 21 37 10.1016/j.watres.2018.12.050 30660095
Sun X Liu T Zhu M Liang J Zhao Y Zhang B Retention and characteristics of microplastics in natural zooplankton taxa from the East China Sea Sci Total Environ 2018 640–641 232 242 10.1016/j.scitotenv.2018.05.308
Sun XX Li QJ Zhu ML Liang JH Zheng S Zhao YF Ingestion of microplastics by natural zooplankton groups in the northern South China Sea Mar Pollut Bull 2017 115 217 224 10.1016/j.marpolbul.2016.12.004 27964856
Takdastan A Niari MH Babaei A Dobaradaran S Jorfi S Ahmadi M Occurrence and distribution of microplastic particles and the concentration of Di 2-ethyl hexyl phthalate (DEHP) in microplastics and wastewater in the wastewater treatment plant J Environ Manage 2021 10.1016/j.jenvman.2020.111851
Too CL Muhamad NA Ilar A Padyukov L Alfredsson L Klareskog L Murad S Bengtsson C My ESG Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case-control study Ann Rheum Dis 2016 75 997 1002 10.1136/annrheumdis-2015-208278 26681695
Torres-Agullo A Karanasiou A Moreno T Lacorte S Overview on the occurrence of microplastics in air and implications from the use of face masks during the COVID-19 pandemic Sci Total Environ 2021 800 149555 10.1016/j.scitotenv.2021.149555 34426330
Uzun P Farazande S Guven B Mathematical modeling of microplastic abundance, distribution, and transport in water environments: a review Chemosphere 2022 288 132517 10.1016/j.chemosphere.2021.132517 34634279
van Dijk F Van Eck G Cole M Salvati A Bos S Gosens R Melgert B Exposure to textile microplastic fibers impairs epithelial growth Eur Respir J 2020 10.1183/13993003.congress-2020.1972
Vroom RJE Koelmans AA Besseling E Halsband C Aging of microplastics promotes their ingestion by marine zooplankton Environ Pollut 2017 231 987 996 10.1016/j.envpol.2017.08.088 28898955
Wang C O'Connor D Wang L Wu WM Luo J Hou D Microplastics in urban runoff: global occurrence and fate Water Res 2022 225 119129 10.1016/j.watres.2022.119129 36170770
Wisniowska E Wlodarczyk-Makula M Evaluation of the adsorption efficiency of carcinogenic PAHs on microplastic (polyester) fibers-preliminary results Appl Water Sci 2022 10.1007/s13201-022-01654-y
Woods MN Stack ME Fields DM Shaw SD Matrai PA Microplastic fiber uptake, ingestion, and egestion rates in the blue mussel (Mytilus edulis) Mar Pollut Bull 2018 137 638 645 10.1016/j.marpolbul.2018.10.061 30503478
Wright SL Ulke J Font A Chan KLA Kelly FJ Atmospheric microplastic deposition in an urban environment and an evaluation of transport Environ Int 2020 136 105411 10.1016/j.envint.2019.105411 31889555
Wu P Li J Lu X Tang Y Cai Z Release of tens of thousands of microfibers from discarded face masks under simulated environmental conditions Sci Total Environ 2022 806 150458 10.1016/j.scitotenv.2021.150458 34592275
Xu Y, Chan FKS, Stanton T, Johnson MF, Kay P, He J, Wang J, Kong C, Wang Z, Liu D, Xu Y (2021) Synthesis ofdominant plastic microfibre prevalence and pollution control feasibility in Chinese freshwater environments. Scienceof The Total Environment 783. 10.1016/j.scitotenv.2021.146863
Yousef S, Eimontas J, Striūgas N, Mohamed A, Abdelnaby MA (2021) Morphology, compositions, thermal behaviorand kinetics of pyrolysis of lint-microfibers generated from clothes dryer. Journal of Analytical and Applied Pyrolysis. 155. 10.1016/j.jaap.2021.105037
Yang Y Liu G Song W Ye C Lin H Li Z Liu W Plastics in the marine environment are reservoirs for antibiotic and metal resistance genes Environ Int 2019 123 79 86 10.1016/j.envint.2018.11.061 30502597
Zantis LJ Carroll EL Nelms SE Bosker T Marine mammals and microplastics: a systematic review and call for standardisation Environ Pollut 2021 269 116142 10.1016/j.envpol.2020.116142 33288297
Zele YT Kumie A Deressa W Bratveit M Moen BE Registered health problems and demographic profile of integrated textile factory workers in Ethiopia: a cross-sectional study BMC Public Health 2021 10.1186/s12889-021-11556-4
Zhang J Wang L Trasande L Kannan K Occurrence of polyethylene terephthalate and polycarbonate microplastics in infant and adult feces Environ Sci Technol Lett 2021 10.1021/acs.estlett.1c00559
Zhang Q Xu EG Li J Chen Q Ma L Zeng EY Shi H A review of microplastics in table salt, drinking water, and air: direct human exposure Environ Sci Technol 2020 54 3740 3751 10.1021/acs.est.9b04535 32119774
Zhao M Huang L Arulmani SRB Yan J Wu LR Wu T Zhang HG Xiao TF Adsorption of different pollutants by using microplastic with different influencing factors and mechanisms in wastewater: a review Nanomaterials-Basel 2022 10.3390/nano12132256
Zhou H Zhou L Ma K Microfiber from textile dyeing and printing wastewater of a typical industrial park in China: Occurrence, removal and release Sci Total Environ 2020 739 140329 10.1016/j.scitotenv.2020.140329 32758965
| 0 | PMC9734713 | NO-CC CODE | 2022-12-14 23:28:30 | no | Rev Environ Contam Toxicol. 2022 Dec 6; 260(1):13 | utf-8 | Rev Environ Contam Toxicol | 2,022 | 10.1007/s44169-022-00015-9 | oa_other |
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Sex Roles
Sex Roles
Sex Roles
0360-0025
1573-2762
Springer US New York
1329
10.1007/s11199-022-01329-7
Original Article
“There’s No Sewing Classes, There’s No Bedazzling Seminars”: The Impact of Masculinity on Social Connectedness and Mental Health for Men Living in Inner-Regional Australia
http://orcid.org/0000-0003-1627-0315
Bonell Sarah [email protected]
12
Trail Katherine 12
Seidler Zac 12
Patel Deepa 3
Oliffe John L. 45
Rice Simon M. 12
1 grid.488501.0 0000 0004 8032 6923 Orygen, Parkville, VIC Australia
2 grid.1008.9 0000 0001 2179 088X Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC Australia
3 Benetas Macedon Ranges Health Centre, Gisborne, VIC Australia
4 Schoolof Nursing, University of British, Vancouver, BC Canada
5 grid.1008.9 0000 0001 2179 088X Department of Nursing, The University of Melbourne, Parkville, VIC Australia
7 12 2022
116
7 10 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Regional Australian masculinities are typified by ‘traditional’ values (e.g., stoicism, self-reliance) known to restrict social connectedness. Thus, these masculinities have been implicated in worsening men’s mental health. What remains unclear, however, is how men living in inner-regional communities (i.e., townships on the fringes of major cities) might uniquely experience masculinity, social connectedness, and mental health. We interviewed 29 boys/men and one non-binary participant (Mage = 43.77 years) living in the Macedon Ranges (an inner-regional Australian community). Using reflexive thematic analysis, we generated three themes. Participants described inner-regional masculinities as traditional and rigid, and attributed the Macedon Ranges’ comparatively high suicide rate to these masculinities. Conversely, migration from the neighbouring city of Melbourne was implicated in introducing more inclusive masculinities to the area that conflicted with existing masculine norms. Thus, Macedon Ranges men were framed as ultimately lacking a cohesive community identity. Proximity to Melbourne was described as encouraging local men to commute daily for work instead of working locally, thereby further weakening community identity. Overall, these phenomena were implicated in damaging the psychosocial wellbeing of local men via reducing social connectedness. Because men’s mental illness is so pervasive within regional Australian communities, these findings have direct implications for policymakers. Namely, policies need to acknowledge that masculinities directly influence mental health and that inner-regional masculinities are impacted by unique place-based considerations distinct from men living in other regional communities.
Keywords
masculinity
gender
rural masculinity
social connectedness
Australia
loneliness
regional masculinity
men’s mental health
North Western Melbourne Primary Health NetworkNorth Western Melbourne Primary Health Network
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pmcAkin to the U.S. and Europe (European Commission, 2018; United States Census Bureau, 2017), approximately 30% of Australian men reside in regional communities (Australian Institute of Health and Welfare, 2019; Regional Australia Institute, 2021); that is, in towns and small metropolises on the fringes of major cities (Bourne et al., 2020; Rawsthorne et al., 2009). Recently, concerns have been raised regarding men’s mental health challenges in these areas. For example, regional men are at higher risk for suicidality than men living in cities (Alston, 2012; Crnek-Georgeson et al., 2017; Fitzpatrick et al., 2021). Existing literature suggests that mental health challenges for regional men are in part accounted for by a lack of social connectedness, such that men living in regional communities are at higher risk for loneliness and social isolation (Alston, 2012; Hurzeler et al., 2021). There is also evidence to suggest that these issues are particularly pronounced for men in inner-regional Australian communities; that is, those located on the fringes of major cities (Boyd et al., 2011; Kelly et al., 2010; Shand et al., 2015).
Some existing literature has examined how constructions of masculinity inform experiences of social connectedness and mental health for men. Traditional masculinity – that is, masculinity characterised by the expression of aggression, control, stoicism, self-reliance, and dominance – has been implicated in limiting social connectedness for men. For example, Blazina and colleagues (2007) found among 179 men from the United States that those who endorsed traditional masculine norms were lonelier than those who did not. This is perhaps because in attempting to demonstrate self-reliance and stoicism, men who perform traditional masculinities emotionally isolate themselves from potential support networks and thus come to feel disconnected from their friends, families, and partners (Keum et al., 2021). Traditional masculinity has also been implicated in damaging men’s mental health. Across a sample of 2,431 young adults, Coleman (2015) found that endorsing traditional masculinity was longitudinally predictive of suicidal ideation. Likewise, Smith and colleagues (2022) found that for 1,794 older White men, conformity to traditional masculine ideals was longitudinally predictive of depressive symptomology. In sum, stereotypically traditional masculine values have been associated with social disconnect and mental ill health for men. The purpose of the current study is therefore to examine how constructions of masculinity and social connectedness contribute to men’s place-based experiences of mental health in inner-regional Australia.
Constructing Regional Australian Masculinity
Prevailing societal contexts (informed by an interplay between gender, culture, and history) characterise how men embody and perform masculinities (Carrington & Scott, 2008; Connell, 2005; Connell & Messerschmidt, 2005; Schlichthorst et al., 2019). Broadly speaking, regional Australian masculinities are typified by traditional values. For example, because regional Australian economies have historically depended on men performing physically demanding agricultural work, regional masculinities tend to idealise physical prowess(Alston, 2012; Alston & Kent, 2008; Bye, 2009; Carrington & Scott, 2008; Liepins, 2000) and knowing and controlling the natural environment. For this same reason, regional masculinities are also more likely to value gendered divisions of labour whereby men are expected to act as primary income earners (Alston, 2012; Alston & Kent, 2008; Liepins, 2000). Finally, regional men are archetypally characterized as stoic and independent and able to withstand financial instability (Alston & Kent, 2008). This may be particularly true for regional men in Australia, where increasingly common weather events (e.g., major floods, bushfires) routinely disrupt agricultural work (Alston, 2012; Alston & Kent, 2008). In sum, while many men in regional Australia now work outside of agriculture, idealized regional masculinities may remain heavily informed by foundational agricultural norms that suggest men ought to adopt ‘traditional’ gender roles.
Regional constructions of masculinities might be more rigid than metropolitan masculinities because these areas are generally less exposed to ethnic, gender, and occupational diversity (Carrington & Scott, 2008). For example, in the early 2000s, the term metrosexual was widely used in Australian cities (and beyond) to describe a type of normative heterosexual masculinity in which fashion and grooming were revered. In Australian cities, men living metrosexually were allowed to engage in stereotypically feminine (i.e., not ‘traditionally masculine’) activities as part of a more inclusive masculinity (Carniel, 2009). However, these freedoms were place-based, with metrosexuality failing to permeate regional Australian cultures and masculinities.
That is not to say, however, that regional constructions of masculinity are entirely fixed. While traditional Australian cultures revere masculine norms of control, stoicism, independence, and strength (Schlichthorst et al., 2019), this archetype is only one of many adaptable and relational masculinities found in Australia. For example, we might consider regional Australian masculinities as being informed by specific place-based gendered norms distinct from those found in Australian cities. Population migration and economic restructuring across the globe have contributed to growing flexibility in regional constructions of masculinity (Bye, 2009; Herron et al., 2020). In Australia, professional skills and experience in administrative positions are now valued as aspects of regional masculinities as they have become increasingly integral for securing employment (Carrington & Scott, 2008). Further, regional masculinities may look different across unique places and contexts. Agricultural towns plagued by resource scarcity, for example, might construct masculinity as more individualistic and competitive than similar towns with an abundance of resources. Similarly, men may express more inclusive masculinities (i.e., allowing for more varied performances; Anderson 2009; Bridges & Pascoe, 2014) at home with family versus in the workplace or at school (Creighton et al., 2017). In this sense, while regional masculinities are stereotypically more rigid and traditional than metropolitan masculinities, there is no one regional masculinity.
Social Connectedness, Gender, and Place
Social connectedness through the bonding and forging of close ties with others (Inagaki, 2018) is integral to men’s mental health (McKenzie et al., 2018). For example, social connectedness can protect men against adverse outcomes after stressful or emotionally painful experiences (Åslund et al., 2014; Maulik et al., 2010; Raffaelli et al., 2013) and buffer the onset of men’s mental ill-health (Kleiman et al., 2014; Panagioti et al., 2014; Teo et al., 2013; Richardson et al., 2022) even found that social support acts as the lone protective factor against the transition from suicidal thoughts to suicide attempts in men. Greater social connectedness has also been associated with increased life expectancy (Giles et al., 2005), life satisfaction (Ambrey et al., 2017), and wellbeing (Brown et al., 2012), and decreased suicide ideation in men (McLaren & Challis, 2009). Improving social connectedness could therefore be one avenue through which we might improve mental health outcomes for men living in regional communities.
Australian men are both significantly less socially connected than women (Flood, 2005; Franklin et al., 2019; Franklin & Tranter, 2008) and significantly less likely than women to engage with help-seeking services to combat loneliness (Franklin et al., 2019). Perhaps this explains why adverse mental health effects associated with loneliness are generally more pronounced for men. For example, Christensen et al., (2013) found that thwarted belongingness predicted suicide ideation for men but not women. In light of these findings, local and federal governments across Australia have worked together to establish over 1,000 Men’s Sheds (i.e., physical spaces for men to congregate and work on projects together). Men’s Sheds have proven effective in improving men’s mental health by increasing experiences of social connectedness (Australian Government Department of Health, 2020). However, while these sheds are popular among older men, younger men (i.e., those at greater risk for loneliness, depression, and suicidality; Australian Government Department of Health, 2019) are unlikely to engage with Men’s Sheds (Beyond Blue, 2013). As such, there is still a gap among policy-makers insofar as understanding and catering to the experiences of Australia’s most at-risk men.
Literature examining whether place (i.e., regional versus city living) influences social connectedness in Australia is mixed. While research suggests that overall regional Australians feel more socially connected than those living in cities (Stone & Hulse, 2007; Wulff & Dharmalingam, 2008), there is also evidence to suggest that men living in regional communities experience less social connection than women or men living in cities (Alston, 2012; Hurzeler et al., 2021). This is perhaps because a heightened valuation of independence and stoicism among regional men contributes to unique experiences of disconnection via diminishing the importance of social relationships (McKenzie et al., 2018). Other individualistic factors may also influence the relationship between place and social connectedness. For instance, sexual minority (Power et al., 2014) and ethnic minority (Wickramaarachchi, 2020) Australians report lower levels of social connectedness when living in regional communities. Because loneliness is a risk factor for a myriad of mental health issues including suicidality (McClelland et al., 2020), it is integral we understand how place-based considerations might influence social connectedness for Australian men.
The Present Study
The Macedon Ranges Shire in Victoria, Australia is an inner regional area with a population of just under 50, 000 (Australian Bureau of Statistics, 2016). The region has a comparatively high male suicide rate relative to state rates, and increasing family violence rates and alcohol-related harms for men (Crime Statistics Agency, 2020; Public Health Information Development Unit, 2021; Turning Point, n.d.). Responding to these trends, local stakeholders identified the need to research attitudes and behaviours of men and boys in the region. The present study was produced as part of The Human Code Project – an initiative funded by the North Western Melbourne Primary Health Network (NWMPHN) aimed at contributing to the identification of healthy masculinity-focused approaches to reducing male suicide in the Macedon Ranges (https://www.benetas.com.au/health-care/macedon-ranges-health/the-macedon-ranges-suicide-prevention-trial-site).
Initially, The Human Code Project did not intend to explicitly examine social connectedness for men living in the Macedon Ranges; rather, the project focused solely on masculinities and mental health (i.e., how attitudes and behaviours of local men placed them at risk of doing or experiencing harm). However, during the interview process we found that participants felt social connectedness played an integral role in the relationship between masculinities and mental health, and that broadly they spoke at length about experiences of social connectedness. As such, the present study sought to address place-based connections between regional Australian masculinities, social connectedness, and men’s mental health.
This is of interest for two reasons. Firstly, as aforementioned, social connectedness plays a pivotal role in mental health (e.g., (McClelland et al., 2020). As such, social disconnection may be contributing in part to the growing mental health crisis among men in the Macedon Ranges. Secondly, the Macedon Ranges is unique in its proximity to a major city in Australia, being only an hour-long drive from the major city of Melbourne (population 5.1 million as at 2022). This means that men who live in the Macedon Ranges often seek employment in Melbourne and commute daily for work. It is therefore unclear whether other constructions of regional masculinity aptly apply to men who live in areas like the Macedon Ranges, as time spent in inner-city Melbourne may expose them to more diverse constructions of masculinity. It is also unclear how participating in daily commutes might influence social connectedness for men in the Macedon Ranges.
Method
Study Background
Ethics Approval (for the ethical treatment of human participants) was obtained from The University of Melbourne (Ethics ID: 2,057,593). Data collection for The Human Code Project ran from September 2020 to August 2021 and involved a community-wide survey, interviews with community stakeholders, and interviews and focus groups with local men and women. The present study utilises data from interviews with local boys and men.
Participants
Twenty-nine boys and men and one non-binary participant ranging in age from 16 to 73 years-old (Mage= 43.77, SD = 16.42) completed individual interviews. Sample size was determined in consultation with the Project Working Group to ensure a sufficient number of participants across broad age groups (i.e., younger, middle-aged, and older men) were represented in the project findings. Most participants identified as heterosexual (n = 27, 90.0%), with the remaining identifying as gay (n = 3, 10.0%). Participants were mostly in a relationship (i.e., married, de facto, or partnered; n = 22, 73.3%). Most were employed in a full-time, part-time, or casual capacity (n = 21, 70.0%). Of 30 participants, 13 had completed either undergraduate or postgraduate level studies (43.3%), 11 a trade certificate or diploma (36.7%), and 6 high school or some high school (20%). Participant demographic information is summarised below (see Table 1). Average interview length was 51 min.
Table 1 Participant Demographic Information
Total
% (n)
Total n 100 (30)
Mean age (SD) 43.77 (16.42)
Age groups
16–25 16.7 (5)
26–40 30.0 (9)
41–60 40.0 (12)
61+ 13.3 (4)
Sexuality
Heterosexual 90.0 (27)
Gay 10.0 (3)
Relationship status
Single/never married 16.7 (5)
Partnered 16.7 (5)
Married/de facto 56.7 (17)
Separated/divorced 10.0 (3)
Employment Status
Full time 53.3 (16)
Part time 13.3 (4)
Casual 3.3 (1)
Not looking for work 6.7 (2)
Retired 10.0 (3)
Student 10.0 (3)
No answer given 3.3 (1)
Education level
Some high school 10.0 (3)
High school 10.0 (3)
Trade/cert/diploma 36.7 (11)
Undergrad degree 13.3 (4)
Postgrad degree 30.0 (9)
Procedure
Ethics Approval was granted by The University of Melbourne Human Research Ethics Committee (2,057,593). Prospective participants were made aware of The Human Code Project through social media advertisements, local distribution of flyers, and through dissemination of project information through relevant community groups and professional networks. Individuals who completed the online survey component of the broader research project were presented with a short blurb regarding the purpose of interviews and invited to register interest by leaving a contact email address. Interested participants were then contacted by the second author (KT), who arranged a time to meet via Zoom video conferencing software (Zoom Video Communications Inc, 2019) or phone to explain the study aims and obtain informed consent.
Prospective participants were also invited to take part in an optional photovoice component of the interview, which was explained at the same time as the general study aim. Participants who consented to the task were asked to take photographs in response to the prompt ‘the stresses and successes of being a man in the Macedon Ranges’. Twelve participants completed the task, providing between 1 and 6 photographs each (Mage = 2.67). Interviews for participants completing the photovoice task were scheduled at least one week after their initial meeting with the researcher, to allow time for them to take photographs.
Following the provision of informed consent, all interviews were conducted virtually using Zoom by KT due to the COVID-19 pandemic. Zoom facilitated ease of data collection given the geographical location of the area of interest, and lowered the time commitment required of participants. Participants were made aware of the requirement of a device and stable internet connection in order to participate in the research. Although there were no notable concerns raised regarding the use of Zoom in this study, this methodology has potential to disadvantage individuals who do not have access to the internet, particularly in regional and rural areas. The benefits and limitations of using Zoom have been discussed recently by Oliffe et al., (2021).
Semi-structured interviews focused on local influences on masculinities and the relationship between masculinities and mental health. Key interview questions included ‘What comes into your mind when you think about being a man?’, ‘How has living in the Macedon Ranges made you the type of man you are?’, and ‘How does your understanding of what it means to be a man affect your mental health?’. Questions did not specifically pertain to participants’ experiences of social connectedness (as per our initial study design), though participants frequently spoke to these experiences. Demographics were obtained via a secure online form hosted on Qualtrics at the commencement of each interview. Participants were reimbursed $30 via electronic bank transfer as a thank you for their time and contributions to the study.
Interviewer Characteristics
All interviews were conducted by KT, a white Australian female in her mid-20s. The gender dynamics of a woman interviewing men about masculinity likely influenced the data collection and analysis (Pini, 2005; Seale et al., 2008). KT kept memos during the data collection process to ensure any presumptions or biases were discussed with the wider research team. The first author, SB, conducted the majority of data analysis for the present study. Therefore, her demographic information may also have influenced the way in which data were interpreted. SB is also a white Australian female in her mid-20s. The wider research team consisted of both male and female researchers with varying degrees of expertise in masculinities, allowing for a diversity of perspectives when looking at the data and increasing study credibility.
Data Analysis
We adopted two data analysis techniques for the present study. First, we used an inductive reflexive thematic analysis approach to analyse our transcript data. This analysis type is ideal for projects such as our own when code and theme generation commence at the conclusion of data collection (Braun & Clarke, 2006, 2021). We also conducted a complementary photovoice analysis to examine our photograph data; that is, photographs were used to inform code and theme generation throughout the research project, with particular photographs chosen to feature in the Results section of our publication to exemplify findings.
Overall, we used a six-step approach for data analysis (Braun & Clarke, 2006). First, KT conducted all interviews. At the conclusion of interviewing, transcripts were obtained. Photographs provided by participants were embedded in transcripts at points where they were discussed during the interview (i.e., photographs appeared in transcripts alongside associated text). Both SB and KT began to independently note their initial observations about the combined transcript and photograph data. Next, both authors separately coded the data, then came together to discuss the codes they had generated (including what they found most relevant to the research question). At this stage, the broader research team was also consulted regarding code overlaps and differences between SB and KT. Thirdly, SB developed initial themes (i.e., patterns of shared meaning, united by a central concept) for the data and decided on which photographs to include in the manuscript. She independently reviewed these themes and photographs and then asked the research team authors to review her choices. Finally, once a draft manuscript was written by SB, all authors again met to finalise themes and exemplar photographs.
Results
Participants spoke at length about their experiences of masculinity, belonging, loneliness, and mental health. From these data, we generated three themes: (i) “Being Unique Here Is Not an Asset”: Uniqueness As Disruptive To Social Connectedness, (ii) “We’re Not Really Merged Yet”: Conflicting Masculinities and Divided Communities, and (iii) “Working Away from The Macedon Ranges Takes Me Away from The Community”. We summarise these three themes below (see Table 2).
Table 2 Definitions And Examples of Each Theme
Theme Description Exemplar Quote
“Being Unique Here Is Not an Asset”: Uniqueness As Disruptive To Social Connectedness Examines how men in the Macedon Ranges who fail to conform to rigid traditional masculinities are excluded and ostracised within the community. “I have to be a certain type of thing to fit in. And that’s okay, to some degree. But that’s the limiting factor as a male human being is I have to be certain things which I really never practiced being as a younger man. I never practiced being the car guy or the muscle building guy, or the gun guy, or the big drinking guy. The going to the footy and yelling, and punching on guy, I never really practiced being that.” (Participant 21)
“We’re Not Really Merged Yet”: Conflicting Masculinities and Divided Communities Examines how tree-change migration (i.e., men immigrating from the city) has disrupted or challenged some elements of rigid masculinity within the Macedon Ranges, and how this disruption has contributed to conflict and disconnect among local men. “It comes down to that divide, I think… The society here’s quite, in some ways, disjointed. There’s the old school country people, and the farming community and so on, and then there’s so many new people that have come from the city, bringing a different way of life and a different perspective. And they haven’t gelled yet…” (Participant 38)
“Working Away from The Macedon Ranges Takes Me Away from The Community” Examines how the Macedon Range’s inner-regional geographic location contributes to some local men’s experiences of social disconnect via work-life estrangement, and how this in turn fosters community-wide poor mental wellbeing. “I think a lot of people around here have big commutes. There’s some stat about… I can’t remember the number but it’s a very high percentage of people who live in the Macedon Ranges and are employed somewhere else. Usually Melbourne. They work somewhere not in the Macedon Ranges. … Squeezing those things that you need to do to live well and you need to do to keep your job, into the day, is tough.” (Participant 27)
“Being Unique Here Is Not an Asset”: Uniqueness As Disruptive To Social Connectedness
This theme broadly reflects how men in the Macedon Ranges feel pressured to conform to rigid and stereotypically traditional constructions of masculinity. Several participants in the present study pointed to these constructions as place-specific – that is, they acknowledged that while masculinities in regional communities were slowly becoming more inclusive and diverse, ultimately dominant masculine cultures were still comparatively narrow and exclusionary (versus in bigger cities).P21: “It’s slightly different when you go to the city than when you come back to town. People expect you to be blokey … You got to have a ute [utility vehicle], you might even have a few guns, might like to shoot, definitely like to drink, you used to play footy [football] or you play footy.”
As a result of local constructions of masculinity, participants reported feeling as though they had to ‘mask’ as more traditionally masculine in the Macedon Ranges or hide parts of their identities in order to fit in with the majority of men in the area. In other words, while participants did not necessarily identify with dominant masculine cultures in the Macedon Ranges, they were often complicit in these cultures in an attempt to form and maintain local friendships. Men in the Macedon Ranges who failed to censor their ‘true selves’ were framed as targeted for social exclusion.P28: “Acting in a way that’s outside of the norm would make people feel like they’re at risk of being outed from the group or being ostracized … so it’s better to keep those thoughts, emotions, and feelings to yourself, kind of live a lie so to speak, and play safe because you know you’re going to be accepted.”
Often, participants described feeling as though they were required to have a specific masculine aesthetic or ‘look’ in order to be included in the community. Evident in these observations was the fact that participants resented and critiqued this sameness, and by extension the lack of freedom available to them when it came to physical appearance.P32: “There’s a lot of mirroring in terms of dressing styles. There’s a lot of men who try to have the same haircuts as other men, dress up the same way as other men. And I find that a bit strange… I don’t think that’s healthy”
Ultimately, clothing was framed as a means through which men might conceal particular parts of their identities from the community. This uniformity is exemplified by a photograph provided by Participant 46, entitled “Oh, the places we could go if only we were brave.” In this photograph, Participant 46 highlights the tension between needing to ‘belong’ in the Macedon Ranges community (as represented by their boot) versus needing to feel true to oneself (as represented by their slipper).
P46: “The pink fluffy slipper represents the life I have here that I don’t take off the property. How I present in Macedon Ranges is in the… boot. How I live my life is in the pink fluffy slipper … This is me curtailing my identity based on fear and shame and stigma.”
In this example, Participant 46’s slipper was framed as symbolic of their queerness. They went on to explain how clothing uniformity among men in the Macedon Ranges is reflective of the systemic homophobia (i.e., local men feared ostracism if they dared to ‘dress queer’) evident in pockets of the community. More broadly, participants spoke to the fact that some Macedon Ranges men (but arguably not community members of other genders) stigmatised and socially excluded sexual and ethnic minorities. For example, when asked to describe a typical man in the Macedon Ranges, Participant 41 (a gay man) claimed the way men in the area treated minorities was “bordering on bullying sometimes”. He went on to clarify:P41: “Some [men in the Macedon Ranges] just don’t have filters … it’s just racism and things like that. Any homophobic things. Yeah, that sort of macho crap thing that annoys the hell out of me, but that’s the typical male that I see in the area.”
Here, it’s evident that restricted gender roles and identities in the Macedon Ranges work to exclude sexual and ethnic minorities from establishing social ties in the area (especially with men who are not also minorities themselves). As such, these groups are at-risk of feeling as though they don’t belong in the broader Macedon Ranges community, even when they are able to find pockets of other minority men with whom to socialise.P33: “I don’t think I’ve ever even seen in passing any of the Aboriginal communities that are around here. I know they exist, but they’re not really connected well into ... There’s whole groups of men that are probably falling a little by the wayside just because they don’t feel like they’re part of every other man.”
It was not only minority men who were described as excluded from Macedon Ranges society. Participants also described hobbies in the Macedon Ranges as inherently gendered, such that there are distinct hobbies (e.g., playing sport and drinking) men in the community are encouraged to engage with. Men who would otherwise ‘fit it’ (e.g., White, heterosexual men) but lacked interest or skill in stereotypically masculine hobbies ultimately described being alienated from male friendship circles because they felt unable to meet the expectations placed on them within these groups.P20: “I have a sense that masculinity around here probably has a fairly... Comes within a narrow range of expression. … Certainly as a non-sporting male … I have always felt like I never met the fundamental expectations of masculinity or did not expect to be socially embraced into basically any group of men because I couldn’t demonstrate those basic... Couldn’t relate on those basic levels.”
On the other hand, other participants described their lack of interest in masculine hobbies as rendering them unable to form ties to the community because ultimately there was no place for them to go to do so; that is, their hobbies physically alienated them from other community members. For example, Participant 46 commented:P46: “Men only really gather in the pub. I mean, there are some sporting groups, but fuck I hate sports. There’s no sewing classes, there’s no bedazzling seminars.”
Participants also felt that the gendered nature of hobbies within the Macedon Ranges worked to stifle cultural change and unique expressions of masculinities within the community, such that men were seldom introduced to new perspectives or types of people. In this sense, gendered hobbies and rigid traditional constructions of masculinity were seen as having a bidirectional relationship whereby each one encouraged the presence of the other in the Macedon Ranges.P28: “They’ll stay insular and drink at someone’s shed, and then there’s not really an exposure to new people, new ideas, new behaviours, new concepts, anything like that.”
Beyond hobbies, participants adopting what might be considered stereotypically feminine roles at home (e.g., stay-at-home dads) or in society (e.g., men who do volunteer work) felt ostracised by the Macedon Ranges community as well. Again, this ostracism was framed as both physical and emotional, such that men who failed to engage in stereotypically masculine social roles struggled both to feel accepted by their peers and to establish networks consisting of men in similar positions to themselves.P35: “My wife has always been... the main income earner … [She’d] quite often be at work or doing things and I’d be at home with the kids. … And we both always had the suspicion that, that caused an angst with other couples within our social network, because their expectation was, the women would be at home doing that.”
P38: “If you want to volunteer, it’s typically women that are accepted and embraced in the role of volunteering around the schools. There’s always that stigma of, ‘Oh, what’s a man want to do there?’ … In some places in some cities, guys have got little groups together of at home dads and so on, and in the Macedon Ranges it doesn’t exist to my mind, I haven’t seen it at all, of a network to go to, to be a part of.”
Finally, participants touched on mental health consequences associated with constructions of masculinity within the Macedon Ranges. The homogeneity of masculinities in the community meant that many participants felt their self-expression lacked authenticity, causing feelings of mental unease.P32: “Trying to create an image for yourself and it’s not a true reflection of who you actually are as a person… your mind is going to start fighting that in the long-term and it’s going to cause issues like depression and anxiety… because you’re not one with your mental self. You’re trying to create a new version of yourself for other people, which is not healthy at all, I don’t think.”
Likewise, participants felt that men who did not abide by societal norms were unable to assimilate into the community and that this contributed to the relatively high suicide rates in the region. In this sense, being ‘different’ as a man in the Macedon Ranges community was framed as a risk factor for suicidality.P46: “There is a one-way, one-shape cookie cutter format you’re supposed to be up here, and that’s the guys ... the guys who can’t fit that are the guys who [die by] suicide.”
“We’re Not Really Merged Yet”: Conflicting Masculinities and Divided Communities
This theme examines how recent tree-change migration (i.e., men moving from Melbourne city to the Macedon Ranges) is encouraging more inclusive masculinities to slowly perforate the Macedon Ranges, and how this cultural shift has contributed to a culture of conflict and disconnect among local men. Newer, progressive masculinities in the Macedon Ranges were described by participants as generally fostering an open-minded approach towards what constitutes masculinity (e.g., vulnerability and emotionality) and emphasising the importance of respecting women, sexual minorities, and people of colour. Several participants directly contrasted these broader constructions of masculinity with the dominant, traditional masculine culture in the Macedon Ranges (i.e., as described in our first theme), noting that these dichotomous masculinities often conflicted and clashed with one another.P36: “The Macedon Ranges broadly, has two demographics. That’s the old world rural culture and a new world tree changers, commuters, that kind of thing. That’s really simplistic to divide it in two like that, but broadly speaking, I think there’s a certain amount of truth to that. I think the old rural values are more conservative and more geared towards a view of masculinity and manhood that is something I feel is pretty antiquated. Whereas, I think that the tree changer lot is more urbane and contemporary, I guess, in its values about that kind of thing.”
While most participants acknowledged that more inclusive and progressive masculinities were still new to the Macedon Ranges, several felt that societal changes brought about by these masculinities were already notable. While these changes were ultimately described as beneficial by participants, several also spoke to how moving away from the ‘status quo’ had resulted in the fracturing of community interests and values in the Macedon Ranges. That is, the Macedon Ranges was framed as going through a ‘teething process’ whereby the community lacked cohesion and sense of belonging was challenged for some residents. This was exemplified by Participant 38 - a volunteer at the Country Fire Authority (CFA). When asked to describe ‘the stresses and successes of being a man in the Macedon Ranges’, he provided the following photograph and explained:
P38: “[The] CFA’s one of the last refuges to just be a blokey bloke, but on the flip side you have to be able to make it an inclusive workplace … And as a bloke that really wants that progress to be made, and gets quite frustrated that it hasn’t been, it’s a mixed world of mixed pressures. You sort of find yourself on the one hand living [in] a new world where women captains and lieutenants are really common. And then you turn around to the next situation [station], and it’s all men, and they’re really being quite blokey, … So it’s a turmoil.”
The turmoil described by Participant 38 was also noted by several other participants, who went on to suggest that by generating conflict and confusion, the introduction of new masculinities in the Macedon Ranges actually served to generate loneliness and isolation among local men. In turn, loneliness and isolation born of conflicting masculinities and a divided male community were said to contribute to growing mental health crises in the area (e.g., the Macedon Ranges’ high suicide rate).P49: “Look, I know the Macedon Ranges has one of the highest suicide rates and it’s that sort of question. And I think there are a few things contributing factors there, is that we are a mix of a rural and urban type environments. So how do you get those two different sort of communities to mix and work together?”
For local men who ascribed to more traditional and conservative masculinities, cultural change brought on by the introduction of new masculinities contributed to a sense of being less able to openly share their thoughts in the Macedon Ranges, given that these once acceptable perspectives were now labelled as politically incorrect. These residents felt they were given less freedom to simply ‘be themselves’ as a result of tree-change migration, and, in a few cases, described feeling shamed for simply being men. As a result, these often long-term residents described feeling socially disconnected from a community that once served to provide them a strong sense of belonging.P37: “The roles of men are changing to a sense that … I’ve become very aware that I’m a man because I’ve been constantly told I am. And that’s the difference. Before, I was just a person, part of the community, get involved. I didn’t go banging my chest and saying I’m a man. It was just a person. But now … 99% of men now have to be aware that they’re being observed, and they have to be careful with what they say, how they say, where they say.”
P49: “With gender equality and everything, the pendulum swung back to the middle or is swinging back to the middle, but in some situations it’s swung to the far side, it’s actually, there’s a lot of people I’ve heard talk about it … There’s a lot of mild shaming that goes on these days … they [women] play the gender bias card and put down men … So it’s just unfortunately one of those things.. they’re [men are] walking away from community groups for that reason … and saying, well, we don’t really feel part of the community anymore. So we’ll just get up in the morning, do whatever we need to do at home, go to work, come home and do whatever we need to do at home and not get involved in the community. So, therefore, the community is no longer the community that it was. It’s just a whole lot of people that live in boxes and go off and do their own things.”
For other residents, conflicts emerging between masculinities in the Macedon Ranges discouraged them from making or maintaining connections with men in the area. That is, men who recently moved to the Macedon Ranges from Melbourne were described as often put off from making local friends because in order to do so they would need to ‘bridge the divide’ between their more progressive ‘city masculinities’ and dominant traditional masculinities in the area. Because of the Macedon Ranges’ unique inner-regional location (i.e., only one hour away from Melbourne), these men often elected to retain their friendship circles in Melbourne at the expense of establishing ‘difficult’ new Macedon Ranges friendships.P49: “Because so many new people have moved in, they don’t actually form any bonds with the community … And that’s becoming I think more prevalent. … [These men are] quite happy to drive them an hour away to go back and play with the sporting teams that they were already involved with rather than transitioning them to a local sporting team. So, a bit of a divide there, or a bit of people, as I said, not engaging with their own community, but still having bonds to the previous communities.”
Finally, when participants who described themselves as valuing inclusive masculinity did attempt to bridge divides between themselves and ‘stereotypical’ local men in the Macedon Ranges, they ultimately described these attempts as failures. For example, participants described facing ostracism when in the past they had attempted to open dialogue with friends surrounding how masculinity in the Macedon Ranges might be changing. In this sense, masculinities in the Macedon Ranges were not only described as dichotomous but also inherently fracturing, whereby men with different constructions of masculinity were often framed as unable to socialise together.P30: “[I] made a decision a few years ago now to not be quiet about things. If I see something that I don’t agree with, I will always speak up, whether it be racism or sexism or somebody saying … something about someone who’s … transgender or whatever … I’ll speak up for people. And I think a lot of times it makes me not very well-liked.”
“Working Away from The Macedon Ranges Takes Me Away from The Community”
This theme examines how the geographic location of the Macedon Ranges contributes uniquely to men’s experiences of estrangement from their local community, and how this in turn fosters poor mental wellbeing. Because prevailing traditional masculinities in the Macedon Ranges still encourage men to be the primary breadwinners for their families, almost all men living in the community are employed full-time. Of these men, a large portion work in Melbourne and commute long hours daily to and from their workplace. This is because the Macedon Ranges are uniquely located approximately 1 h from a major city - a phenomenon exclusive to inner-regional areas. As such, participants in the present study frame inner-regional communities as encouraging place-based negative psychosocial outcomes for men.
Firstly, the majority of participants emphasised that loneliness was a problem that exclusively afflicted men in the Macedon Ranges (i.e., not other genders) due to men’s expected roles as breadwinners and subsequent daily commuting.P20: “It was embodied for me by in the expression of one dad who I met at one stage, and he goes, ‘Oh, my wife knows everyone. She knew everyone within six weeks. I know nobody. … It feels to me like women and or young mums in this community can find a lot of their social needs met within the framework of their daily running around and whereas for the commuting partner, there’s certainly this dislocation between their social lives and their town and their home life … And without actively working against that, then it just says by default, isolation seems to be the destiny of so many middle-aged men.”
Participants also emphasised that the effect of commuting was not only felt by men during the week (i.e., unable to socialise before/after work), but also on weekends. For example, because commuting men are absent from the home during the week and hence avoid childcare duties during these periods, these duties are often fulfilled instead over the weekend (i.e., to alleviate the burden placed on their partners). In this way, any socialising that might normally take place over the weekend is also neglected.P33: “I’d say the average person is probably a dad, probably working at least three or four days down in Melbourne. So probably not really connected into the community during the weekdays, and probably focused on their family more, so they’re not necessarily having the opportunity to connect into the community.”
In line with this, female partners were described as gate-keeping men’s social lives within the community; that is, men had to ‘apply’ for permission to socialise on weekends because of otherwise-prioritised family demands. In this sense, men’s social needs were not only neglected but were also entirely out of their control. Participant 20 exemplifies this loss of control when talking about tree changer men attempting to maintain social connections in Melbourne after moving to the Macedon Ranges:P20: “It might be that once a month, or once every six weeks, they [men] kind of applied for a leave pass in their head, that was their perception to go and stay in Melbourne for night and catch up with their Melbourne mates and have some big drinking night and then just be commuting, getting back in time to shovel down some dinner and go to bed.”
Some participants emphasised how a lack of socialisation brought on by daily commuting negatively affects men’s mental health. Namely, social disconnection among men in the Macedon Ranges was framed as a leading contributor to the community’s relatively high suicide rate.P20: “We had two men of about my age at the time, maybe early 40s who [died by] suicide, and I just kind of went, look, we can’t, we can’t let this go on. We can’t let this go unaddressed. That this pattern that clearly happens that ... so many of them [men] were not addressing their social needs at all were totally ignoring their own social needs.”
Participants not only recognised that men who commuted to Melbourne daily lacked social connection; they also emphasised that these men experienced a myriad of other negative lifestyle outcomes as a result of their daily commutes that also contributed to worsening mental health. For example, the loss of time available for exercise was exemplified by Participant 27. He provided the following photograph and accompanying narrative to explain his experiences as a commuter living in the Macedon Ranges:
P27: “That’s my bike on the V-line and I’m, at the moment one day a week, I get up a bit earlier, I ride that to the station, take the train in, and then ride the rest of the way to work. Which is good. There’s a lot of wins for that. It doesn’t cost me much in terms of opportunities, so I can still get home by about 7:30 and see the kids. I won’t have dinner with them, but I’ll be home in time to help put them to bed usually. If I’m not doing that, then that opportunity for that exercise just doesn’t exist on a day to day basis because the commute takes up a huge amount of time so if you’re doubling up time with exercise and commute, you’re getting that benefit out of it. Squeezing those things that you need to do to live well and you need to do to keep your job, into the day, is tough.”
Participant 27’s account highlights how men who commute daily struggle to find time to fulfil practices they feel are integral to mental wellbeing; daily commuting not only takes a toll on men’s ability to experience social connectedness but also directly influences other key variables necessary to maintain good mental health. Thus, the Macedon Ranges’ geographic location serves to both socially isolate men and alienate them from coping strategies (e.g., exercise) that might otherwise serve to offset the psychological damage associated with loneliness.
Discussion
Findings from the present study broadly spoke to how men living in an inner-regional Australian community experience masculinities and social connectedness, and how these two phenomena interact to affect mental health. The first of our themes – “Being Unique Here Is Not an Asset”: Uniqueness As Disruptive To Social Connectedness – detailed participants’ accounts of rigid masculinities within the Macedon Ranges; participants described traditional masculine norms as being favoured and deviations from these norms as being punishable by social rejection. Conversely, our second theme – “We’re Not Really Merged Yet”: Conflicting Masculinities in the Macedon Ranges – described ways in which conflicts between these dominant traditional masculinities and emerging, inclusive masculinities are resulting in a fractured community and loss of social cohesion among some men in the Macedon Ranges. Finally, our third theme – “Working Away from The Macedon Ranges Takes Me Away from The Community” – examined how the Macedon Ranges’ unique geographical location is also driving community disconnect; that is, men who undergo long commutes to work daily are subject to isolation and loneliness. Across all themes, masculinities were implicated in affecting social connectedness for men in the Macedon Ranges. This lack of social connectedness in turn was implicated in damaging men’s psychosocial wellbeing and generating mental health crises such as increased male deaths by suicide within the Macedon Ranges.
Existing literature describes regional Australian masculinities as more rigid and traditional than city masculinities (Carrington & Scott, 2008) but acknowledges that this rigidity is softening over time (Hogg & Carrington, 2006; Pease, 2010). These trends are mirrored in the present study. In line with existing Australian literature, our participants described how being ‘unique’ was detrimental to their feeling of inclusion in the Macedon Ranges. For example, Whiteness (Waling, 2019), heterosexuality (Power et al., 2014), and engaging in archetypal masculine hobbies and social roles (Alston, 2012; Alston & Kent, 2008; Carniel, 2009; Liepins, 2000) were framed as integral, albeit rigid constructions of Macedon Ranges masculinities. Deviations from these norms often resulted in ostracism, such that alternate masculinities were not only considered abnormal but were also largely unwelcome in the Macedon Ranges. Because of this, participants described engaging in what Connell would define as complicit masculinity (Connell, 1991; Tseole & Vermaak, 2020); participants performed dominant cultural masculinities and benefitted from them without necessarily identifying with these masculinities (e.g., queer men remained ‘closeted’, while other men played sports to establish social circles despite not being that interested in sports). Several participants suggested that this complicit masculinity accounted for the Macedon Ranges’ comparatively high suicide rate, such that men were unable to express their authentic identities and thereby lacked meaningful social connections. This mirrors consistent links made between the role of thwarted belongingness in suicidality for Australian men (Christensen et al., 2013).
In an attempt to challenge and diversify what was framed as a stagnant and often harmful status quo, tree change migration from the city was portrayed as introducing the Macedon Ranges community to more inclusive masculinities (Hogg & Carrington, 2006; Pease, 2010). While the introduction of new masculinities was described as ultimately beneficial for the community (i.e., improved treatment of women and other minority groups), this shift was also implicated in causing conflict among Macedon Ranges men. Men in the area who ascribed to dominant traditional constructions of masculinity described feeling as though newfound socio-political changes in the Macedon Ranges challenged their sense of belonging, such that what was once accepted and celebrated in their community (e.g., conservatism) was now criticised and condemned.
Likewise, men who identified as more progressive and inclusive in their masculinities described being both unwilling and unable to ‘break down the barrier’ between themselves and more traditional men in the area, thereby failing to socially integrate. Conflicting masculinities were ultimately represented as a ‘teething process’ whereby men in the Macedon Ranges were struggling to learn to live and socialise with one another. This teething process was implicated in harming community identity. Even when individuals within a given community form social ties to particular subgroups, community identity (i.e., feeling connected to their community as a whole) is still integral in formulating an individual sense of belonging and connectedness (Puddifoot, 1995; Ratanakosol et al., 2016). As such, the lack of community identity evident among men in the Macedon Ranges likely has implications for local men’s mental health.
In line with local constructions of masculinity, men in the Macedon Ranges were described as generally serving as primary breadwinners for their families. Because of the Macedon Ranges’ unique location (i.e., inner-regional), most men were employed in the city of Melbourne and commuted to work daily. Participants noted that this place-based phenomenon contributed uniquely to local men’s experiences of social isolation. Men were described as far less capable of making and maintaining friendships than women due to the time constraints associated with commuting upwards of two hours daily for work. Participants argued that this directly contributed to the area’s relatively high suicide rate, such that the social isolation experienced by commuting men led to worsening mental health. This theory aligns with existing literature that suggests there is an association between greater commute time and poorer mental health for Australians (Milner et al., 2017).
Limitations and Future Research Directions
Small-scale qualitative research only has the capacity to represent the experiences of specific, targeted groups of individuals. In this sense, the present study can only speak to the experiences of men living in the Macedon Ranges, to the exclusion of alternative genders and/or men living in other regional communities or cities. While this is not a limitation per se (but rather fundamentally part of the nature of qualitative research), it does still limit the generalizability of our findings and as such is worth noting. Furthermore, the interview guide used for the present study intended to address multiple research questions posed by our research team in conjunction with the project working group. As such, lines of inquiry directly pertaining to the present study made up only part of our total interview guide. Data collected for the present study may therefore have been limited by feasibility requirements during the interview process – multiple topics needed to be covered in a set amount of time during interviewing, meaning that perhaps at times participants were not afforded the opportunity to elaborate on certain discussion points pertaining to our research question (i.e., to examine inner-regional masculinities and men’s mental health through the lens of social connectedness). .
The fact that findings from the present study often reflected the Macedon Ranges’ proximity to Melbourne has implications for regional masculinities research conducted in Australia and globally. Namely, it suggests that (at least in part) the lived experiences of men living in inner-regional areas are distinct from those living further from major cities; that is, inner-regional masculinity cultures are more likely to be informed by norms in major cities and by the unique challenges faced by commuter-heavy populations. These differences ought to be acknowledged in future literature, with inner-regional masculinities ideally being studied independently. Future research might continue to examine how conflicting masculinities and commuter populations both uniquely and collectively contribute to a loss of community identity in inner-regional areas and/or how this loss of identity subsequently impacts men’s mental health.
As aforementioned, the present study was limited by its large scope. Thus, future research is needed to expand on our findings pertaining to social connectedness. Our research established that geographic proximity to Melbourne and inner-regional constructions of masculinity often contribute to place-based experiences of social disconnect for men living in the Macedon Ranges. However, most of our participants spoke about social disconnect for inner-regional men in the abstract or as a systemic issue; not as many shared their own personal experiences of loneliness or social isolation. We therefore recommend that future literature less limited by feasibility and time constraints expand on our lines of inquiry by seeking first-hand narrative accounts of inner-regional men’s lived experiences of social disconnect (e.g., what does social disconnect mean to them, how does it impact them, what might policymakers do to better support them). It is through rich, complex, participant-centred narratives that we may come to better understand the experiences and unmet needs of men living in inner-regional Australian communities.
Practice Implications
Findings represent the experiences of men living in an inner-regional community in Australia, distinct from other regional communities in its proximity to a major city. Regional areas are undergoing rapid population expansion both in Australia and worldwide. Recently, concern has been raised regarding the pervasiveness of mental ill health among men living in regional communities (Alston, 2012; Crnek-Georgeson et al., 2017; Fitzpatrick et al., 2021). Mental health risk is considered especially high for men living in inner-regional communities (Boyd et al., 2011; Kelly et al., 2010; Shand et al., 2015). Thus, it is integral that we understand the unique challenges men living in inner-regional communities face. In assisting policymakers to implement tailored community support to inner-regional areas, the outputs of this research might serve as case study exemplars for application in similar contexts worldwide.
Participants in the present study spoke at length about how Macedon Ranges men were divided and disconnected. Notably, men who deviated from the societal ‘status quo’ (e.g., minority men or those interested in stereotypically feminine hobbies) were described as socially alienated and likely to experience mental health struggles as a result. As well as this, the Macedon Ranges’ inner-regional location was said to uniquely contribute to experiences of conflicting masculinities within the area, whereby participants felt that Macedon Ranges men lacked a cohesive community identity. As such, we recommend that policymakers in inner-regional communities pay special attention to implementing change that allows diverse groups of men to connect with one another and learn and grow as a cohesive community. If local councils in inner-regional communities made available more diverse recreational activities through well-marketed male-oriented spaces and places, men might be afforded the opportunity to get to know one together in settings that are more inclusive of alternative masculinities (e.g., a greater focus on developing infrastructure to support the arts). In addition, participants spoke to how long commute times served as a unique place-based contributor to social disconnect among Macedon Ranges men. As such, inner-regional councils may also wish to establish resources that allow men who are not always present in communities to still feel connected. For example, ride sharing initiatives (where men travel together) to and from work in Melbourne may serve as an avenue through which local men are able to form and maintain social connections with one another while not spending much time in the community itself. Overall, our findings provide policymakers place-based tailored recommendations for improving men’s mental health in inner-regional communities both in Australia and worldwide.
Conclusion
In sum, this study examined men’s experiences of masculinity and social connectedness in the Macedon Ranges – an inner regional community located approximately one hour out of Melbourne, Australia. We found that men living in this community uniquely constructed masculinities. While traditional masculine norms remain prevalent, the community’s proximity to a large metropolitan city and subsequent commuter population has also meant that more inclusive and diverse masculinities are perforating the community. Changes to, and clashes in, masculinities within the local community have contributed to increased experiences of social disconnection among men. This is heightened by time spent away from the community (i.e., commuter population) and a lack of diversity prevalent among both Macedon Ranges men themselves (i.e., a lack of ethnic or gender diversity) and the recreation made available to them (i.e., a lack of diverse activities in which men are able to engage outside of sports and alcohol). Identifying the specific challenges men in inner-regional areas face allows us to move towards an understanding of how we might use policy to improve the experiences of men living in these communities worldwide.
Statements and Declarations
This study was funded by the North Western Melbourne Primary Health Network. The authors have no relevant financial or non-financial interests to disclose. Participants provided written informed consent prior to participation.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Alston M Rural male suicide in Australia Social Science and Medicine 2012 74 4 515 522 10.1016/j.socscimed.2010.04.036 20541304
Alston M Kent J The big dry: The link between rural masculinities and poor health outcomes for farming men Journal of Sociology 2008 44 2 133 147 10.1177/1440783308089166
Ambrey C Ulichny J Fleming C The Social Connectedness and Life Satisfaction Nexus: A panel data analysis of women in Australia Feminist Economics 2017 23 2 1 32 10.1080/13545701.2016.1222077
Anderson, E. (2009). Inclusive masculinity. Routledge.
Åslund C Larm P Starrin B Nilsson KW The buffering effect of tangible social support on financial stress: influence on psychological well-being and psychosomatic symptoms in a large sample of the adult general population International Journal for Equity in Health 2014 13 1 85 10.1186/s12939-014-0085-3 25260355
Australian Bureau of Statistics (2016). 2016 Census QuickStats - Macedon Ranges. https://www.abs.gov.au/census/find-census-data/quickstats/2016/LGA24130#:~:text=In%20the%202016%20Census%2C%20there,up%200.6%25%20of%20the%20population.%26text=The%20median%20age%20of%20people,(S)%20was%2042%20years
Australian Government Department of Health (2019). National Men’s Health Strategy 2020–2030. http://www.dpmc.gov.au/government/commonwealth-coat-arms
Australian Government Department of Health.(2020). About men’s sheds. https://www.Health.Gov.Au/Initiatives-and-Programs/Mens-Sheds/about-Mens-Sheds#who-Provides-Mens-Sheds
Australian Institute of Health and Welfare (2019). Rural & remote health. https://www.aihw.gov.au/reports/rural-remote-australians/rural-remote-health
Beyond Blue (2013). Men’s sheds in Australia. https://mensshed.org/wp-content/uploads/2022/05/Ultrafeed-beyondblue-Mens-Shed-in-Australia-Final-Executive-Report-2013.pdf
Blazina C Eddins R Burridge A Settle A The relationship between masculinity ideology, loneliness, and separation-individuation difficulties The Journal of Men’s Studies 2007 15 1 101 109 10.3149/jms.1501.101
Bourne, K., Houghton, K., How, G., Achurch, H., & Beaton, R. (2020). The big movers: Understanding population mobility in regional Australia. https://regionalaustralia.org.au/Web/Web/Media/Editorials/THE-BIG-MOVER-UNDERSTANDING-POPULATION-MOBILITY-IN-REGIONAL-AUSTRALIA.aspx
Boyd C Hayes L Nurse S Aisbett D Francis K Newnham K Sewell J Preferences and intention of rural adolescents toward seeking help for mental health problems Rural & Remote Health 2011 11 1582 10.22605/RRH1582 21319934
Braun V Clarke V Using thematic analysis in psychology Qualitative Research in Psychology 2006 3 2 77 101 10.1191/1478088706qp063oa
Braun V Clarke V One size fits all? What counts as quality practice in (reflexive) thematic analysis? Qualitative Research in Psychology 2021 18 3 328 352 10.1080/14780887.2020.1769238
Bridges T Pascoe CJ Hybrid masculinities: New directions in the sociology of men and masculinities Sociology Compass 2014 8 3 246 258 10.1111/soc4.12134
Brown KM Hoye R Nicholson M Self-esteem, self-efficacy, and social connectedness as mediators of the relationship between volunteering and well-being Journal of Social Service Research 2012 38 4 468 483 10.1080/01488376.2012.687706
Bye LM How to be a rural man”: Young men’s performances and negotiations of rural masculinities Journal of Rural Studies 2009 25 3 278 288 10.1016/j.jrurstud.2009.03.002
Carniel J Sheilas, wogs and metrosexuals: Masculinity, ethnicity and Australian soccer Soccer and Society 2009 10 1 73 83 10.1080/14660970802472676
Carrington, K., & Scott, J. (2008). Masculinity, rurality and violence. In British Journal of Criminology (Vol. 48, Issue 5, pp. 641–666). 10.1093/bjc/azn031
Christensen H Batterham PJ Soubelet A MacKinnon AJ A test of the Interpersonal Theory of Suicide in a large community-based cohort Journal of Affective Disorders 2013 144 3 225 234 10.1016/j.jad.2012.07.002 22862889
Coleman D Traditional masculinity as a risk factor for suicidal ideation: Cross-sectional and prospective evidence from a study of young adults Archives of Suicide Research 2015 19 3 366 384 10.1080/13811118.2014.957453 25383764
Connell RW Live fast and die young: The construction of masculinity among young working-class men on the margin of the labour market The Australian and New Zealand Journal of Sociology 1991 27 2 141 171 10.1177/144078339102700201
Connell, R. W. (2005). Masculinities (2nd ed.). University of California Press.
Connell RW Messerschmidt JW Hegemonic masculinity: Rethinking the concept Gender and Society 2005 19 6 829 859 10.1177/0891243205278639
Creighton G Oliffe J Ogrodniczuk J Frank B “You’ve gotta be that tough crust exterior man”: Depression and suicide in rural-based men Qualitative Health Research 2017 27 12 1882 1891 10.1177/1049732317718148 28936927
Crime Statistics Agency. (2020). Family incidents, other parties and affected family members Macedon Ranges, Year ending June 2020.
Crnek-Georgeson, K. T., Wilson, L. A., & Page, A. (2017). Factors influencing suicide in older rural males: A review of Australian studies. Rural and Remote Health, 17(4020), 10.22605/RRH4020
European Commission (2018). EU rural areas in numbers. https://Ec.Europa.Eu/Info/Strategy/Priorities-2019-2024/New-Push-European-Democracy/Long-Term-Vision-Rural-Areas/Eu-Rural-Areas-Numbers_en#:~:Text=30.6%25%20of%20the%20EU’s%20population,Age%20groups%20below%2050%20years
Fitzpatrick, S. J., Handley, T., Powell, N., Read, D., Inder, K. J., Perkins, D., & Brew, B. K. (2021). Suicide in rural Australia: A retrospective study of mental health problems, healthseeking and service utilisation. Plos One, 16(7 July), 10.1371/journal.pone.0245271
Flood, M. (2005). Mapping loneliness in Australia. https://australiainstitute.org.au/report/mapping-loneliness-in-australia/
Franklin A Barbosa Neves B Hookway N Patulny R Tranter B Jaworski K Towards an understanding of loneliness among Australian men: Gender cultures, embodied expression and the social bases of belonging Journal of Sociology 2019 55 1 124 143 10.1177/1440783318777309
Franklin, A. S., & Tranter, B. (2008). Loneliness in Australia.
Giles LC Glonek GFV Luszcz MA Andrews GR Effect of social networks on 10 year survival in very old Australians: The Australian longitudinal study of aging Journal of Epidemiology and Community Health 2005 59 7 574 579 10.1136/jech.2004.025429 15965141
Herron, R., Ahmadu, M., Allan, J. A., Waddell, C. M., & Roger, K. (2020). “Talk about it”: Changing masculinities and mental health in rural places? Social Science and Medicine, 258. 10.1016/j.socscimed.2020.113099
Hogg, R., & Carrington, K. (2006). Policing the rural crisis. Federation Press.
Hurzeler T Buckley NA Noghrehchi F Malouf P Page A Schumann JL Chitty KM Alcohol-related suicide across Australia: A geospatial analysis Australian and New Zealand Journal of Public Health 2021 45 4 394 399 10.1111/1753-6405.13122 34097331
Inagaki TK Opioids and social connection Current Directions in Psychological Science 2018 27 2 85 90 10.1177/0963721417735531
Kelly BJ Stain HJ Coleman C Perkins D Fragar L Fuller J Lewin TJ Lyle D Carr VJ Wilson JM Beard JR Mental health and well-being within rural communities: The Australian rural mental health study Australian Journal of Rural Health 2010 18 1 16 24 10.1111/j.1440-1584.2009.01118.x 20136810
Keum BTH Oliffe JL Rice SM Kealy D Seidler ZE Cox DW Levant RF Ogrodniczuk JS Distress disclosure and psychological distress among men: The role of feeling understood and loneliness Current Psychology 2021 10.1007/s12144-021-02163-y
Kleiman EM Riskind JH Schaefer KE Social support and positive events as suicide resiliency factors: Examination of synergistic buffering effects Archives of Suicide Research 2014 18 2 144 155 10.1080/13811118.2013.826155 24620940
Liepins R Making men: The construction and representation of agriculture-based masculinities in Austrilia and New Zealand Rural Sociology 2000 65 4 605 620 10.1111/j.1549-0831.2000.tb00046.x
Maulik PK Eaton WW Bradshaw CP The effect of social networks and social support on common mental disorders following specific life events Acta Psychiatrica Scandinavica 2010 122 2 118 128 10.1111/j.1600-0447.2009.01511.x 20618174
McClelland H Evans JJ Nowland R Ferguson E O’Connor RC Loneliness as a predictor of suicidal ideation and behaviour: A systematic review and meta-analysis of prospective studies Journal of Affective Disorders 2020 274 880 896 10.1016/j.jad.2020.05.004 32664029
McKenzie SK Collings S Jenkin G River J Masculinity, social connectedness, and mental health: Men’s diverse patterns of practice American Journal of Men’s Health 2018 12 5 1247 1261 10.1177/1557988318772732
McLaren S Challis C Resilience among men farmers: The protective roles of social support and sense of belonging in the depression-suicidal ideation relation Death Studies 2009 33 3 262 276 10.1080/07481180802671985 19353822
Milner A Badland H Kavanagh A Lamontagne AD Time spent commuting to work and mental health: Evidence from 13 waves of an Australian cohort study American Journal of Epidemiology 2017 186 6 659 667 10.1093/aje/kww243 28453601
Oliffe JL Kelly MT Montaner G Yu Ko WF Zoom interviews: Benefits and concessions International Journal of Qualitative Methods 2021 20 160940692110535 10.1177/16094069211053522
Panagioti M Gooding PA Taylor PJ Tarrier N Perceived social support buffers the impact of PTSD symptoms on suicidal behavior: Implications into suicide resilience research Comprehensive Psychiatry 2014 55 1 104 112 10.1016/j.comppsych.2013.06.004 23972619
Pease B Reconstructing violent rural masculinities: Responding to fractures in the rural gender order in Australia Culture Society and Masculinities 2010 2 2 154 164 10.3149/csm.0202.154
Pini B Interviewing men: Gender and the collection and interpretation of qualitative data Journal of Sociology 2005 41 2 201 216 10.1177/1440783305053238
Power J Brown R Schofield MJ Pitts M Mcnair R Perlesz A Bickerdike A Social connectedness among lesbian, gay, bisexual, and transgender parents living in metropolitan and regional and rural areas of Australia and New Zealand Journal of Community Psychology 2014 42 7 869 889 10.1002/jcop.21658
Public Health Information Development Unit (2021). Social health atlas of Australia: Victoria local government areas. https://Phidu.Torrens.Edu.Au/Current/Maps/Shaaust/Lga-Single-Map/Vic/Atlas.Html
Puddifoot JE Dimensions of community identity Journal of Community & Applied Social Psychology 1995 5 5 357 370 10.1002/casp.2450050507
Raffaelli M Andrade FCD Wiley AR Sanchez-Armass O Edwards LL Aradillas-Garcia C Stress, social support, and depression: A test of the stress-buffering hypothesis in a Mexican sample Journal of Research on Adolescence 2013 23 2 283 289 10.1111/jora.12006
Ratanakosol, K., Pathumcharoenwattana, W., & Kimpee, P. (2016). Learning process for creating community identity. SHS Web of Conferences, 26. 10.1051/shsconf/20162601067
Rawsthorne M Healy K Hillman W Families on the fringe: Mental health implications of the movement of young families to non-metropolitan areas Rural Society 2009 19 4 306 317 10.5172/rsj.351.19.4.306
Regional Australia Institute (2021). What is regional Australia? https://regionalaustralia.org.au/Web/Web/About-Us/What-is-Regional-Australia.aspx
Richardson, C., Robb, K. A., McManus, S., & O’Connor, R. C. (2022). Psychosocial factors that distinguish between men and women who have suicidal thoughts and attempt suicide: Findings from a national probability sample of adults. Psychological Medicine, 1–9. 10.1017/S0033291721005195
Schlichthorst M King K Turnure J Phelps A Pirkis J Engaging Australian men in masculinity and suicide – A concept test of social media materials and a website Health Promotion Journal of Australia 2019 30 3 390 401 10.1002/hpja.246 30919504
Seale C Charteris-Black J Dumelow C Locock L Ziebland S The effect of joint interviewing on the performance of gender Field Methods 2008 20 2 107 128 10.1177/1525822X07313837
Shand FL Proudfoot J Player MJ Fogarty A Whittle E Wilhelm K Hadzi-Pavlovic D Mctigue I Spurrier M Christensen H What might interrupt men’s suicide? Results from an online survey of men Open 2015 5 8172 10.1136/bmjopen-2015
Smith, D. T., Mouzon, D. M., Elliott, M., & the U.S. (2022). Hegemonic masculinity and mental health among older White men in: The role of health and wealth decline. Sex Roles, 86(11–12), 605–619. 10.1007/s11199-022-01291-4
Stone, W., & Hulse, K. (2007). Housing and social cohesion: An empirical exploration. https://melbourneinstitute.unimelb.edu.au/assets/documents/hilda-bibliography/other-publications/pre2010/Stone_etal_Housing_and_social_cohesion_an_empirical_explorationpdf.pdf
Teo, A. R., Choi, H., & Valenstein, M. (2013). Social relationships and depression: Ten-year follow-up from a nationally representative study. Plos One, 8(4), Article e62396. 10.1371/journal.pone.0062396
Tseole, N. P., & Vermaak, K. (2020). Exploring the influences of hegemonic and complicit masculinity on lifestyle risk factors for noncommunicable diseases among adult men in Maseru, Lesotho. American Journal of Men’s Health, 14(6), 10.1177/1557988320958931
Turning Point. (n.d.). AODstats- Victoria alcohol and drug statistics. Hospital admissions. https://Aodstats.Org.Au/Explore-Data/Hospitaladmissions/
United States Census Bureau (2017). One in five Americans live in rural areas. https://Www.Census.Gov/Library/Stories/2017/08/Rural-America.Html
Waling, A. (2019). White masculinity in contemporary Australia. Routledge.
Wickramaarachchi N Expansion of commuter facilities and a diminishing sense of place among migrants in a rural Australian town Rural Society 2020 29 1 44 58 10.1080/10371656.2020.1753329
Wulff M Dharmalingam A Retaining skilled migrants in regional Australia: The role of social connectedness Journal of International Migration and Integration 2008 9 2 147 160 10.1007/s12134-008-0049-9
Zoom Video Communications Inc (2019). Zoom meetings & chat. https://Zoom.Us/Meetings
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Transportation (Amst)
Transportation (Amst)
Transportation
0049-4488
1572-9435
Springer US New York
10351
10.1007/s11116-022-10351-3
Article
A latent class analysis to understand riders’ adoption of on-demand mobility services as a complement to transit
Wang Yiyuan [email protected]
1Dr. Yiyuan Wang
is a recent graduate of the Interdisciplinary PhD Program in Urban Design and Planning at the University of Washington. He is interested in applying economic theories and models to investigate the impact of new transportation technologies on individual travel behavior and public policymaking. His most recent works include studying public transit agencies’ initiative to supplement tranditional transit with on-demond shared mobility modes.
Shen Qing [email protected]
12Dr. Qing Shen
is Professor and Chair of the Interdisciplinary PhD Program in Urban Design and Planning at the University of Washington. His primary areas of interest are urban economics and metropolitan transportation planning and policy. Professor Shen has developed new methodological frameworks for analyzing urban spatial structure, examined the social and environmental consequences of automobile-oriented metropolitan development, and investigated the differential impacts of information and communication technologies on various population groups. His current work focuses on new challenges and opportunities for transportation demand management in the age of shared mobility. He earned his PhD in City and Regional Planning from University of California, Berkeley.
1 grid.34477.33 0000000122986657 Interdisciplinary PhD Program in Urban Design and Planning, University of Washington, Seattle, WA 98195 USA
2 grid.34477.33 0000000122986657 Department of Urban Design and Planning, University of Washington, Seattle, WA 98195 USA
6 12 2022
119
31 10 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
On-demand app-based shared mobility services have created new opportunities for complementing traditional fixed-route transit through transit agencies’ efforts to incorporate them into their service provision. This paper presents one of the first studies that rigorously examine riders’ responses to a pilot aimed at providing such a transit-supplementing service. The study conducts latent class analysis on riders of the Via to Transit program, a mobility pilot in the Seattle region where on-demand service was offered to connect transit riders to light rail stations. The analysis identifies three distinct rider groups with heterogenous responses to the on-demand service: (1) riders who previously used private cars or ride-hailing; (2) riders who were pedestrians and bikers but switched likely because of safety concern; (3) mostly socio-economically disadvantaged riders who previously relied on the bus, but switched to the new service for the convenience and speed. These results point to rich transportation policy implications, which can inform decision-making by public transit agencies as they are exploring alternative ways to deliver the mobility services.
Supplementary Information
The online version contains supplementary material available at 10.1007/s11116-022-10351-3.
Keywords
Public transit
On-demand shared mobility
Latent class analysis
Heterogeneous travel behavior responses
Built environments
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pmcIntroduction
The emerging app-based on-demand shared mobility modes (e.g., ride-hailing, bike-sharing, micro-transit) have greatly impacted how transportation services are provided in the cities. Historically, fixed-route transit has long been the primary form of public transportation service. But for a long time, public transit has been struggling to attract and retain riders despite increasing investments (Lee and Lee 2022; Manville et al. 2018; Watkins et al. 2019). The recent growth of shared mobility services, with their convenience and flexibility, may have the potential to be better integrated with public transit and fill in the gaps where traditional fixed-route transit is too costly to operate (Feigon and Murphy 2018).
Transit agencies in the United States have started to explore incorporating shared mobility modes to serve as first-mile/last-mile solutions to transit, guaranteed ride home, or replacement of some high-cost transit routes (Gifford et al. 2021; Grellier 2020; Miller et al. 2021; Shen et al. 2021). These efforts often require building partnerships with the mobility service companies and incentivizing transit riders to adopt the new services. They may also integrate fare payment and/or trip planning of the two modes. In this paper, we use the term Transit Incorporating Mobility on Demand (TIMOD) to be consistent with the naming of Federal Department of Transportation and accurately capture the supplementary roles played by shared mobility services in enhancing public transit. Similar terminologies, including multimodal integrations, innovative mobility programs, shared mobility public–private partnerships (King County Metro 2022; Wang et al. 2022), have appeared in the literature, each with a somewhat different emphasis.
Early evaluations suggest many existing TIMOD pilots achieved promising results. For example, several evaluations reported that the on-demand services were popularly adopted by riders (Gifford et al. 2021; King County Metro 2020; Miller et al. 2021). However, the exact impacts of incentivizing on-demand shared mobility on rider’s travel behavior remain largely unknown, and more rigorous examinations are needed for the following reasons.
First, introducing and incentivizing on-demand mobility services offers riders in the service area a competitive option for travel, and draws riders from different travel modes. However, most of the evaluations of existing TIMOD pilots were limited to simple descriptive statistics, and little is known about riders’ heterogeneous responses to the pilots and subsidies. For example, the policy implications of adopting on-demand modes are different between riders who switch from walking and those who switch from driving, between commuters and non-commuters, or between riders who value convenience and riders who value cost. Without a granular understanding of whom TIMOD programs primarily serve, it is difficult for transit agencies to tailor future mobility policy innovations to specific rider groups.
Second, TIMOD programs often invest a substantial amount of funds to incentivize on-demand shared modes, with the hope that such subsidies can benefit those who are socio-economically disadvantaged and mobility challenged (Gifford et al. 2021; King County Metro 2020; Miller et al. 2021). However, the social equity implications in the distributions of the investments remain a question, as the nature of the app-based travel may create technological barriers to access and use of the service (Moudon 2020). For example, Shen et al. (2021) found that incentivizing app-based carpooling for commuting in the Seattle region had the unintended consequence of disproportionally benefiting high-income employees. Therefore, it is important to analyze and compare among different groups of riders who adopt the on-demand services, and make sure that socio-economically disadvantaged riders at least benefit equally from the pilots.
This research aims to fill in these gaps as one of the first studies examining the impacts of TIMOD on riders’ travel behavior. The study uses a TIMOD pilot, Via to Transit in the Seattle region, as a case study. Specifically, the study aims to answer the following questions:Are there distinct patterns in the adoption and usage of on-demand mobility services among riders?
Can these distinct differences be explained by riders’ socio-demographic statuses and built-environment characteristics?
Learning from the answers to the above two questions, what should transit agencies consider when designing and implementing TIMOD programs in the future?
To answer these questions, this study conducts latent class analysis (LCA) using survey data on Via to Transit riders. LCA is a statistical modeling technique that can systematically identify latent (unobserved) subgroups that share certain (observed) commonalities within a population. The paper proceeds with a literature review of how riders perceive and use the on-demand services as complements to traditional transit. Then the paper introduces Via to Transit program, data, and the methodological details of LCA. Next, the paper presents and interprets the latent classes identified by the LCA. The paper concludes with discussions and policy implications derived from the LCA results.
Literature review
On-demand shared mobility modes as complements to public transit
Even without transit agencies’ explicit efforts to integrate and incentivize shared mobility modes, riders have ‘naturally’ adopted them as complementary modes to public transit, most commonly to mass transit such as light rail and bus rapid transit. At the individual level, associations between a person’s usage of shared mobility modes (especially app-based ride-hailing) and public transit use were often reported (Grahn et al. 2020; Tirachini 2020; Young and Farber 2019). At the aggregate level, the introduction of app-based ride-hailing was shown by researchers to be positively associated with transit ridership in some cities, which implied the use of app-based ride-hailing as a complement mode for transit (Hall et al. 2018). However, these studies did not provide evidence that these two modes were taken in junction with each other.
A few recent studies directly modeled the mode choices of access and egress modes for transit using discrete choice models. For example, Zgheib et al. (2020) modeled the choices of feeder modes to transit with stated-preference data collected from Beirut, and their results show that app-based ride-hailing was perceived as a popular choice, especially among younger commuters. Azimi et al. (2021) employed data from an onboard transit rider survey in Orlando, FL, and found positive associations between using app-based ride-hailing as a feeder to transit and household income, trip distance, and specific trip purposes such as going to airports and universities.
Why are TIMOD programs desirable?
The results from the above literature demonstrate the potential of integrating on-demand shared mobility modes with public transit. However, the literature suggests that only ‘natural’ or purely market-driven adoptions may fail to fully achieve the transit-supplementing potential of on-demand shared mobility modes.
Both Zgheib et al. (2020) and Azimi (2021) indicated that the ‘natural’ adoption of on-demand modes as feeder modes was constrained to a niche market. The riders of TIMOD largely overlapped with the early adopters and frequent users of new transportation technologies in general, who were young, central-city dwellers, and tech-savvy (Circella et al. 2018; Clewlow and Mishra 2017; Vij et al. 2020; Young and Farber 2019). Even among them, the use of on-demand modes was still occasional (Tirachini 2020), and only for specific trip purposes such as getting to airports or avoiding drunk-driving (Azimi et al. 2021; Young and Farber 2019). A major barrier to choosing on-demand modes to access/egress transit is the high market-priced fare of on-demand modes, as Zgheib et al. (2020) demonstrated. Other barriers may include the lack of an integrated payment system and difficulties in multi-modal trip planning. It is thus interesting to know whether, with the subsidies provided and better-integrated services, TIMOD programs can overcome some of the barriers and provide more inclusive mobility access.
In addition, a ‘natural’ adoption of using on-demand shared mobility modes may not be sufficient to promote the use of transit for societal benefits. From an urban economics perspective, public transit is often advocated for its promise of positive externalities through reducing congestion, environmental pollution, and road collisions when compared with private car use (O’Sullivan 2012, Chapter 11). TIMOD programs are essentially a new form of transit subsidies that reduce a rider’s total generalized cost for accessing/egressing public transit. They may therefore help realize and internalize the positive externalities of the transit.
On the other hand, the literature pointed out that the level of mobility sharing (i.e., the passenger occupancy rate) of app-based ride-hailing, the most widely adopted shared mobility mode, tended to be low (Henao and Marshall 2018; Shen et al. 2021). As a result, it exacerbated road congestion instead of reducing it (Diao et al. 2021). TIMOD programs can thus be opportunities for transit agencies to strategically select alternative mobility service providers (e.g., ride-pooling, micro-transit) to partner with, and thus encourage “deeper sharing” (Shen et al. 2021). They can also purposefully deploy vehicles with a high level of capacity (Tirachini et al. 2020). This is particularly promising in the case of first-mile/last-mile solutions, as riders would share the same origins or destinations (i.e., the transit stops), and thus the trips can be more ‘sharable’.
Riders’ preferences and adoptions of TIMOD programs
As most of the pilots of TIMOD in the United States are still under development, few studies were able to use real-world observed data collected from these pilots to examine riders’ adoption. Most studies instead have used stated preference surveys to collect riders’ preferences and choices under the scenarios where a hypothetical on-demand, transit-supplementing service was offered. Yan et al. (2019) forecasted the adoption of a proposed TIMOD pilot on a college campus using survey data collected from students, staff, and faculty. Yan et al. (2021) and Wang et al. (2022) were a series of efforts that analyzed the attitude of residents in low-income neighborhoods toward TIMOD. They found associations between preferences towards the proposed TIMOD pilot and the respondent’s characteristics, and identified major barriers to the adoption of pilot if implemented. These studies, although offering timely insights for transit agencies, were largely exploratory because they did not observe riders’ behavior in a real-world TIMOD pilot.
Background, data, and methodology
This study examines riders’ adoption of a TIMOD service using survey data collected from Via to Transit program, supplemented by riders’ complete service usage records.
Via to transit program
Via to Transit is a TIMOD program implemented by King County Metro (KCM), the primary transit operator in the Seattle region, in partnership with Via, a private mobility service provider. Before the COVID-19 pandemic in 2020, the pilot provided first-mile/last-mile solutions to five Link Light Rail stations (Mount Baker, Columbia City, Othello, Rainier Beach, and Tukwila International Blvd Station) in south Seattle. Figure 1 shows the service areas and the locations of the five Link light rail stations served. The service was on-demand, operated using Via minivans, and could be booked through the Via app or phone calls. Riders would be requested to walk for a short distance for easier pick-up or drop-off,1 and the trips were often shared by multiple groups of riders. The service only cost riders standard transit fares ($2.75 for most riders). Based on the information provided by KCM, census tracts within two-mile buffers of the five light rail stations had a population of 279,487. The percentage of racial minorities of the population ranged from 60% in Mount Baker station area to 75% in Rainier Beach station area. The percentage of low-income households that are below the poverty level ranged from 15% in Mount Baker station area to 23% in Rainier Beach station area. Appendix A and Appendix B contain additional information, including the neighborhood income and the land use, of the study area.Fig. 1 Via to Transit service areas and Link Light Rail stations
We believe that studying the adoption and usage of riders of Via to Transit offers timely, transferrable insights for both KCM and other transit agencies. KCM is, in many ways, a representative transit agency that serves a medium-to-large sized U.S. metropolitan area, and the Link Light Rail is currently the primary rail transit and the ‘backbone’ of the public transit system in the region. Via to Transit thus provides meaningful mobility access in the five-station service areas. Prior to the COVID-19 pandemic, Via to Transit lasted for a year from April 16, 2019, to March 23, 2020, carrying about 230,000 trips. Its outcomes can shed light on the long-term impacts of such mobility pilots on riders. In addition, the five-station service areas consist of neighborhoods with relatively high percentages of racial minorities and low-income populations. Studying Via to Transit thus can generate invaluable knowledge regarding the social equity implications of TIMOD programs.
Data
This research primarily uses Via to Transit rider survey data while integrating some information from Via to Transit trip records. Via rider survey was administrated by King County Metro and distributed to all 8154 Via to Transit riders by sending an email with the survey link. The survey collection started on December 3, 2019, about 8 months after the launch of the Via to Transit project, and ended on January 20, 2020. Survey respondents were offered a chance to draw a $100 Visa gift card. The survey questionnaire consisted of two sections, one asking questions related to Via to Transit service and Link Light Rail usage, and the other covering respondents’ basic personal and household information. Survey respondents can be linked to Via trip data through a unique, anonymous ID. The raw data contains 1272 samples with a response rate of 15.6%.2 We followed a data cleaning procedure as in Table 1 and obtained an effective sample size of 925.Table 1 Via rider survey data cleaning process
Step N (remaining)
1 Original raw data 1272
2 Riders who had at least one completed Via trip recorda 1208
3 Riders who did not skip the socio-demographic section of the survey 1110
4 Riders who took Via for first-mile/last-mile solution for Link Light Railb 988
5 Riders who responded to all survey questions except for household incomec 925
aThe rest could be riders who used the app and requested rides, but did not complete the trip. Or it could be riders who used credit card instead of the ORCA card (the transit smart card in the region) to pay Via to Transit, which results in survey data unable to be linked to the trip records
bThe rest did not use Via to Transit as the access/egress mode to public transit. It is possible that their travel origins/destinations are near the light rail stations. These riders did not answer questions related to Link Light Rail usage, and thus needed to be dropped
cDue to the fact that a large number of survey respondents (n = 227) chose not to disclose their household income, we tested two models, one with N = 698 and the household income variable containing three levels: 0—$49,999, $50,000—$100,000, and > $100,000), and the other one with N = 925 and the household income variable having four income levels: 0—$49,999, $50,000—$100,000, > $100,000, and prefer not to answer income. The latent classes identified in LCA between the two models are largely consistent. The one with larger sample comes with smaller standard errors, which helps interpret and explain the identified classes. In this paper, we present the model with N = 925
Methodology
This study employs LCA, a statistical technique that identifies latent, unobserved subgroups (or classes) within a population using manifested, observed characteristics (Vermunt and Magidson 2004). LCA has two components, as illustrated in Fig. 2, a measurement model that determines latent classes from observed indicators, and a membership model that explains the identified latent classes using a series of covariates. In this study, the indicators in the first component are variables related to the service usage and travel behavior changes associated with Via to Transit, and therefore the latent classes represent heterogeneity in the riders’ responses to the TIMOD service provided. The measurement model detects latent groups by maximizing the differences in indicators across latent classes. In the second component, the covariates are riders’ socio-demographics and built-environment characteristics, and thus the membership model explains the associations between these covariates and the probability of a rider belonging to a specific class. The two components of LCA are estimated jointly.Fig. 2 LCA model framework
LCA and its extensions are increasingly popular in travel behavior research, and in particular, on the attitude, adoption, and usage of new transportation technology (Alemi et al. 2018; Lee et al. 2022; Vij et al. 2020; Wang et al. 2022). However, its pros and cons compared to commonly used regression models, need to be more thoroughly discussed. The most distinct feature of LCA is that it is ‘person-oriented’ (Weller et al. 2020). Instead of being ‘variable-oriented’ and finding associations between variables, LCA finds associations across individuals and groups them. This approach thus can better inform the outcomes of transportation policy at the individual level. Second, as a direct result of the above feature, instead of narrowly focusing on a limited number of dimensions of the travel behavior (i.e., mode choice or service use frequency), the results of the LCA give us an elegant, interpretable representation of individuals’ variations in much greater dimensions. With that being said, unlike traditional regression models, the indicators are jointly explained by the class membership, and it is not easy to obtain from LCA models some quantities that might be of interest to policymakers, such as marginal effects and elasticities between variables.
A few additional features of the LCA make it an appropriate method for our study: (1) LCA uses individuals’ responses to categorical indicator variables, which works well with data collected from survey questionnaires; (2) LCA determines class from the data, and does not require prior assumptions regarding the model specifications (Alemi et al. 2018; Weller et al. 2020).
Tables 2 and 3 show the list of indicators and covariates used in the LCA of this study, respectively. Most indicators came directly from the Via to Transit rider survey. We regrouped the categories of several indicators from raw survey data to ensure a balanced distribution of observations among categories. Two additional indicators, the number of Via to Transit trips and average Via to Transit trip distance (which is the in-vehicle distance travelled with Via to Transit), were obtained from the Via trip data and transformed from a continuous scale to a categorical one, as LCA requires the indicators in the measurement model to be categorical. Regarding covariates, in addition to using the information from the Via to Transit rider survey, we obtained four additional built-environment measures for each Via to Transit rider’s most frequent travel location3 from the Smart Location Database (Chapman et al. 2021). These built-environment variables are at the Census Block Group (CBG) level and represent the location’s density, land use diversity, street design, and frequencies of transit services. We log-transformed three of them because the original distributions (shown in Appendix C) were severely right-skewed. Variance inflation factors (VIF) of all covariates in the membership model were screened, and all variables had VIF of less than 3, which suggested that the extent of multicollinearity was moderate.Table 2 List of indicators—variables used to determine class membership
Categories Source
Number of via to transit trips
(one-year period)
K = 5
(1–4; 5–14; 15–49; 50–99; > 100)a
Via trip data
Avg. via to transit trip distance of the rider K = 2
(< 1.5 miles; > = 1.5 miles)
Via trip data
Mode replaced K = 5
(Personal car; bus; walk and bike; ride-hailing; others)
Via survey data
Days of using the link light rail per week K = 4
(Less than once; 1 or 2 days; 3 or 4 days; 5 or more days)
Via survey data
Via usage if the price doubles K = 3
(Won’t use anymore; use less; use the same)
Via survey data
Safety is one of the reasons for switching to via K = 2
(Yes; No)
Via survey data
Convenience/faster travel is one of the reasons for switching to via K = 2
(Yes; No)
Via survey data
Cost is one of the reasons for switching to via K = 2
(Yes; No)
Via survey data
Has utilitarian trip purpose (work, school, errands) K = 2
(Yes; No)
Via survey data
Has recreational trip purpose K = 2
(Yes; No)
Via survey data
aWe chose K = 5 to make sure that there were sufficient numbers of samples in each category (i.e., K was not too large), and categories together represented rich variation in number of Via to Transit trips (i.e., K was not too small)
Table 3 List of covariates – variables used to explain class membership
Variable type Source
Rider’s socio-demographics
Gender Categorical, K = 2
(Female; male and other)
Via survey data
Age Categorical, K = 4
(< 25; 25–44; 45–64; > 65)
Via survey data
Race Categorical, K = 2
(White; other)
Via survey data
Household size Categorical, K = 3
(1; 2; 3 or more)
Via survey data
Household income Categorical, K = 4
(< $50,000; $50,000–$100,000; > $100,000; *Prefer not to answer)
Via survey data
Car available for the trip Categorical, K = 2
(Yes; No)
Via survey data
Having a checking account Categorical, K = 2
(Yes; No)
Via survey data
Disability Categorical, K = 2
(Yes; No)
Via survey data
Built-environment characteristics of rider’s most frequent travel location at Census Block Group level
Population density (log) Continuous
Gross population density (people/acre) on unprotected landa
EPA smart location data, 2021
Employment and household entropy Continuous
This variable uses five-tier employment categories and the number of occupied housing units to calculate the entropy. It represents land use mix
EPA smart location data, 2021
Street intersection density (log) Continuous
Number of street intersections (auto-oriented intersections eliminated) per square mile
EPA smart location data, 2021
Frequency of transit service per square mile (log) Continuous
Aggregate frequency of transit service per hour per square mileb
EPA smart location data, 2021
aUnprotected land means land that is not protected from development, for example, a park or conservation land. It is used by EPA to calculate density-related measures
bThe frequency of transit service was calculated by aggregating the frequency per hour of all transit routes within 0.25 miles crow-fly distance of the boundary of the CBG during weekday peak hours. The frequency was then divided by land area to get frequency per square mile
For LCA, the number of latent classes needs to be pre-determined. Model fit and interpretability are two important factors when making such a decision. One common approach is to run LCA with different numbers of classes and choose the one with the best model fit, measured by the Akaike information criterion (AIC) or Bayesian information criterion (BIC). Table 4 shows the model fit with different class numbers, where a smaller AIC or BIC suggests a better fit. Based on the results, AIC favored 4 classes and BIC favored 3 classes. After examining the model outputs in these two models, we chose the one with 3 classes because its classes are more distinctive from each other and thus the results are more interpretable, which lead to relatively clear policy implications. The model was estimated using the ‘poLCA’ package in R.Table 4 Model fit with different number of classes
2 classes 3 classes 4 classes
AIC 15,024 14,710 14,589
BIC 15,275 15,125 15,169
Results
Results of the measurement model
Table 5 shows the three classes identified by the measurement model.4 The first row shows that the sizes of Class 1, 2, and 3 are 34%, 39%, 27% of the total sample size (N = 925), respectively. Each value starting from the second row is the posterior probability of riders within the class being in the corresponding category of the indicator. For example, the first number, 0.59, indicates that 59% of riders in Class 1 made 1–4 Via to Transit trips during the one-year pilot. The bold numbers are the highest values for each row. For example, among three classes, Class 1 has the highest percentage of riders that made 1–4 Via to Transit trips. Table 5 thus presents an easy-to-interpret way to understand the three classes by reading the class-specific distribution of indicators.Table 5 Results of the estimated LCA measurement model (N = 925)
Indicators Categories Class 1 Class 2 Class 3
Class size 34% 39% 27%
Number of via to transit trips (one-year) 1–4 0.59 0.19 0.10
5–14 0.31 0.25 0.17
15–49 0.08 0.30 0.25
50–99 0.01 0.14 0.19
> 100 0.00 0.11 0.30
Avg. via to transit trip distance < 1.5 miles 0.64 0.99 0.25
≥ 1.5 miles 0.36 0.01 0.75
Mode replaced Personal car 0.41 0.13 0.31
Bus 0.12 0.21 0.46
Walk/bike 0.27 0.60 0.08
Ride-hailing 0.14 0.01 0.09
Other 0.05 0.05 0.06
Days of using the link station per week Less than once 0.82 0.14 0.15
1 or 2 days 0.17 0.21 0.20
3 or 4 days 0.02 0.30 0.32
5 or more days 0.00 0.35 0.34
Via usage if the price doubles Won’t use it anymore 0.19 0.39 0.39
Use less 0.48 0.45 0.43
Use the same 0.32 0.16 0.18
Reason for switching—safety Yes 0.19 0.44 0.33
No 0.81 0.56 0.67
Reason for switching—convenience & faster travel Yes 0.70 0.78 0.84
No 0.30 0.22 0.16
Reason for switching—cost Yes 0.22 0.07 0.22
No 0.78 0.93 0.78
Trip purpose: utilitarian Yes 0.52 0.99 0.98
No 0.48 0.01 0.02
Trip purpose: recreation Yes 0.70 0.46 0.37
No 0.30 0.54 0.63
Bold numbers indicate the highest value for each row
Class 1 has the highest share of riders who used Via to Transit occasionally, with 59% of them only taking 1–4 Via to Transit trips, and 31% of them taking 5–14 trips. The class has the highest share of riders who switched from private motorized modes, i.e., personal car (41%) and ride-hailing (14%). It is the class that was least dependent on the Light Rail, with 82% of riders only using the Light Rail less than once a week and 17% of them using it 1 or 2 days a week, which also explained the infrequent use of Via to Transit. The class is least sensitive to price with the highest percentage of riders indicating they would still use Via to Transit even if the price increased. This class is least likely to adopt Via to Transit because of safety (19%), least likely to travel for utilitarian purposes (52%), and most likely to travel for recreational purposes (70%).
Class 2 consists of a higher percentage of riders whose Via to Transit trip distance was on average less than 1.5 miles (99%) than the other two groups, which makes sense as this class has the highest share of riders who previously walked or biked to the station (60%), although about 35% of the class still took motorized modes. More riders in this class needed to access the Light Rail frequently as 35% of them rode the Link 5 or more days a week. The class is more price-sensitive than Class 1, with 39% of them would stop using Via to Transit if the price increased. The class has the highest share of riders who switched because of safety (44%). Almost all of them had utilitarian trip purposes (i.e., work, school, or personal errands) (99%).
Class 3 contains a higher percentage of frequent Via to Transit riders than the two groups, as 19% of them took 50–99 Via to Transit trips and 30% of them took more than 100 trips in a year. They were more likely to be riders whose trip distance on average exceeded 1.5 miles (75%). They were likely to be frequent transit riders. The class has the highest share of riders who previously took the bus to access Link stations (46%), although 31% of them drove to the station. The class has a relatively high percentage of riders who took Link Light Rail 3 or 4 days (32%) or 5 days or more (34%) in a week. Similar to Class 2, Class 3 is also price sensitive as 39% of them would stop using Via to Transit if the price increased. A large proportion of riders (84%) in Class 3 switched because of Via to Transit’s convenience and savings in travel time. Regarding trip purpose, almost all riders in Class 3 had utilitarian purposes (98%), and they were the least likely ones to have recreational purposes (37%).
To summarize, three latent classes identified in the measurement model were distinctive from each other and represented substantial variations in their Via to Transit usage, mode choices, reasons for switching, and trip purposes. We will further discuss the role Via to Transit played in their travel and the corresponding policy implications in the discussion section.
Results of the membership models
Table 6 presents the second component of the model, where socio-demographics and built-environment covariates were used to explain the membership of three latent classes identified from the measurement model. In such a way, the membership model resembles a multinomial logistic regression, where the dependent variable is a categorical variable with three categories, and the estimated coefficients represent the associations between a one-unit change of the independent variables and the changes in the log-odds of belonging to a class relative to the reference class, when holding other variables constant. The reference class is Class 1.Table 6 Results of the estimated LCA membership model (N = 925)
Coefficient Class 2
(Ref. class 1) Class 3
(Ref. class 1)
Gender: female − 0.011 − 0.36
Age: < 25 (ref. 25–44) 0.54 0.23
Age: 45–64 (ref. 25–44) − 0.48* − 0.78**
Age: > 65 (ref. 25–44) − 2.35*** − 1.63***
Race: racial minorities (ref. white) 0.31 1.20***
HH size: 1 (ref: 2) − 0.26 0.265
HH size: 3 or more (ref: 2) 0.61** − 0.00
Household income: < $ 50,000 (ref: $50,000–$100,000) 0.51 0.13
Household income: > $ 100,000 (ref: $50,000–$100,000) − 0.20 0.32
Household income: prefer not to answer (ref: $50,000–$100,000) − 0.1 − 0.118
Car available: yes − 0.59** − 0.82**
Having a checking account: yes − 0.27 − 1.04*
Disability: yes − 0.12 − 0.36
Population density (log) 0.79** − 0.37
Employment and household entropy 2.29*** − 4.71***
Intersection density (log) − 0.003 − 2.10***
The total frequency of transit service per sq. mile (log) 0.83*** − 0.98***
Intercept − 6.34*** 18.35***
*p < 0.1; **p < 0.05; ***p < 0.01
Among socio-demographic variables, the model finds that riders who were older (over 45 years old) and who had greater access to cars were significantly less likely to be in Class 2, while riders with larger household sizes were significantly more likely to be in Class 2. Riders who traveled to places that were denser with greater land-use mix and transit service were more likely to belong to Class 2 than to Class 1, and these associations were statistically significant. These findings are in general consistent with the travel behavior of Class 2, as Class 2 consists of more pedestrians and bikers than Class 1, and their origins or destinations were closer to the Light Rail stations as well.
Regarding the coefficients for Class 3 versus Class 1, the model finds that older riders were significantly less likely to be in Class 3. Being a racial minority was significantly associated with a greater likelihood of belonging to Class 3. Having access to a car and access to a checking account were both negatively associated with the likelihood of belonging to Class 3. All these results suggested that riders in Class 3 were more likely to be more disadvantaged compared to Class 1, which is consistent with their higher dependency on transit and higher price sensitivity, as reflected in the measurement model. The results for the built-environment covariates for Class 3 are particularly interesting, as riders who traveled to places with lower land use mix, lower street intersection density, and lower frequencies of transit services were significantly more likely to belong to Class 3. One possible explanation is that Via to Transit greatly expanded the travel destination options for those who were previously more transit-dependent (i.e., Class 3). Before Via to Transit was available, their travel was constrained to narrow corridors along the bus lines. And Via to Transit allowed them to freely travel to places that existing buses could not reach. Another possible explanation is that such associations are a reflection of Class 1 and Class 3’s distinct trip purposes. Riders in Class 1 took more Via to Transit trips for non-utilitarian purposes and therefore they traveled to places where social and commercial activities took place. While riders in Class 3 took Via to Transit trips for utilitarian purposes, and more of their trips started or ended at their homes, where the built environments were more residential. Either way, the results strongly suggest that Via to Transit better connected Class 3 to Link stations from places with limited convenient access to jobs and services, unfriendly street design to active travel, and relatively poor transit services, as shown by the results for the built-environment covariates in Table 6.
Mapping three classes
Figure 3 shows the spatial distributions of the most frequent travel locations of riders belonging to each class, as well as the median household income of census block groups in the area.Fig. 3 Heatmaps of three identified classes (darker color = higher rider counts) and median household income. (Color figure online)
The travel locations of riders in Class 1 were in general dispersed across the area, reflecting their travel was less spatially constrained because of their better access to personal vehicles. There were a few concentrations of riders belonging to Class 1 in relatively high-income neighborhoods along the waterfront on the right of the map. Compared to Class 1, more of Class 2’s travel locations were in areas immediately surrounding the Light Rail stations, reflecting the fact that Class 2 consists of higher percentage of riders who previously walked or biked to stations. Class 3, which consists of higher percentage of riders who were previously bus riders, had travel needs from and to areas in the bottom-right of maps, where many neighborhoods were with lower median household income. Their locations were also further away from the Light Rail stations. Such clustering of riders of Class 3 further demonstrates the equity implications of Via to Transit, which enables riders in socio-economically disadvantaged neighborhoods to get better connected to the Light Rail stations.
Discussions and policy recommendations
Rich policy implications can be drawn from the above results. Class 1 is the class with the least frequent use of Via to Transit. It consists of more riders who were previously personal car or ride-hailing users, infrequent Link Light Rail riders, less price-sensitive, less safety-concerned, and primarily recreational travelers. Socio-demographically, they tended to be older and had better access to cars compared to the other two groups. Via to Transit converted a higher percentage of riders in Class 1 from driving alone and ride-hailing to Via to Transit. For travelers who did not take Link Light Rail prior to the pilot, such conversion came with many social and environmental benefits because it could reduce the use of vehicles and the number of vehicle trips. And for travelers who previously used personal cars as first-mile/last-mile solutions to Link, Via to Transit reduced the demand for parking facilities near the Light Rail stations. This class’s profile to some degree aligns with the early adopters of on-demand shared mobility modes (Tirachini 2020; Vij et al. 2020; Young and Farber 2019), as members were likely to be wealthier and to use Via to Transit for recreational purposes, likely, for avoiding drunk-driving. However, the fact that riders in Class 1 were older shows that with subsidies and greater integration between transit and on-demand modes, TIMOD programs have the potential to expand rider groups beyond what can be achieved in a natural, market-driven adoption, where in general riders are young and tech-savvy.
Riders in Class 2 and Class 3 shared some similarities. For example, they were more sensitive to prices, accessed the Light Rail more frequently, and were more likely to use Via for utilitarian purposes. However, the two classes adopted Via to Transit for different reasons. For riders in Class 2, they were more likely to be pedestrians and bikers who were concerned about safety5 when walking and biking to or from the stations. Therefore, Via to Transit offered a safer travel means for this class of riders. By doing this, Via to Transit took riders away from non-motorized, active modes, which may have adverse environmental consequences. To address riders’ safety concern, encouraging mode switch might be an effective temporary solution, but long-range planning and transportation policies are also needed. For example, providing and maintaining adequate streetlight in the neighborhoods and creating mixed-use streets that are welcoming to pedestrians and bikers. If such safety issues can be properly addressed, alternative on-demand modes (e.g., bike-sharing or scooter-sharing) might be more suitable to meet the needs of these riders, given the fact that Class 2’s trip distance were relatively short. We recommend that future TIMOD pilots should explore these alternatives.
Riders in Class 3 were more likely to be those who faced mobility challenges in travel. On one hand, they lacked access to personal vehicles and previously relied on buses to access to/egress from the Light Rail. On the other hand, they had greater needs to travel to/from places that were hard to access without a personal vehicle. In addition, this class consists of a higher percentage of racial minorities. These findings suggested that Via to Transit provided a more convenient and faster first-mile/last-mile solution for riders in Class 3. Furthermore, Via to Transit expanded the places that they could access beyond corridors along the bus lines, although admittedly Via to Transit trips were still bounded by the service area boundary that KCM designated. However, Via to Transit service directly took riders away from existing bus lines in the service areas as it provided a much more convenient service. When implementing future TIMOD programs, transit agencies should investigate ways to better design and deploy TIMOD so that the newly provided services can better fill in the gaps of existing bus transit, and the comparative advantages of both bus and on-demand modes can be realized.
These empirical results provide timely insights for transit agencies that are exploring new shared mobility options to supplement traditional fixed-route transit. However, because the dataset collected from the transit agency was primarily focused on the first-mile/last-mile travel, it is not sufficient for gaining a more general understanding of TIMOD’s impacts on riders’ travel behavior. Future research should consider designing a more comprehensive rider survey, and perhaps employing travel logs, to fill in the remaining gaps. A more comprehensive rider survey can also help better understand riders’ price sensitivity to TIMOD services. Furthermore, future data collection and analysis should include TIMOD programs that serve other trip purposes/destinations in addition to access/egress to rail transit stations. For example, it is conceivable that TIMOD can replace an entire low-efficiency bus route or high-cost paratransit services. Similarly, transit agencies can greatly benefit from research that comparatively examines multiple TIMOD pilots implemented in different cities and evaluates various design and implementation strategies characterized by on-demand mode, incentive amount and structure, and service integration scheme. A broader understanding of how different TIMOD programs may generate different efficiency and equity outcomes will be essential for transit agencies to develop their programs to best serve the targeted population groups.
Conclusion
This work is one of the first studies that use methods beyond simple descriptive statistics to evaluate riders’ responses to a completed TIMOD pilot. Employing LCA on survey data collected from riders of the Via to Transit program serving several light rail station areas in the Seattle region, the study revealed transportation policy trade-offs for each of the three latent rider classes identified. We found that the TIMOD service in Seattle converted some riders who previously used private cars or ride-hailing to a public transit service, provided a safer mobility option for those who used to be pedestrians and bikers, and made accessing Light Rail stations more convenient for those who previously relied on the bus.
Given the findings that TIMOD service impacted the travel behavior of different rider groups and benefited them in different ways, transit agencies must clearly define their policy goals before designing and implementing their TIMOD programs. This requires an in-depth understanding of the socio-demographic and built-environment characteristics of the areas the programs intend to serve. Transit agencies should also actively engage with riders to better understand their travel needs and barriers.
The empirical research presented in this paper focused on a TIMOD pilot designed to serve the first-mile/last-mile travel of light rail riders in the Seattle region, and therefore the insights provided here, while timely and informative, are far from being sufficient to support decision-makings for different kinds of TIMOD programs. Future research must aim at achieving a more general understanding of TIMOD’s likely impacts on population groups in diverse contexts. It will necessitate many studies of TIMOD programs designed to serve different trip purposes, implemented in different cities, and operated by various mobility service providers.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 803 KB)
Author contributions
Conceptualization: QS, YW; Data curation: QS, YW; Software: YW; Methodology: QS, YW; Formal analysis and investigation: QS, YW; Writing - Original Draft: QS, YW; Writing - Review & Editing: QS, YW; Visualization: YW; Project administration: QS, YW; Supervision: QS
Declarations
Conflict of interest
The authors declare that they have no conflict of interest.
1 Except for late nights and early mornings.
2 Based on Gifford et al. (2021), the survey respondents are representative of Via to Transit riders in the sense that the survey was distributed to all of them, but the responses indicate some over-representation of frequent riders. In addition, comparing the socio-demographic characteristics of the survey respondents to those of all transit riders in the area shown in the results of a pre-Via intercept survey, the youth, people of colors, and low-income population are slightly underrepresented in the survey, but the survey still captures quite a large proportion of these groups (for example, 42% of all respondents are people of colors).
3 This was obtained by joining the unique ID of the survey data to Via to Transit trip data. Since trip purpose information was not available for each trip, we were not able to know whether the most frequent travel location was the rider’s home, workplace, favorite restaurants, or other places. The only thing we knew for sure was that this was one end (either origin or destination) of the Via to Transit trip (the other end is the Light Rail station), and this was the location that the riders most traveled to.
4 The algorithm of LCA is sensitive to the initialization. We therefore had ‘poLCA’ package re-run the model for multiple times, which automated the search for the global, rather than local optimum.
5 Although the exact meaning of the ‘safety’ was not clearly articulated in the survey questionnaire, the authors believe it is more likely to refer to concerns over crime/harassment than traffic safety. One evidence to support this belief is that the KCM learned from community feedback that late-night safety was a prominent issue in the service areas.
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References
Alemi F Circella G Mokhtarian P Handy S Exploring the latent constructs behind the use of ridehailing in California J. Choice Model. 2018 29 47 62 10.1016/j.jocm.2018.08.003
Azimi G Rahimi A Lee M Jin X Mode choice behavior for access and egress connection to transit services Int. J. Transp. Sci. Technol. 2021 10 2 136 155 10.1016/j.ijtst.2020.11.004
Chapman, J., Fox, E.H., Bachman, W., Frank, L.D., Thomas, J., Reyes, A.R.: Smart location database technical documentation and user guide, version 3.0. In: Environmental Protection Agency EPA (2021). https://www.epa.gov/sites/default/files/2021-06/documents/epa_sld_3.0_technicaldocumentationuserguide_may2021.pdf
Circella, G., Alemi, F., Tiedeman, K., Handy, S., & Mokhtarian, P.: The Adoption of Shared Mobility in California and Its Relationship with Other Components of Travel Behavior. UC Davis: National Center for Sustainable Transportation (2018). Retrieved from https://escholarship.org/uc/item/1kq5d07p
Clewlow, R.R., Mishra, G.S.: Disruptive transportation: The adoption, utilization, and impacts of ride-hailing in the United States. In: Institute of Transportation Studies, University of California, Davis (Issue October) (2017). https://escholarship.org/uc/item/82w2z91j
Diao M Kong H Zhao J Impacts of transportation network companies on urban mobility Nature Sustainability 2021 10.1038/s41893-020-00678-z
Feigon, S., Murphy, C.: Broadening understanding of the interplay between public transit, shared mobility, and personal automobiles. In: Broadening Understanding of the Interplay Between Public Transit, Shared Mobility, and Personal Automobiles (2018). 10.17226/24996
Gifford, C., Chazanow, A., Hallenbeck, M.E.: Mobility on demand sandbox demonstration: Puget sound first/last mile partnership with via, final report. In: Federal Transit Administration, U.S. Department of Transportation (2021). 10.21949/1520669
Grahn R Harper CD Hendrickson C Qian Z Matthews HS Socioeconomic and usage characteristics of transportation network company (TNC) riders Transportation 2020 47 6 3047 3067 10.1007/s11116-019-09989-3
Grellier, P.: Mobility on demand (MOD) sandbox demonstration : Limited access connections, final report. In: Federal Transit Administration, U.S. Department of Transportation (2020). 10.21949/1518350
Hall JD Palsson C Price J Is Uber a substitute or complement for public transit? J. Urban Econ. 2018 108 36 50 10.1016/j.jue.2018.09.003
Henao A Marshall WE The impact of ride-hailing on vehicle miles traveled Transportation 2018 46 6 2173 2194 10.1007/s11116-018-9923-2
King County Metro.: Ride2 Fact Sheet (2020). https://kingcounty.gov/~/media/depts/metro/accountability/reports/2020/ride2-summary-report-03-02-20.pdf
King County Metro.: Innovative Mobility Program—Programs & Projects—King County Metro Transit—King County Metro (2022). https://kingcounty.gov/depts/transportation/metro/programs-projects/innovation-technology/innovative-mobility.aspx
Lee Y Lee B What’s eating public transit in the United States? Reasons for declining transit ridership in the 2010s Transp. Res. Part A Policy Pract. 2022 157 126 143 10.1016/j.tra.2022.01.002
Lee Y Chen GY-H Circella G Mokhtarian PL Substitution or complementarity? A latent-class cluster analysis of ridehailing impacts on the use of other travel modes in three southern U.S. cities Transp. Res. Part D Transp. Environ. 2022 104 103167 10.1016/j.trd.2021.103167
Manville M Taylor B Blumenberg E Transit in the 2000s: Where does it stand and where is it headed? J. Public Transp. 2018 21 1 104 118 10.5038/2375-0901.21.1.11
Miller, S., Huang, E., Sullivan, M., Shavit, A.: Mobility on demand (MOD) sandbox demonstration: LA metro first/ last mile partnership with via. In: Federal Transit Administration, U.S. Department of Transportation (2021). 10.21949/1520687
Moudon AV Plaut PO Shach-Pinsly D Epilogue, looking into near future of information and communication technology–enabled travel Digital Social Networks and Travel Behaviour in Urban Environments 2020 Routledge 221 229
O’Sullivan A Urban economics 2012 8 New York McGraw-Hill/Irwin
Shen Q Wang Y Gifford C Exploring partnership between transit agency and shared mobility company: An incentive program for app-based carpooling Transportation 2021 10.1007/s11116-020-10140-w
Tirachini A Ride-hailing, travel behaviour and sustainable mobility: An international review Transportation 2020 47 4 2011 2047 10.1007/s11116-019-10070-2
Tirachini A Chaniotakis E Abouelela M Antoniou C The sustainability of shared mobility: Can a platform for shared rides reduce motorized traffic in cities? Transp. Res. Part C Emerging Technol. 2020 117 102707 10.1016/j.trc.2020.102707
Vermunt JK Magidson J Latent class analysis Sage Encycl. Soc. Sci. Res. Methods 2004 2 549 553
Vij A Ryan S Sampson S Harris S Consumer preferences for mobility-as-a-service (MaaS) in Australia Transp. Res. Part C Emerging Technol. 2020 117 102699 10.1016/j.trc.2020.102699
Wang X Yan X Zhao X Cao Z Identifying latent shared mobility preference segments in low-income communities: Ride-hailing, fixed-route bus, and mobility-on-demand transit Travel Behav. Soc. 2022 26 134 142 10.1016/j.tbs.2021.09.011
Watkins, K., McDonald, N., Ruth, S., Williams, B.: Transit in the Era of shared mobility. In Southeastern Transportation Research, Innovation, Development and Education Center (STRIDE) (2019). https://stride.ce.ufl.edu/wp-content/uploads/2017/03/STRIDE-Project-G-Final.pdf
Weller BE Bowen NK Faubert SJ Latent class analysis: A guide to best practice J. Black Psychol. 2020 46 4 287 311 10.1177/0095798420930932
Yan X Levine J Zhao X Integrating ridesourcing services with public transit: An evaluation of traveler responses combining revealed and stated preference data Transp. Res. Part C Emerging Technol. 2019 105 683 696 10.1016/j.trc.2018.07.029
Yan X Zhao X Han Y van Hentenryck P Dillahunt T Mobility-on-demand versus fixed-route transit systems: An evaluation of traveler preferences in low-income communities Transp. Res. Part A Policy Pract. 2021 148 481 495 10.1016/j.tra.2021.03.019
Young M Farber S The who, why, and when of Uber and other ride-hailing trips: An examination of a large sample household travel survey Transp. Res. Part A Policy Pract. 2019 119 December 2018 383 392 10.1016/j.tra.2018.11.018
Zgheib N Abou-Zeid M Kaysi I Modeling demand for ridesourcing as feeder for high capacity mass transit systems with an application to the planned Beirut BRT Transp. Res. Part A Policy Pract. 2020 138 70 91 10.1016/j.tra.2020.05.019
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Acta Polit
Acta Politica
0001-6810
1741-1416
Palgrave Macmillan UK London
274
10.1057/s41269-022-00274-3
Original Article
Associative issue ownership in a highly fragmented multiparty context: The Netherlands (2021)
http://orcid.org/0000-0002-6164-2926
van der Meer Tom [email protected]
1Tom van der Meer
is a Professor of Political Science, in particular Legitimacy, Inequality, and Citizenship, at the University of Amsterdam. In 2017 and 2021, he was Co-director of the Dutch Parliamentary Election Study. His main research interests are political trust, electoral behavior, and social capital.
Damstra Alyt 2Alyt Damstra
holds a research position as a Member of the Scientific Staff of the Netherlands Scientific Council for Government Policy (WRR). She is also a Postdoctoral Researcher at the Department of Political Science of the University of Amsterdam. Her research focused on the triangular relationship between the economy, news government, and public opinion.
1 grid.7177.6 0000000084992262 Department of Political Science, University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands
2 grid.7177.6 0000000084992262 Department of Communication Science (University of Amsterdam), Netherlands Scientific Council for Government Policy (WRR), Amsterdam, The Netherlands
8 12 2022
121
15 11 2022
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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Associative issue ownership (AIO) has proven its value in describing issue competition and explaining voting behavior. Yet, it is unclear whether and to what extent AIO also differentiates parties and influences vote choice in highly fragmented, multiparty systems. In such a context, parties must differentiate from many electoral competitors, which makes AIO worth pursuing. At the same time, obtaining unequivocal ownership may be a very difficult endeavor in the face of so many rivals. This paper aims to assess these questions empirically by employing the Dutch Parliamentary Election Study 2021 on a system with 17 elected parties (ENPP = 8). At the aggregate level, we find unequivocal issue ownership for 4 of the 14 issues under study. AIO of most other issues is contested, either by parties with very similar policy positions (within-block competition) or by parties with opposing positions (between-block competition). A final set of issues remain unclaimed. At the individual level, perceptions of issue ownership explain the composition of voters’ party consideration sets (pre-elections) and their actual vote choice (post-elections). These impacts are stronger when voters associate the party with an issue they find important. We conclude that AIO perceptions are an important factor to consider when studying party dynamics and voting behavior in a context of highly fragmented multipartyism.
Supplementary Information
The online version of this article (10.1057/s41269-022-00274-3) contains supplementary material, which is available to authorized users.
Keywords
Issue ownership
Voting behavior
Issue competition
Fixed effects modeling
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pmcIntroduction
Over the past decades, national elections have become increasingly volatile across Western Europe (Mair 2008). For most electorates, socioeconomic orientations have lost much of their predictive power, simultaneously weakening and realigning the connections between parties and citizens (Kriesi et al. 2006). As voters began to choose, party politics has become more competitive and more fragmented (Borman and Golder 2013). Traditional mass and niche parties can no longer rely on a steady base of supporters. Volatility and fragmentation made it more important for parties to differentiate themselves from the pack, but these very same trends simultaneously made it more difficult for them to do so.
Stimulated by its highly proportional electoral system, the Netherlands has been a forerunner in these trends. Since the turbulent elections of 2002, high levels of electoral volatility have remained a permanent feature of Dutch politics. In 2017, more than a quarter of all Lower House seats switched from one party to another. In 2021, the Dutch electorate voted a post-war record of 17 parties (including four new ones) into the 150 seats parliament.1 The effective number of parties remained approximately 8 in both election years.
In a highly competitive environment, political parties have different strategies to appeal to voters. One of these strategies builds on the idea of issue ownership (Van der Brug 2017; Walgrave et al. 2012, 2015) to which political parties have resorted in response to the declining relevance of socioeconomic determinants and the rising importance of issue competition (Van der Brug 2004). At its core, issue ownership theories state that voters link some themes more closely to one party (the issue owner) than to other parties (Petrocik 1996). This might be particularly useful in multiparty systems, where parties compete with ideologically similar parties: “In order to be competitive they [parties] would want to emphasize those issues that help to distinguish them from their direct competitors” (Van der Brug 2017, p. 531). The literature distinguishes between two types of issue ownership: competence and associative issue ownership (AIO; Walgrave et al. 2012). The former emphasizes performative judgements, centered on the question which party has the best reputation in managing an issue according to voters. The latter emphasizes salience, centered on the question which party is most closely tied to an issue, for instance because that theme is most important to them.
AIO has been developed by “comparativists who mainly study multiparty systems” (Van der Brug 2017, pp. 530–531), if only because competence issue ownership (CIO) is a more contested concept in systems that encompass multiple parties that never had government responsibility (the majority of parties in the Netherlands). In these circumstances, competence-based issue ownership approaches would conflate government experience with issue ownership more strongly.
Yet, while AIO theory has proven its value in empirical research, it has mainly been tested in less fragmented multiparty systems. Van der Brug (2004) developed the concept in the Netherlands for six parties across five issues. Lachat (2014) applied the concept in Switzerland for seven parties and six issues. And Walgrave and Lefevere (2017) tested the concept in Belgium for 13 parties (albeit split in 2 separate party systems) and 5 issues. It is unclear whether and to what extent AIO differentiates parties and issues at the macro-level in highly fragmented, crowded party systems. At the micro-level, it is not clear to what extent AIO helps to explain party consideration and vote choice in this specific context.
This paper aims to assess empirically the presence and predictive power of AIO in a highly fragmented multiparty system. Hence, our study covers 14 political parties and 14 political issues in the 2021 parliamentary elections in the Netherlands. We investigate the concept of AIO with three foci: as a trait of issues, as a trait of political parties, and as a determinant of voting behavior. Thereby this paper aims to contribute to the literature in three distinct ways. First, we assess the presence and strength of AIO in a multiparty context across a wide range of issues, in comparison to a large number of electoral competitors. To this end, we propose a more fine-grained measurement, based on the distance between ‘first owning’ and ‘second owning’ parties and on the extent to which ownership perceptions are present across different segments of the electorate. Second, we test the impact of individual issue ownership perceptions in explaining both stages of the two-stage process of voting behavior in multiparty systems: (i) determination of the party consideration set (pre-elections), and (ii) the actual vote choice within these party consideration sets. Earlier studies mainly tested the effects of ownership on vote choice (second stage). Third, we integrate AIO theory with voter perceptions of the most important problems facing society. This informs a tentative understanding of campaign dynamics during the 2021 elections and provides a more specific test of issue ownership theory at the micro-level. Our fixed effects models control for rivaling voter–party connections (ideological proximity; leadership sympathy) and assess the unconditional and conditional effects of AIO on voting behavior.
Theory: issue ownership against the backdrop of volatility and fragmentation
Electoral volatility in the Netherlands
Until the 1960s, during the time of pillarization, Dutch voters exhibited a remarkable level of electoral stability, spurred by their segregation into internally coherent societal systems with their own political party. As these pillars eroded from the 1970s onwards, socioeconomic and demographic traits became less decisive factors predicting vote choice. This culminated in the twenty first century, which consistently saw high levels of electoral volatility. While floating voters have been on the rise across Western Europe (Drummond 2006), the Netherlands stands out from a comparative perspective (Mair 2008). An average of more than 20% of the parliamentary seats changed ownership in each subsequent parliamentary election since 2000, with peaks in 2002 (> 30%) and 2017 (> 25%).
Evidently, context matters. Proportional and multiparty systems facilitate electoral volatility because voters are offered more options (Tavits 2005). This is in line with recent studies that demonstrate how vote switching often takes place between parties that are ideologically close (Van der Meer et al. 2012). The presence of multiple parties with similar worldviews that must compete for electoral support makes vote switching more likely than in two-party systems in which the election campaign is between parties that propagate ideologically opposing programs.
On an individual level, research has pointed to the weakening attachment between parties and voters, due to the declining impact of social cleavages (e.g., Aarts and Thomassen 2008). Increasing volatility can be considered the result of an emancipation process in which voters are no longer bounded by traditional loyalties but instead make independent, informed political choices. Hence, to understand the volatility of party preferences, it is important to bring issues, parties, and candidates into the equation (Dalton 2010).
Issue ownership
Traditionally, voting models have focused on factors such as ideological proximity (e.g., Downs 1957) and party and candidate evaluations (e.g., Hopmann et al. 2010) to explain voting behavior. Against the backdrop of increased electoral volatility, issues attracted scholarly attention as an additional factor influencing vote choice. One central component of this strand of research is the idea of issue ownership, which refers to the fact that specific political parties are, in voters’ minds, identified with specific policy issues (Van der Brug 2004; Walgrave et al. 2015). The party most strongly linked to an issue is said to ‘own’ it and may greatly benefit from the salience of this issue during an election campaign, as perceived issue ownership allows it to stand out in comparison to potential rivals.
Following priming theory (Iyengar and Kinder 1987), highly salient issues are expected to be most central in voters’ considerations when evaluating political actors. When citizens link an issue to a specific party and perceive this party as the legitimate owner, they are more likely to vote for this party at the ballot box (Geers and Bos 2017). Issue ownership becomes a strategic asset for parties, particularly when their owned issues become salient in the run-up to elections (Budge 2015; Damstra et al. 2021). Parties have a strong incentive to focus their campaign efforts on their own ‘owned’ issues, to force their competitors to speak out on these themes, and to sidestep the issues that may benefit their competitors.
The literature distinguishes between two dominant conceptualizations of issue ownership (Walgrave et al. 2012; Van der Brug 2017). The first refers to competence: people link a given issue to a party based on the perceived competence of that party to manage the issue (e.g., Green and Hobolt 2008; Petitpas and Sciarini 2022; Petrocik 1996). In this conceptualization, the party that is considered to be the most capable of handling or resolving a problem of concern by voters is perceived owner of that issue. The second conceptualization is more freely associative. It refers to the spontaneous connection of parties with issues in the minds of voters, regardless of whether voters consider the party most competent (Walgrave et al. 2012, p. 772). Competence and AIO may overlap. Yet, they represent different dimensions of ownership that are independent determinants of voting behavior, not only conceptually but also empirically (Walgrave et al. 2012; Lachat 2014).
AIO is a more appropriate concept in multiparty systems (Van der Brug 2017). Especially in the case of high fragmentation, the opportunities for political parties to gain a reputation of competence on specific policy issues are scarce and skewed. In the Netherlands in 2021, only 6 of the 17 parties elected into parliament have ever been part of a national government coalition. The other eleven parties never had this sort of responsibility, depriving them from the possibility to profile on specific policy dossiers in terms of (proven) competence. In addition, CIO comes with challenges of endogeneity. Due to its motivational component, CIO is as much the result of party preference and vote choice as it is a driver of it (e.g., Stubager 2018; Walgrave et al. 2016). Perceptions of AIO lack this motivational component and are less likely to suffer from endogeneity issues in explanatory models of voting behavior (cf. Lachat 2014). Even without the motivational component, AIO is a strategic benefit to parties, as it enables them to stand out from their rivals. This is even more imperative in an electoral system in which many parties must compete along multiple political dimensions.
Yet, fragmentation makes it hard to achieve undisputed issue ownership. First, while ownership tends to be rather stable over time (e.g., Christensen et al. 2015; Seeberg 2017), especially the associative dimension (Tresch et al. 2015), new parties can emphasize and claim new issues that arise (Walgrave and De Swert 2007). Particularly in multiparty systems, some issues remain de-emphasized, whereas the ownership of other issues is challenged by multiple parties (Green-Pedersen and Mortensen 2010, 2015). Second, as the electoral size of political parties shrinks and as the effective number of parties increases, the classification of parties as issue owners becomes problematic: “In a fragmented party system with six parties, it is very tough for a party to pass the 50-percent threshold” (Walgrave and De Swert 2007). Therefore, we propose a set of criteria to assess the strength of ownership in a fragmentized, multiparty context:(i) the absolute percentage of citizens who associate the issue with a specific party;
(ii) the difference between that percentage of associations and the percentage of citizens associating the issue with the runner-up; and
(iii) the degree to which different subgroups of voters share the same issue-party association.2
Based on these criteria, we are able to identify issues that are convincingly owned by a single party, issues for which ownership is still undecided as multiple parties compete for it, and issues that are not owned at all. Hence, our macro-level analyses on AIO will focus on these three criteria.
The impact of issue ownership on voting behavior
Voting behavior in multiparty systems can be characterized as a two-stage process (Oscarsson and Rosema 2019). Voters do not place the same level of consideration on all relevant political parties on election day; rather, they first tend to reduce the number of parties they consider as true alternative options. This subset of parties that voters take into consideration is called a consideration set. The actual vote choice tends to take place within this consideration set. Voting as a two-stage process offers an explanation for the paradox that voters’ political positions can be relatively consistent at the aggregate level over time, even when the actual vote distributions are not (e.g., Van Holsteyn and Den Ridder 2018): most voters switch within blocks of parties that are ideologically close (Van der Meer et al. 2012), i.e., within ideological relatively consistent consideration sets. Variation in issue ownership offers a tentative explanation for the composition of and the choice that is made within consideration sets.
Empirically, voter perceptions of issue ownership influence voting behavior, next to factors such as ideological proximity and general party and candidate sympathy (e.g., Van der Brug 2004; Bélanger and Meguid 2008; Green and Hobolt 2008; Walgrave et al. 2012; Lachat 2014). Any form of issue ownership may help to give profile to political parties, making it more likely not only that they will be elected (Karlsen and Aardal 2016; Petitpas and Sciarini 2022) but also that voters include them in their choice sets. However, these effects are unlikely to be unconditional. Voters will be particularly swayed by ownership of issues that they consider salient (Bélanger and Meguid 2008; Walgrave et al. 2012; Lachat 2014).
Based on these considerations, we expect that the influence of perceived AIO on the probability of a party being included in voters’ consideration sets and on the chance of receiving the vote increases when issue salience is high. In sum, the above considerations can be formalized in the following set of hypotheses:
H1a
Perceptions of AIO increase the probability of being included in voters’ consideration set of political parties.
H1b
This probability is higher when the owned issue is salient to voters.
H2a
Perceptions of AIO increase the probability of voting for a party, given inclusion in the consideration set of political parties.
H2b
This probability is higher when the owned issue is salient to voters.
Data and method
To answer our research questions and test our hypotheses, we rely on panel survey data of the Dutch Parliamentary Election Studies (DPES) 2021 (Sipma et al. 2021). Data were collected during two waves, the first in the months preceding the parliamentary elections of March 17, 2021, and the second in the weeks after the elections. Fieldwork was carried out by I&O Research and CentERdata.
Independent variables
We measure AIO in the pre-electoral wave of the DPES by means of the following questions: ‘What party comes to mind in the first place when you think about [issue]?’ and ‘What party comes to mind in the second place when you think about [issue]?’ The list of 14 parties covers those that were already elected into parliament before 2021 complemented with new party JA21 (for which polls predicted that it would win at least one parliamentary seat in the 2021 elections). In addition, respondents could fill in another party (not from the list), by choosing the open-ended answer category ‘other party.’ The selection of 14 issues is based on an analysis of the most important or prominent policy dossiers in the years preceding the 2021 election, including political as well as valence issues.
The literature does not offer a standardized measure of AIO (Walgrave et al. 2015). Our operationalization, as the spontaneous association of a party to a given issue, is very similar to earlier operationalizations (Walgrave et al. 2012; Lachat 2014).
Moderator
The saliency of issues was measured by means of a question in the post-election wave: ‘What do you think are the most important national problems in our country?’ Respondents could give multiple answers to this open-ended question (which led to a maximum of nine problems per respondent). We recoded the open-ended answers into 24 broad categories (see first column Table 3, “Appendix”). Some but not all of these categories could be connected to the 14 issues included in the issue ownership battery. Models that include issue salience therefore only cover the issues (from the issue ownership question battery) and the categories (of national problems) that can be linked to each other.3
Dependent variables
In line with the two-stage model of voting behavior in multiparty systems, we employ two dependent variables: party consideration set inclusion (pre-election) and vote choice (post-election).
To establish each voter’s party consideration set, we rely on the reported propensity to vote (PTV) for a party (Van der Brug 2004). In line with the model of the process (Oscarsson and Rosema 2019), this question was posed in the pre-election wave and reads: “Would you please indicate on a scale from 1 to 10 how probable it is that you will ever vote for [party]? On this scale, ‘1’ means that you will never vote for this party and ‘10’ means that you will certainly vote for this party sometime.” This question has been raised for the same 14 parties that are included in the issue ownership question battery. PTV measures have various advantages over the categorical measure of vote choice, providing detailed information on utility (Van der Eijk et al. 2006). We use these PTV scores to operationalize the composition of the consideration set along the two common principles behind establishing consideration sets (Oscarsson et al. 1997; Oscarsson and Rosema 2019): the relative gap (the distance between the PTVs of parties in the consideration set should not be too large) and the absolute preference (the non-negativity of PTVs of parties in the consideration set). The procedure proposed by Van Holsteyn and Den Ridder (2018) balances both.4 To be included in respondents’ consideration sets, the party needs to have been assigned the highest PTV by the respondent or one or two steps lower. Inclusion in the consideration set is thus a dichotomous variable for each party. Respondents who report little chance to vote for any of the 14 parties (PTV < 5)5 and respondents who do not differentiate between parties (0 or more than 10 parties in their consideration set) are treated as missing.
The second dependent variable, vote choice, was measured as the reported party choice at the 2021 Lower House election. This question is asked in a straightforward way: “Which party did you vote for in the 2021 parliamentary elections?” We excluded non-voters and voters for parties other than the main 14 on the list from the explanatory analyses.
Control variables
The multivariate models control for rivaling explanations of consideration set inclusion and vote choice. The first is perceived ideological distance between the respondent and the party (cf. Van der Brug 2004; Lachat 2014). We operationalize this ideological distance as the absolute difference between self-placement and the perceived party position on an 11-point left–right scale. The second is party leader sympathy (cf. Van der Brug 2017, p. 534), measured on a scale from 0 (no sympathy) to 10 (complete sympathy). Both questions (perceived positions and leader sympathy) have been asked in the pre-election wave for the same 14 parties mentioned before.
Method
To assess the impact of AIO on consideration set composition and vote choice at the individual level, we rely on fixed effects models. We transposed the data from the wide format in DPES2021 (unique variables for each party) to the long format. In other words, we nest respondent-party dyads (as level 1 observations) in respondents (level 2). By estimating fixed effects models in Stata 14 (employing the xtlogit, fe command), we eliminate the impact of respondent traits and focus on within-respondent variation. This has the advantage of mitigating the statistical noise that occurs in between-person comparisons.
We build up the analyses sequentially. First, we analyze the general impact of perceived ownership unconditionally, i.e., regardless of the salience that respondents attach to these issues. In these models, we include all 14 issues. Next, we specify that model to assess the relevance of issue salience, testing whether perceived ownership of salient issues has an additional explanatory effect. These analyses are blind to the substance of the issues, in order to focus on the overall effects of issue ownership.6
The models of consideration set composition encompass all 14 parties in the standard data set. These 14 parties collected 93.7% of the votes. The models of vote choice do not encompass all 14 parties; rather, for each respondent, we only include the parties that were mentioned as part of the consideration set in the pre-election wave.7 Missing values on any of the variables led to list-wise deletion from the analysis.
Descriptive analyses I: issues and salience
To explore the extent to which issue ownership can be observed in a highly fragmented, multiparty context, we start by examining the essential part of associative ownership: the connection between issues and parties that is made in the minds of voters. In the weeks before the 2021 parliamentary elections, we presented Dutch voters a list of policy issues and asked them to indicate, for each issue, whether they could spontaneously name a political party that they associated with it. Figure 1 displays the degree of ownership per issue. The bars indicate the percentage of voters not having any party association. Issues with many party associations are on the left side of the figure; issues with few party associations at the right.Fig. 1 Percentage of respondents not having any party association per issue
Associative ownership varies greatly across issues. Several issues are frequently linked to a political party: the economy, climate change, and discrimination stand out: less than 15% of the respondents does not connect these issues to a party. On the other end of the scale, we observe the issues for which fewer people have a spontaneous party association. Safety, euthanasia, and housing are still relatively open to party ownership.
However, for ownership to have electoral consequences, the issue at hand must have a certain level of societal relevance. We asked respondents at the time of the 2021 elections what they considered the most important national problems. We recoded this open-ended question into a nominal variable consisting of 24 problem categories (for the complete list, see Table 3 in “Appendix”). Given the focus of the current study, we only use the eleven categories that can be linked to one of the issues examined in the context of party associations. Figure 2 plots the share of respondents mentioning each of these issues, arranged from the issues most often mentioned (left-hand side) to the ones least often mentioned (right-hand side). Climate change stands out in terms of perceived societal relevance, followed by housing, healthcare, and immigration. The high salience of housing is interesting considering that this issue scored ‘lowest’ on party association.Fig. 2 Percentage respondents mentioning each issue as important national problem
Descriptive analyses II: patterns of AIO
To assess the strength of issue-party associations in a fragmented, multiparty context, we look at three distinct features: (i) the absolute association, (ii) the extent to which there is a clear gap between the first issue owner and a challenger, and (iii) the similarity of ownership perceptions among different segments of the electorate. AIO is strongest when many voters associate the party to the issue, when the gap with potential challengers is large, and when ownership perceptions are shared by partisans and non-partisans.
The aggregate data set reports the percentage of respondents associating each of 14 parties with each of 14 issues. We employ exploratory factor analyses (PCA, Varimax rotation) to identify overarching structures behind party–issue associations (i.e., clusters of issues with similar patterns of issue ownership).8 We find four such structures. Figure 3 displays the issues that make up each cluster, together with the parties that score highest on ownership per issue. Remarkably, these clusters align well with the clusters identified in a different context by Seeberg (2017, p. 479).Fig. 3 Percentage of respondents naming party as issue owner, by issue (four clusters)
The first cluster consists of five issues that are mostly associated with parties at the right-hand side of the political spectrum: the economy, the European Union, safety, democracy, and norms and values. As associative owner of these issues, voters most often mention the liberal conservatives (VVD), followed by the Christian-democrats (CDA) and the progressive liberals (D66). In the second cluster, we observe four issues that stem from the socioeconomic sphere: poverty, health care, employment, and housing. Voters connect these issues primarily to economically left-wing parties Labour (PvdA) and the Socialists (SP), followed by their main traditional antagonist on these issues, the liberal–conservatives (VVD). Only two issues make up the third cluster: immigration and discrimination. Voters associate the radical-right populist Freedom Party (PVV) with these themes, followed by the extreme-right Forum for Democracy (FVD). Finally, the fourth cluster consists of three issues that voters mainly link to progressive parties: climate change, euthanasia, and education. Progressive parties most frequently associated with these topics are the Greens (GroenLinks) and the progressive liberals (D66). For euthanasia, however, there is a group of voters that assigns associative ownership to the orthodox Christian parties: the Reformed (SGP) and the ChristianUnion (CU).
To assess the strength of AIO in a fragmented, multiparty context, absolute numbers are not a sufficient indicator. A cut-off point of 50% may be an unlikely threshold (cf. Walgrave and De Swert 2017, who argued this for 6 rather than 14 parties). Hence, we propose an alternative measurement by adopting two additional criteria: the gap in issue associations between the modal party and the runner-up, and the agreement of ownership perceptions across different segments of the electorate.
In the first issue cluster, two issues are owned unequivocally. First, we observe strong ownership by the liberal conservatives (VVD) on the economy. No fewer than 70% of the respondents spontaneously associates the issue with this party, compared to 35% for the runner-up.9 This association is made across groups of voters: even among those who do not consider voting for the VVD, a majority (66%) spontaneously associates the economy with this party. In a similar vein, though less clear-cut, we observe associative ownership by the liberal conservatives on the safety issue: 48% of the respondents spontaneously connects this theme to this party, followed by 26% for the runner-up. However, party preference plays a larger role: among respondents who do not consider voting for the VVD perceived ownership is much lower (38%).
In the second cluster, we find very small differences in party-issue associations. This suggests that there may be latent conflict between parties on the ownership of these issues. Indeed, across these issues, perceived ownership is (much) higher among the actual voters of these parties than among the potential voters and the non-voters.
In the third cluster, we find another clear case of AIO. The immigration issue is strongly owned by the radical-right Freedom Party (PVV). The distance to the runner-up is substantial (55% versus 31%), and the spontaneous association is made by different segments of the electorate, even by respondents who do not consider voting for the PVV (55.4%). By contrast, the issue of discrimination does not work at all as a measure for issue ownership. Response patterns show that different logics are at play.10 Some associate discrimination with a party because it puts the issue on the political agenda as a societal problem; others associate discrimination with a party because of perceived discriminatory rhetoric or policies by that party. Because of this inherent duality, we refrain from using this issue in further analyses.
Finally, in the fourth cluster, we observe strong ownership on climate change. The Greens clearly dominate this issue, the distance to the second owning party is big (68% versus 30%), and ownership perceptions are broadly shared, even by voters who would never consider the Greens (66%).
All in all, AIO exists even in a highly fragmented multiparty context. We only find strong party ownership for 4 of the 13 issues under study (excluding discrimination): the economy and safety (owned by the liberal conservative VVD), immigration (owned by the radical-rightwing PVV), and climate change (owned by the Greens). On the other issues, ownership is not that clear-cut. Finally, ownership of some issues is being contested by electoral rivals. This is most notably for the issues of poverty and health care, where particularly Labour (PvdA) and the Socialists (SP) are in fierce competition.
Explanatory analyses: AIO and voting as a two-stage process
Next, we test to what extent AIO is an electoral boon. Table 1 presents the effects of AIO on the inclusion of 14 parties in voters’ consideration sets. Model 1 shows the linear effect of generic issue ownership: The more issues a party owns in the perception of respondents, the more likely it will be included in these respondents’ consideration sets (b = 0.43). Next to issue ownership, we find a significant negative effect of ideological distance and a positive effect of leadership sympathy. Model 2 replicates model 1, but now only using the subset of ten issues that we could connect reliably to the most important problems facing the Netherlands according to the respondents. The results confirm that AIO has an effect beyond ideological distance and leadership sympathy. This supports Hypothesis 1a. Model 3 adds ownership of salient issues as a determinant. We find that, in addition to the general effect of AIO, being the owner of at least one issue that respondents find salient provides an additional boost to the likelihood of being included in these respondents’ consideration sets (b = 0.43). Model 4 adds the number of salient issues of which parties are the owner. That addition proves to be non-significant (b = − 0.03, ns), suggesting that owning at least one salient issue is all that matters. All in all, we find support for Hypothesis 1b.Table 1 Explaining inclusion of parties in voters’ consideration sets, logistic fixed effect models (Stata: xtlogit, fe)
Model 1 Model 2 Model 3 Model 4
b s.e. Significance b s.e. Significance b s.e. Significance b s.e. Significance
Issues owned (full set) 0.43 0.01 ***
Issues owned (subset) 0.56 0.01 *** 0.51 0.02 *** 0.51 0.02 ***
Issue owner of salient problem (dichotomous) 0.43 0.05 *** 0.46 0.11 ***
Issue owner of salient problems (number) − 0.03 0.09
Left–right distance − 0.42 0.01 *** − 0.43 0.01 *** − 0.43 0.01 *** − 0.43 0.01 ***
Party leader sympathy 0.46 0.01 *** 0.48 0.01 *** 0.49 0.01 *** 0.49 0.01 ***
n(observations) 30,713 30,610 23,196 23,196
n(respondents) 2688 2677 1996 1996
*p < .05; **p < .01; ***p < .001
Next, we turn to the second step of the voting process in fragmented multiparty systems (see Table 2): vote choice, given parties’ inclusion in respondents’ consideration sets. Again, the control variables have consistently large and significant effects. In line with the literature, leadership sympathy has a particularly strong effect in this second stage of the voting process (b = 0.82 in model 5). It also fits the interpretation of the Dutch elections according to political commentators, who emphasized that sitting Prime Minister (and VVD party leader) Mark Rutte primarily campaigned on the theme of leadership and was challenged on precisely that theme by runner-up D66 party leader (and sitting Minister) Sigrid Kaag.Table 2 Explaining party choice given consideration set, logistic fixed effect models (Stata: xtlogit, fe)
Model 5 Model 6 Model 7 Model 8
b s.e. Significance b s.e. Significance b s.e. Significance b s.e. Significance
Issues owned (full set) 0.17 0.02 ***
Issues owned (subset) 0.18 0.02 *** 0.5 0.03 *** 0.14 0.03 ***
Issue owner of salient problem (dichotomous) 0.24 0.09 ** 0.19 0.16
Issue owner of salient problems (number) 0.05 0.11
Left–right distance − 0.23 0.03 *** − 0.24 0.03 *** − 0.25 0.03 *** − 0.25 0.03 ***
Party leader sympathy 0.82 0.04 *** 0.85 0.04 *** 0.85 0.04 *** 0.85 0.04 ***
n(observations) 6403 6379 4919 4919
n(respondents) 1794 1787 1384 1384
*p < .05; **p < .01; ***p < .001
The conclusions are similar to the ones related to Table 1. We find significant effects of issue ownership, regardless of the salience of these issues. Based on the full set of issues, AIO has a significant, positive effect in model 5 (b = 0.17); and so does issue ownership of the subset of ten issues in model 6 (b = 0.18). This supports Hypothesis 2a. Owning at least one salient issue has an additional positive effect on vote choice, according to model 7 (b = 0.24). Yet, again, this effect is not linear: The addition of a linear effect in model 8 is not significant (b = 0.05, ns) and does not improve the model fit. All in all, we find support for Hypothesis 2b.11
Discussion
This paper aimed to assess empirically to what extent AIO (Walgrave et al 2012; Van der Brug 2017) is a useful concept in a highly fragmented, multiparty context. On the one hand, obtaining or maintaining issue ownership may be a way for parties to differentiate themselves from their rivals. On the other hand, unequivocal ownership may be nigh impossible in the face of so many competitors. To this end, we focused on the 2021 parliamentary elections in the Netherlands, which resulted in a severely scattered parliament of 17 parties (including four new ones). The rather extreme Dutch case functions as a Petri dish. Precisely because of its high proportionality and large (effective) number of political parties, it allows us to isolate mechanisms behind party consideration and voting behavior. Particularly, it shows the use of approaching voting behavior as a two-stage process, and the value of AIO when there are many parties that compete along many issues on many dimensions.
First, we explored the presence and strength of AIO on the aggregate level by looking into patterns of issue–party associations made by citizens. These analyses confirm that AIO exists, even in the face of severe fragmentation. We identified four issues on which a single party has established undisputed ownership: economy, safety, immigration, and climate change. Partisanship plays a very modest role on issue ownership perceptions on these issues. On other issues, AIO is not (yet) decided, as multiple parties are still in fierce competition and ownership perceptions are more strongly related to partisanship, although in different ways. In some cases, parties that compete for ownership represent opposing views and opposing electoral blocks on the issue at hand (such as progressive versus conservative positions on ethical issues). Ownership effects may hold, though primarily within party blocks and corresponding subsets of the electorate. In other cases, the competing parties come from ideologically congruent party blocks (such as the socialists and the social democrats), that likely share the same consideration sets of voters. Finally, we observe a set of issues that are simply not owned yet. Housing is a particularly intriguing one: although many citizens consider this issue highly relevant, it has not yet been claimed.
Second, we examined the applicability of AIO by its impact on individual vote choice. To account for the fragmentized, multiparty context, we adopted the idea of voting as a two-stage process (cf. Oscarsson and Rosema 2019): the determination of a consideration set, followed by actual vote choice. The analyses indicate that AIO matters. Above and beyond the impact of ideological distance and leadership sympathy, perceived issue ownership has a positive effect on voting behavior (particularly when the issue is salient). These effects are not limited to the second stage (the final vote, given the consideration set composition) but also apply to the first stage (composition of the consideration set). This finding challenges a silent assumption in models of voting behavior. All in all, we conclude that even in a highly fragmented, multiparty system, the associative dimension of issue ownership is a relevant factor to consider when studying party dynamics and voting behavior.
There are some implications to employing AIO in a fragmented multiparty setting. First, absolute percentages do not suffice to assess the strength of AIO, even though we found similar clusters of issue associations as in comparative studies (cf. Seeberg 2017). We therefore proposed a measurement that also looks at (i) the discrepancy between the parties that are most associated with an issue, and the runner-up and (ii) the breadth of the electoral support base. This allowed us to obtain a more fine-grained understanding of patterns of issue ownership. We distinguish between issues with undisputed party ownership, with contested but not crystallized issue ownership, and with no ownership. Second, we show that AIO has relevant explanatory power at both stages of the voting process. In multiparty systems, it is important to distinguish between (i) inclusion into a consideration set, and (ii) actual vote choice (Oscarsson and Rosema 2019). AIO explains both elements, thereby contributing to competition within as well as between blocks of parties.
Unfortunately, our analyses could not capture time dynamics beyond a single election to assess the stability of composition sets (Rekker and Rosema 2019) and perceived issue ownership (Christensen et al. 2015; Seeberg 2017). Although AIO perceptions tend to be rather stable over time (Tresch et al. 2015), they are not set in stone, especially not when issues are contested. Because issue salience has a moderating impact and can vary greatly over time, a long-term perspective would have allowed us to isolate the underlying mechanisms driving the effects of AIO. This is particularly relevant for three reasons. First, a longitudinal perspective enables a better understanding of the dynamics between parties’ campaign strategies, media attention, and perceived issue ownership, as all face stronger constraints in a fragmented multiparty setting. Second, a long-term panel perspective will offer more clarity on the contested causal relationship between issue ownership and voting behavior. Third, our data stem from the first months of 2021, amidst the severe COVID-19 pandemic. The pandemic affected the Dutch election campaign, not least because Prime Minister (and VVD party leader) Mark Rutte, repeatedly sought to reduce televised debates to discussions about leadership and crisis management. Consequently, our findings that AIO matters in fragmented multiparty systems may even have been a conservative estimation of the dynamics of issue competition under more regular circumstances.
Supplementary Information
Below is the link to the electronic supplementary material. (DOCX 16 kb)
Appendix
See Table 3.Table 3 Connection between issues related to salience and ownership
Most important national problem Issue: ownership party No match
V061–9 N46–73
1 Economy/financial situation Economy 1
2 Social security Poverty 1
3 Politics X
4 Crime Security
5 Defense X
6 Healthcare Healthcare
7 Education Education
8 Income/price levels/taxes Economy 2
9 Employment Employment
10 Traffic/mobility X
11 Housing Housing
12 Environment Climate change
13 Population X
14 Minorities Immigration 1
15 Norms and values Norms and values
16 Media X
17 European integration X
18 Inequality/poverty Poverty 2
19 Intolerance/discrimination Discrimination
20 Foreign policy/international security X
21 Regulation/big government X
22 Polarization/dividedness X
23 Immigration Immigration 2
24 Corona X
There are two ways in which we might want to measure the number of respondents that mention the economy as the most important national problem. First a narrow operationalization, covering only those respondents who gave an answer that was grouped under the heading ‘economy/financial situation’ (variable: mip_economy1). Second, a broader operationalization, covering those respondents whose answers were categorized as ‘economy/financial situation’ and/or ‘income/price levels/taxes’ (variable: mip_economy2). Similarly, mip_poverty1 refers to those respondents whose answers were grouped under ‘inequality/poverty’ (more narrow operationalization) and mip_poverty2 refers to those respondents whose answers were grouped under ‘inequality/poverty’ and/or ‘social security’ (broader operationalization).
Declarations
Conflict of interest
The authors hereby state that there is no conflict of interest—social, financial, or otherwise—with regards to this manuscript.
1 After the elections, 3 additional parties split, leading to 20 parties in parliament.
2 For each party, we distinguish three electoral segments: voters, potential voters, and non-voters. Voters are those who voted for [party] during the 2021 elections. Potential voters did not vote for [party] during these elections but score at least a 6 on the PTV-scale for [party] that runs from 1 to 10 (thus above absolute midpoint). Non-voters did not vote for [party] and score a 5 or lower on the PTV-scale for [party]. See also Damstra and van der Meer (2021).
3 Some issues mentioned by respondents are not part of this study: politics, defense, traffic/mobility, population, media, European integration, foreign policy/international security, regulation/big government, polarization/dividedness, and corona. Similarly, some issues in the issue ownership battery are not included in the multivariate analyses on the role of salience: euthanasia, European Union, and democracy.
4 To assess the robustness of this approach, we employed two alternative operationalizations of the consideration set measure. The first is based on simple absolute scores: parties are included when scoring a higher PTV than the absolute midpoint (i.e., > 5.5) (cf. Petitpas and Sciarini 2022). The second is based on the largest gap size in PTV scores (cf. Oscarsson et al. 1998). Respondents’ PTV scores are ranked, the maximum gap between scores serves as the cut-off point: those parties (or party) above the gap are included in the consideration set, those parties (or party) below the gap are not. Crucially, our findings are robust to these alternative measures in direction, significance, and size.
5 This specific demand excludes 0.6% of the respondents. Half of these did not vote in 2017; half not in 2021. Their exclusion did not affect any of our findings substantively.
6 Alternative options—including 10 separate interaction effects in a single model; or modeling 10 interaction effects separately—would offer identification problems and does not test the overarching effects of issue ownership.
7 In a very small share of the cases, the respondent reported voting for a party in the post-election wave that had not been included in the consideration set in the pre-election wave. Those cases dropped out of the analysis of vote choice, as they lacked within-person variation in the outcome variable.
8 The EFA provides four components that explain more than the average constituting variable (Eigen values higher than 1). Together these four explain 85.2% of all variance (after Varimax rotation respectively 33.8%, 23.3%, 15.6%, and 12.4%). Some issues load on multiple clusters: Employment and housing load not only on the second cluster but also weakly on the first; education not only on the fourth but also more weakly on the first. The data structure is very robust. EFA with Oblimin rotation and correspondence analysis both led to very substantially similar results.
9 The Christian-democrats often take a runner-up position in relation to the issues owned by the liberal conservatives, their biggest electoral rival.
10 On all other issues, party supporters associate their party more strongly with a theme; for the issue of discrimination, this is not evident.
11 Additional analyses confirm the finding of Lachat (2014) that the effect of issue ownership is stronger when the ideological distance to the party is smaller. We find this effect not only on party choice but also on consideration set composition.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Aarts K Thomassen J Dutch voters and the changing party space 1989–2006 Acta Politica 2008 43 2–3 203 234 10.1057/ap.2008.6
Bélanger É Meguid BM Issue salience, issue ownership, and issue-based vote choice Electoral Studies 2008 27 3 477 491 10.1016/j.electstud.2008.01.001
Borman N-C Golder M Democratic Electoral Systems around the world, 1946–2011 Electoral Studies 2013 32 360 369 10.1016/j.electstud.2013.01.005
Budge I Issue emphases, saliency theory and issue ownership: A historical and conceptual analysis West European Politics 2015 38 4 761 777 10.1080/01402382.2015.1039374
Christensen L Dahlberg S Martinsson J Changes and fluctuations in issue ownership: The case of Sweden, 1979–2010 Scandinavian Political Studies 2015 38 2 137 157 10.1111/1467-9477.12040
Dalton RJ LeDuc L Niemi RG Norris P Ideology, partisanship, and democratic development Comparing democracies 3: Elections and voting in the 21st century 2010 London SAGE Publications 143 164
Damstra A Jacobs L Boukes M Vliegenthart R The impact of immigration news on anti-immigrant party support: Unpacking agenda-setting and issue ownership effects over time Journal of Elections, Public Opinion and Parties 2021 31 1 97 118 10.1080/17457289.2019.1607863
Damstra, A. and T.W.G. van der Meer (2021) De rol van thema’s: issue ownership van partijen. In: Versplinterde vertegenwoordiging: Nationaal Kiezersonderzoek, ed. T. Sipma, M. Lubbers, T.W.G. van der Meer, N. Spierings, and K. Jacobs 76–84. https://www.dpes.nl/
Drummond A Electoral volatility and party decline in Western democracies: 1970–1995 Political Studies 2006 54 3 628 647 10.1111/j.1467-9248.2006.00617.x
Geers S Bos L Priming issues, party visibility, and party evaluations: The impact on vote switching Political Communication 2017 34 3 344 366 10.1080/10584609.2016.1201179
Green J Hobolt SB Owning the issue agenda: Party strategies and vote choices in British elections Electoral Studies 2008 27 3 460 476 10.1016/j.electstud.2008.02.003
Green-Pedersen C Mortensen PB Who sets the agenda and who responds to it in the Danish Parliament? A new model of issue competition and agenda-setting European Journal of Political Research 2010 49 2 257 281 10.1111/j.1475-6765.2009.01897.x
Green-Pedersen C Mortensen PB Avoidance and engagement: Issue competition in multiparty systems Political Studies 2015 63 4 747 764 10.1111/1467-9248.12121
Hopmann DN Vliegenthart R De Vreese C Albæk E Effects of election news coverage: How visibility and tone influence party choice Political Communication 2010 27 4 389 405 10.1080/10584609.2010.516798
Iyengar S Kinder DR News that matters: Television and American opinion 1987 Chicago University of Chicago Press
Kriesi H Grande E Lachat R Dolezal M Bornschier S Frey T Globalization and the transformation of the national political space: Six European countries compared European Journal of Political Research 2006 45 6 921 956 10.1111/j.1475-6765.2006.00644.x
Lachat R Issue ownership and the vote: The effects of associative and competence ownership on issue voting Swiss Political Science Review 2014 20 4 727 740 10.1111/spsr.12121
Mair P Electoral volatility and the Dutch party system: A comparative perspective Acta Politica 2008 43 2 235 253 10.1057/ap.2008.1
Oscarsson H Rosema M Consideration set models of electoral choice: Theory, method, and application Electoral Studies 2019 57 256 262 10.1016/j.electstud.2018.08.003
Oscarsson, H., M. Gilljam, and D. Granberg. 1997. The concept of party set: A viable approach or just another way to slice the same cheese? In Paper presented at the annual meeting of the Swedish Political Science Association, 1997, Uppsala, Sweden.
Petitpas A Sciarini P Competence issue ownership, issue positions and the vote for the Greens and the Social Democrats Swiss Political Science Review 2022 28 230 253 10.1111/spsr.12509
Petrocik JR Issue ownership in presidential elections, with a 1980 case study American Journal of Political Science 1996 40 3 825 850 10.2307/2111797
Rekker R Rosema M How (often) do voters change their consideration sets? Electoral Studies 2019 57 284 293 10.1016/j.electstud.2018.08.006
Seeberg HB How stable is political parties’ issue ownership? A cross-time, cross-national analysis Political Studies 2017 65 2 475 492 10.1177/0032321716650224
Sipma T Jacobs K Lubbers M Spierings N Van der Meer TWG Dutch Parliamentary Election Study 2021 (DPES/NKO 2021): Research description and codebook 2021 Nijmegen SKON
Stubager R What is issue ownership and how should we measure it? Political Behavior 2018 40 2 345 370 10.1007/s11109-017-9403-y
Tavits M The development of stable party support: Electoral dynamics in post-Communist Europe American Journal of Political Science 2005 49 2 283 298 10.1111/j.0092-5853.2005.00123.x
Tresch A Lefevere J Walgrave S ‘Steal me if you can!’ The impact of campaign messages on associative issue ownership Party Politics 2015 21 2 198 208 10.1177/1354068812472576
Van der Brug W Issue ownership and party choice Electoral Studies 2004 23 2 209 233 10.1016/S0261-3794(02)00061-6
Van der Brug W Arzheimer K Evans J Lewis-Beck MS Issue ownership: An ambiguous concept The SAGE handbook of electoral behaviour 2017 London SAGE Publications 521 537
Van der Eijk C Van der Brug W Kroh M Franklin M Rethinking the dependent variable in voting behavior: On the measurement and analysis of electoral utilities Electoral Studies 2006 25 424 447 10.1016/j.electstud.2005.06.012
Van der Meer T Lubbe R Van Elsas E Elff M Van der Brug W Bounded volatility in the Dutch electoral battlefield: A panel study on the structure of changing vote intentions in the Netherlands during 2006–2010 Acta Politica 2012 47 4 333 355 10.1057/ap.2012.5
Van Holsteyn JJ Den Ridder J Verandering in continuïteit: Houdingen en gedragingen van Nederlandse kiezers Bestuurskunde 2008 3 39 46
Walgrave S De Swert K Where Does Issue Ownership Come From? From the Party or from the Media? Issue-party Identifications in Belgium, 1991–2005 Press/Politics 2007 12 4 778 796
Walgrave S Lefevere J Long-term associative issue ownership change: A panel study in Belgium Journal of Elections, Public Opinion and Parties 2017 27 4 484 502 10.1080/17457289.2017.1285305
Walgrave S Lefevere J Tresch A The associative dimension of issue ownership Public Opinion Quarterly 2012 76 4 771 782 10.1093/poq/nfs023
Walgrave S Tresch A Lefevere J The conceptualisation and measurement of issue ownership West European Politics 2015 38 4 778 796 10.1080/01402382.2015.1039381
Walgrave S Van Camp K Lefevere J Tresch A Measuring issue ownership with survey questions. A question wording experiment Electoral Studies 2016 42 90 299 10.1016/j.electstud.2015.12.001
| 0 | PMC9734719 | NO-CC CODE | 2022-12-14 23:28:30 | no | Acta Polit. 2022 Dec 8;:1-21 | utf-8 | null | null | null | oa_other |
==== Front
J Autism Dev Disord
J Autism Dev Disord
Journal of Autism and Developmental Disorders
0162-3257
1573-3432
Springer US New York
36484965
5859
10.1007/s10803-022-05859-7
Original Paper
The Impact of Emergency Pandemic HCBS Funding on the Continuity and Security of People with Intellectual and Developmental Disabilities
http://orcid.org/0000-0002-7150-4041
Friedman Carli [email protected]
CQL | The Council on Quality and Leadership, 100 West Road, Suite 300, Towson, MD 21204 USA
9 12 2022
110
30 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
This study’s aim was to examine the impact of pandemic emergency Home- and Community-Based Services (HCBS) payments on the continuity and security of people with intellectual and developmental disabilities (IDD). Using a multilevel logistic regression, we analyzed secondary Personal Outcome Measures interviews from 738 people with IDD (March 2020 through April 2022), and state pandemic emergency HCBS payment data from 16 states. The odds of people with IDD experiencing continuity and security during the pandemic increased by 3% for every 1% states increased their payment rates, and by 398% when states offered retainer payments. Increased reimbursement rates and retainer payments can help providers maintain operations and promote the continuity and security of people with IDD.
Keywords
Medicaid Home- and Community-Based Services (HCBS)
COVID-19 pandemic
People with intellectual and developmental disabilities
Reimbursement rates
Personal outcomes
==== Body
pmcIntroduction
Continuity and security includes people’s basic needs being met and people having the economy security to plan their lives and futures (security), and people having minimal negative change and disruption in their lives that is outside of their control (continuity; The Council on Quality and Leadership, 2017). People’s continuity and security are often related as changes in people’s lives may have economic consequences, among others; economy security can also help people prevent or recover from changes or disruption in their lives. In fact, while instability adversely impacts people with intellectual and developmental disabilities’ [IDD’s (including autism)] mental health, continuity and security positively impact people with IDD’s mental and behavioral health, and quality of life (American Psychological Association, 2020; Centers for Disease Control and Prevention, 2020; Friedman, 2022b). While the COVID-19 pandemic impacted all peoples’ lives, with most people feeling less secure as a result of the pandemic (American Psychological Association, 2020), people with IDD were particularly vulnerable. Not only are people with IDD more likely to contract and die of COVID-19 (Centers for Disease Control, 2022), they also have less economic security and are more likely to live in poverty than nondisabled people (Pinilla-Roncancio & Alkire, 2021).
In addition to being higher risk for infection and mortality, the pandemic had a wide ranging impact on the lives of people with IDD. People with IDD were more isolated during the pandemic as a result of sheltering-in-place and lockdown restrictions due to the threat COVID-19 represented to them and/or because they lived in congregate settings where COVID-19 spreads rapidly (ANCOR Foundation, & United Cerebral Palsy, 2021; Bradley, 2020; Embregts et al., 2022; Lund et al., 2020; Lunsky et al., 2022; Pettinicchio et al., 2021; Scheffers et al., 2021). In addition to increased loneliness, people with IDD are more stressed, anxious, bored, and depressed during the pandemic (Desroches et al., 2021; Embregts et al., 2022; Hewitt et al., 2020; Lund et al., 2020; Lunsky et al., 2022; Pettinicchio et al., 2021; Scheffers et al., 2021). In fact, given the high infection and mortality rates among this population, the pandemic was likely especially traumatic for people with IDD as they lost friends, housemates, and self-advocacy leaders to COVID-19 (Lund et al., 2020).
In addition to the negative impact on people with IDD’s mental and physical health, the pandemic resulted in many people with IDD losing their jobs, having their work hours reduced, or having their day programs close (Bradley, 2020). Moreover, even when lockdown restrictions were lifted, many people with IDD had fewer opportunities to participate in their communities due to politices and practices that were not designed with their needs in mind (e.g., masking, vaccine prioritization, etc.), and staff shortages (Embregts et al., 2022). In fact, many people with IDD have experienced disrupted routines and services, rapid support staff turnover, a lack of support availability, and decreased quality of support during the pandemic (ANCOR Foundation, & United Cerebral Palsy, 2021; Bradley, 2020; Embregts et al., 2022; Lund et al., 2020; Scheffers et al., 2021).
People with IDD’s “dependence on [human service] organization[s] often links changes in people’s lives to organizational changes” (The Council on Quality and Leadership, 2017, p. 25). The COVID-19 pandemic negatively impacted and disrupted the provision of Home- and Community-Based Services (HCBS), upon which many people with IDD depend as an alternative to institutional care (Centers for Medicare and Medicaid Services, 2020). HCBS provides wrap-around community-based services and supports to promote the community living of people with IDD. In addition to attending to acute care needs, such as health and safety, HCBS also often includes services that promote the continuity and security, quality of life, and community integration of people with IDD, such as residential supports, assistive technology, and employment supports.
As a result of the pandemic, many HCBS service providers are struggling to function and adequately support people with IDD. For example, during the COVID-19 pandemic, direct support professional (DSP) turnover increased significant as a result of DSPs’ fears of infection, increased workloads, and DSPs needing to take care of their own family members (ANCOR Foundation, & United Cerebral Palsy, 2021; Luterman, 2020). Unfortunately, DSP turnover hinders HCBS provision and negatively impacts people with IDD’s health, safety, and quality of life (Friedman, 2018a, 2021c). HCBS providers have been negatively impacted by increased DSP turnover and staff shortages, government orders closing some service lines/types (e.g., day services), and a lack of resources and funding (ANCOR Foundation, & United Cerebral Palsy, 2021; Avalere Health, 2020). These difficulties intensified the struggles of a system that was already underfunded and fractured—prior to the pandemic, the average provider only had enough “cash on hand to maintain operations” for a single month (ANCOR Foundation, & United Cerebral Palsy, 2021, p. 6). During the pandemic, 32% of IDD service providers lost revenue because of closing service lines due to government orders (Avalere Health, 2020); the result of which led some providers to total collapse (Avalere Health, 2020), thereby hindering the continuity and security of the people with IDD they supported. In fact, people with IDD were significantly less likely to experience continuity and security in 2020 than they were in 2019 (Friedman, 2021a).
Pandemic Changes to HCBS
Since the COVID-19 pandemic is a significant threat to the health and safety of people with IDD, and the stability of the HCBS service system at large, states began making emergency changes to their HCBS programs to meet the needs of people with IDD during the pandemic. Given the increased expenditures and financial concerns of providers during the pandemic, many states temporarily increased the rates they paid providers for HCBS (Friedman, 2022a). In fact, 90% of states temporarily increased payment rates for IDD HCBS during the pandemic in order to expand providers’ capacity to deliver services to people with IDD (Friedman, 2022a). Increasing reimbursement rates was aimed at compensating providers for emergency staffing needs, lost revenue due to changing service lines, additional service delivery and administrative costs. While on average states increased IDD HCBS service reimbursement by 23%, the rates for some service lines rates were increased up to 160%; states most frequently offered increased payments for residential supports services (Friedman, in press).
Another mechanism states used to promote stability of IDD HCBS was introducing retainer payments (Friedman, 2022a). Retainer payments allow providers to receive payments for services even when the person with IDD’s is not able to participate in certain services, such as closed day services, or temporarily while a person is in the hospital (Centers for Medicare and Medicaid Services, n.d.). Retainer payments allow providers to continue their operations and maintain their workforce, while helping compensate for lost revenue and increased expenditures (Friedman, 2022a). During the pandemic, 78% of states offered retainer payments for IDD HCBS (Friedman, 2022a).
Emergency changes to HCBS, including increased payment rates and retainer payments, were aimed at improving the stability of the IDD service system, and, by extension, the continuity and security of people with IDD during the pandemic. For this reason, the aim of this study was to examine the impact of pandemic emergency HCBS payments—increased payment rates and retainer payments—on the continuity and security of people with IDD who received HCBS. We had the following research question: did increased payment rates and retainer payments in HCBS improve the continuity and security of people with IDD? To explore this research question, we analyzed secondary data about the continuity and security of 738 people with IDD who received HCBS from Personal Outcome Measures® (POM) interviews (March 2020 through April 2022), and state pandemic emergency HCBS payment data from the 16 states in which they lived.
Methods
Data and Measures
Continuity and Security: Personal Outcome Measures® (Level 1: Individual)
Secondary data about the continuity and security of people with IDD who received HCBS came from the POM, a validated person-centered quality of life tool (Friedman, 2018b; The Council on Quality and Leadership, 2017). Developed in 1993 based on focus groups with people with disabilities, family members, and other stakeholders about what really mattered in people with disabilities’ lives, the POM has been further refined over its 30 years of administration through pilot testing, expert reviews, a Delphi survey, feedback from advisory groups, and continued validity and reliability testing (Friedman, 2018b). In addition, interviewers are required to pass (85% or higher) interrater reliability tests with expert interviewers before being certified to conduct interviews.
POM administration occurs in three stages. In the first stage, the interviewer has an in-depth, open-ended guided conversation with the person with IDD about 21 different areas of quality of life, ranging from health and safety to rights to community integration. During the second stage, the interviewer speaks with someone who knows about the organizational supports the person with IDD receives and asks them about those supports. If needed, record reviews or observations can also be conducted; otherwise, in the final stage the interviewer completes decision trees [see The Council on Quality and Leadership (2017) for decision-trees] using all of the data gathered to determine if each of the 21 quality of life areas are present (1) or not (0).
One quality of life outcome the POM measures is continuity and security. For people with IDD to have the continuity and security outcome present (1; not present [0]) all of the following conditions must be met: (1) the person with IDD must have economic resources to meet their basic needs; (2) their control over changes in their lives in the past 2 years must be similar to people not receiving services; (3) the changes in their lives in the past 2 years must be due to the person with IDD’s informed personal choice; (4) changes in their lives in the past 2 years must not have had a negative impact on people with IDD’s lives; and, (5) the changes in their lives in the past 2 years must have been planned in advanced to minimize the disruption (The Council on Quality and Leadership, 2017).
The POM data used in this study were originally collected between March 2020 and April 2022 from organizations that provide services to people with IDD, including: residential services; employment and other work/day services; family and individual supports; behavioral health care; service coordination; case management; non-traditional supports (micro-boards and co-ops); and human services systems. The data were de-identified and transferred to the research team. The data contained POM interviews for 1001 people with IDD, 73.7% of which were Medicaid HCBS beneficiaries. People with IDD who were not Medicaid HCBS beneficiaries (n = 263) were removed from the sample. As a result, the final sample included a total of 738 people with IDD who received HCBS. The people with IDD in the sample lived in 16 states: Alabama; Colorado; Connecticut; Georgia; Illinois; Indiana; Iowa; Minnesota; Missouri; New Mexico; New York; North Carolina; North Dakota; Ohio; South Dakota; and Tennessee.
Emergency Pandemic HCBS Payments: Appendix K HCBS Amendments (Level 2: State)
Data about the emergency payments states made to their IDD HCBS programs came from Appendix K: Emergency Preparedness and Response HCBS amendments, as analyzed by Friedman (2022a, in press). States use Appendix Ks to document to the Centers for Medicare and Medicaid Services (CMS) how they will temporarily change each of their HCBS 1915(c) waiver programs during the COVID-19 pandemic (Centers for Medicare and Medicaid Services, n.d.). Between March 2020 and April 2022, states submitted 294 Appendix Ks to temporarily change their HCBS waiver programs for people with IDD.
Increased Payment Rates Specifically, data about the 16 states’ temporary increases to their payment rates for IDD HCBS came from Friedman’s (in press) analysis of increased pandemic payment rates in IDD HCBS. In that study, we analyzed the data states provided in section K-2-f of Appendix K waivers, to determine if each state increased payment rates for IDD HCBS waiver services, and, if so, how much they increased the payment rates (average percent increase). For this study, we used the increased payment rates (%) data from Friedman (in press) for each of the applicable 16 states as one of the independent variables.
Retainer Payments Data about the 16 states’ temporary retainer payments for IDD HCBS came from Friedman’s (2022a) analysis of emergency pandemic changes to IDD HCBS waivers. As part of that study, we analyzed the data states provided in section K-2-j of Appendix K waivers to determine if each state temporarily offered retainer payments. For this study, we used the retainer payment status [offered (1), did not offer (0)] data from Friedman (2022a) for each of the 16 states as one of the independent variables.
Demographics
The average age of people with IDD who received HCBS (Level 1) was 47.4 years old (SD = 16.4; Table 1). Slightly more than half of people with IDD who received HCBS were men (58.7%). Most people with IDD who received HCBS were White (76.3%), communicated through verbal/spoken language (82.8%), and had some form of guardianship (72.4%). About one-fifth (20.2%) of people with IDD who received HCBS had complex medical support needs (12+ h of skilled nursing care) and one-third (29.6%) had comprehensive behavior support needs (requiring 24-h supervision due to risk of harm to self/others). People with IDD who received HCBS most commonly lived in provider owned/operated homes (e.g., group homes; 54.3%), their own homes (21.6%), or with family members (15.1%). The most common additional disabilities/diagnoses people with IDD had were: anxiety disorder (22.0%); mood disorder (21.1%); and ‘behavior challenges’ (14.4%).Table 1 Demographics
Characteristic n %
Individuals (level 1; n = 738)
Age [M (SD)] 47.4 (16.4)
Gender (n = 728)
Man 427 58.7%
Woman 301 41.3%
Race (n = 730)
White only 557 76.3%
Black only 130 17.8%
Latinx only 25 3.4%
Other or multiracial 18 2.5%
Primary communication method (n = 726)
Verbal/spoken language 601 82.8%
Other 125 17.2%
Decision-making authority (n = 735)
Independent decision making 203 27.6%
Some form of guardianship 532 72.4%
Complex support needs (n = 682)
None 418 61.3%
Complex medical support needs 138 20.2%
Comprehensive behavior support needs 202 29.6%
Residence type (n = 753)
Provider owned/operated home 400 54.3%
Own home 159 21.6%
Family home 111 15.1%
Host family/family foster care 33 4.5%
Other 33 4.5%
Disabilities/diagnoses
Anxiety disorder 162 22.0%
Autism 155 21.0%
Behavior challenges 106 14.4%
Cerebral palsy 86 11.7%
Down syndrome 35 4.7%
Hearing loss severe or profound/deaf 20 2.7%
Impulse control disorder 80 10.8%
Limited or no vision/blind 23 3.1%
Mood disorder 156 21.1%
Personality/psychotic disorder 60 8.1%
Physical disability 54 7.3%
Seizure disorder 105 14.2%
Other intellectual/developmental disability 673 91.2%
Other psychiatric disability 81 11.0%
State pandemic changes to HCBS (Level 2; n = 16)
Increase in payment rates [%; M (SD)] 14.8% (16.1%)
Offered retainer payments
Yes 11 68.8%
No 5 31.3%
People could have more than one complex support need and disability/diagnosis
Among the 16 states (Level 2), the average increase in HCBS IDD payment rates during the pandemic was 14.8% (SD = 16.1%), ranging from 0% (4 states) to 50.0%. The majority of states (68.8%) offered temporary retainer payments for HCBS IDD during the pandemic.
Analyses
We first analyzed descriptive statistics. Next, we explored the impact of pandemic emergency HCBS payments on the continuity and security of people with IDD who received HCBS. To do so, due to the nested structure of the data between individuals with IDD and states, we used a multilevel logistic regression. In the first model, we ran an intercept-only unconditional model with continuity and security from the POM as the primary outcome and the random intercept to examine the variation in continuity and security by state. In the second model, we entered all sociodemographic variables as fixed-effects. In the third model, we added state pandemic emergency HCBS payments—increased payment rates and retainer payments—as fixed-effect variables. For all three models, we calculated intraclass correlation coefficients (ICCs) to indicate variance in continuity and security attributed to different states. We calculated ICC according to the following formula (Sommet & Morselli, 2017):ICC=ResidualvarianceResidualvariance+(π2/3)
In addition to ICC, we calculated likelihood-ratio tests [LR χ2 (1)] to determine if each model improved the goodness of fit; we calculated LR χ2 (1) by subtracting the deviance of each model (Sommet & Morselli, 2017). Confidence intervals (CIs) for all odds ratios (ORs) were set at 95%.
Results
Between May 2020 and April 2022, 36.9% of people with IDD who received HCBS experienced continuity and security (n = 272), while 63.1% of people with IDD who received HCBS did not (n = 465).
Model 1: Unconditional
To explore if continuity and security differed depending on pandemic emergency HCBS payments, multilevel logistic models were utilized. In the first unconditional (null) model, which was calculated without any covariates, the ICC indicated 13.0% of the total variation in continuity and security was attributed to differences between states (Table 2).Table 2 Likelihood of people with IDD who received Medicaid HCBS experiencing continuity and security during the COVID-19 pandemic
Variables Model 1 (null) Model 2: demographics [OR (CI)] Model 3: state HCBS [OR (CI)]
Fixed effects
Individuals (level 1)
Age 1.01 [1.00, 1.03]* 1.01 [0.99, 1.03]
Woman (ref: man) 0.72 [0.49, 1.06] 0.56 [0.34, 0.91]*
Race (ref: White only)
Black only 1.21 [0.74, 1.99] 1.11 [0.63, 1.94]
Latinx only 1.32 [0.50, 3.52] 0.86 [0.20, 3.61]
Other or multiracial 0.41 [0.08, 1.98] 0.62 [0.12, 3.30]
Primary communication method: verbal/spoken (ref: other) 1.36 [0.79, 2.35] 1.55 [0.73, 3.30]
Independent decision making (ref: guardianship) 2.02 [1.27, 3.21]* 2.34 [1.34, 4.11]**
Complex medical support needs (ref: no) 1.02 [0.58, 1.79] 0.97 [0.50, 1.88]
Comprehensive behavior support needs (ref: no) 0.83 [0.52, 1.34] 1.20 [0.67, 2.16]
Residence type (ref: provider owned/operated home)
Own home 1.12 [0.62, 2.02] 1.02 [0.54, 1.92]
Family home 2.21 [1.15, 4.24]* 2.54 [1.23, 5.28]*
Host family/family foster care 1.63 [0.64, 4.20] 1.28 [0.48, 3.42]
Other 3.07 [0.93, 10.21] 3.48 [1.02, 11.89]*
Disabilities/diagnoses
Anxiety disorder 1.24 [0.76, 2.02] 1.12 [0.54, 2.29]
Autism 1.06 [0.62, 1.81] 0.82 [0.38, 1.74]
Behavior challenges 0.83 [0.47, 1.44] 0.49 [0.19, 1.27]
Cerebral palsy 0.94 [0.47, 1.87] 0.80 [0.35, 1.80]
Down syndrome 1.32 [0.52, 3.38] 0.82 [0.25, 2.62]
Hearing loss severe or profound/deaf 1.59 [0.53, 4.74] 1.53 [0.38, 6.11]
Impulse control disorder 1.10 [0.59, 2.05] 0.87 [0.35, 2.16]
Limited or no vision/blind 2.36 [0.87, 6.39] 0.49 [0.05, 4.75]
Mood disorder 1.18 [0.74, 1.89] 0.79 [0.41, 1.55]
Personality/psychotic disorder 1.00 [0.49, 2.06] 0.91 [0.37, 2.23]
Physical disability 1.67 [0.79, 3.53] 0.85 [0.26, 2.79]
Seizure disorder 0.85 [0.49, 1.49] 1.15 [0.59, 2.26]
Other intellectual/developmental disability 0.64 [0.31, 1.35] 0.36 [0.15, 0.88]*
Other psychiatric disability 0.39 [0.20, 0.76]** 0.42 [0.20, 0.86]*
State pandemic changes to HCBS (level 2)
Increase in payment rates (average %) 1.02 [1.00, 1.05]*
Offered retainer payments (ref: no) 4.98 [2.25, 10.99]***
Random effects
Deviance (Bayesian) 3367.80 2905.96 2191.73
LR χ2 (1) 461.84*** 714.23***
Variance (residual) 0.49 [0.18, 1.36] 0.79 [0.26, 2.34] 0.15 [0.007, 3.11]
ICC 0.13 [0.02, 0.29] 0.19 [0.07, 0.42] 0.04 [0.002, 0.49]
*p < 0.05; **p < 0.01; ***p < 0.001
Model 2: Individual Sociodemographics
Model 2 incorporated the individual-level sociodemographic characteristics. After adjusting for sociodemographic covariates, the variation in intercepts between states (ICC) was 19.4%. The addition of individual-level sociodemographics significantly improved the goodness of fit [LR χ2 (1) = 461.84, p < 0.001]. A number of sociodemographic covariates were significant. Controlling for all other sociodemographic characteristics, for every 1-year increase in age, the odds of people with IDD who received HCBS experiencing continuity and security increased by 1.4% [OR(CI) 1.01 (1.00, 1.03)]. Controlling for all other sociodemographic characteristics, people with IDD who received HCBS with independent decision-making were 2.02 times [CI (1.27, 3.21)] more likely to experience continuity and security than people with IDD who received HCBS with guardianship. Controlling for all other variables, people with IDD who received HCBS who lived with their families were 2.21 times [CI (1.15, 4.24)] more likely to experience continuity and security than people with IDD who received HCBS who lived in provider owned/operated homes. Controlling for all other variables, people with IDD who received HCBS who also had ‘other psychiatric disability’ were 2.56 times [OR(CI) 0.39 (0.20, 0.76)] less likely to experience continuity and security than people with IDD who received HCBS who did not also have ‘other psychiatric disability.’
Model 3: State Pandemic Emergency Payments
Model 3 incorporated state pandemic emergency payments—increased payment rates and retainer payments. After adjusting for state pandemic emergency payments in Model 3, the variation in intercepts between states (ICC) reduced to 4.4%, suggesting state pandemic emergency payments partly explain the variation in continuity and security of people with IDD who received HCBS. The addition of state pandemic emergency payments significantly improved the goodness of fit [LR χ2 (1) = 714.23, p < 0.001].
The model indicated the more states increased their HCBS payment rates during the pandemic on average, the more likely people with IDD who received HCBS were to experience continuity and security during the pandemic. For every 1% increase in the average payment rates, the odds of people with IDD who received HCBS experiencing continuity and security increased by 2.5% [OR(CI) 1.02 (1.00, 1.05); Fig. 1]. For example, controlling for all other variables, when a person with IDD who received HCBS lived in a state that had an average increased payment rate of 10.0%, the probability of the person experiencing continuity and security was 16.2%; in comparison, when a person with IDD who received HCBS lived in a state that had an average increased payment rate of 40.0%, the probability of the person experiencing continuity and security was 28.8%.Fig. 1 The relationship between state increased payment rates and people with IDD experiencing continuity and security. Figure description This graph shows that as the state increase in payment rates (average %) increases, so does the probability of people with IDD experiencing continuity and security
In addition, the model indicated when states implemented retainer payments, people with IDD who received HCBS were significantly more likely to experience continuity and security during the pandemic. Controlling for all other variables, people with IDD who received HCBS who lived in states that offered retainer payments were 4.98 times [CI (2.25, 10.99)] more likely to experience continuity and security than people with IDD who received HCBS who lived in states that did not offer retainer payments (Fig. 2).Fig. 2 The relationship between state retainer payments and people with IDD experiencing continuity and security. Figure description This graph shows that when states do not offer retainer payments, the probability of people with IDD experiencing continuity and security is 13.2%. When states do offer retainer payments, the probability of people with IDD experiencing continuity and security is 43.0%
In addition to state emergency payments, several sociodemographic covariates were also significant in Model 3. Controlling for all other variables (including state payments), women with IDD who received HCBS were 1.79 times [OR(CI) 0.56 (0.34, 0.91)] less likely to experience continuity and security than men with IDD who received HCBS. Controlling for all other variables, compared to people with IDD who received HCBS who lived in provider owned/operated homes, those who lived in family homes were 2.54 times [CI (1.23, 5.28)] more likely to experience continuity and security, and those who lived in ‘other’ residential settings 3.48 times [CI (1.02, 11.89)] more likely. Controlling for all other variables, people with ‘other intellectual/developmental disability’ who received HCBS were 2.78 times less likely [OR(CI) 0.36 (0.15, 0.88)] to experience continuity and security compared to people with IDD without ‘other intellectual/developmental disability’ who received HCBS. Controlling for all other variables, people with IDD who received HCBS who also had ‘other psychiatric disability’ were 2.38 times [OR(CI) 0.42 (0.20, 0.86)] less likely to experience continuity and security than people with IDD who received HCBS who did not also have ‘other psychiatric disability.’
Discussion
During the COVID-19 pandemic, there was mass destabilization of the IDD HCBS system. States implemented emergency changes to their HCBS programs through Appendix K in hopes that doing so would promote the continuity and security of people with IDD; the aim of our study was to examine the impact of states doing so. We found that when states introduced emergency HCBS payments, people with IDD who received HCBS were significantly more likely to experience continuity and security during the pandemic. In fact, the odds of people with IDD experiencing continuity and security during the pandemic increased by 3% for every 1% states increased their payment rates on average, and by 398% when states offered retainer payments. Increased payment rates and retainer payments allow providers to continue their operations and maintain their workforce by helping providers compensate for lost revenue due to changing service lines, additional service delivery, and administrative costs, and pay for emergency staffing needs, such as hazard pay and overtime due to shortages (Edwards et al., 2020). Retainer payments in particular allow providers to maintain their staff, who would without pay need to seek other employment, and help prevent the costs—time, financial, and quality—involved in needing to find new employees and get them onboarded and trained (Edwards et al., 2020).
While increased reimbursement rates and retainer payments help providers maintain operations (Friedman, 2022a), they can also help promote the continuity and security of people with IDD, and, by extension, the health and quality of life of people with IDD. Continuity and security is a social determinant of health—“conditions in the environments in which people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks” (United States Office of Disease Prevention and Health Promotion, n.d.). For example, when people with IDD experience continuity and security there is a 66% decrease in emergency department visits (Friedman, 2021d). In addition to helping promote the health and safety of people with IDD, continuity and security plays a key role in people with IDD’s quality of life (Friedman, 2022b). For example, the odds of people with IDD exercising their rights increases by 503% when they experience continuity and security (Friedman, 2022b). In addition to the immediate impact continuity and security has on people with IDD’s lives, provider instability can also hinder people with IDD’s future quality of life; if providers go out of business, people with IDD will have fewer opportunities to thrive in their communities (ANCOR Foundation, & United Cerebral Palsy, 2021). As such, by increasing payments during the pandemic, states were helping promote the continuity and security of people with IDD, both in the short-term and the long-term.
Sociodemographic Differences in Continuity and Security
There were also a number of sociodemographic characteristics which were correlated with people with IDD’s likelihood of experiencing continuity and security, regardless of if their states made emergency changes to HCBS. For example, women with IDD were less likely to experience continuity and security during the pandemic than men with IDD; this finding parallels previous research which has found similar disparities for women specific to continuity and security, and other areas of quality of life more broadly (Friedman, 2021a).
People with IDD with any form of guardianship were less likely to experience continuity and security than people with IDD with independent decision-making. Past research indicates people with IDD with guardianship frequently face disparities in quality of life outcomes compared to those without guardianship, including when it comes to the opportunity to make choices about the changes in their lives (Friedman, 2021b; Friedman & VanPuymbrouck, 2019). The lack of continuity and security people with IDD with guardianship experienced during the pandemic may in part be due to the fact that they often receive fewer organizational supports to facilitate their quality of life (Friedman, 2021b; Friedman & VanPuymbrouck, 2019). In addition, in the United States, guardianship is often applied to people with IDD in a broad sweeping manner, resulting in people having significantly less control over their lives, which may have particular implications when it comes to continuity and security (Salzman, 2011).
People with IDD who lived in provider homes were less likely to experience continuity and security than people with IDD who lived in family homes and ‘other’ settings, regardless of the changes their states made to HCBS payments. Research indicates people with IDD have the most favorable outcomes, including experiencing less DSP turnover, in individual settings, including living in their own homes and in family homes, compared to congregate settings, such as provider group homes (Friedman, 2018a, 2019, 2020; Hemp et al., 2014; Larson et al., 2013). In addition, people with IDD who live in congregate settings are more likely to experience a lack of continuity and security because they are often more dependent on the service system, having fewer choices about where and with whom they live (Friedman, 2020).
People with IDD with ‘other intellectual/developmental disability’ were less likely to experience continuity and security. As this is a large umbrella category, including a large list of disabilities, ranging from muscular dystrophy to Fragile X to Tourette’s syndrome, we believe more research is needed to examine differences in continuity and security between people with different types of IDD to explore not only if there are differences among those subgroups but also the factors contributing to those differences. People with IDD who also had ‘other psychiatric disability’ were significantly less likely to experience continuity and security during the pandemic. This finding is especially problematic given people with IDD who also have psychiatric disabilities, often called dual diagnosis, are at higher risk for re/institutionalization—the destabilizing effect of a lack of continuity and security may lead to a greater risk of people with dual diagnosis becoming institutionalized because of a lack of community infrastructure to support people with IDD in times of mental and behavioral crisis (Lulinski & Heller, 2021).
Limitations
When interpreting findings from this study, a number of limitations should be noted. As people with IDD volunteered to participate in POM interviews, there is a chance of self-selection bias. As this was an analysis of secondary data, we did not have the opportunity to ask follow-up questions or ask additional questions. For example, we had no way to determine what subgroups fell into the category ‘other intellectual/developmental disability.’ People’s pandemic experiences, especially related to continuity and security, likely changed significantly during different periods of the pandemic; yet, POM data only came from one point in time per person interviewed. In addition, as the people with IDD in the sample lived in 16 states, the data on state pandemic HCBS changes only came from 16 states. Also, states were able to amend their HCBS programs using Appendix K multiple times; our analysis was of the cumulus changes states made between March 2020 and April 2022. Rate and retainer payment changes may have been added, amended, or removed throughout this period; in addition, while most states implemented Appendix K changes effective retroactively, providers may have received the increased rates or retainer payments after March 2020 due to a lag in reimbursement time.
Implications
While our findings suggest increased payment rates and retainer payments improved the continuity and security of people with IDD, it is important to recognize that the emergency changes states made to their HCBS programs were done through temporary authorities (Appendix K). When the public health emergency is declared over, these emergency HCBS changes will revert to pre-pandemic design, resulting in a decrease in payment rates and a loss of retainer payments. How this will impact the IDD HCBS system, which was underfunded and disjointed prior to the pandemic, remains to be seen (ANCOR Foundation, & United Cerebral Palsy, 2021); however, it could lead to provider instability and collapse due to continued high operating costs and further DSP turnover due to burnout (ANCOR Foundation, & United Cerebral Palsy, 2021; Avalere Health, 2020). To promote the continuity and security of people with IDD, the HCBS infrastructure must be strengthened, with permanent changes made beyond Appendix K. While ten states across the nation have suggested they hope to continue increased rates for HCBS (not IDD specific) after the end of the public health emergency (Centers for Medicare and Medicaid Services, 2022), additional federal efforts to improve the HCBS infrastructure would be beneficial. Yet, to date, HCBS has not been prioritized in federal relief packages. For example, although funding for HCBS was originally included in the most recent federal relief package, the Inflation Reduction Act, funding for HCBS was completely removed prior to it becoming law (Autistic Self Advocacy Network, 2022).
Moreover, additional research would be beneficial to help ensure that policy and funding changes, including during the COVID-19 pandemic, flow downward to actually improve people with IDD’s continuity and security, and quality of life. For example, while this study examined the impact of Appendix K rate changes and retainer payments on people with IDD’s continuity and security, future research should explore the impact on quality of life more broadly. In addition, to determine best practices for future pandemics and times of emergency, it would be beneficial to explore if, and, how, other changes states made improved people with IDD’s quality of life during the pandemic. For example, did adding services, expanding who could qualify for HCBS, or changing rules for service provision during the COVID-19 pandemic translate to improved outcomes? Examining provider differences that impacted people with IDD’s continuity and security during the pandemic would also be fruitful for future research.
Conclusion
The COVID-19 pandemic significantly disrupted the lives of people with IDD, including those who received HCBS. Hoping to minimize this disruption, states made emergency changes to their HCBS programs, including by increasing reimbursement rates and introducing retainer payments. In this study, we found that people with IDD who lived in states that increased HCBS payment rates and offered HCBS retainer payments were more likely to experience continuity and security during the pandemic. Our findings suggest policy decisions not only directly impact people with IDD’s lives, but also that HCBS spending can help increase the stability of the service system, including in times of crisis. Investing in HCBS is an investment in the quality of life of people with IDD.
Thank you to Mary Kay Rizzolo for reviewing this manuscript and providing feedback.
Author Contributions
CF: Conceptualization; Methodology; Formal analysis and investigation; Writing; Resources.
Funding
No funds, grants, or other support was received.
Declarations
Conflict of interest
The author has no relevant financial or non-financial interests to disclose.
Research Involving Human Participants
As this study used secondary deidentified data, our IRB at University of Illinois at Chicago determined it was exempt from review.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
American Psychological Association. (2020). Stress in the time of COVID-19. https://www.apa.org/news/press/releases/stress/2020/stress-in-america-covid.pdf
ANCOR Foundation, & United Cerebral Palsy. (2021). The case for inclusion 2021: A special report on the sustainability of community disability services in America. https://caseforinclusion.org/application/files/2416/1376/5849/Case_for_Inclusion_2021_Special_Report.pdf
Autistic Self Advocacy Network. (2022). Congress leaves disability community priorities out of Inflation Reduction Act. Retrieved August 16, 2022 from https://autisticadvocacy.org/2022/08/congress-leaves-disability-community-priorities-out-of-inflation-reduction-act/
Avalere Health. (2020). Impact of COVID-19 on organizations serving individuals with intellectual and developmental disabilities. American Network of Community Options and Resources (ANCOR). https://www.ancor.org/sites/default/files/impact_of_covid-19_on_organizations_serving_individuals_with_idd.pdf
Bradley VJ How COVID-19 may change the world of services to people with intellectual and developmental disabilities Intellectual and Developmental Disabilities 2020 58 5 355 360 10.1352/1934-9556-58.5.355 33032314
Centers for Disease Control. (2022). Brief summary of findings on the association between disabilities and severe COVID-19 outcomes. https://www.cdc.gov/coronavirus/2019-ncov/downloads/clinical-care/C-Disability-Review.pdf
Centers for Disease Control and Prevention Mental health, substance use, and suicidal ideation during the COVID-19 pandemic—United States, June 24–30, 2020 Morbidity and Mortality Weekly Report 2020 69 32 1049 1057 10.15585/mmwr.mm6932a1 32790653
Centers for Medicare and Medicaid Services. (2020). Long-term services and supports rebalancing toolkit. Centers for Medicare and Medicaid Services. https://www.medicaid.gov/medicaid/long-term-services-supports/downloads/ltss-rebalancing-toolkit.pdf
Centers for Medicare and Medicaid Services. (2022, May 11). After the Public Health Emergency: Changes to Home and Community-Based Services and delivery methods [Webinar]. https://acl.gov/news-and-events/announcements/cms-webinar-changes-home-and-community-based-services-hcbs-and
Centers for Medicare and Medicaid Services. (n.d.). 1915(c) Home and Community-Based Services waiver instructions and technical guidance: Appendix K: Emergency preparedness and response. https://www.medicaid.gov/state-resource-center/downloads/1915c-appendix-k-instructions.pdf
Desroches ML Ailey S Fisher K Stych J Impact of COVID-19: Nursing challenges to meeting the care needs of people with developmental disabilities Disability and Health Journal 2021 14 1 101015 10.1016/j.dhjo.2020.101015 33184022
Edwards E Machledt D Lav J Retaining Medicaid COVID-19 changes to support community living Saint Louis University Journal of Health Law & Policy 2020 14 2 391 428
Embregts PJ van den Bogaard KJ Frielink N Voermans MA Thalen M Jahoda A A thematic analysis into the experiences of people with a mild intellectual disability during the COVID-19 lockdown period International Journal of Developmental Disabilities 2022 15 2 168 196 10.1080/20473869.2020.1827214
Friedman Carli Direct support professionals and quality of life of people with intellectual and developmental disabilities Intellectual and Developmental Disabilities 2018 56 4 234 250 10.1352/1934-9556-56.5.234 30024847
Friedman Carli The personal outcome measures ® Disability and Health Journal 2018 11 3 351 358 10.1016/j.dhjo.2017.12.003 29274792
Friedman Carli The influence of residence type on personal outcomes Intellectual and Developmental Disabilities 2019 57 2 112 126 10.1352/1934-9556-57.2.112 30920914
Friedman, C. (2020). There's no place like home: A national study of how people with intellectual and/or developmental disabilities and their families choose where to live. The Arc of the United States, & CQL | The Council on Quality and Leadership. https://futureplanning.thearc.org/assets/CFP_Housing_Survey_Technical_Report-80e6eb718c816d07a15a9972df06a6e73b1393d5b56ae145acc058fce243cd93.pdf
Friedman Carli The COVID-19 pandemic and quality of life outcomes of people with intellectual and developmental disabilities Disability and Health Journal 2021 14 4 101117 10.1016/j.dhjo.2021.101117 34144897
Friedman, C. (2021b). Disparities in social determinants of health amongst people with disabilities. International Journal of Disability Development and Education, 1. 10.1080/1034912X.2021.2004299
Friedman Carli The impact of direct support professional turnover on the health and safety of people with intellectual and developmental disabilities Inclusion 2021 9 1 63 73 10.1352/2326-6988-9.1.63
Friedman Carli Managed care and value-based payment: The relationship between quality of life outcomes and emergency room utilization Intellectual and Developmental Disabilities 2021 59 1 22 38 10.1352/1934-9556-59.1.22 33543275
Friedman, C. (2022a). Emergency COVID-19 pandemic changes to home- and community-based services for people with intellectual and developmental disabilities. Inclusion. http://aaidd.org/publications/journals/articles-accepted-for-publication
Friedman Carli The impact of continuity and security on quality of life Intellectual and Developmental Disabilities 2022 60 2 101 112 10.1352/1934-9556-60.2.101 35297986
Friedman, C. (in press). Increased payment rates for HCBS for people with intellectual and developmental disabilities during the COVID-19 pandemic. Journal of Developmental & Physical Disabilities.
Friedman Carli VanPuymbrouck Laura The impact of people with disabilities choosing their services on quality of life outcomes Disability and Health Journal 2019 12 2 187 194 10.1016/j.dhjo.2018.11.011 30527886
Hemp, R., Braddock, D., & King, M. (2014). Community-based Medicaid funding for people with intellectual and developmental disabilities. In National Conference of State Legislatures LegisBrief (Vol. 22, pp. 1–2).
Hewitt, A., Pettingell, S., Kramme, J., Smith, J., Dean, K., & Kleist, B. (2020). Results of the direct support workforce and COVID-19 national survey 2020. Institute on Community Integration. https://publications.ici.umn.edu/community-living/covid19-survey/overview
Larson S Lakin C Hill S Behavioral outcomes of moving from institutional to community living for people with intellectual and developmental disabilities: U.S. studies from 1977 to 2010 Research and Practice for Persons with Severe Disabilities 2013 37 4 235 246 10.2511/027494813805327287
Lulinski A Heller T Community capacity to provide mental/behavioral health services for people with IDD transitioning from state-operated developmental centers Intellectual and Developmental Disabilities 2021 59 3 224 238 10.1352/1934-9556-59.3.224 34030183
Lund EM Forber-Pratt AJ Wilson C Mona LR The COVID-19 pandemic, stress, and trauma in the disability community: A call to action Rehabilitation Psychology 2020 65 4 313 322 10.1037/rep0000368 33119381
Lunsky Y Jahoda A Navas P Campanella S Havercamp SM The mental health and well-being of adults with intellectual disability during the COVID‐19 pandemic: A narrative review Journal of Policy and Practice in Intellectual Disabilities 2022 19 1 35 47 10.1111/jppi.12412 35601014
Luterman, S. (2020). The neglect of disability care.The American Prospect. https://prospect.org/familycare/the-neglect-of-disability-care/
Pettinicchio D Maroto M Chai L Lukk M Findings from an online survey on the mental health effects of COVID-19 on Canadians with disabilities and chronic health conditions Disability and Health Journal 2021 14 3 101085 10.1016/j.dhjo.2021.101085 33744158
Pinilla-Roncancio M Alkire S How poor are people with disabilities? Evidence based on the global multidimensional poverty index Journal of Disability Policy Studies 2021 31 4 206 216 10.1177/1044207320919942
Salzman L Guardianship for persons with mental illness: A legal and appropriate alternative? Saint Louis University Journal of Health Law & Policy 2011 4 279 330
Scheffers F van Vugt E Moonen X Assessing the quality of support and discovering sources of resilience during COVID-19 measures in people with intellectual disabilities by professional carers Research in Developmental Disabilities 2021 111 103889 10.1016/j.ridd.2021.103889 33578230
Sommet N Morselli D Keep calm and learn multilevel logistic modeling: A simplified three-step procedure using Stata, R, Mplus, and SPSS International Review of Social Psychology 2017 30 1 203 218 10.5334/irsp.90
The Council on Quality and Leadership. (2017). Personal outcome Measures®: Measuring personal quality of life (3rd ed.). The Council on Quality and Leadership.
United States Office of Disease Prevention and Health Promotion. (n.d.). Social determinants of health. United States Office of Disease Prevention and Health Promotion. https://www.healthypeople.gov/2020/topics-objectives/topic/social-determinants-of-health
| 36484965 | PMC9734720 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Autism Dev Disord. 2022 Dec 9;:1-10 | utf-8 | J Autism Dev Disord | 2,022 | 10.1007/s10803-022-05859-7 | oa_other |
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Environ Sci Pollut Res Int
Environ Sci Pollut Res Int
Environmental Science and Pollution Research International
0944-1344
1614-7499
Springer Berlin Heidelberg Berlin/Heidelberg
36462076
24444
10.1007/s11356-022-24444-0
Research Article
Spatio-temporal evolution analysis of the coupling situation of economic-social-ecological system in Guangdong
Qiao Guotong [email protected]
12
http://orcid.org/0000-0002-4026-9798
Chen Fei [email protected]
1
Wang Na 1
Zhang Dandan 1
1 grid.440648.a 0000 0001 0477 188X School of Economics and Management, Anhui University of Science and Technology, Huainan, 232001 Anhui China
2 grid.440648.a 0000 0001 0477 188X Dean’s Office and Innovation College, Anhui University of Science and Technology, Huainan, 231001 Anhui China
Responsible Editor: Philippe Garrigues
3 12 2022
121
27 4 2022
23 11 2022
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The economic and social structures of Chinese cities are constantly transforming in recent years. The coordinated development of economic, social, and ecological environment is an important path to achieving the construction of high-quality development. Taking Guangdong Province, the largest economic province in China, as an example, the evaluation index systems of economic development system (ED), social development system (SD), and ecological environment system (EE) are constructed, respectively. The entropy weight method and comprehensive evaluation method are applied to measure the evaluation indexes of economic, social, and ecological environment levels of each city in Guangdong Province from 2010 to 2020. The coupled coordination model is used to measure the spatial and temporal evolution of the coupled ED-SD-EE coordination of Guangdong cities and explore the impact of the epidemic on the coupling coordination degree. The results concluded that (i) the economic, social, and ecological environment of each city in Guangdong Province will be more harmonious from 2010 to 2020. ED-SD-EE coupling coordination of Guangdong cities shows a “rising and then declining” trend, but it is still in a “high coupling-low coordination” development state. (ii) The lagging development of the coupled ED-SD-EE system in Guangdong cities is mainly the ecological environment system. (iii) Epidemic harms the coupling and coordination of Guangdong cities, with the most negative effect on the coordination development of the EE. The paper findings clarify the current state of ED-SD-EE coupling and coordination in Guangdong cities, with a view to providing a reference basis for policy formulation and research on quality urban development.
Keywords
Coupling coordination model
ED-SD-EE
High quality development
Epidemic
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pmcIntroduction
How to achieve the harmonization of city economy, society, and ecological environment has become a major theoretical and practical issue common to the construction of city ecosystems in the world. Since the reform and opening-up, China’s city construction and economic construction have taken off, and China’s industrialization and urbanization have made great achievements. But China’s pre-crude economic development model and huge industrial system have consumed numerous resources and energy, and the impact and pressure on the ecological environment have become more obvious, while the shortage of resources and the deterioration of the ecological environment have also brought constraints and limitations to city economic and social development. The contradiction between ecological environment and development has become increasingly prominent in cities (Zhang and Liu 2019; Jiang et al. 2017).
Therefore, the Chinese government also attaches great importance to the harmonization of urban ecosystems and economic\social development. Since 2012, China has successively proposed new urbanization, ecological civilization construction, and new development concept. The core requirement and objective of these plans and concepts is to achieve the harmonization of economic, social, and ecological development. But high-quality coordinated urban development studies require continuous optimization according to the cities’ current economic, social, and ecological environment and an accurate grasp of the evolutionary trends and directions of urban ecosystems. Timely and well coordinating the relationship between the cities’ economic, social, and ecological environment is a necessary path to promote the cities’ green and sustainable development, which is important for accelerating China’s ecological civilization construction, ensuring sustainable urban development and improving the cities’ liable environment (Wang et al. 2016).
There has been a rise in research into the coordination of the various subsystems of the city in recent years. Some researchers have used mathematical models such as system dynamics (Wang et al. 2012) and discrete mathematics (Dou et al. 2021) to study the urban ecosystem’s coordinated development. In the study of geography, the main ones are watersheds (Ariken et al. 2020; Liu et al. 2021), provinces (Zuo et al. 2021; Liu et al. 2020), and rural areas (Yang Y et al. 2020; Zhu et al. 2021). And the use of coupled coordination models for the coordinated development of cities is increasingly being studied (Wang et al. 2020; Li 2019; Yang C et al. 2020; Xie et al. 2021; Sun and Zhang 2021). This indicates the widespread recognition of the coupling coordination degree model use for system coordination studies in various regions, especially at the city scale.
However, urban ecosystems are complex nature-economy-society complex systems (Sun et al. 2017). In the available research, the cities’ coupling coordination has been mainly studied between ecological and economic and social integrated systems (Wang et al. 2020; Yang C et al. 2020; Xie et al. 2021). Meantime, China’s rapid economic growth and urbanization have led to continuous changes in social and economic structures as well as production and lifestyle (Li et al. 2012b). Studies by Chiaravalloti et al. (2021), Laurent (2021) has shown that economic and social drivers of various types of systems do not coincide and that developments between the two are not necessarily synchronized. Therefore, the distinction between economic and social development, and thus the coupling and coordination of multiple systems, is also increasingly being considered by researchers (Zuo et al. 2021; Chiaravalloti et al. 2021).
Based on this, the paper conducts an empirical study on the basis of existing research based on data availability, scientific validity, and consideration of the specificity of the study area, using city-level data from 2010 to 2020 for the largest economic province in China, Guangdong Province. In constructing a three-system indicator system for economic development (ED), social development (SD), and ecological environment (EE) for 21 prefecture-level cities, the entropy method measures the comprehensive development level index of each subsystem and analyzes the comprehensive index to derive the relative development type of each municipality and the relative lagging system. Combined with the coupled coordination model to measure the temporal development characteristics of coupled ED-SD-EE coordination in each city of Guangdong, ArcGIS10.4 software was used to visualize and analyze the spatial and temporal evolution characteristics and types of coupled coordinated development in each city. The paper also explores the impact of the COVID-19 epidemic on the coupling and coordination among urban social, economic, and ecological systems. It is expected to provide reference suggestions for the construction of coordinated and high-quality development of economy, society, and ecological environment in Guangdong at this stage and to lay the foundation for governments to carry out scientific decision-making and seek optimal solutions for the interests of ecological, economic, and social parties.
Subject and data
Study area
Guangdong Province is located in the south of China, where downstream of the Pearl River, at latitude 20°22′–25°52′ north and longitude 109°66′–117°30′ east. The climate is mid-subtropical, south-subtropical, and tropical from north to south, dominated by mountains and hills. Guangdong Province, with 21 prefecture-level cities under its jurisdiction, is a pioneering region in China’s reform and opening up and the introduction of foreign investment, and it is at the forefront of the urbanization process in China. It can be said that the transition to coordinated urban development in Guangdong Province in the context of “high-quality development” and “new urbanization” has received national attention. However, from a regional perspective, the PRD region (nine prefecture-level cities) will account for 80.82% of the province’s GDP in 2020, amounting to 8,952.3 billion CNY. In contrast, the development of the eastern, western, and northern of Guangdong eco-development zones is relatively backward and polarized, and the different resource endowments and economic structures of Guangdong’s municipalities create significant disparities in economic development between them. Due to the “Matthew effect,” these disparities have been widening over time, and the problem of regional economic-social-ecological disparities has become increasingly prominent, becoming a shortcoming that restricts Guangdong from achieving high-quality economic and social development (Cai et al. 2013). Therefore, the study on the coordination of economic-social-ecological development of Guangdong will help Guangdong to optimize the allocation of resources and the spatial layout of productive forces, accelerate the formation of a regional economic layout with obvious main functions, complementary advantages and high-quality development, build a higher level of modernized regional coordinated development system, and realize green economic and social transformation.
Indicator system
System construction
In the paper, based on the systematic, regional, scientific, operable, quantitative, and data disclosure degree of each city in Guangdong Province, a total of 38 indicators are selected to build a coupling and coordination of ED-SD-EE evaluation indicator system for cities, and the indicators are classified according to the classification, definition, and characteristics of Chinese cities by relevant researchers [10,18,22–31]. The 38 indicators were properly classified according to the classification, definition, and characteristics of Chinese cities (Table 1) (Zuo et al. 2021; Sun and Zhang 2021; Lee and Goh 2016; Li 2019; Alfaro et al. 2004; Stuetzer et al. 2018; Li et al. 2012a; Shi et al. 2019; Ke et al. 2020; Qiu et al. 2020; Xia et al. 2021; Chaerun et al. 2020).Table 1 ED-SD-EE indicator system
Target layer Criteria layer Index layer Attribute
Economic development system (ED) Economic development structure Percentage of added value of primary industry* (%) −
Percentage of added value of secondary industry* (%) −
Percentage of added value of tertiary industry* (%) +
Economic development situation Urbanization rate* (%) +
GDP per capita* (yuan) +
Total gross domestic product* (100,000,000 CNY) +
Consumer price index* +
Total investment in fixed assets* (100,000,000 CNY) +
Foreign direct investment* (10,000 CNY) +
Total import and export volume of foreign enterprises* (100,000,000 USD) +
Economic development potential Deposits and loans in renminbi in all financial institutions* (billion CNY) +
Savings deposit by household in all financial institutions* (100,000,000 CNY) +
Social development system (SD) Population situation Natural population growth rate** (%) +
Population density *(p/sq. km) −
Education and technology Expenditure for education per capita* (yuan/p) +
Proportion of educational practitioners in the whole society* (%) +
Internal expenditure on R&D of industrial enterprises* (100,000,000 CNY) +
Collections of public libraries per 10 persons*** (copy) +
Public health Number of medical beds per 10,000 people* (bed) +
Number of medical technical personnel* (person) +
Social insurance Proportion of environmental and public facilities’ practitioners in the whole society*** (%) +
Proportion of public management and social organization practitioners in the whole society*** (%) +
Local government general budgetary revenue* (100,000,000 CNY) +
Social welfare Public transportation vehicles per 10,000 people* (unit) +
Area of parks and green land per capita* (sq. m) +
Local government general budgetary expenditure* (100,000,000 CNY) +
Average wages of fully employed staff and workers in urban units* (yuan) +
Ecological environment system (EE) Environmental pressure Electricity consumption* (100 million kwh) −
Volume of waste water discharged *(100 million tons) −
Total volume of industrial waste gas emission* (100 million cu·m) −
Volume of industrial soot (dust) emission* (10,000 tons) −
Volume of industrial solid wastes produced* (10,000 tons) −
Water use per capita ~ (cu·m) −
Environmental state Water resource per capita ~ (cu·m) +
Average annual rainfall ~ (mm) +
Cultivated land area** (ha) +
Environmental response Rate of sewage treatment* (%) +
Rate of consumption waste treatment* (%) +
*Guangdong Provincial Statistical Yearbook or Municipal Statistical Yearbooks
**Municipal Statistical Bulletins or Annual Survey Reports
***China Urban Statistical Yearbook
~Guangdong Water Resources Bulletin
+Positive indicator
−Negative indicator
There are 12 indicators in the economic development system. Based on existing research, the paper divides the 12 indicators into three categories: economic development structure, status, and potential. There are 15 indicators in the social development system. Based on the internal division of the Guangdong Provincial Statistical Yearbook and related studies, this paper divides them into five parts: social demographic status, education, and science and technology services, public health services, social security, and social welfare, with the aim of building a relatively complete subsystem of cities’ social development. There are 11 indicators of cities’ ecological environment system. The paper refers to the environmental pressure-state-response model (Rapport 1989; Chuan 2000), which is often used to construct the ecological environment quality evaluation index system and selects the complete and available cities’ ecological environment data to represent the current situation and development of cities’ ecological environment.
Indicator description
Among the indicators of the economic development subsystem constructed in the paper, foreign direct investment (FDI), deposits, and loans in renminbi in all financial institutions and savings deposit by household in all financial institutions are not much applied and classified in various studies. But some researchers have defined FDI as part of GDP (Li 2019), and some researchers have studied the role of FDI on economic development (Alfaro et al. 2004). Therefore, this paper includes FDI in the ED system, together with related indicators to indicate the state of economic development. Meanwhile, some researchers regard the deposits and loans in renminbi in all financial institutions as the financial capital of regional economic development (Stuetzer et al. 2018), while household deposits are part of it, but household deposits can better reflect the consumption potential of regional residents. So the paper regards them as potential financial capital that can promote regional economic development, and the two together constitute the development potential layer of the economic development subsystem.
Among the social development subsystem, average wages of fully employed staff and workers in urban units are gradually considered by Chinese scholars to reflect the level of talent skills (Peijian and Jing 2021) and the fairness of social distribution (Binbin 2021). Some Chinese scholars believe that a good average wage level and rate of increase can reflect the first advantage of high-quality development of cities (Li 2021). Therefore, based on data availability, the paper adopts the average wages of fully employed staff and workers in urban units to reflect the overall average wage level of the region, which is used to represent the degree of high-quality development of talents in regional social development. A large scale of government expenditure and fully functional government functions can effectively promote social harmony and stability. Existing studies have mostly used public expenditure to measure the scale of local governments (Li et al. 2012a); the paper uses local government general budgetary expenditure to measure the scale of local governments and reflect the government’s ability to sustain support for social welfare. The paper also uses local government general budgetary revenue as a measure of the government’s ability to sustain healthy development and to cover spending on various social services. In addition, indicators such as number of medical technical personnel (Shi et al. 2019), internal expenditure on R&D of industrial enterprises (Ke et al. 2020), expenditure for education per capita (Qiu et al. 2020), and collections of public libraries per 10 persons (Xia et al. 2021; Chaerun et al. 2020) have been classified into the social development system through relevant literature studies.
The indicators of the cities’ ecosystem are mainly selected in terms of the state of regional water and soil resources, energy consumption, pollutant emission pressure, and the effectiveness of cities’ environmental management, while combining the PSR model and data availability to filter out the appropriate indicators.
Data sources and declarations
The data for the paper were obtained from the statistical yearbooks, statistical bulletins, and annual survey reports of Guangdong Province and municipalities from 2011 to 2021, as well as the China Urban Statistical Yearbook and the Guangdong Water Resources Bulletin. Where some data differed between the provincial and municipal yearbooks and where the data differed from year to year, the Guangdong Statistical Yearbook and the latest yearbook data prevail. Due to the outbreak of the COVID-19 epidemic in 2020, some data for that year (natural population growth rate, public library collections, the proportion of environmental and public facilities’ practitioners in the whole society, proportion of public management and social organizations’ practitioners in the whole society, etc.) are not available. The missing data were predicted by index smoothing projections using Excel 2019 software.
Empirical framework
Determination of indicator weights
Due to the different levels of development of each municipality, the degree of influence of each indicator on urban development varies at different times. The paper uses the entropy method (Qiyue 2010) to determine the indicator weights based on the development characteristics of each city and then carry out the calculation of the coupling and coordination degree of each system. The indicator weights calculated in the paper for each city are detailed in Appendix 1.
Dimensionless treatment of the indicator system:1 gij′=gij-mingjmaxgj-mingj,Positiveindicatorgij′=maxgj-gijmaxgj-mingj,Negativeindicatori=1,2,⋯,m,j=1,2,⋯,n
where it is assumed that there are m evaluation objects and n evaluation indicators, and gij denotes the j indicator of the i object. Calculate the weight of the j sample indicator value under the i indicator Pij (Eq. (2)), determine the entropy value ei (Eq. (3)), and when Pij=0, let Pij×lnPij=0. Finally, calculate the entropy weight ωj of the i ωj of the i indicator (Eq. (4)).2 Pij=gij′∑i=1mgij′
3 ei=-1lnm×∑i=1mPij×lnPij
4 ωj=1-ei∑i=1m1-ei
Coupling and coordination degree model
The study of urban system coupling helps to clarify the coupling process and the evolution law of ED-SD-EE systems, find the shortcomings of cities’ economic, social, and ecological development, and has important practical significance for establishing a sustainable and efficient model of green, sustainable, and high-quality urban development. As a popular method for the analysis of the coordinated development of various systems, the coupled coordination model is widely used in the coupling analysis of ecological and other systems (Ariken et al. 2020; Liu et al. 2021; Zuo et al. 2021; Liu et al. 2020; Yang Y et al. 2020; Zhu et al. 2021; Wang et al. 2020; Li et al. 2019; Yang C et al. 2020; Xie et al. 2021). The coupling degree and coordination degree are used to quantify the coupling and coordination degree of each indicator within the system, which can reflect the degree of coordination and the relative development level of the system (Zhang et al. 2019). It can visually and quantitatively reveal the interaction between cities’ ED-SD-EE systems and identify the relative lagging systems of cities’ development, which helps cities focus on the shortcomings of development and promote comprehensive economic-social-ecological to coordinated development.
Referring to the three-system coupling degree formulae of some scholars (Jianhua et al. 2015; Zhong and Liu 2012), a three-system economic-social-ecological coupling degree measurement model is constructed, which is calculated as follows.5 C=F×G×H/F+G+H/331/3
where C is the coupling degree; the F\G\H are the comprehensive indices of the social, economic, and ecological subsystems, respectively. To further reflect the degree of coupling and coordination of cities’ ED-SD-EE system, the coupling degree of ED-SD, SD-EE, and ED-EE systems is calculating and combines the coupling and coordination degree of the three composite systems to comprehensively reflect the measurement model of coupling degree of cities’ ED-SD-EE systems (Liu et al. 2005). Calculations are as in Eq. (6).6 C=F×G/F+G/221/2C=F×H/F+H/221/2C=H×G/H+G/221/2
T is the integrated economic-social-ecological evaluation index, and the calculation is shown in Eq. (7), where α, β, and γ are the weights. In the paper, we believe that the three aspects of ED-SD-EE in sustainable urban development in the context of new urbanization are equally important. So the weights in the comprehensive evaluation index T for the three systems are α=β=γ=1/3. The weights in the calculation of the comprehensive evaluation index for the two systems are 0.5.7 T=αF+βG+γHT=αF+βGT=αF+γHT=βG+γH
Finally, the coupling coordination is calculated as in Eq. (8), where D is the degree of coupling coordination.8 D=C×T
Classification method of coupling and coordination degree in city
In the paper, the degree of coupling coordination is classified according to relevant studies and also according to the characteristics of the calculation results, on the premise that the spatial and temporal evolution of the coupling coordination development can be more clearly shown (Table 2).Table 2 Determination of coupling coordination standard
Coupling degree (C) Coupling phase Coordination degree (D) Coordination phase
0<C≤0.25 Not coupling 0<D≤0.25 Incoordination
0.25<C≤0.40 Low coupling 0.25<D≤0.40 Low coordination
0.40<C≤0.55 Moderate coupling 0.40<D≤0.55 Moderate coordination
0.55<C≤0.70 Basic coupling 0.55<D≤0.70 Basic coordination
0.70<C≤0.85 High coupling 0.70<D≤0.85 High coordination
0.85<C≤1.00 Excellent coupling 0.85<D≤1.00 Excellent coordination
At the same time, based on the comparison between the comprehensive evaluation indices of the ED-SD-EE subsystems of each city, the lagging systems of each city are identified, and the degree and type of lagging of each subsystem are determined (Table 3). In order to clarify the importance and urgency of the balanced ED-SD-EE system development of cities, the paper assigns scores to the relative lagging degree among the subsystems, identifies the shortcomings of the balanced development of cities, and provides a basis for such plans as “new urbanization,” “green and sustainable,” and “high-quality development.” This will provide reasonable and scientific suggestions for governments to formulate targeted policies.Table 3 Comparison relation of F/G/H and assigned to a score
F>G G/F≥0.8 0.5≤G/F<0.8 G/F<0.5
Basic types The ED system lags behind the SD system The ED system lags significantly behind the SD system The ED system is extremely lagging behind the SD system
G>F F/G≥0.8 0.5≤F/G<0.8 GF/G<0.5
SD system is lagging SD system is seriously lagging SD system is extremely lagging
G>H H/G≥0.8 0.5≤H/G<0.8 H/G<0.5
EE system is lagging EE system is seriously lagging EE system is extremely lagging
H>G G/H≥0.8 0.5≤G/H<0.8 G/H<0.5
ED system is lagging ED system is seriously lagging ED system is extremely lagging
H>F F/H≥0.8 0.5≤F/H<0.8 F/H<0.5
SD system is lagging SD is seriously lagging SD systems is extremely lagging
F>H H/F≥0.8 0.5≤H/F<0.8 H/F<0.5
EE system is lagging EE system is seriously lagging EE system is extremely lagging
Score 1 2 3
In the paper, the relative lagging systems of each subsystem in Table 3 are evaluated and scored, and then the scores are summed to give a final score for each subsystem, ranging from 0 to 6, which indicates the priority of each subsystem for coordinated development. Higher scores are being given priority in the coordinated development of the city. The scores are analyzed on a step-by-step basis to judge the urgency of optimizing a particular system in a three-system city. When the final score of a subsystem is 0/1, it means that the system has a low impact on the overall urban ecosystem lag and requires only a little attention in the subsequent cities’ development process. When subsystem A has a final score of 2, two scenarios can be distinguished as follows: (i) it lags badly compared to subsystem B + subsystem C has no impact (i.e., 2 + 0). (ii) it lags relatively well for both systems (i.e., 1 + 1), meaning that the city needs to invest some effort in focusing on the coordinated development of the system. When the final score is 3 (i.e., there are 1 + 2 and 3 + 0) or 4 (i.e., 1 + 3 and 2 + 2), local governments should be aware that at this point the system is already affecting the balanced development of the city more seriously and more effort needs to be invested to properly deal with the lag between this system and other systems. When the final score is 5 (i.e., 2 + 3) or 6 (i.e., 3 + 3), it means that the development of the system is severed from the other systems and has seriously affected the balanced development of the city, and it is urgent to deal with the lagging problem of the system.
Empirical results and analysis
Coupling analysis
In terms of the degree of coupling between the ED-SD-EE systems, most of Guangdong Province and its subordinate cities are in an extremely coupling state from 2010 to 2020 (Fig. 1a). The coupling degree of Guangdong Province as a whole in 2010 is 0.73002, which is in the basic coupling state, while the coupling degrees of Guangzhou, Huizhou, Yangjiang, and Dongguan in the rest of 2010 are 0.75665, 0.80887, 0.84014, and 0.84869, respectively. While the coupling degree of Dongguan in 2019 is 0.84803, and the coupling degrees of Shanwei, Meizhou, and Dongguan in 2020 are 0.80333, 0.83710, and 0.82613, respectively, and all are in a highly coupled state. Although there are slight differences in the temporal changes of the coupling degree of different cities, the overall trend is similar, and the overall trend of coupling degree is inverted U-shaped (Fig. 2), showing an increasing trend, followed by a decreasing trend. Since the onset of the COVID-19, strong epidemic prevention and control measures in China have brought about tangible epidemic prevention and control effects, while also having a huge impact on resource consumption and economy and society (Chen et al. 2021). The paper therefore presents a comparative analysis of urban coupling coordination in 2019 and 2020 to explore the impact of the COVID-19 on the coordination development and coupling mechanism of cities.Fig. 1 a Coupling degree of ED-SD-EE, b coupling degree of ED-SD, c coupling degree of SD-EE, d coupling degree of ED-EE
Fig. 2 Trends in panel data based on coupling between Guangdong and municipalities
In terms of coupling degree, it can be concluded that the COVID-19 has a negative impact on the coupling between the ED-SD-EE subsystems of cities (Fig. 1a), with most of the coupling decreasing in 2020 (Shenzhen, Zhuhai, and Chaozhou’s coupling has increased, compared to 2019). But it is still in an extremely coupled state. An analysis of Fig. 1b shows that the epidemic does not have a significant impact on the coupling between the city’s SD and ED subsystems; the degree of ED-SD coupling is mostly at excellent coupling (except for Guangzhou, which is at high coupling in 2010). And the degree of ED-SD coupling does not change much after 2014, implying a high degree of city economic-social coupling. This also matches the fact that many researchers usually consider the economic and social combinations when researching (Chen et al. 2019). It is also in Fig. 1c, the SD-EE coupling of Shenzhen, Zhuhai, and Chaozhou increased, while this coupling of other cities showed a decreasing trend, and the coupling of Guangdong, Shantou, Heyuan, Meizhou, Huizhou, and Yangjiang decreased from excellent coupling to highly coupling, and even Shantou decreased from excellent coupling to highly coupling, indicating that the epidemic would have a negative impact on the SD-EE system coupling in most cities in Guangdong. An analysis of Fig. 1d shows that the ED-SD coupling decreases in all cities except Zhuhai, implying that the epidemic also has a negative impact on the coupling of ecology and economy.
Coupling coordination analysis
From the change trend of the coupling and coordination degree of each city (Fig. 3), the development of the coupling and coordination degree of the two systems and the three systems basically shows a similar time change pattern, and the coupling and coordination degree of Guangdong Province and each city basically shows a stable upward trend. Combined with Fig. 4, the degree of coupling coordination of the ED-SD-EE systems has increased from uncoordinated (Guangzhou, Heyuan, and Meizhou) or low coordination in 2010 to moderate coordination in 2020. The degree of coupling coordination of the ED-SD system improves from uncoordinated (Guangzhou, Heyuan, Meizhou, and Zhanjiang) or low coordination in 2010 to basic coordination in 2020. The degree of coupling coordination of the SD-EE system, on the other hand, has increased from low or moderate coordination (Shenzhen, Zhongshan, Qingyuan, and Jieyang) to moderate coordination or basic coordination in general, with Zhongshan and Shenzhen being at the moderate coordination level for a long time. The analysis of the visualized coordination between 2019 and 2020 shows that the epidemic has a negative impact on the SD-EE coupling coordination of cities, but the overall change of coupling coordination degree is not significant. With the SD-EE in Maoming rising from moderate coordination in 2019 to basic coordination, the coupling coordination of ED-EE increased or maintained from low or moderate coordination (Qingyuan, Zhaoqing, Yunfu, Yangjiang, Jiangmen, Zhongshan, Jieyang, and Chaozhou) in 2010 to basic coordination (Guangzhou, Qingyuan, Zhaoqing, Yunfu, Jiangmen, Jieyang, Heyuan, and Shaoguan) or moderate coordination in 2019; and Guangdong Province was also in basic coordination in 2019. However, in 2020, except for Shenzhen and Zhuhai, which improve to a state of basic coordination, the coupling coordination of ED-EE in other cities decreases or is in a state of moderate coordination (Foshan and Dongguan are still in a state of moderate coordination in 2020, although their ED-EE coordination has improved). In general, the coupling coordination degrees of each city do not vary much, and the trends of change are similar.Fig. 3 a Coupling and coordination degree of ED-SD-EE. b Coupling and coordination degree of ED-EE. c Coupling and coordination degree of ED-SD. d Coupling and coordination degree of SD-EE. (*Calculated results for the 2010–2020 dataset)
Fig. 4 Spatial distribution of coupling and coordination degree in Guangdong from 2010 to 2020 (calculated results for the 2010–2020 dataset)
At the same time, in 2016, the coupling and coordination of most cities rose from low to moderate coordination after the requirement of new urbanization, and construction of ecological civilization was introduced in 2012. It is easy to see that in 2017, after the introduction of high-quality development, the coupling coordination also rose towards basic coordination, but the arrival of the COVID-19 interrupted this upward trend.
Taken together, the above analysis reveals that the coupling and coordination of Guangdong’s municipalities are by and large progressing towards a better trend until 2019. However, the epidemic in 2020 has a negative impact on the ED-SD-EE systems’ coupling in most of the cities in Guangdong, especially causing a fragmentation of the interactions between the ecological environment subsystem and the other two subsystems. However, it is also not difficult to find that Zhuhai’s coupling in 2019–2020 is on the rise in all categories, and the epidemic has a smaller impact on Zhuhai’s development coupling mechanism. Subsequent researchers can conduct research and analysis on the coupling in Zhuhai and try to identify the factors that condition the joint progress of the long-term epidemic prevention and control requirements and the high-quality coordinated development of the city. It can be seen that most cities, after experiencing the epidemic, have a reduced ability to interact between social development, economic development, and ecological environment systems. Subsequent governments need to consider ecological environment factors comprehensively when formulating relevant policies, especially policies on epidemic prevention and control and economic development and emergency response to major public health events.
In order to consider the change trend of the coupling coordination degree of Guangdong cities before the impact of the epidemic, the paper excludes the data of 2020 and uses the dataset of Guangdong cities from 2010 to 2019 to recalculate the index weights and coupling coordination degree, and the results are detailed in Figs. 5 and 6. An analysis of Fig. 5 shows that the coupling coordination degrees calculated from the 2010 to 2019 dataset show an increasing trend. The results of Fig. 5 show an increasing trend. Figure 6 shows that after excluding the 2020 data, the coupling coordination of ED-EE and SD-EE increases more significantly in 2019 (compared with Fig. 4, calculated for the 2010–2020 dataset), and the coupling coordination of the ED-EE system in Heyuan even reaches a high level of coordination in 2019. Therefore, it can be concluded that the impact of the COVID-19 on the ED-SD-EE coupling coordination of the city mainly acts on the coupled coordination between the ecological environmental systems and other systems. Combined with the analysis of Figs. 3 and 4, we can also learn that the level of coordination between the EE system and other systems is a long-term constraint affecting the coordination development of cities in Guangdong Province, even if the coordination between the EE system and economic development and social development systems still decreases when the epidemic also hinders the economy and society to a certain extent. Of course, although some data in the paper are supplemented by exponential smoothing predictions over 20 years, the data predicted have a relatively small weighting (see Appendix 1 for details) and have a small impact. So the conclusions drawn can be considered relatively reliable.Fig. 5 a Coupling and coordination degree of ED-SD-EE. b Coupling and coordination degree of ED-EE. c Coupling and coordination degree of ED-SD. d Coupling and coordination degree of SD-EE. (Calculated results for the 2010–2019 dataset)
Fig. 6 Spatial distribution of coupling and coordination degree in Guangdong from 2010 to 2019 (calculated results for the 2010–2019 dataset)
Types of urban economic-social-ecological system development
By calculating F/G/H, the final scores were calculated by comparing each other and assigning scores to obtain the system lag score table (see Appendix 2 for details). From the results of the assignment, we can see that the lagging score of the city EE system shows an upward trend with time migration. The lagging of the EE system in all cities basically reaches more than 5 points in 2020 (3 points in Zhongshan and 4 points in Shenzhen). The overall development between the EE system and the ED and SD system shows extreme lagging (Zhongshan and Shenzhen are seriously lagging), and some cities (Guangzhou, Foshan, etc.) rose from no lagging influence to extreme lagging. At the same time, the scores of the SD system and the ED system vary from city to city. But except for Zhuhai, the final scores of ED system in Guangdong and in the rest of the cities basically show a decreasing trend, while the lagging impact of the SD system is relatively small (or basically no impact). Therefore, the lagging types of Guangdong cities (except Zhuhai) are mostly “seriously lagging in EE, relatively low impact of lagging SD, relatively leading in EE.” The lagging stage of Zhuhai is, however, in the lagging stage of “seriously lagging in EE, relatively leading in SD, relatively low impact of lagging EE.” From a comprehensive perspective, the relatively lagging EE system is an important reason limiting the coupling and coordination development of ED-SD-EE systems in various cities in Guangdong. To achieve high-quality and coordination development in subsequent places, it is necessary to focus on ecological and environmental management and make up for the ecological shortcomings.
Discussion
The paper presents an empirical analysis of the coupled coordination of the three systems in 21 cities of Guangdong Province from the perspectives of economic development, social development, and ecological environment. Meanwhile, an attempt is made in the paper to construct a system lag type assignment system based on the ratio of the composite index of each subsystem, which is used to study the shortcomings of the cities’ coordinated development. The results show that:The spatial and temporal evolution of the coupling and coordination between 2010 and 2020 shows that the coupling and coordination between social, economic, and ecological systems in each city shows a trend of “increasing before decreasing.” However, the overall trend is still on the rise, and the cities’ ED-SD-EE system is at the stage of “high coupling-moderate coordination” in 2020. The degree of ED-SD-EE coordination among Guangdong’s cities is still insufficient, and the lagging impact of the ecological system is serious. The coupling of ED-SD-EE systems in Guangdong’s prefecture-level cities is inadequate. Subsequent government policies need to focus on the coordination between the ecological environment and economic and social.
The most economically developed region in Guangdong is the PRD region (Guangzhou, Shenzhen, Dongguan, Foshan, Zhongshan, Zhuhai, Jiangmen, Zhaoqing, and Huizhou), and there is no significant difference between its ED-SD-EE coupling and coordination degree and that of other non-PRD cities. The degree of coupling and coordination of “social-ecological” and “ecological-economic” is similar, and the degree of coupling and coordination of the two is slightly lower than that of “economic-social”.
In the Pearl River Delta region, especially in Guangzhou, Zhuhai, Shenzhen, Foshan, and Dongguan, many highly polluting and inefficient factories have been relocated since the introduction of plans and requirements such as “New Urbanization” in 2012 and “High Quality Development” in 2017. The introduction of enterprises with high technology content, for example, the introduction of Huawei in Dongguan and the creation of high-tech industrial clusters in Foshan mean that governments around the world are paying more and more attention to the harmonization of environmental and economic benefits. However, the economic, social, and ecological coordination of PRD cities is still in a relatively weak state, and the difference in the degree of coupling and coordination between ED, SD, and EE systems is not obvious.
Under the conditions defined by the data set, based on the results of the coupling coordination measurement combined with the analysis, it can be known that the epidemic has caused a certain negative impact on the coupling coordination of urban economy-society-ecology. In particular, it has caused a serious fragmentation of the urban ecological system from the economy and society, and ecological development has become a serious lagging factor in the high-quality and coordinated development of cities. Guangdong’s cities need to assess the extent to which previous policies have been implemented, how effective they have been, and the need for more scientific and better suited policy regulations for the long-term effects of the epidemic. However, Zhuhai was able to improve the degree of coupling and coordination after the onset of the epidemic. Subsequently, researchers can conduct relevant analyses of Zhuhai’s practices and industrial restructuring to provide lessons for other cities under the long-term effects of the epidemic.
Conclusion
The paper distinguishes between economic and social dimensions and constructs a three-system indicator system of urban economy-society-ecology and environment, which more comprehensively reflects the degree of coupled and coordinated development of social, economic, and ecological systems in cities. However, as the economy and society of cities are vast and complex systems, among which there are also the quality of public space for housing (Zhao et al. 2021), social media (Liu et al. 2022) and urban housing prices (Wu et al. 2018), which are all important components of the economic and social systems and can all have an impact on the economic and social development of cities.
Therefore, subsequent researchers can refer to the indicator system in the paper and add relevant available and scientific data from it to construct a more comprehensive indicator system for research on urban coupling and coordination and comprehensive evaluation of system development. The slow update of 2021 and subsequent yearbooks affects the author’s further research, and the article only tentatively points out the fragmentation of the coupling and coordination between ecological, environmental, social, and economic systems by the epidemic. Subsequent studies could construct a more comprehensive indicator system for cities (based on data availability) to explore the long-term effects of the epidemic on each system. This will help to eliminate the negative impact of the epidemic on the coordinated development of the city and to realize the potential of a good ecological environment to promote economic and social development.
To sum up, the possible marginal contributions of the paper are: (i) Through literature review, a comprehensive development evaluation index system for social, economic, and ecological systems at the municipal level in Guangdong Province is constructed. (ii) Distinguishing between economic and social development systems, the spatio-temporal evolutionary links between social, economic, and ecological systems are explored from the analysis of the coupling and coordination mechanism. (iii) By defining the temporal scope of the dataset, the impact of the epidemic on the degree of coupling and coordination among the social, economic, and ecological systems and the direction of its effects are explored. The results of the paper can provide scientific reference for the coordinated development of economic, social, and ecological systems in urban Guangdong Province.
Appendix
Table 4 Indicator weights for Guangdong Province and municipalities
Region U1 U2 U3 U4 U5 U6 U7 U8 U9
Guangdong 0.02487 0.03367 0.02284 0.02835 0.02591 0.02390 0.03536 0.03396 0.02104
Guangzhou 0.02754 0.03499 0.01665 0.03269 0.02309 0.02549 0.02899 0.03272 0.04033
Shenzhen 0.03000 0.02451 0.02452 0.01932 0.01821 0.02362 0.02276 0.04431 0.03305
Zhuhai 0.03408 0.02187 0.02761 0.04866 0.02357 0.02757 0.01899 0.02752 0.03013
Shantou 0.02530 0.03405 0.02831 0.02174 0.02618 0.02566 0.02667 0.03371 0.02565
Foshan 0.02223 0.04594 0.03518 0.02953 0.02971 0.02526 0.03480 0.03092 0.03055
Shaoguan 0.02096 0.02708 0.01138 0.03502 0.02077 0.02109 0.02806 0.01838 0.03781
Heyuan 0.01822 0.03893 0.02933 0.04104 0.02158 0.02043 0.02028 0.03529 0.02128
Meizhou 0.03340 0.02501 0.02240 0.03158 0.02347 0.02179 0.03995 0.03737 0.02293
Huizhou 0.01551 0.04677 0.01821 0.03050 0.01913 0.02078 0.05723 0.02735 0.02847
Shanwei 0.02384 0.03713 0.04109 0.03080 0.02356 0.02185 0.01916 0.03214 0.03104
Dongguan 0.01682 0.02813 0.02219 0.04170 0.02910 0.02341 0.02644 0.03075 0.03134
Zhongshan 0.02663 0.03320 0.01398 0.02954 0.01253 0.01740 0.02791 0.02027 0.02221
Jiangmen 0.01816 0.03113 0.02931 0.03308 0.02734 0.02807 0.05088 0.03369 0.02176
Yangjiang 0.01907 0.01968 0.03729 0.03323 0.01600 0.01648 0.04582 0.01587 0.05478
Zhanjiang 0.02755 0.03829 0.01805 0.02834 0.01851 0.01833 0.03327 0.03015 0.04256
Maoming 0.01788 0.02704 0.03388 0.02940 0.02098 0.02190 0.02893 0.02784 0.04487
Zhaoqing 0.02568 0.02604 0.01595 0.04430 0.02259 0.02289 0.02443 0.02868 0.04200
Qingyuan 0.01222 0.02279 0.01970 0.04648 0.02359 0.02402 0.03210 0.02821 0.05082
Chaozhou 0.01289 0.03602 0.02065 0.02439 0.01930 0.01791 0.03413 0.02866 0.03464
Jieyang 0.01837 0.03065 0.04637 0.02961 0.01880 0.01786 0.02957 0.03192 0.05674
Yunfu 0.02421 0.02511 0.03724 0.03705 0.02416 0.02415 0.05003 0.02191 0.03603
U10 U11 U12 U13 U14 U15 U16 U17 U18
Guangdong 0.02015 0.03374 0.02690 0.01589 0.03034 0.01972 0.05540 0.02403 0.03326
Guangzhou 0.01203 0.03581 0.02735 0.02836 0.03229 0.01843 0.02231 0.02515 0.04341
Shenzhen 0.02489 0.03515 0.02898 0.01633 0.02747 0.01846 0.04874 0.02490 0.01964
Zhuhai 0.03748 0.03841 0.02545 0.01709 0.02004 0.01909 0.03451 0.03184 0.02889
Shantou 0.02102 0.02946 0.02789 0.03165 0.03569 0.02176 0.02421 0.02055 0.03884
Foshan 0.02331 0.02867 0.02881 0.03387 0.03197 0.01587 0.01658 0.01843 0.05543
Shaoguan 0.01279 0.02586 0.02776 0.01636 0.01510 0.02106 0.01526 0.01770 0.02360
Heyuan 0.03750 0.02699 0.02364 0.01381 0.02614 0.02507 0.03088 0.01852 0.05281
Meizhou 0.01651 0.02944 0.02513 0.05243 0.04172 0.02275 0.01251 0.01145 0.04333
Huizhou 0.02401 0.03633 0.02642 0.04588 0.02990 0.01510 0.04727 0.02056 0.02767
Shanwei 0.02207 0.03084 0.02374 0.03007 0.03622 0.02387 0.01980 0.01412 0.05003
Dongguan 0.01402 0.02729 0.02140 0.05038 0.04061 0.01526 0.06341 0.03018 0.01487
Zhongshan 0.01509 0.03060 0.02739 0.05193 0.03566 0.01393 0.01961 0.01522 0.06175
Jiangmen 0.01775 0.03115 0.02726 0.02157 0.02280 0.02179 0.03397 0.02179 0.04192
Yangjiang 0.01513 0.02552 0.02568 0.02267 0.02345 0.01732 0.01667 0.01930 0.03150
Zhanjiang 0.03387 0.02546 0.02257 0.03405 0.01914 0.02029 0.02082 0.02238 0.05743
Maoming 0.03098 0.03086 0.02754 0.01153 0.02068 0.02501 0.01188 0.01860 0.06063
Zhaoqing 0.01496 0.03070 0.02739 0.01794 0.02177 0.01918 0.05156 0.01875 0.02443
Qingyuan 0.02949 0.03088 0.02859 0.03685 0.02791 0.02258 0.06523 0.02057 0.05112
Chaozhou 0.01958 0.02277 0.02297 0.03652 0.03723 0.02312 0.02645 0.01317 0.09794
Jieyang 0.01711 0.02077 0.02240 0.02141 0.02958 0.02034 0.01279 0.02175 0.02877
Yunfu 0.01707 0.02754 0.02666 0.01860 0.01878 0.02842 0.02398 0.01378 0.03943
U19 U20 U21 U22 U23 U24 U25 U26 U27
Guangdong 0.02005 0.02741 0.02674 0.05338 0.02386 0.01138 0.01596 0.02695 0.03028
Guangzhou 0.01787 0.03166 0.02556 0.04278 0.02334 0.02429 0.01406 0.03068 0.03592
Shenzhen 0.02052 0.02722 0.03776 0.02780 0.02666 0.04436 0.02214 0.03125 0.03351
Zhuhai 0.01574 0.03727 0.01663 0.02188 0.02557 0.01328 0.01953 0.03404 0.02398
Shantou 0.02740 0.02614 0.01977 0.05810 0.01713 0.04345 0.01728 0.02564 0.02559
Foshan 0.01106 0.02870 0.01515 0.04780 0.02524 0.01034 0.03364 0.03175 0.02802
Shaoguan 0.02593 0.02532 0.02583 0.05027 0.02075 0.03062 0.06346 0.02635 0.03137
Heyuan 0.03153 0.03064 0.03296 0.03266 0.01857 0.02854 0.03835 0.02423 0.02318
Meizhou 0.02981 0.02991 0.02277 0.03637 0.01986 0.03966 0.03732 0.02535 0.02572
Huizhou 0.01818 0.02234 0.01857 0.02859 0.02063 0.02329 0.01514 0.02358 0.02337
Shanwei 0.03244 0.02500 0.01263 0.02984 0.02298 0.05306 0.01762 0.02787 0.02678
Dongguan 0.01385 0.02443 0.04084 0.05614 0.02154 0.02035 0.02665 0.02315 0.02556
Zhongshan 0.02218 0.02839 0.02332 0.06522 0.01684 0.03590 0.01793 0.02348 0.02776
Jiangmen 0.02196 0.02691 0.01758 0.03763 0.02695 0.01407 0.01664 0.02922 0.03006
Yangjiang 0.02401 0.02224 0.04198 0.01735 0.01441 0.03912 0.06977 0.02385 0.02436
Zhanjiang 0.02920 0.02277 0.04491 0.03900 0.01503 0.02498 0.01599 0.02370 0.02914
Maoming 0.03128 0.02735 0.01974 0.04285 0.02029 0.04628 0.02499 0.02529 0.02514
Zhaoqing 0.02348 0.02826 0.01237 0.03000 0.02258 0.03683 0.02452 0.02720 0.03021
Qingyuan 0.02551 0.02235 0.01573 0.02144 0.01764 0.03094 0.02098 0.02824 0.02566
Chaozhou 0.01590 0.02291 0.01164 0.05606 0.01624 0.02451 0.02264 0.02777 0.02450
Jieyang 0.03743 0.02900 0.02057 0.03174 0.01456 0.04201 0.02936 0.02373 0.02203
Yunfu 0.04222 0.02476 0.01843 0.04758 0.01908 0.01436 0.04280 0.03298 0.02857
U28 U29 U30 U31 U32 U33 U34 U35 U36
Guangdong 0.02341 0.02755 0.02688 0.01182 0.03676 0.02835 0.02064 0.02093 0.02405
Guangzhou 0.02754 0.02349 0.02648 0.01447 0.02462 0.03075 0.01921 0.01532 0.02344
Shenzhen 0.02382 0.02567 0.02246 0.01026 0.01041 0.04361 0.02223 0.02033 0.03030
Zhuhai 0.02545 0.01648 0.02534 0.02194 0.01360 0.08225 0.01809 0.01793 0.02280
Shantou 0.02807 0.02094 0.02147 0.01805 0.01374 0.01624 0.03033 0.02705 0.02522
Foshan 0.03368 0.03425 0.02028 0.02087 0.01879 0.02008 0.01912 0.01492 0.01364
Shaoguan 0.01852 0.04385 0.02386 0.02117 0.02224 0.03843 0.03637 0.03269 0.04676
Heyuan 0.02465 0.01570 0.01418 0.01459 0.00909 0.02270 0.04609 0.04337 0.02935
Meizhou 0.01903 0.01538 0.01456 0.01274 0.01684 0.01873 0.04307 0.03003 0.02662
Huizhou 0.02437 0.02208 0.03597 0.02234 0.03722 0.04177 0.02352 0.01691 0.02592
Shanwei 0.02124 0.01525 0.03046 0.01033 0.02641 0.02233 0.02928 0.02466 0.02841
Dongguan 0.01996 0.03329 0.01615 0.00995 0.03149 0.02163 0.02271 0.01969 0.02139
Zhongshan 0.02747 0.02172 0.03144 0.01932 0.03096 0.03234 0.02282 0.02287 0.02626
Jiangmen 0.02696 0.02075 0.01337 0.02309 0.04743 0.03928 0.02015 0.02434 0.02693
Yangjiang 0.02151 0.02013 0.02851 0.00976 0.02233 0.06535 0.02358 0.02702 0.02535
Zhanjiang 0.01859 0.02820 0.02598 0.01101 0.02390 0.01678 0.03032 0.03076 0.02759
Maoming 0.02157 0.01936 0.01039 0.01341 0.03018 0.01754 0.03759 0.02240 0.03092
Zhaoqing 0.03567 0.03701 0.02662 0.02601 0.02781 0.04885 0.01461 0.01658 0.02807
Qingyuan 0.01695 0.01421 0.01707 0.02712 0.02366 0.02753 0.01773 0.01718 0.02692
Chaozhou 0.01898 0.01472 0.04319 0.01549 0.01113 0.03542 0.02512 0.02689 0.02300
Jieyang 0.03587 0.03874 0.02305 0.00951 0.02636 0.04648 0.02615 0.02052 0.02001
Yunfu 0.02535 0.01234 0.03845 0.01419 0.01793 0.03832 0.01587 0.01824 0.02734
U37 U38
Guangdong 0.02119 0.01307
Guangzhou 0.02418 0.01669
Shenzhen 0.02289 0.01194
Zhuhai 0.00905 0.02632
Shantou 0.03068 0.00937
Foshan 0.01457 0.02106
Shaoguan 0.00931 0.01088
Heyuan 0.00960 0.00827
Meizhou 0.00897 0.01409
Huizhou 0.00962 0.00951
Shanwei 0.02189 0.01018
Dongguan 0.01469 0.00920
Zhongshan 0.00967 0.01923
Jiangmen 0.01048 0.01278
Yangjiang 0.00849 0.01542
Zhanjiang 0.02251 0.00860
Maoming 0.03219 0.01081
Zhaoqing 0.01004 0.01402
Qingyuan 0.01391 0.01606
Chaozhou 0.02588 0.00972
Jieyang 0.01865 0.00944
Yunfu 0.00999 0.01705
U1, percentage of added value of primary industry; U2, percentage of added value of secondary industry; U3, percentage of added value of tertiary industry; U4, urbanization rate; U5, GDP per capita; U6, total gross domestic product; U7, price index; U8, total investment in fixed assets; U9, foreign direct investment; U10, total import and export volume of foreign enterprises; U11, deposits and loans in renminbi in all financial institutions; U12, savings deposit by household in all financial institutions; U13, natural population growth rate; U14, population density; U15, expenditure for education per capita; U16, proportion of educational practitioners in the whole society; U17, internal expenditure on R&D of industrial enterprises; U18, collections of public libraries per 10 persons; U19, number of medical beds per 10,000 people; U20, number of medical technical personnel; U21, proportion of environmental and public facilities practitioners in the whole society; U22, proportion of public management and social organizations practitioners in the whole society; U23, local government general budgetary revenue; U24, public transportation vehicles per 10,000 people; U25, area of parks and green land per capita; U26, local government general budgetary expenditure; U27, average wages of fully employed staff and workers in urban units; U28, electricity consumption; U29, volume of waste water discharged; U30, total volume of industrial waste gas emission; U31, volume of industrial soot (dust) emission; U32, volume of industrial solid wastes produced; U33, water use per capita; U34, water resource per capita; U35, average annual rainfall; U36, cultivated land area; U37, rate of sewage treatment; U38, rate of consumption waste treatment
Table 5 Subsystem lagging assignment
Guangdong ED SD EE Guangzhou ED SD EE Shenzhen ED SD EE Zhuhai ED SD EE
2010 3 5 0 3 5 0 2 3 1 3 5 0
2011 2 3 0 2 3 2 0 3 4 2 3 0
2012 2 3 0 2 3 2 0 2 4 2 3 1
2013 2 2 1 1 2 0 0 2 3 2 2 1
2014 1 1 1 1 2 1 1 1 1 0 2 3
2015 1 1 1 1 2 1 0 1 3 0 2 5
2016 0 1 2 0 1 2 1 0 2 0 1 4
2017 0 1 4 0 1 4 0 1 4 1 0 5
2018 0 1 6 0 1 5 1 0 4 1 0 6
2019 0 2 6 0 1 5 0 2 5 1 0 6
2020 0 2 6 0 1 6 0 1 4 2 0 5
Shantou ED SD EE Foshan ED SD EE Shaoguan ED SD EE Heyuan ED SD EE
2010 3 4 0 4 3 0 3 3 0 3 5 0
2011 1 1 1 3 2 0 3 2 0 0 1 3
2012 2 3 0 2 1 0 4 3 0 4 3 0
2013 2 3 0 0 1 2 2 2 0 3 2 0
2014 1 2 1 0 1 3 1 2 0 1 0 3
2015 2 1 0 2 2 1 2 2 1 0 1 4
2016 1 1 1 0 1 3 2 2 1 1 2 2
2017 0 1 6 0 1 4 0 2 5 0 1 6
2018 0 2 5 0 1 6 0 2 5 0 2 6
2019 0 2 6 0 1 6 0 2 3 0 2 5
2020 0 2 6 0 1 6 0 2 5 0 2 6
Meizhou ED SD EE Huizhou ED SD EE Shanwei ED SD EE Dongguan ED SD EE
2010 5 3 0 3 4 0 5 3 0 3 5 0
2011 4 2 0 3 2 0 3 2 0 0 1 2
2012 4 2 0 2 2 1 3 2 0 1 1 1
2013 3 2 0 0 2 3 2 4 0 0 1 3
2014 0 1 4 0 1 2 2 3 0 1 0 4
2015 0 2 5 1 2 2 0 2 3 0 1 3
2016 0 2 3 1 2 2 1 2 2 0 1 2
2017 0 2 6 0 1 6 0 2 5 0 2 5
2018 0 2 6 0 2 6 0 2 6 0 2 6
2019 0 2 6 0 1 6 0 2 6 0 3 6
2020 0 2 6 0 1 6 0 2 6 0 2 6
Zhongshan ED SD EE Jiangmen ED SD EE Yangjiang ED SD EE Zhanjiang ED SD EE
2010 3 3 0 4 3 0 4 3 0 3 5 0
2011 1 2 2 1 0 2 4 2 0 3 2 0
2012 2 2 1 2 2 0 3 4 0 4 2 0
2013 2 3 2 2 2 0 2 3 0 3 2 0
2014 1 2 1 0 1 3 0 2 3 1 2 0
2015 2 2 1 1 2 1 0 2 3 1 2 1
2016 1 3 1 1 2 1 0 2 3 1 2 2
2017 0 2 4 0 2 3 0 2 5 0 2 5
2018 0 2 5 0 1 5 0 1 4 0 2 5
2019 0 2 5 0 1 5 0 2 5 0 1 6
2020 0 2 3 0 1 6 0 2 6 0 1 6
Maoming ED SD EE Zhaoqing ED SD EE Qingyuan ED SD EE Chaozhou ED SD EE
2010 3 3 0 3 2 0 4 2 0 5 3 0
2011 1 2 1 3 2 0 2 0 5 4 3 0
2012 2 3 0 2 3 0 2 2 0 2 1 1
2013 2 3 0 2 2 0 2 3 0 2 2 0
2014 0 1 3 0 2 4 1 2 1 1 0 2
2015 0 1 2 0 2 4 2 2 1 0 2 3
2016 0 2 3 0 2 3 1 2 2 0 2 3
2017 0 2 5 0 1 6 0 1 5 0 2 6
2018 0 2 4 0 1 4 0 1 6 0 2 5
2019 0 2 5 0 1 4 0 2 5 0 2 5
2020 0 2 5 0 1 6 0 2 6 0 2 5
Jieyang ED SD EE Yunfu ED SD EE
2010 3 3 0 3 3 0
2011 3 2 0 2 2 1
2012 2 2 0 3 2 0
2013 2 2 1 1 0 2
2014 1 0 4 0 1 4
2015 0 1 4 0 1 3
2016 0 1 3 0 2 5
2017 0 2 5 0 2 5
2018 0 2 6 0 2 5
2019 0 2 4 0 1 5
2020 0 2 5 0 2 6
ED economic development system, SD social development system, EE ecological environment system
Author contribution
All the authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Fei Chen, Na Wang, and Dandan Zhang. The first draft of the manuscript was written by Fei Chen and Guotong Qiao, and all the authors commented on the previous versions of the manuscript.
Data availability
In addition to the above sources, all the raw data in the paper can also be obtained from the FIGSHARE website: “Spatio-temporal evolution analysis of the coupling situation of economic-social-ecological system in Guangdong. figshare. Dataset. https://doi.org/10.6084/m9.figshare.21430668.v1.”
Declarations
Ethical approval
Not applicable.
Consent to participate
In the paper, all the authors of the paper have agreed to be the authors of this study.
Consent for publication
All the authors have approved the manuscript and agreed with its submission to ESPR.
Competing interests
Not applicable.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Alfaro L Chanda A Kalemli-Ozcan S FDI and economic growth: the role of local financial markets[J] J Int Econ 2004 64 1 89 112 10.1016/S0022-1996(03)00081-3
Ariken M Zhang F Liu K Coupling coordination analysis of urbanization and eco-environment in Yanqi Basin based on multi-source remote sensing data[J] Ecol Ind 2020 114 106331 10.1016/j.ecolind.2020.106331
Binbin C Analysis of wage changes of employed persons in urban units and income disparity between industries[J] Stat Theory Pract 2021 06 62 68 10.13999/j.cnki.tjllysj.2021.06.012
Cai X, Xu S, LiI Z et al (2013) Regional ecological function analysis based on ecosystem health case of Guangdong province[J]. Guangdong Agric Sci 40(10):176–180
Chaerun SK Syarif R Wattimena RK Bacteria incorporated with calcium lactate pentahydrate to improve the mortar properties and self-healing occurrence[J] Sci Rep 2020 10 1 1 9 10.1038/s41598-020-74127-4 31913322
Chen H Qian W Wen Q The impact of the COVID-19 pandemic on consumption: learning from high-frequency transaction data[C] AEA Papers and Proc 2021 111 307 11 10.1257/pandp.20211003
Chen J Ding T Wang H Research on total factor productivity and influential factors of the regional water-energy- food nexus: a case study on Inner Mongolia, China[J]. Food nexus: a case study on Inner Mongolia, China[J] Int J Environ Res Public Health 2019 16 17 3051 10.3390/ijerph16173051 31443532
Chiaravalloti R, Freitas D, de Souza R et al (2021) Resilience of social-ecological systems: drastic seasonal change is associated with economic but not social flexibility among fishers in the Brazilian Pantanal[J]. Ecol Soc 26(2):30
Chuan T Review on environmental indicator research[J] Res Environ Sci 2000 13 4 53 55
Dou C, Zheng L, Wang W et al (2021) Evaluation of urban environmental and economic coordination based on discrete mathematical model[J]. Math Probl Eng 2021:1–11
Jiang L Bai L Wu YM Coupling and coordinating degrees of provincial economy, resources and environment in China[J] J Nat Resour 2017 32 5 788 799
Jianhua D Halik W Yuping Z Coupling coordinated development of population, economic and ecological system in the turpan area of China[J] J Desert Res 2015 35 1 260 266
Ke H Yang W Liu X Does innovation efficiency suppress the ecological footprint? Empirical evidence from 280 Chinese cities[J] Int J Environ Res Public Health 2020 17 18 6826 10.3390/ijerph17186826 32962066
Laurent É (2021) From welfare to farewell: the European socio-ecological state beyond economic growth[J]. ETUI Res Pap-Work Pap 2021
Lee KM Goh KI Strength of weak layers in cascading failures on multiplex networks: case of the international trade network[J] Sci Rep 2016 6 1 1 9 28442746
Li C Gao X He BJ Coupling coordination relationships between urban-industrial land use efficiency and accessibility of highway networks: evidence from Beijing-Tianjin-Hebei urban agglomeration, China[J] Sustain 2019 11 5 1446 10.3390/su11051446
Li G Spatiotemporal dynamics of ecological total-factor energy efficiency and their drivers in China at the Prefecture level[J] Int J Environ Res Public Health 2019 16 18 3480 10.3390/ijerph16183480 31540523
Li H (2021) Average wage data of 31 provinces reflect the current situation of regional industries[N]. China Econ Times 2021:003. [in Chinese ] 10.28427/n.cnki.njjsb.2021.002620
Li H Yang Z Yao X Entrepreneurship, private economy and growth: evidence from China[J] China Econ Rev 2012 23 4 948 961 10.1016/j.chieco.2012.04.015
Li WW, Sheng GP, Zeng R J et al (2012b) China’s wastewater discharge standards in urbanization[J]. EnvironSci Pollut Res 19(5):1422–1431
Liu J Jin X Xu W A new framework of land use efficiency for the coordination among food, economy and ecology in regional development[J] Sci Total Environ 2020 710 135670 10.1016/j.scitotenv.2019.135670 31787311
Liu K Qiao Y Shi T Study on coupling coordination and spatiotemporal heterogeneity between economic development and ecological environment of cities along the Yellow River Basin[J] Environ Sci Pollut Res 2021 28 6 6898 6912 10.1007/s11356-020-11051-0
Liu L Wang R Guan WW Assessing reliability of Chinese geotagged social media data for spatiotemporal representation of human mobility [J] ISPRS Int J Geo Inf 2022 11 2 145 10.3390/ijgi11020145
Liu YB Li RD Song XF Analysis of coupling degrees of urbanization and ecological environment in China[J] J Nat Resour 2005 20 1 105 112
Peijian Q, Jing L (2021) Shanghai releases market wage levels for skilled personnel in enterprises [N]. Workers Daily News 2021:007. [in Chinese] 10.28277/n.cnki.ngrrb.2021.005662
Qiu Y Li H Yang Z The prevalence and economic burden of pain on middle-aged and elderly Chinese people: results from the China health and retirement longitudinal study[J] BMC Health Serv Res 2020 20 1 1 10 10.1186/s12913-020-05461-6
Qiyue C Structure entropy weight method to confirm the weight of evaluating index[J] Syst Eng Theory Pract 2010 30 7 1225 1228
Rapport DJ What constitutes ecosystem health?[J] Perspect Biol Med 1989 33 1 120 132 10.1353/pbm.1990.0004
Shi Z Wu F Huang H Comparing economics, environmental pollution and health efficiency in China[J] Int J Environ Res Public Health 2019 16 23 4827 10.3390/ijerph16234827 31805634
Stuetzer M Audretsch DB Obschonka M Entrepreneurship culture, knowledge spillovers and the growth of regions[J] Reg Stud 2018 52 5 608 618 10.1080/00343404.2017.1294251
Sun X Zhang Z Coupling and coordination level of the population, land, economy, ecology and society in the process of urbanization: measurement and spatial differentiation[J] Sustain 2021 13 6 3171 10.3390/su13063171
Sun Y Liu N Shang J Sustainable utilization of water resources in China: a system dynamics model[J] J Clean Prod 2017 142 613 625 10.1016/j.jclepro.2016.07.110
Wang D Jiang D Fu J Comprehensive assessment of production-living-ecological space based on the coupling coordination degree model[J] Sustain 2020 12 5 2009 10.3390/su12052009
Wang J Han J Hu C Research of urban compound ecological system symbiosis model and its application[J] China Popul Resour Environ 2012 22 11 291 296
Wang L Xu G Liu M Analysis and forecasting of shanghai urban ecosystem evolution based on information entropy and GM (1, 1)[J] Acta Sci Circum 2016 36 6 2262 2271
Wu H Jiao H Yu Y Influence factors and regression model of urban housing prices based on internet open access data[J] Sustain 2018 10 5 1676 10.3390/su10051676
Xia X Lin K Ding Y Research on the coupling coordination relationships between urban function mixing degree and urbanization development level based on information entropy [J] Int J Environ Res Public Health 2021 18 1 242 10.3390/ijerph18010242
Xie X Sun H Gao J Spatiotemporal differentiation of coupling and coordination relationship of tourism-urbanization -ecological environment system in China's major tourist cities[J] Sustain 2021 13 11 5867 10.3390/su13115867
Yang C Zeng W Yang X Coupling coordination evaluation and sustainable development pattern of geo-ecological environment and urbanization in Chongqing municipality, China[J] Sustain Cities Soc 2020 61 102271 10.1016/j.scs.2020.102271
Yang Y Bao W Liu Y Coupling coordination analysis of rural production-living-ecological space in the Beijing-Tianjin-Hebei region[J] Ecol Ind 2020 117 106512 10.1016/j.ecolind.2020.106512
Zhang L Zheng XQ Meng C Spatio-temporal difference of coupling coordination degree of land use functions in Hunan province[J] China Land Sci 2019 33 85 94
Zhang XY Liu JJ The evolution and orientation choice of environmental regulation policy in PRC from 1949 to 2019[J] J Reform 2019 10 16 25
Zhao J Peng Z Liu L Evaluation on the internal public space quality in affordable housing based on multi-source data and IPA analysis[J] Land 2021 10 10 1000 10.3390/land10101000
Zhong Y Liu W Economic features of modern service cluster and their implications [J] Trop Geogr 2012 32 568 574
Zhu C Lin Y Zhang J Exploring the relationship between rural transition and agricultural eco-environment using a coupling analysis: a case study of Zhejiang Province, China[J]. study of Zhejiang Province, China[J] Ecol Indic 2021 127 107733 10.1016/j.ecolind.2021.107733
Zuo Z Guo H Cheng J How to achieve new progress in ecological civilization construction?-Based on cloud model and coupling coordination degree model[J]. How to achieve new progress in ecological civilization construction?-Based on cloud model and coupling degree model[J] Ecol Indic 2021 127 107789 10.1016/j.ecolind.2021.107789
| 36462076 | PMC9734722 | NO-CC CODE | 2022-12-14 23:28:30 | no | Environ Sci Pollut Res Int. 2022 Dec 3;:1-21 | utf-8 | Environ Sci Pollut Res Int | 2,022 | 10.1007/s11356-022-24444-0 | oa_other |
==== Front
Curr Psychol
Curr Psychol
Current Psychology (New Brunswick, N.j.)
1046-1310
1936-4733
Springer US New York
4112
10.1007/s12144-022-04112-9
Article
Exploring the associations among perceived teacher emotional support, resilience, Covid-19 anxiety, and mental well-being: evidence from Chinese vocational college students
Fan Chunhong [email protected]
12
http://orcid.org/0000-0002-6658-7321
Liu Shujie [email protected]
1
1 grid.412638.a 0000 0001 0227 8151 College of Education, Qufu Normal University, Qufu City, Zip: 273165 Shandong Province China
2 Shandong Polytechnic College, Jining City, Zip: 272000 Shandong Province China
8 12 2022
111
29 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
This study aimed to examine the relations between perceived teacher emotional support, Covid-19 anxiety, resilience, and mental well-being among Chinese vocational college students during Covid-19 pandemic. A sample of Chinese vocational college students (n = 1469) were surveyed with an online questionnaire composed of Teacher Emotional Support, Covid-19 Anxiety Scale, Brief Resilience Scale and Mental Well-being in Chinese version. Path analysis was employed in the study and the results showed that teacher emotional support was an important promoter for building up mental well-being but not a buffer for Covid-19 within Chinese cultural context, and the Covid-19 anxiety was significantly and negatively related to mental well-being. Resilience hindered the incidences of Covid-19 anxiety and was a significant protector for mental well-being. Covid-19 anxiety mediated the both relations between teacher emotional support and mental well-being, and resilience and mental well-being. These findings provided practical implications for coping with psychological problems and flourishing mental well-being among Chinese vocational college students.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12144-022-04112-9.
Keywords
Teacher emotional support
Resilience
Covid-19 anxiety
Mental well-being
==== Body
pmcIntroduction
The worldwide Covid-19 pandemic has being lasting for more than two years, with occasional emergencies of extremely serious conditions in some areas. Covid-19 was considered to be the first worldwide pandemic causing unpredictable psychological, social and economic consequences (WHO, 2020). Some people are faced with inadequate access to supplies, restricted physical exercise and entertainment activities (Brooks et al., 2020). While people adjust their behaviors, thoughts and emotions to the threatening changes, anxiety and stress are generally considered as the common responses to the threat in the emotional, cognitive, and behavioral domains (Borkovec, 2002; Zysberg & Zisberg, 2020), which bring about severe impact on mental health. All age groups were reported to have adverse mental and psychological health problems caused by the pandemic, among whom college students were considered as one of the vulnerable groups. They were at more increased risk for anxiety because of the disruptions of abnormal academic study and restricted social life on campus, and the pre-existing higher level of psychological distress (e.g., Ye et al., 2022). In China, most vocational college students come from the background of low economical status, and tend to be more anxious about their academic achievements and future work than their counterparts in other types of higher education (e.g., Yang, 2020). What’s more, social discrimination against vocational education makes them be faced with more pressure (Zhang, 2019). Thus, they may become even more worried about the aggravated uncertainty of their future during the pandemic. Accumulating studies demonstrated that high level of anxiety among college students has increased around the world (e.g., Amerio et al., 2020). As the most common psychological response to emergencies, anxiety leads to many obvious negative results, one of which is the decrease of the mental well-being now and in future (Qiu et al., 2020; Stallings et al., 1997; Xu et al., 2020). Mental well-being embodied people’s physical health, psychological health, and social adaption and even academic or work achievements (Diener et al., 2018). It is an important indicator for life quality and reflects the over whole valuation concerned with society, economy and even environment. Therefore, researchers have proposed various strategies to cope with the hinders for mental well-being, especially with the background of Covid-19.
The Covid-19 epidemic irregularly happened in some areas in 2022. When that occurred, some restrictions were implemented in response to the Covid-19 pandemic in China. In-person learning, non-essential activities, and social interaction activities were limited in students’ daily life at vocational colleges (Burns et al., 2020). The epidemic was not far away from Chinese vocational college students, which suddenly increased students’ worries about their family members’ health, academic achievement, and uncertainty of future work, which resulted into various psychological problems and has caused attention from college faculty and society (Tan et al., 2021). Against this backdrop, colleges have reaffirmed the importance of applying multiple measures to student mental health following the Covid-19 pandemic (e.g., He & Jin, 2022). Correspondingly, researchers proposed mental health determinants to cope with the successive psychological problems and enhance mental well-being based on theory or empirical studies (e.g., Yalçın et al., 2022). Therefore, it is necessary to measure the prevalence and severity of anxiety among vocational college students via well-designed studies to explore students perceptions of teacher emotional support and their resilience to comprehend the impact of preventive behaviors on anxiety and mental health and identify relevant protective factors to cope with the anxiety efficiently and effectively during the Covid-19 pandemic (Cheng et al., 2020). As such, testing a path model among perceived teacher emotional support, Covid-19 anxiety, resilience and mental well-being at the height of the pandemic crisis and lockdown for the vocational colleges seems both appropriate and timely. The present study explored the relations between teacher emotional support and Covid-19 anxiety, teacher emotional support and mental well-being, Covid-19 anxiety and mental well-being, resilience and Covid-19 anxiety, and resilience and mental well-being. We also studied effects of the mediator of Covid-19 between teacher emotional support and mental-welling, as well as resilience and mental well-being.
Literature review
Teacher emotional support, anxiety, and mental well-being
Support is often identified as a key component of solid relationships and strong psychological health. Theoretically, emotional support is categorized into general and specific ones. Specific emotional support, according to the sources of support, is also divided into parental support, teachers support, peers support and others (Yasin & Dzulkifli, 2010), which are considered as an essential component of social support. These supports perceived by students have been demonstrated as an important factor to improve students’ ability to deal with various difficulties and boost academic performance (e.g., Cao et al., 2020). In practice, several dimensions of teacher support are identified, such as emotional, informational, appraisal, and instrumental support (Federici & Skaalvik, 2014).
Teacher emotional support is a critical factor for students in their life, as it has been shown to have significant impact on psychological health. Except for daily support at schools, teacher emotional support also comes in the form of warmth, trust, respect, love and care when students are confronted with various reverse situations (e.g., Lakey & Cohen, 2000). A large number of literature showed that teacher emotional support is a protective element that can help students who were socially anxious to reduce psychological problems, such as loneliness, depression and anxiety (Federici & Skaalvik, 2014; Yang et al., 2018).
Some studies showed that teacher emotional support was a buffer for anxiety and helped manage psychological problems (Cao et al., 2020; Yalçın et al., 2022; Yang, 2020). Elliot and Gramling (1990) for example found that teacher emotional support helped the college students to cope with and lessen anxiety. Yang (2020) empirically showed that support from family members, friends and teachers was negatively related with anxiety among vocational college students. Other studies also found that anxiety happened more frequently to vocational college students who were in short of support than those with desired support (e.g., Zhang, 2019). There are also studies about teacher emotional support on anxiety caused by the burden of academic workload (Villanova & Bownas, 1984). For example, perceived teacher emotional support in mathematics lessons reduced the impact of anxiety on math achievement among students (Federici & Skaalvik, 2014).
Reversely, there are certain differences in the results and degrees of the impact of students’ perceived teacher support on anxiety, as the levels of anxiety may also depend on the levels of the support perceived or experienced by individuals. Or in other words, a greater level of anxiety may have a more negative impact on one’s perception of teacher emotional support. Munir and Jackson (1997) reported that socially anxious women have been shown to be eager for a higher level of social support, but to be reported to perceive lower levels of social support than non-anxious women.
A substantial number of studies have also demonstrated a close relation between teacher emotional support and psychological health (e.g., Yasin & Dzulkifli, 2010). The previous studies showed that teacher emotional support was positively related with mental well-being and tended to directly enhance students’ happiness and satisfaction. When teacher emotional support was perceived as resultant feelings of belonging, relatedness, safeness and other positive emotional experiences, it explained positive impact on students’ well-being (Baumeister & Leary, 1995). While other researches demonstrated the indirect effect from teacher emotional support on mental well-being through decreasing the negative and unpleasant emotional experience (Anser et al., 2021).
However, there are rare studies exploring whether and how perceived teacher emotional support can influence Chinese vocational college students’ anxiety during the Covid-19 pandemic. The extent to which perceived teacher emotion support has effect on Chinese vocational college students’ mental well-being is yet to be studied. Based on the previous literature, the study aimed to exam how and to what extent perceived teacher emotional support exerts its effects on Covid-19 anxiety and mental well-being among vocational college students in Chinese educational context, and the following hypotheses are put forward.H1: Perceived teacher emotional support is negatively related to Covid-19 anxiety.
H2: Perceived teacher emotional support has a positive effect on students’ mental well-being (MWB).
Anxiety and mental well-being
Mental well-being is considered to be a general psychological factor reflecting people’s physical health, psychological health, and social adaption (Munir & Jackson, 1997). Based on the bottom-up model, the negative emotion of anxiety experienced by individuals may cause the decrease in quality of the whole life (Poole et al., 2017; Stallings et al., 1997). Conversely, empirical studies have shown that college students who enjoyed a higher sense of happiness tended to have lower depression compared with their peers. Anxiety is generally described as typically emotional, cognitive, and behavioral responses to threat, disaster and other unfamiliar environments. Thus, it may be the most common response pattern to the pandemic crisis among vocational college students. Covid-19 anxiety increases the incidence of psychological problems, and poses threats to mental well-being of college students across countries (Cao et al., 2020; Wang et al., 2021). The existing evidences showed that Covid-19 anxiety was negatively related to well-being (e.g., Yıldırım & Arslan, 2022). It increases the negative impact of adverse events on mental well-being. Studies also demonstrated that people who had experienced natural disasters tended to live with poor mental health (Qiu et al., 2020; Tan et al., 2021), and the same was true for the vocational college students going through the pandemic.
Aforementioned literature described the relationship between anxiety and mental well-being, but less was known about how Covid-19 anxiety amplified or ameliorated mental well-being. This study tends to make use of a testing model to exam the extent to which Covid-19 anxiety exerts the influence on mental well-being and how Covid-19 anxiety influences mental well-being and the relation between teacher emotional support and mental well-being to provide theoretical basis for the protective strategies. The following hypothesis is put forward.H3: The Covid-19 anxiety negatively predicts mental well-being.
Resilience, anxiety, and mental well-being
Resilience is generally considered as a protective factor to decrease the level of distress (Cheng et al., 2020; Gundogan, 2021) or a kind of ability to survive or even thrive in an adverse or changing circumstances (e.g. Smith et al., 2008). It is closely related with people’s thriving and thus has an obviously positive influence on not only individual development but also personal emotions. Research has shown that resilience is an important psychological resource that can lessen people’s anxiety emerging from life’s adversities in different disciplines and cultures (Yang et al., 2018). Constant studies also revealed resilience exerted positive effects on a variety of mental health and well-being during the pandemic (e.g., Arslan, 2019).
The resilience interventions have been revealed to help protect college students from various mental disorders and make them keep in good mental conditions (e.g., Millear et al., 2008). The previous studies have widely reported that the levels of resilience were positively related to the extent of the quality of life which was one of the key factors reflecting mental well-being (Arslan, 2019; Liossis et al., 2009). Liu et al. (2019) found that students with stronger resilience had a lower level of depression which resulted from the stress of negative events, while Poole et al. (2017) found that resilience contributed to the mental health of adults who experienced abuse in childhood. Most recently, two studies of health care staff and college students respectively showed that individuals with stronger resilience experienced lower depression during the Covid-19 pandemic than those with weaker resilience (Labrague & De los Santos, 2020; Luceño-Moreno et al., 2020).
Based on the previous research, it is found that resilience has not been measured in vocational college students in relation to Covid-19 anxiety and mental well-being. This study aims to exam the variables of resilience, Covid-19 anxiety and mental well-being in relation to one another for proposing protective factors for improving vocational college students’ mental well-being during the critical times. The following hypotheses are put forward.H4: Resilience is negatively related with Covid-19 anxiety.
H5: Resilience is positively related with mental well-being.
Mediating role of anxiety
Anxiety is identified as a sustained mental health problem and closely related to support and mental well-being. Some studies proved that anxiety mediated the relationship between support and mental well-being (e.g., Guo et al., 2020). Social support affected students’ mental well-being not only directly but also through anxiety. Huang et al. (2021) explored the mediating mechanism in the relationship between social support and mental well-being, and found that anxiety partly mediated the association between them. Guo et al. (2020) also demonstrated that teacher support was indirectly associated with mental well-being via negative emotions (e.g., depression, anxiety and stress) among adolescents.
In the literature, much attention was paid to the mediating effect of anxiety between resilience and well-being. Gundogan (2021) empirically identified fear of COVID-19 as a potential mediator in the relationship between resilience and life satisfaction. However, few studies examined whether anxiety mediated the relationship between resilience and well-being. Surzykiewicz et al. (2021) examined the mediating effect of Covid-19 anxiety in the link between resilience and mental well-being in the Polish population.
Based on the extant literature, the present study aims to exam whether the Covid-19 anxiety mediates the relationship between perceived teacher emotional support and mental well-being, and that between resilience and mental well-being. The following hypotheses are put forward.H6: Covid-19 anxiety mediates the relationship between perceived teacher emotional support and mental well-being.
H7: Covid-19 anxiety mediates the relationship between resilience and mental well-being.
Teacher emotional support, resilience, and mental well-being
Amount of literature revealed that resilience is closely related with perceived support, well-being, academic achievement, coping behaviors and the other aspects concerned with psychology (Hu et al., 2018; Yasin & Dzulkifli, 2010). Some studies demonstrated the interrelationship between social support and resilience in practical application. In fact, being able to turn to others for support is a key component of being resilient which like wise can be enhanced by various protective behaviors, such as social support (Yang et al., 2018). Ye et al. (2022) examined the relation between perceived parental support and resilience among college students during Covid-19 and found that there was a significantly positive correlation between them. A bi-directional relationship has been identified between teacher emotional support and resilience (e.g., Labrague & De los Santos, 2020). They enhance each other and subsequently lead to better emotional and psychological adjustment. In addition, resilience partially played a moderating role but an intermediary role between anxiety and emotional support (Hu et al., 2018), while teacher emotional support exerted both direct and indirect influence on mental health to reduce anxiety and improve well-being because of its direct relation with mental emotions (Ryan & Deci, 2000).
It also has been well demonstrated that both resilience and social support exerted a direct influence on anxiety and well-being (Federici & Skaalvik, 2014). Recent studies showed that perceived social support and resilience were factors for promoting the prosperity of mental health under increasing anxiety (e. g., Hu, et al., 2018). They both directly related to psychological problems and reduced the levels of anxiety (Hu et al., 2018). It is even revealed that perceived social support, resilience and mental well-being have great influence on psychological anxiety among university students (Elliot & Gramling, 1990).
The extant literature revealed that although some studies explored the relations between support and resilience, more research was focused on social support and the mediating effects of the both variables were examined. In such, this study examines the relationship between resilience and perceived teacher emotional support among vocational college students during specific period of the pandemic, and explores how and to what extent they influence anxiety and mental well-being in order to provide theoretical base for making suggestions to reduce anxiety and promote mental well-being among vocational college students during emergent times.
Present study
The literature has addressed the relationship among variables of teacher emotional support, resilience, Covid-19 anxiety and mental well-being. However, few literature focus on the phenomenon that Chinese vocational college students tend to be more vulnerable in times of crisis. The present study aimed to explore whether teachers in vocational colleges provide students with effective support for coping with psychological problems and check if resilience could be chosen as an alternative way to help students deal with Covid-19 anxiety to foster mental well-being. The study also examined the mediating effects of Covid-19 anxiety in the relationship between teacher emotional support and mental well-being, and that between resilience and mental well-being to assess the influence of Covid-19 anxiety on the construction of mental well-being of vocational college students. Corresponding strategies were proposed for teachers to provide effective and sufficient support for Chinese vocational college students to cope with psychological problems and facilitate college students’ mental well-being. The framework and hypotheses of the research are presented as in Fig. 1.
Method
Participants
The participants of the study were composed of 1469 Chinese vocational college students, consisting of freshmen, sophomores, and juniors, 582 (39.6%) females and 887 (60.3%) males. This was a convenient sample legitimating for statistical analysis (Coladarci & Cobb, 2013). All participants filled out a consent form and participated in the study between March and April 2022 when vocational colleges were locked down because of outbreak of Covid-19. In China, most vocational college students study and live on campus dormitories. In such, their couldn’t go out dating with limited social activities and their entertainment was restricted to campus because of the lockdown. The vocational college students surveyed in this study have a three-year academic system with study during the first two years and practice in enterprises in the third year. All of the participants were selected to voluntarily fill out the online survey package. Four contact teachers responsible for managing students affairs in vocational college shared the link of the questionnaire and informed the purpose of the study. They were granted the right to give up answering the questions or withdraw while answering the questions at any time. The confidentiality of their data was ensured. Finally, a sample of 1469 was valid after deleting those which were unfinished or noncompliance with requirements. Among the 1469 participants, 1170 (79.6%) were freshmen; 239 (16.3%) were sophomores and 59 (4.0%) were juniors. Their family incomes varied: 46.8% with income below 50,000 yuan, 25% with income from 50,000 to 60,000, 16.2% with income from 60,000 to 100,000, and 12% with income over 100,000.
Measures
Teacher Emotional Support (TES)
Students’ perceptions of the teachers emotional support were measured by the modified Teacher Emotional Support, the original scale of which has been previously tested (Federici & Skaalvik, 2014; Skaalvik & Skaalvik, 2013). It was composed of six items designed to gauge students’ feelings of being liked, respected, and valued by teachers during the pandemic, which was considered as students’ perceived emotional dimension of the teacher-student relationship (Federici & Skaalvik, 2014). For instance, the item of “I feel that my math teacher cares about me.” and “My math teacher wants what is best for me.” were included in the questionnaire. The response categories for all items were ranged on a 5-point scale from 1 (not applicable to me) to 5 (very applicable to me). In the current sample, Cronbach’s alpha for the entire questionnaire was 0.907.
Brief Resilience Scale (BRS)
The Brief Resilience Scale (BRS) (Smith et al., 2008) was modified into Covid-19 context for measuring participants resilience. It was composed of six items to assess an individual’s ability to bounce back after the negative influence of epidemic. The extent to which participates thought the items were applicable to them ranged from 1 ( not applicable to me) to 5 (very applicable to me). Three items were reverse scored for the scale, including “I have a hard time making it through Covid-19 lockdown”, “It is hard for me to snap back when something bad happens during Covid-19 period”, and “I tend to take a long time to get over set-backs caused by Covid-19”. Thus, the BRS was scored by reverse coding the three items. The scale was proved to have an adequate reliability (α = 0.707).
Covid-19 Anxiety Scale (CAS)
Covid-19 Anxiety Scale (CAS) ( Silva et al., 2022), consisted of seven items, which was designed to accurately measure/gauge the fluctuant psychology in anxiety levels caused by Covid-19. Five-likert scoring method was used ranging from 1 (not applicable to me) to 5 (very applicable to me) to indicate how much each item applied to their behavior during the pandemic period. A total of the seven items, such as “I feel bad when thinking about Covid-19”, “I feel anxious about Covid-19 anxiety” and “I am afraid of being infected with Covid-19”, were reversed into Chinese context. Two experts were invited to checked the content of the CAS and showed agreement on its suitability for Chinese vocational college students. In the current sample, Cronbach’s alpha for the entire questionnaire was 0.932, showing an adequate reliability.
Mental Well-being (MWB)
MWB was assessed using the World Health Organization’s 5-item Well-being Index (WHO-5) which is a short and generic global rating scale, only containing positively phrased items. While WHO considers positive well-being to be another term for mental health (Jahoda, 1958), this study adopted WHO-5 to measure the mental well-being. The participants expressed their attitude toward each of the statements on a 5-point scale ranging from 1 (not applicable to me) to 5 (very applicable to me). The WHO-5 has been examined by the item response theory model formulated by Rasch (Rasch, 2012), and measured in different European countries and in clinical trials, and proved good reliability and validity (e.g., Surzykiewicz et al., 2021). When the WHO-5 was used in the current sample, the result of the scale showed good reliability (α = 0.893).
Analytical procedures
In the present study, SPSS22.0 was applied to check the validity of each scale by exploratory factor analysis (EFA) and then obtain Cronbach’s alpha. The normality of data distribution was assessed by skewness (SK) and kurtosis (KU). Descriptive analysis procedures (mean, standard deviation) were performed for all the studied variables. And then Pearson correlation analysis was to explore associations between various variables (TES, CBRS, CAS and MWB). After that, the model of path analysis was established on the results of previous analysis. Then, Mplus was adopted to construct paths and their results were interpreted using standardized path estimate (β) scores and squared multiple correlations (R2) to explore the relations among variables and check if Covid-19 mediated the relationship between teacher emotional support and mental well-being and that between resilience and mental well-being. In addition, the bootstrap method with 5000 resamples was used to estimate the 95% confidence intervals (CIs) to investigate the indirect effect between variables (Hayes, 2017) in the study.
Results
Descriptive and pearson’s correlation results
The skewness coefficients of TES, Resilience, Covid-19 anxiety, and MWB were -0.495, 0.695, 0.598, -0.385 and the kurtosis coefficients were -0.272, 0.357, -0.272, -0.464, falling between -1 and 1. The data was good for analysis with a robust estimate (Lei, 2005; Muthen & Kaplan, 1985). The means, standard deviations, scale reliabilities, and Pearson correlations for teacher emotional support, Covid-19 anxiety, resilience, and mental well-being are presented in Table 1. It shows that teacher emotional support is positively correlated with mental well-being (β = 0.809, p < 0.001) and resilience (β = 0.351, p < 0.001). However, it has negative relation with Covid-19 anxiety to some extent (β = -0.041, p > 0.05). A negative and strong relationship was observed between Covid-19 anxiety and mental well-being (β = -0.143, p < 0.001). Resilience is negatively associated with Covid-19 anxiety (β = -0.352, p < 0.001) but has positive correlation with mental well-being (β = 0.391, p < 0.001).
Model of path analysis
After the descriptive statistics, path analysis model was constructed to examine the relations between teacher emotional support and Covid-19 anxiety, teacher emotional support and mental well-being, Covid-19 anxiety and mental well-being, resilience and Covid-19 anxiety, and resilience and mental well-being. The path from teacher emotional support to Covid-19 anxiety to mental well-being and another path from resilience to Covid-19 anxiety to mental well-being was also constructed.
As presented in Fig. 2, the results of the path model showed that teacher emotional support (TES) was a significant positive predictor for mental well-being (MWB) but showed direct positive effect on Covid-19 anxiety. Covid-19 anxiety was a buffer for mental well-being. Resilience was a promoter for mental well-being but negatively related to Covid-19 anxiety. As showed in Table 2, TES significantly predicted mental well-being with direct positive path to it (β = 0.773, p < 0.001), while it exerts direct positive effect on Covid-19 anxiety (β = 0.094, p < 0.001) which in turn had a significant negative path to mental well-being (β = -0.078, p < 0.001). On the other hand, resilience showed significant paths to Covid-19 anxiety, mental well-being and teacher emotional support. In details, it had a significant positive path to mental well-being (β = 0.092, p < 0.001) and a significant negative path to Covid-19 anxiety (β = -0.386, p < 0.001). Finally, teacher emotional support and resilience were significantly interrelated and the double paths between them were significant (β = 0.351, p < 0.001). The squared multiple correlation of Covid-19 anxiety is 0.133 (R2 = 0.133) and that of the mental well-being is 0.672 (R2 = 0.672).
Furthermore, there were statistically significant mediating effects of Covid-19 anxiety among vocational college students as the path model was constructed with teacher emotional support and resilience as independent variables, Covid-19 anxiety as mediator and mental well-being as dependent variable. The first path is from teacher emotional support to Covid-19 anxiety to mental well-being (β = -0.007, p < 0.01), that is, teacher emotional support significantly predicted mental well-being indirectly through Covid-19 anxiety. The total effect from teacher emotional support to mental well-being was significant (β = 0.016, p < 0.001). Thus Covid-19 anxiety partially mediated the relation between teacher emotional effect and mental well-being. The second path is from resilience to Covid-19 anxiety to mental well-being (β = 0.030, p < 0.01), that is, resilience significantly predicted mental well-being indirectly through Covid-19 anxiety. The total effect from resilience to mental well-being was significant (β = -0.294, p < 0.001). Thus Covid-19 anxiety partially mediated the relation between resilience and mental well-being.
Discussion
The present study examined relations among perceived teacher emotional support, resilience, Covid-19 anxiety, mental well-being among vocational college students during the period of the pandemic outbreak. We first hypothesized that perceived teacher emotional support would have direct effects on Covid-19 anxiety, mental well-being and resilience. Results from the path analysis indicated that perceived teacher emotional support positively predicted both Covid-19 anxiety and mental well-being. Covid-19 anxiety was significantly and negatively related with mental well-being. The second and third hypotheses in the study are supported except for the first one. The results suggested that the more emotional support vocational college students perceived from their teachers, the more mental well-being they would have during the Covid-19 period, and the vocational college students with lower Covid-19 anxiety tended to be more happy and in a better state of mental well-being. These findings were consistent with those of the previous studies (Wang et al., 2021; Yıldırım & Arslan, 2022). The result also indicated that perceived teacher emotional support was significantly and positively predicted Covid-19 anxiety. Vocational college students who perceived teachers’ care, warmth and respect felt nervous or even anxious during the period of pandemic outbreak. This finding is consistent with few studies (Munir & Jackson, 1997; Zysberg & Zisberg, 2020) but contrary to many others (Yang et al., 2018; Yasin & Dzulkifli, 2010).
The first hypothesis that teacher emotional support is negatively related to Covid-19 anxiety is not supported in the present study. The reason may be that the present study was carried out in Chinese context among vocational college students almost all of whom are adults and educated to be independent and cope with problems by themselves. They are shy and reluctant to be over cared because of the features of youth age and the deep influence of the old saying “The demands that a gentleman makes are upon himself; those that a mean man makes are upon others” by Confucius (Beijing Sihai Classic Culture Communication Center, 2018).
Based on person-environment fit theory, there is a mutual relationship between the individual and the environment, and vocational college students are worried with not only their study but also future work as soon as they entered colleges, as they are enrolled into colleges because of their lower academic achievement in the nationwide College Entrance Examination and two years of courses at vocational college is much shorter than that of other types of higher education. Thus, teachers are suggested to recognize which types of emotional support is most strongly associated with Covid-19 anxiety and construct a supportive environment that meets vocational college students multiple needs.
On the other hand, teachers disregard of personal and interpersonal factors that potentially moderate teacher-student relationship and oversimplify emotional support. The possible interpretation may be that teachers show unexpected concerns about students’ psychological health and physical health, or pay extremely more attention to vocational college students during the pandemic. Therefore, students may suppose that the pandemic is worse. They become more concerned about their family, doubt about their psychological health and physical health and thus feel uneasy (Elliot & Gramling, 1990). Thus the perceived teacher emotional support turn out to be a source of Covid-19 anxiety. Teachers are suggested to take into consideration of the interpersonal and personal factors in the process of providing emotional support for vocational college students (He & Jin, 2022).
In addition, the social recognition of vocational education is comparatively low and different types of source of student make perceptions varied. On the other hand, Novice teachers are generally assigned to be in charge of vocational college students management. Therefore they have to strengthen students management under greater pressure (Lin, 2022), and are over concerned with students affairs especially during the early phase of pandemic outbreak. But excessive emotional support makes vocational students experience more controlled environment which undermines self-determination and increases psychological problems (Karimi & Fallah, 2021; Ryan & Deci, 2000). Coyne and DeLongis (1986) also argued that excessive involvement, protectiveness, and intrusiveness in teacher-student relationship were very distressing and increased anxiety. Vocational colleges should consider organizing trains for novice teachers to empower them skills in comprehensive integration of education and management.
Next, the findings of the present study empirically confirmed the hypothesis that resilience has a direct and significant effect on both Covid-19 anxiety and mental well-being. The results showed that vocational college students with higher resilience tend to feel less anxious and have higher mental well-being, which indicated that resilience could reduce the level of Covid-19 anxiety and play an importantly protective role in psychological health and mental well-being. Thus, vocational college students with high levels of resilience feel better quickly after unpleasant experiences or return to original life after being hurt caused Covid-19. As a result, the fourth and fifth hypotheses were both supported in the study. The findings obtained in this study are also supported by the results of other studies in the literature (e.g., Cheng et al., 2020; Yang et al., 2018). Millear et al. (2008) found that high levels of resilience improved mental health and well-being. Teachers in vocational colleges should carry out valuable activities with diversity, rich forms and strong attraction to help students build up resilience which is a critical tool to facilitate emotional regulation among Chinese vocational college students (Cheung et al., 2020).
Finally, it is worthy to note that the present study showed Covid-19 anxiety mediated both relationships between teacher emotional support and well-being, and between resilience and mental well-being. The sixth and seventh hypotheses were supported. The results were consistent with some previous studies (e.g., Gundogan, 2021; Guo et al., 2020). The results also proved that perceived teacher emotional support and resilience had a close relation with each other. Teacher emotional support helps vocational college students build up resilience and reversely, resilience helped promote students’ perception of the support from teachers. The previous study also showed that support significantly correlated with resilience (Yang et al., 2018; Ye et al., 2022). In addition the findings in the study showed that the Covid-19 anxiety has a partial mediating role in the relationships between teacher emotional support and mental well-being, as well as between resilience and mental well-being, that is, both teacher emotional support and resilience have effects on Covid-19 anxiety and Covid-19 anxiety affects mental well-being. There is no study in the literature directly supporting the results of this study except for similar findings. Gundogan (2021) found that the fear of COVID-19 had a mediating role in the relationship between psychological resilience and life satisfaction. Tan et al. (2021) showed that resilience and environmental stress indeed affected college students’ well-being during the pandemic. Thus, it can be argued that mental well-being may be strengthened during the pandemic by direct and indirect influence from teacher emotional support and resilience. Therefore, teachers should provide emotional support for vocational college students to enhance their resilience ability, especially during emergent period.
Implication
People can be at great risk of psychological problems and mental health during Covid-19 pandemic. The present study constructed a path model to explore multiple paths from teacher emotional support and resilience on mental well-being.
First, the present study identified teacher emotional support as a prominently protective factor in promoting mental well-being in times of crisis, but increased negative impact of anxiety among Chinese vocational college students during pandemic if teachers showed concerns and warmth to students in a tangible way. Therefore, college teacher should be encouraged to utilize strategies when providing affective emotional support for students to reduce their anxiety and enhance their mental well-being during challenging period.
Second, the study demonstrated the importance of resilience in buffering Covid-19 anxiety and flourishing mental well-being. Resilience should be targeted at intervention and prevention for negative affects caused by unexpected incidents. According to the results, teachers are proposed to organize educational programs and conduct psychologically supportive activities to increase the psychological resilience and reduce the negative effects of Covid-19 anxiety among vocational college students.
Third, the result showed that teacher emotional support and resilience strengthened and promoted each other among the Chinese vocational college students during the crisis, and they are both crucial in helping vocational college students build up mental well-being. In view of extrapolating perceived teacher support to social and parental support for a strong social support network, we suggest that teachers strengthen communication with students’ parents and appeal for more supports from parents, society and government to help vocational college students develop emotional regulation strategies, improve adoptive ability and enhance resilience, which boosts students’ protective strategies against psychological problems and consequently improves mental well-being on a large scale during pandemic crisis.
Limitations
The paper suffered from several limitations. At first, significant positive relation between perceived teacher emotional support and COVID 19 anxiety was demonstrated because of particularity of management in vocational college, so a increased sample is needed to explore the phenomena in other colleges to testify whether their relation is influenced by Chinese culture or students’ majors. What’s more, we conducted the survey by collecting data through releasing online questionnaire, which is vulnerable to subjective judgment of socially desirable bias and personal desires. In addition, although we recommended usable suggestions, they may be restricted to Chinese vocational colleges. Other scholars can offer advice which is applicable to different cultural contexts.
Conclusion
The present study found that perceived teacher emotional support increased students’ anxiety if it was managed improperly by teachers during the Covid-19 pandemic period but it significantly promoted mental well-being. Resilience reduced vocational college students Covid-19 anxiety and was a crucial protector for mental well-being. In addition, perceived teacher emotional support and resilience were closely related and they developed and promoted each other. Both teacher emotional support and resilience affected mental well-being directly and indirectly through the effect of Covid-19 on mental well-being. The study showed a frame for perceived teacher emotional support, Covid-19 anxiety, resilience and mental well-being, and provided us intervention programs for psychological problems to enhance happiness during public health crisis, such as Covid-19 pandemic.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary file1 (SAV 51 kb)
Appendix
Figure 1Fig. 1 Conceptual mediation model
Figure 2Fig. 2 Results of the study model. Note: ***p < 0.001
Table 1Table 1 Descriptive statistics and correlation results
Variables M SD α 1 2 3 4
Teacher emotional Support 22.085 6.456 0.907 -
Resilience 21.028 3.795 0.707 0.351** -
Covid-19 anxiety 15.560 6.903 0.932 -0.041 -0.352** -
Mental well-being 18.107 5.527 0.893 0.809** 0.391** -0.143** -
**p < 0.01
Table 2Table 2 Standardized direct and indirect effects for the model
Model pathways Estimated 95%-confidence interval
Lower Upper
Direct effect
TES—Covid-19 anxiety 0.094 0.034 0.151
TES—MWB 0.773 0.742 0.805
Covid-19 anxiety—MWB -0.078 -0.112 -0.047
Resilience—Covid -19 anxiety -0.386 -0.434 -0.335
Resilience—MWB 0.092 0.056 0.131
Indirect effect
TES—Covid-19 anxiety—MWB -0.007 -0.013 -0.003
Resilience-Covid-19 anxiety- MWB 0.030 0.018 0.044
N 1469; TES Teacher emotional support; MWB Mental well-being
Data availability
The data used in this study has been uploaded as supplementary material to Current Psychology. So reviewers can obtain data by contacting the editor.
Declarations
Ethical issue and consent form claims
On the title page since there are author’s institution listed on it.
Ethical issue
Before data collection, we submitted an approval of this study to the institute office of Shandong Polytechnic College and the administrators agreed on the data collection after reviewing the proposal. During the data collection, the contact teachers of the study explained to the participants that they were granted confidence to withdraw or give up answering the questionnaire. Consent form was submitted to all the participants by four contact teachers. All participants agreed with this study.
Conflict of interest
The authors claim that there is no any potential conflicts of interest.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Amerio, A., Bianchi, D., Santi, F., Costantini, L., Odone, A., Signorelli, C., ..., & Aguglia, A. (2020). Covid-19 pandemic impact on mental health: A web-based cross sectional survey on a sample of Italian general practitioners. Acta Biomedica Atenei Parmensis, 91(2), 83–88. 10.23750/abm.v91i2.9619
Anser M Saddique A Chong SC Almas A Munir S Impact of perceived social support, resilience, and subjective well-being on psychological distress among university students: Does gender make a difference? The International Journal of Academic Research in Business and Social Sciences 2021 11 27 41 10.6007/IJARBSS/v11-i2/8331
Arslan G Mediating role of the self–esteem and resilience in the association between social exclusion and life satisfaction among adolescents Personality and Individual Differences 2019 151 109514 10.1016/j.paid.2019.109514
Baumeister RF Leary MR The need to belong-desire for interpersonal attachments as a fundamental human-motivation Psychological Bulletin 1995 117 3 497 529 10.1037/0033-2909.117.3.497 7777651
Beijing Sihai Classic Culture Communication Center. (2018). The Analects of Confucius (pp. 108), Beijing, Huaxia Publishing House. In Chinese
Borkovec TD Life in the future versus life in the present Clinical Psychology: Science and Practice 2002 9 1 76 80
Brooks SK Webster RK Smith LE Woodland L Wessely S Greenberg N Rubin GJ The psychological impact of quarantine and how to reduce it: Rapid review of the evidence The Lancet 2020 395 10227 10.1016/S0140-6736(20)30460-8
Burns D Dagnall N Holt M Assessing the Impact of the Covid-19 pandemic on student wellbeing at universities in the united kingdom: A conceptual analysis Frontiers in Education 2020 5 204 214 10.3389/feduc.2020.582882
Cao W Fang Z Hou G Han M Xu X Dong J Zheng J The psychological impact of the Covid-19 epidemic on college students in China Psychiatry Research 2020 287 112934 10.1016/j.psychres.2020.112934 32229390
Cheng J Zhao YY Wang J Sun YH Academic burnout and depression of Chinese medical students in the pre-clinical years: The buffering hypothesis of resilience and social support Psychology, Health & Medicine 2020 25 9 1094 1105 10.1080/13548506.2019.1709651
Cheung S Xie X Huang C Mind over matter: Mindfulness, income, resilience, and life quality of vocational high school students in China International Journal of Environmental Research and Public Health 2020 17 5702 10.3390/ijerph17165701 32784560
Coladarci T Cobb CD Fundamentals of Statistical Reasoning in Education 2013 4 Wiley
Coyne J DeLongis A Going beyond social support: The role of social relationships in adaptation Journal of Consulting and Clinical Psychology 1986 54 454 460 10.1037/0022-006X.54.4.454 3745597
Diener E Oishi S Tay L Advances in subjective well-being research Nature Human Behaviour 2018 2 253 260 10.1038/s41562-018-0307-6
Elliot TR Gramling SE Personal assertiveness and the effects of social support among college students Journal of Counseling Psychology 1990 37 4 427 436 10.1037//0022-0167.37.4.427
Federici RA Skaalvik EM Students’ perception of instrumental support and effort in mathematics: The mediating role of subjective task values Social Psychology of Education 2014 17 527 540 10.1007/s11218-014-9264-8
Gundogan S The mediator role of the fear of COVID-19 in the relationship between psychological resilience and life satisfaction Current Psychology 2021 40 12 6291 6299 10.1007/s12144-021-01525-w 33716474
Guo J Liu L Zhao B Wang D Teacher support and mental well-being in Chinese adolescents: The mediating role of negative emotions and resilience Frontiers in Psychology 2020 10 3081 10.3389/fpsyg.2019.03081 32038425
Hayes AF Introduction to mediation, moderation, and conditional process analysis: A regression-based approach 2017 Guilford Publications
He LW Jin YJ Challenges faced by ideological and political education in colleges under the “epidemic information” and the countermeasures College Instructor 2022 4 75 19 24
Hu T Xiao J Peng J Kuang X He B Relationship between resilience, social support as well as anxiety/depression of lung cancer patients: A cross-sectional observation study Journal of Cancer Research and Therapeutics 2018 14 72 77 10.4103/jcrt.JCRT_849_17 29516963
Huang, Z., Zhang, L., Wang, J., Xu, L., Liu, Z., Wang, T., ..., & Lu, H. (2021). Social support and subjective well-being among postgraduate medical students: The mediating role of anxiety and the moderating role of alcohol and tobacco use. Heliyon, 7(12), 8621. 10.1016/j.heliyon.2021.e08621
Jahoda M Current Concepts of Positive Mental Health 1958 Basic Books Publisher
Karimi MN Fallah N Academic burnout, shame, intrinsic motivation and teacher affective support among Iranian EFL learners: A structural equation modeling approach Current Psychology 2021 40 2026 2037 10.1007/s12144-019-0138-2
Labrague LJ De los Santos JAA Covid-19 anxiety among front-line nurses: Predictive role of organizational support, personal resilience and social support Journal of Nursing Management 2020 28 7 1653 1661 10.1111/jonm.13121 32770780
Lakey, B., & Cohen, S. (2000). Social support theory and measurement. In S. Cohen, L. G. Underwood, & B. H. Gottlieb (Eds.), Social support measurement and intervention: A guide for health and social scientists (pp. 29–52). Oxford University Press. 10.1093/med:psych/9780195126709.003.000210
Lei M The effect of varying degrees of nonnormality in structural equation modeling Structural Equation Modeling 2005 12 1 1 17 10.1207/s15328007sem1201_1
Lin PH The current management of vocational colleges students under the background of diversified student sources and optimization strategy Western China Quality Education 2022 8 10 173 175
Liossis PL Shochet IM Millear PM Biggs H The promoting adult resilience (PAR) program: The effectiveness of the second, shorter pilot of a workplace prevention program Behaviour Change 2009 26 97 112 10.1375/bech.26.2.97
Liu W Zhou L Wang X Yang B Wang Y Jiang J Mediating role of resilience in relationship between negative life events and depression among Chinese adolescents Archives of Psychiatric Nursing 2019 33 6 116 122 10.1016/j.apnu.2019.10.004 31753216
Luceño-Moreno L Talavera-Velasco B García-Albuerne Y Martín-García J Symptoms of post-traumatic stress, anxiety, depression, levels of resilience and burnout in Spanish health personnel during the Covid-19 pandemic International Journal of Environmental Research and Public Health 2020 17 15 5514 10.3390/ijerph17155514 32751624
Millear P Liossis P Shochet IM Biggs H Donald M Being on PAR: Outcomes of a pilot trial to improve mental health and well being in the workplace with the Promoting Adult Resilience (PAR) program Behavior Change 2008 25 215 228 10.1375/bech.25.4.215
Munir SS Jackson DW Social support, need for support and anxiety among women graduate students Psychological Reports 1997 80 2 383 386 10.2466/pr0.1997.80.2.383 9129357
Muthen B Kaplan D A comparison of some methodologies for the factor analysis of non-normal Likert variables British Journal of Mathematical and Statistical Psychology 1985 38 171 180 10.1111/j.2044-8317.1985.tb00832.x
Poole JC Dobson KS Pusch D Childhood adversity and adult depression: The protective role of psychological resilience Child Abuse & Neglect 2017 64 89 100 10.1016/j.chiabu.2016.12.012 28056359
Qiu J Shen B Zhao M Wang Z Xie B Xu Y A nationwide survey of psychological distress among Chinese people in the Covid-19 epidemic: Implications and policy recommendations General Psychiatry 2020 33 2 e100213 10.1136/gpsych-2020-100213 32215365
Rasch, G. (2012). From Guttman’s pioneer work to item response theory analysis (IRT). In Bech (ed): Clinical Psychometrics. Oxford, Wi-ley-Blackwell
Ryan RM Deci EL Intrinsic and extrinsic motivations: Classic definitions and new directions Contemporary Educational Psychology 2000 25 54 67 10.1006/ceps.1999.1020 10620381
Silva WAD de Sampaio Brito TR Pereira CR Covid-19 anxiety scale (CAS): Development and psychometric properties Current Psychology 2022 41 8 5693 5702 10.1007/s12144-020-01195-0 33204058
Skaalvik EM Skaalvik S School goal structure: Associations with students’ perceptions of their teachers as emotionally supportive, academic self-concept, intrinsic motivation, effort, and help seeking behavior International Journal of Educational Research 2013 61 5 14 10.1016/j.ijer.2013.03.007
Smith BW Dalen J Wiggins K Tooley E Christopher P Bernard J The brief resilience scale: Assessing the ability to bounce back International Journal of Behavioral Medicine 2008 15 3 194 200 10.1080/10705500802222972 18696313
Stallings MC Dunham CC Gatz M Baker LA Bengtson VL Relationships among life events and psychological well-being: More evidence for a two-factor theory of well-being Journal of Applied Gerontology 1997 16 1 104 119 10.1177/073346489701600106
Surzykiewicz J Konaszewski K Skalski S Dobrakowski PP Muszynska J Resilience and mental health in the Polish population during the COVID-19 lockdown: A mediation analysis Journal of Clinical Medicine 2021 10 21 4974 10.3390/jcm10214974 34768494
Tan Y Huang C Geng Y Cheng SP Zhang S Psychological well-being in Chinese college students during the Covid-19 pandemic: Roles of resilience and environmental stress Frontiers in Psychology 2021 12 671553 10.3389/fpsyg.2021.671553 34122262
Villanova, P. & Bownas, D. A. (1984). Dimension of college student of the Southeastern Psychological Association. ERIC Document Reproduction Service, No. ED262690
Wang, Z., Luo, S., Xu, J., Wang, Y., Yun, H., Zhao, Z., ..., & Liu, W. (2021). Well-being reduces Covid-19 anxiety: A three-wave longitudinal study in China. Journal of Happiness Studies, 22(8), 3593-3610. 10.1007/s10902-021-00385-2
WHO. (2020). WHO Director-General’s opening remarks at the media briefing on Covid-19. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-Covid-19%2D%2D-11-march-2020. Accessed 25 July 2022 through Qufu Normal University Library
Xu J Ou J Luo S Wang Z Chang EC Claire N Perceived social support protects lonely people against Covid-19 anxiety: A three-wave longitudinal study in China Frontiers in Psychology 2020 11 2759 2770 10.3389/fpsyg.2020.566965
Yalçın İ Can N Mançe Çalışır Ö Yalçın S Çolak B Latent profile analysis of Covid-19 fear, depression, anxiety, stress, mindfulness, and resilience Current Psychology 2022 41 1 459 469 10.1007/s12144-021-01667-x 33821112
Yang C Xia M Han M Liang Y Social support and resilience as mediators between stress and life satisfaction among people with substance use disorder in China Frontiers in Psychiatry 2018 9 436 1 7 10.3389/fpsyt.2018.00436 29410632
Yang J Research on the influencing factors on higher vocational students’ mental health under the background of big data Modern Vocational Education 2020 8 2 100 101
Yasin MD Dzulkifli MD The relationship between social support and psychological problems among students International Journal of Business and Social Science 2010 1 3 110 116
Ye B Zhao S Zeng Y Chen C Zhang Y Perceived parental support and college students’ depressive symptoms during the Covid-19 pandemic: The mediating roles of emotion regulation strategies and resilience Current Psychology 2022 10.1007/s12144-022-03049-3
Yıldırım M Arslan G Exploring the associations between resilience, dispositional hope, preventive behaviours, subjective well-being, and psychological health among adults during early stage of Covid-19 Current Psychology 2022 41 8 5712 5722 10.1007/s12144-020-01177-2 33223782
Zhang XH Research on the current mental health of vocational college students and intervention measures Youth & Society 2019 24 179 180
Zysberg L Zisberg A Days of worry: Emotional intelligence and social support mediate worry in the Covid-19 pandemic Journal of Health Psychology 2020 27 2 268 277 10.1177/1359105320949935 32811195
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Geometric tumor embolic budding characterizes inflammatory breast cancer
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6 3 2022
15 11 2022
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Purpose
Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli especially within dermal lymphatics. The explanation remains a mystery.
Methods
This study combines experimental studies with two different IBC xenografts with image algorithmic studies utilizing human tissue microarrays (TMAs) of IBC vs non-IBC cases to support a novel hypothesis to explain IBC’s sina qua non signature of florid lymphovascular emboli.
Results
In the human TMAs, compared to tumor features like nuclear grade (size), mitosis and Ki-67 immunoreactivity which show that IBC is only modestly more proliferative with larger nuclei than non-IBC, what really sets IBC apart is the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers indicate geometric or exponential differences between IBC and non-IBC. In the experimental xenograft studies, Mary-X gives rise to tight spheroids in vitro which exhibit dynamic budding into smaller daughter spheroids whereas Karen-X exhibits only loose non-budding aggregates. Furthermore Mary-X emboli also bud dramatically into smaller daughter emboli in vivo. The mechanism that regulates this involves the generation of E-cad/NTF1, a calpain-mediated cleavage 100 kDa product of 120 kDa full length membrane E-cadherin. Inhibiting this calpain-mediated cleavage of E-cadherin by blocking either the calpain site of cleavage (SC) or the site of binding (SB) with specific decapeptides that both penetrate the cell membrane and mimic either the cleavage site or the binding site on E-cadherin, inhibits the generation of E-cad/NTF1 in a dose-dependent manner, reduces spheroid compactness and decreases budding.
Conclusion
Since E-cad/NFT1 retains the p120ctn binding site but loses the α-and β-catenin sites, promoting its 360° distribution around the cell’s membrane, the vacilating levels of this molecule trigger budding of both the spheroids as well as the emboli. Recurrent and geometric budding of parental emboli into daughter emboli then would account for the plethora of emboli seen in IBC.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10549-022-06819-6.
Keywords
Lymphovascular tumor emboli
IBC
Tumor embolic budding
Spheroidgenesis
Calpain-mediated proteolysis of E-cadherin
E-cadherin fragments
http://dx.doi.org/10.13039/100000005 U.S. Department of Defense BC990959 BC024258 BC053405 Barsky Sanford H. the Dr. Carolyn S. Glaubensklee Endowed Cancer Center Directorship.
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pmcBackground
The sina qua non of inflammatory breast cancer (IBC) is numerous lymphovascular tumor emboli within the breast and especially within overlying dermal lymphatics where they are thought responsible for the clinical signs of IBC including rubor, calor, dolor and swelling [1–3]. All molecular subtypes of IBC exhibit this unifying phenotype whose mechanism remains unknown [4].
Previous studies by us and others using human xenograft models of inflammatory breast cancer and related cell lines have shed some light on the mechanisms responsible for the genesis of tumor clumps and derived emboli in the metastatic cascade of IBC [5–10]. In these studies membrane E-cadherin is an important adhesion molecule and its overexpression responsible for the tumor clumping that occurs [10–12]. Although E-cadherin generally is also considered a tumor suppressor gene / protein in tumor invasion and metastasis whose loss contributes to epithelial-mesenchymal transition (EMT) [13–15], in the setting of the tumor cell clump or the lymphovascular embolus of IBC, E-cadherin acts more like a dominant oncogene. [16–18]
However, these previous observations do not explain the plethora of emboli that occur in IBC, especially within dermal lymphatics. Certainly E-cadherin overexpression while contributing to the tumor cell clump and the tumor cell embolus can not alone account for the plethora of lymphovascular emboli observed in IBC.
For these reasons we sought explanations that might be responsible for this unique phenotype of IBC. We had collected a number of cases of human breast cancer of all types including IBC and non-IBC that were available to study through TMA digital algorithmic image analysis for detailed human observational studies. We also had pooled microdissected emboli available from the IBC cases. We had also established two contrasting xenograft models of IBC, Mary-X and Karen-X, to use in experimental studies to explain the unique phenotype of florid lymphovascular emboli observed in IBC.
Methods
Institutional approvals and initial establishment of the xenografts
Collection and use of human tissues from patients with breast cancer including non-IBC as well as IBC cases, completely anonymized, was approved by The Ohio State University Cancer Institutional Review Board (IRB) under protocol 2006C0042.
Both Mary-X and Karen-X were derived from patients with a biopsy proven diagnosis of IBC in the 1990’s and made into transplantable xenografts. Patient consents were obtained and studies were conducted under the UCLA’s Human Subject Protection Committee and the Chancellor’s Animal Research Committee (Certification 95–127-11). Mary-X was derived from a biopsy of primary IBC whereas Karen-X was derived from a biopsy of a hepatic metastases. Mary-X exhibited triple (ER, PR and Her-2/neu) negativity whereas Karen-X was weakly estrogen receptor (ER) positive. Both xenografts have been phenotypically stable for over 25 years of passage.
Both patient-derived xenografts (PDX) initially were directly implanted into the 4th mammary fat pad of both nude as well as Scid mice. When tumors emerged, they were both serially transplanted as well as placed in suspension culture. Both Mary-X and Karen-X spontaneously formed spheroids. The spheroids of Mary-X were tight and highly dense whereas the spheroids of Karen-X appeared as loose aggregates. Neither line formed monolayers on either plastic or fibronectin, vitronectin or collagen coated plastic. 103 spheroids (100µ diameter) with each spheroid consisting of approximately 103 cells or a total of 106 cells were also injected into the 4th mammary fat pad. In the case of both serially transplants or injected spheroids, tumors emerged which illustrated a stable phenotype and a characteristic histopathology. Over the years the sites of injection in the mice were varied to include the other mammary fat pads and non-orthotopic sites. Irrespective of the site of injection, both the phenotypes, histopathology and biology of Mary-X and Karen-X remained constant with passage. In previous studies with Mary-X, sorted signal cells, eg. stem cells, were also obtained on the basis of several stem cell markers and reinjected with the maintenance of a stable phenotype [19, 20]. Cells lacking stem cell markers were not tumorigenic.
Continuing animal studies were approved by The Ohio State University’s Institutional Animal Care and Use Committee (IACUC), protocol 2007A0218 and by The Ohio State University’s Institutional Biosafety Committee, protocol 2007R0057. Additional animal studies were approved by the University of Nevada’s School of Medicine and the Nevada Cancer Institute’s IACUC, protocols 00439 and 00440 when the corresponding author of this study was affiliated with these previous institutions. Final animal studies were conducted under an Interinstitutional Agreement between the California University of Science and Medicine and Anticancer, Inc. using the latter’s IACUC protocol D16-00503 and Office of Animal Welfare (OLAW) A3873-01.
ATCC patent deposits and cell identification
Mary-X and its in vitro derived spheroids were deposited in the American Type Culture Collection (ATCC) cell repository (Manassas, VA) as PTA-2737 and PTA-27376, respectively, and recently verified and re-verified to be both novel and human in origin (STRA4993). Likewise Karen-X and its in vitro derived spheroidal aggregates were deposited in the ATCC cell repository as PTA-126676 and PTA-126677 respectfully and recently verified to be both novel and human in origin (STRA4980). Mary-X is a well-known transplantable model of inflammatory breast cancer and has been used in numerous previous studies [19–21]. Karen-X has not previously been reported, although it has been ATCC deposited.
Observational studies
Cases of IBC
2000 cases of non-IBC and 100 cases of IBC were randomly selected from a database and The Ohio State University’s Information Warehouse and anonymized.
TMA construction
Multiple 2-mm tissue cores of tumor from each paraffin-embedded donor block (average of 10 cores / block) were arrayed into recipient TMA blocks, each of which contained 100 cores. All retrieved cases were processed in this manner.
Histological and immunohistochemistry studies
Primary antibodies used included rat anti-human Ki-67 (DakoCytomation, Carpinteria, CA), D2-40 anti-podoplanin (clone D2-40, Dako, catalog number M3619) and anti-CD31 (rabbit polyclonal, Spring Bioscience, catalog number E11114). The appropriate secondary antibodies were linked to an identifying chromogen.
Imaging analysis and quantitation of Ki-67 index, mitotic count, nuclear size (grade) and lymphovascular tumor emboli (embolic density, shape and size)
Our specific TMA algorithms carried out virtual alignment, image processing, and the application of the epithelial recognition algorithms (ERAs) and specific recognition algorithms (SRAs), the latter based upon immunocytochemical studies that quantitated nuclear Ki-67 immunoreactivity [22–25]. Additional specific morphological algorithms included a mitosis algorithm [26], a nuclear grade (size) algorithm [27], and epithelial clustering algorithms quantitating embolic density and measuring embolic shape (elongation ratio: short/long axis) and size (perimeter) utilizing ImageJ software [28]. Image acquisition by either the Aperio ScanScope T2 System (Aperio, Vista, CA) or the iSCAN System (BioImagene, Inc, Cupertino, CA.) produced equivalent results. The imaging apparatus captured sequential fields of view (FOV) from each core to cover the core in its entirety. Modes and means ± standard deviations (SD) were calculated for all these measurements. All experiments were performed in quintuplicate.
Experimental studies
Continued xenograft studies
Athymic (nude) mice as well as Scids on BALB/c backgrounds, 4 week old females, purchased from Anticancer, Inc. (San Diego, CA) were derived from their respective breeding colonies. Mary-X and Karen-X were grown as transplantable xenografts. At selected intervals ranging up to 4 months, the mice were euthanized with 25 mg/ml ketamine, 2 mg/ml xylazine and acepromazine and subjected to necropsy. Routine histological and immunocytochemical studies were carried out on excised tumors. Antibodies used included biotinylated E-cadherin rabbit mAb (24E10) (Santa Cruz Biotechnology, Santa Cruz, CA) which recognized both full length E-cadherin (E-cad/FL) and its E-cadherin/N-terminal fragment1 (E-cad/NTF1), followed by a labeled Streptavidin–Biotin Complex (Santa Cruz Biotechnology, Santa Cruz, CA). DAB chromogen was used to develop the brown color.
In vitro studies
Both Mary-X and Karen-X were placed in culture and 2 mm thick slices of each tumor were minced in RPMI media with 10% fetal calf serum giving rise to liberated loose aggregates in suspension culture. These aggregates were then passed through cell strainers whose pore sizes ranged from 40 to 500 µm. The morphology of the aggregates were observed over the next 24–72 h by phase contrast microscopy using the CytoSMART Lux2 (CytoSmart Technologies B.V. The Netherlands).
Confocal single and double label immunofluorescence experiments on Mary-X and Karen-X
Mary-X spheroids and Karen-X loose aggregates were subjected to single label immunofluorescence studies using Alexa Fluor 488-conjugated 24E10 (#3199) (Cell Signaling Technology, Inc.) which recognized both E-cad/FL as well as E-cad/NTF1. In order to immobilize the spheroids and loose aggregates, glass-bottom dishes were coated with Cell-TEK adhesive. The adherent spheroids were then fixed with 4% paraformaldehyde, after permeabilizing with TX-100 and blocking with normal goat serum. After washing with PBS 4–5 times, each for 10 min, the spheroids and aggregates were incubated with 24E10. The dishes were finally mounted with Vectorshield mounting medium with DAPI (#H-1200) (Vector Laboratories) and viewed with a Olympus Fluoview-1000 confocal scanning system.
Mary-X and Karen-X were also subjected to double label immunofluorescence studies. Double label immunofluorescence experiments were carried out using the following combinations of antibodies: Alexa Fluor 488-conjugated 24E10 which recognized both E-cad/NTF1 as well as E-cad/FL and goat polyclonal antibody to mouse podoplanin or CD31 (R&D Systems, Inc.) which recognized murine lymphatics or blood vessels followed by Alexa Fluor 594-conjugated donkey anti-goat (#A11058) (Invitrogen, Inc.). Tumor emboli were recognized by E-cadherin positivity surrounded by circumferential podoplanin (lymphatics) or CD31 positivity.
Isolation of Circulating Tumor Cells (CTCs) using EpCAM microbeads
CTCs were isolated from 10 mice each harboring the Mary-X and Karen-X xenografts. Blood from mice harboring at least 2 cm in diameter tumors were obtained by cardiac puncture and CTCs isolated with Epithelial Cell Adhesion Molecule (EpCAM) microbeads [29].
Laser capture microdissection
Frozen Sects. (8 µm) of Mary-X and human IBC cases were obtained, fixed in 70% ethanol, stained with hematoxylin and progressively dehydrated. Tumor emboli and non-embolic solid areas of Mary-X and human IBC cases were microdissected using a Pixcell II Laser Capture Microdissection 788 Laboratory System (Arcturus, Inc., Mountain View, CA) and stored at − 80 °C. 100 microdissected emboli /case from 10 cases were pooled together in individual aliquots. A total of 20 aliquots were prepared and stored for future studies.
Preparation of protein lysates and western blot analysis
The xenografts and laser-captured microdissected and pooled frozen IBC emboli were lysed using ice-cold RIPA lysis buffer (Pierce Biotechnology, Inc, Rockford, IL). For western blot analysis, boiled protein was loaded onto a 4–12% precast gradient gel (Invitrogen, Inc.), transferred to nitrocellulose membranes (Bio-rad, Hercules, CA) and incubated with either E-cadherin rabbit mAb (24E10) or rabbit anti-human ectodomain E-cadherin (H108) (Santa Cruz Biotechnology, Santa Cruz, CA) followed by anti-rabbit IgG, HRP-linked antibody (Cell Signaling Technology Inc., Danvers, MA). Rabbit mAb (13E5) was used to a housekeeping protein, ACTB. Bound antibodies were detected by a chemiluminescent detection system (West Femto) (Pierce Biotechnology, Inc.) according to the manufacturer's instructions. The relative intensity of the bands was determined by densitometric analysis.
Synthesis, labelling and use of SC and SB decapeptides
The calpain cleavage and binding sites on full length E-cadherin were used as a template to design mimicking decapeptides to block calpain cleavage and binding. Two decapeptides: the site of cleavage (SC) peptide: DARPEVTRND and the site of binding (SB) peptide: GGEEDQDFDL were purchased and used in concentration ranges of 50 nM to 50 µM (ThermoFisher Scientific, Inc., Waltham, MA). The same decapeptides were also obtained labelled, respectively, with Alexa Fluor 488 and Alexa Fluor 594 at their NH2-terminal ends and used in the same concentration ranges. Both the labelled and unlabelled decapeptides were studied in vitro for their abilities to penetrate into the spheroidal aggregates of both Mary-X and Karen-X, transgress the cell membrane, block E-cad/NTF1 generation and affect spheroidgenesis. Specifically dose response effects of the decapeptides on E-cad/NTF1 generation and effects on both spheroid disadherence and budding were observed and recorded. Decapeptides with random amino acid sequences in the same concentration ranges of 50 nM–50 µM served as negative controls in both the studies of E-cad/NTF1 generation as well as spheroidgenesis.
Statistical analysis
For Ki-67 index, mitotic count and nuclear grade (size) and measurements of embolic density, shape (elongation ratio) and size, both modes and means ± SD values were determined. All experiments were performed in quintuplicate and representative results depicted showing %cases, modes or means ± standard deviations. All stated or calculated differences imply differences of statistical significance, assessed by the two tailed students t test as well as analysis of variance (ANOVA).
Results
Observational studies
In the human TMA studies, compared to other tumor features like nuclear grade (size), mitosis and Ki-67 immunoreactivity which showed that IBC is only modestly more proliferative with larger nuclei than non-IBC, what really distinguished IBC was the markedly greater number of tumor emboli and distinctly smaller emboli (Fig. 1). IBC cases compared to non-IBC cases showed a modestly greater Ki-67 mean index (p = 0.05) (Fig. 1A), a modesty higher mean mitotic count (p = 0.05) (Fig. 1B) and a modestly increased mean nuclear grade (p = 0.05) (Fig. 1C) but the distribution of these tumor features showed considerable overlap. In contrast, mean embolic density in IBC dwarfed non-IBC by a factor of 100-fold (p = 0.0001) (Fig. 1D). Furthermore although the overall mode and mean shape of the emboli in IBC v non-IBC did not differ (p = 0.5) (Fig. 1E), the modal and mean size of the IBC emboli were significantly smaller (p = 0.01) (Fig. 1F).Fig. 1 Image and algorithmic analyses of multiple histological and immunocytochemical parameters in IBC v non-IBC human cases. A Ki-67 immunoreactivity (left), specific algorithmic recognition (middle) and Ki-67 index quantitation (right) in IBC v non-IBC are illustrated. B Mitosis histology (left), specific algorithmic recognition (middle) and mitotic count determination (right) in IBC v non-IBC are illustrated. C Nuclear histology (left), specific algorithmic quantitation (middle) and nuclear grade (size) distribution (right) in IBC v non-IBC are illustrated: yellow, < 20 µm; green, 20–30 µm; red, 31–50 µm. D Tumor embolic histology (left) and density determinations (right) in IBC v non-IBC are illustrated. E Tumor embolic histology (left) and algorithmic imaging shape determinations (right) in IBC v non-IBC are illustrated. F Tumor embolic imaging (left) and algorithmic perimeter determinations (right) in IBC v non-IBC are illustrated. Scale bars are provided. For each of these parameters, the graph depicts %cases, modal values (plotted) and calculated means ± SD. Differences of significance are depicted. All experiments were performed in quintuplicate
Experimental studies
Initial xenograft studies
Mary-X grew equally well in both athymic (nude) mice as well as Scids as a transplantable xenograft (Fig. 2A). Mary-X exhibited a stable phenotype for over 25 years. Mary-X grew in a nodular fashion with islands of tumor cells embedded within a murine fibrovascular matrix (Fig. 2B). The nodules of Mary-X expressed strong membrane E-cadherin immunoreactivity (Fig. 2D). Mary-X gave rise to large numbers of CTCs (Fig. 2F: inset) which measured out at 10–15 cells / 100 µl blood as well as distal metastases including pulmonary metastases (Fig. 2F). These metastases also strongly expressed E-cadherin.Fig. 2 Xenograft Properties. A The growth of Mary-X and Karen-X are depicted. Each time point displays the mean ± standard deviation of 10 mice. Routine histology of Mary-X (B) and Karen-X (C) shows similar nodular islands of tumor cells. E-cadherin immunocytochemistry shows more intense and more circumferential membrane immunoreactivity in Mary-X (D) compared to Karen-X (E). Mary-X gives rise to E-cadherin positive pulmonary metastases (F) as well as CTCs (F: inset) whereas Karen-X lacks both (G, G: inset). Scale bars are provided.
Karen-X, in contrast, grew only in Scids as a transplantable xenograft (Fig. 2). Karen-X also exhibited a stable phenotype for over 25 years. Karen-X exhibited a significantly longer latency than Mary-X but once a tumor emerged exhibited a similar rate of growth (Fig. 2A). Karen-X was similar to Mary-X histologically (Fig. 2C). Karen-X also expressed E-cadherin membrane immunoreactivity which overall was less intense and less circumferential (Fig. 2E) than that expressed in Mary-X. In contrast to Mary-X, Karen-X did not generate CTCs (Fig. 2G: inset) or metastases (Fig. 2G).
In vitro studies
Mary-X and Karen-X exhibited markedly different in vitro properties when grown in suspension culture (Fig. 3). When their respective xenografts were excised and minced in culture, both initially gave rise to loose tumor aggregates. After 24–48 h, the Mary-X aggregates tightened to form high density spheroids (Fig. 3A) whereas the Karen-X aggregates remained loosely associated and did not tighten (Fig. 3G). After an ensuing 24 h–96 h period, the Mary-X spheroids exhibited both partial budding as well as complete budding. We counted over 1000 spheroids over a 96 h period and observed partial budding in 15 ± 5% and complete budding in 5 ± 3%. Partial budding was defined as budding that had not yet completely separated and complete budding was defined as full separation with the appearance of daughter spheroids. When observed with time-lapsed photography, the budding of Mary-X spheroids was rapid and quite dynamic, occurring over minutes (Supplement 1). In this time-lapsed photography, one parent spheroid divided into two and the two divided into four, illustrating a geometric progression. Still images from the time-lapsed video demonstrate this unique budding of Mary-X spheroids (Fig. 3B-3F). Mary-X budding gave rise to daughter spheroids which were smaller in size (Fig. 4A) which nevertheless expressed strong E-cadherin immunoreactivity (Fig. 4B). In contrast, Karen-X spheroids did not bud over time in suspension culture (Supplement 2). Still images of the Karen-X spheroids confirmed the lack of budding and their persistence as loose aggregates (Fig. 3G). Neither Mary-X nor Karen-X ever attached or grew as monolayers even when grown on fibronectin or vitronectin-coated dishes (data not shown). Furthermore, both Mary-X and Karen-X spheroids grew only minimally in suspension culture and then underwent a growth arrest. Initially, Ki-67 immunoreactivity in both Mary-X and Karen-X spheroids was high but then decreased over several weeks in culture. In contrast both the Mary-X and the Karen-X xenografts grew fairly rapidly with a relatively high Ki-67 index (> 50%). Yet despite the growth latency in vitro, both Mary-X and Karen-X spheroids were fully tumorigenic when reinjected into mice, even after 6 months in culture.Fig. 3 In Vitro Clump Properties. Time-lapsed phase contrast microscopy depicts Mary-X spheroids growing in suspension culture as tight aggregates which completely bud into daughter spheroids (Supplement 1). Still images of this dynamic budding are depicted (A–F). In contrast, Karen-X spheroids remain as loose aggregates which do not bud (Supplement 2). Still images confirm this absence of budding (G, H)
Fig. 4 Complete Budding both In Vitro and In Vivo. Complete budding of Mary-X with phase contrast (A) and single label E-cadherin immunofluorescence (B). E-cadherin immunoreactivity remains intense even at the points of the budding (B). DAPI was used as a nuclear counterstain. White arrows indicate budding points. Time-lapse photography confirms the dynamics of the budding process (Supplement 1). Double label immunofluorescent studies demonstrate tumor emboli exhibiting green immunofluorescence within podoplanin-positive lymphovascular channels exhibiting red immunofluorescence with DAPI used as a nuclear counterstain. Dramatic complete embolic budding is also observed in vivo (C). E-cadherin immunoreactivity remains intense even at the points of the budding. White arrows indicate budding points. As a result of this geometric budding, large numbers of tumor emboli are propagated (D). Scale bars are provided
Additional xenograft studies
Double label immunofluorescence studies of the excised Mary-X xenograft showed florid tumor embolic lymphovascular budding (Fig. 4C). In contrast the Karen-X xenograft showed no lymphovascular invasion and no budding (data not shown). The parental tumor embolic budding of Mary-X gave rise to a dramatic geometric increase in the number of smaller tumor emboli within lymphovascular channels (Fig. 4C, D). Both parental and daughter tumor emboli retained strong membrane E-cadherin immunofluorescence (Fig. 4C, D). Non-embolic tumoral areas of Mary-X showed no evidence of budding.
Studies of Mary-X and Karen-X E-cadherin proteolysis
Our previous Mary-X studies had demonstrated the transcriptome equivalence of xenograft-generated spheroids with the lymphovascular emboli in mice with both structures also demonstrating E-cadherin overexpression and specific proteolytic processing with calpain and other proteases, producing a number of specific E-cadherin fragments including Ecad/NTF1-4 and Ecad/CTF1-4 [21, 30]. Western blots with either E-cadherin rabbit mAb (24E10) or rabbit anti-human ectodomain E-cadherin (H108) in the present study confirmed the high levels of both E-cad/FL as well as E-cad/NTF1 in the Mary-X spheroids but absent E-cad/NTF1 in the Karen-X aggregates (Fig. 5A). Laser capture microdissected pooled lymphovascular tumor emboli from patients (100 emboli / case from 10 cases with IBC) (Fig. 5B) showed similarly high levels of both E-cad/FL as well as E-cad/NTF1 (Fig. 5C).Fig. 5 Expression of E-cad/FL and E-cad/NTF1. Western blot using H108 reveals both E-cad/FL and E-cad/NTF1 in Mary-X but essential absence of E-cad/NTF1 in Karen-X (A). Laser capture microdissection of tumor emboli (B) from cases of IBC also confirm the presence of E-cad/NTF1 by Western blot (C)
Because calpains, as intracellular proteases, have many different actions on many different targets, blocking calpains with calpastatin would not be expected to solely block only the cleavage of E-cadherin and the generation of its E-cad/NTF1 fragment. So in the present study, we used specific oligopeptides (decapeptides) that mimicked, respectively, either calpain’s site of cleavage (SC) or site of binding (SB) on the full length E-cadherin molecule. Both decapeptides by Western blot significantly inhibited the generation of E-cad/NTF1 in a dose-dependent manner confirmed by densitometric analysis (Fig. 6A). No effects on the generation of E-cad/NTF1 were observed in the Karen-X spheroids likely because Karen-X spheroids did not generate E-cad/NTF1 de novo (Fig. 6B).Fig. 6 Effects of SC and SB decapeptides. Dose response of SC and SB decapeptides on E-cad/NTF1 generation in Mary-X spheroids (A). Each decapeptide singly and in combination was effective at blocking calpain generation of E-cad/NTF1 illustrated by Western blots. In Karen-X spheroids, since there was no or negligible E-cad/NTF1, these decapeptides exerted no effects (B). In vitro delivery and action of fluorescently labelled decapeptides on tumor clumps are depicted (C). SC peptide labelled with Alexa Fluor 488 (green fluorescence) (top row, left panel) and the SB peptide labelled with Alexa Fluor 594 (red fluorescence) (top row, center panel) both singly and in combination (yellow fluorescence) (top row, right panel), penetrated the cell membranes (bottom row, left and right panels) and caused increased disadherence and decreased budding (D). Effects of both decapeptides were synergistic. Scale bars are provided
Using the same SC and SB decapeptides as before but now labelled, respectively, with Alexa Fluor 488 and Alexa Fluor 594, the decapeptides were administered to the Mary-X spheroids. Each peptide singly and in combination penetrated the spheroids (Fig. 6C). The effects on the Mary-X spheroids were significant in terms of both increased disadherence (p < 0.05), decreased partial and complete budding (p < 0.05) (Fig. 6D). The effects of the SB peptide were greater than the inhibitory effects of the SC peptide on E-cad/NTF1 generation (p < 0.05) but both peptides promoted disadherence, and decreased budding equally. The effects of the two peptides in combination were synergistic on inhibition of E-cad/NTF1 generation (p < 0.05), increased disadherence and decreased budding (p < 0.05). There were no measurable effects of these decapeptides on the loose aggregates of Karen-X (data not shown). Decapeptides with random amino acid sequences which served as negative controls in both the E-cad/NFT1 inhibition experiments as well as in the studies of spheroidgenesis and budding exerted no effects.
Discussion
IBC is the deadliest type of human breast cancer that presents with florid tumor emboli especially involving overlying dermal lymphatics [1–5]. These lymphovascular tumor emboli also reoccur locally, making skin-sparing and breast-conserving surgery not a usual option. [31–35]
In our human TMA studies, our detailed image analysis with artificial intelligence algorithms demonstrated what really set IBC apart was the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers exhibited dramatic geometric or exponential differences. That novel observation together with our in vitro / murine in vivo observations supported our hypothesis that IBC emboli bud into daughter and smaller emboli in patients. These emboli likely were the source of numerous CTCs and metastases [36, 37] although more recent studies have questioned whether the density of lymphovascular emboli necessarily correlate with numbers of CTCs [38]. The budding of Mary-X in vitro was dynamic, dramatic and fairly rapid (occurring in minutes).
We used only two xenografts, Mary-X and Karen-X, xenografts we originated and established in immunodeficient mice because although there have a number of other aggressive triple negative breast cancer (TNBC) lines and xenografts reported in the literature and studied, we are not aware of any published studies that show that they spontaneously form spheroids in suspension culture or bud or form tumors as xenografts that also bud into daughter emboli. In our study we are attempting to take advantage of the fact that one of our PDX models, Mary-X still metastasizes, forms lymphovascular emboli through budding whereas our other model, Karen-X, neither metastasizes, forms lymphovascular emboli nor buds, arguing that these three properties are causally related. We do plan in future studies to study both Mary-X and Karen-X in mice whose immune system has been restored and humanized. [39, 40]
In a previous study [21] we reported the calpain-mediated cleavage in Mary-X and the generation of E-cad/NTF1. In that study and in our present work, we note that calpain cleaves E-cadherin at amino acid site: 782 and the size fragments expected from that cleavage are 100 kDa for the NH2-terminal end and 10 kDa for the COOH terminal end. We used two different E-cadherin antibodies, H108 and 24E10 that recognized amino acid sites: 695–701 and 778–781, respectively, to distinguish the different cleavage products produced by the different proteases including calpain (Fig. 7A).Fig. 7 Generation of E-cadherin and its fragments by different proteases. A Schematic (adapted by permission from Macmillan Publishers Ltd,; The EMBO Journal 2000; 21: 1948–1956, ref 71) depicts cleavage sites of calpain, caspase-3, MMP and γ-secretase including its obligate PS1 binding domain (highlighted) which is also thought to be the site of calpain binding as well and 8 of the E-cadherin fragments (E-cad/NTF1-4; E-cad/CTF1-4) generated by these specific cellular proteases. EC1-5 denote the extracellular E-cadherin repeats. TM indicates transmembrane domain (also highlighted). The sites of binding of two anti-E-cadherin antibodies, H108 and 24E10 are also depicted. Schematic adapted from Fig. 3, ref 71. B Schematic of E-cad/NTF1 membrane mobility depicts the structure of E-cad/NTF1 bound to p120ctn but not to β- or α-catenin nor the actin cytoskeleton. Therefore while E-cad/FL is tethered to the membrane in traditional CAJs, E-cad/NTF1 becomes more mobile, redistributing itself along adjacent areas of the membrane, contributing to increased budding
Our current work significantly advances this observation in several ways: it shows that the lymphovascular emboli of Mary-X exhibit complete budding both in vitro by time-lapsed photography and in murine studies with the generation of completely intact and smaller daughter emboli and that this budding can be inhibited in vitro by blocking calpain cleavage of E-cadherin and the generation of E-cad/NTF1 with decapeptides that mimic either the cleavage site or the binding site on E-cadherin in a dose-dependent manner.
Metastases is a complex process regulated by multiple determinants so just because calpain-mediated cleavage of E-cadherin into E-cad/NTF1 that contributes to a budding phenomenon is observed in IBC, it does not follow necessarily that reduced calpastatin which would contribute to increased calpain or increased calpain alone would be responsible for increased metastases and poor survival across the board if the rate-limiting steps of metastasis of other cancers including non-IBC were governed by other pathways such as adhesion or proliferation. Furthermore while certainly our studies suggest that E-cadherin/NTF1 could be a marker of poor prognosis and this should be studied, other markers characteristic of other pathways could well be confounding in other tumor types. For starters, we do plan to measure E-cad/NTF1 levels in lymphovascular emboli retrieved by laser capture microdissection in a cohort of just IBC cases and see whether the levels predict disease-free survival and overall survival.
In our study we are distinguishing geometric budding of emboli from the phenomenon that triggers initial lymphovascular invasion in the first place, which, in itself remains unexplained. The recognition of the lymphovascular embolus as an entity unto itself has catalyzed larger observations that many cancers invade and metastasize as clumps or clusters [41–48]. Up until relatively recently, most scientists considered cancers to metastasize as single cells and their increased locomotion and degradation of the extracellular matrix with subsequent lymphovascular invasion as a manifestation of so called epithelial-mesenchymal transition (EMT) [13–15]. Models epitomizing this phenomenon in the breast included infiltrating lobular cancers where cells lose E-cadherin expression and infiltrate as single cells. [49, 50]
The study of tumor cell clumps or clusters became important not only in vivo but also in vitro because tumor clumps in suspension culture provided 3D models which were uniformly superior to 2D monolayer cultures of cancer cell lines. In vitro 3D models were thought to better recapitulate the 3D situation of in vivo cancer and to more faithfully recapitulate in vivo gene expression, provide better evaluation of physiological factors such as hypoxia and improved testing of anticancer pharmacological strategies. [51–53]
Most 3D models take the form of spheroids in suspension culture. The majority of these spheroids or multicellular aggregates (MTCs), however, need to be induced to grow as spheroids by growing them on agar or other repellent surface that interferes with the cancer cells natural proclivity to grow as monolayers. [54–63]
Some of these spheroids when injected into immunocompromised mice will develop into tumors but these tumors do not exhibit obvious lymphovascular invasion or tumor emboli formation. Furthermore no previous models have demonstrated the equivalence of in vitro spheroids with in vivo tumor emboli. In contrast, our in vitro spheroids of Mary-X spontaneously form and when re-injected into mice develop into tumors showing florid tumor emboli, which by Principal Component Analysis (PCA) not only express the transcriptome equivalence of Mary-X spheroids but also the equivalence of microdissected tumor emboli from cases of IBC [21, 30]. And the emboli of Mary-X and their in vitro equivalent, i.e., the spheroids are what undergo geometric budding.
Although budding per se of tumor cells has also been observed and studied in vivo in other studies, that budding applies to invasion of the primary cancer and not specific budding of the lymphovascular tumor embolus [64–66]. Budding per se from the lymphovascular tumor embolus has not previously been observed or studied.
It is interesting that the hypothesis of EMT still dominates the thinking of the metastatic process even when applied to metastasizing clumps and budding where E-cadherin overexpression is also observed [46–48]; [67–69]. Despite this observation, the evidence suggests that the mechanism of budding responsible for geometric embolic propagation in our model does not involve either complete or partial EMT. Our time-lapsed photography indicates that complete in vitro budding occurs in minutes and that both the bud as well as the parent spheroid or embolus overexpress E-cadherin even at the incident point of budding. It makes more sense that budding results not from EMT followed by MET but rather from pre-existing molecules like E-cad/NTF1. Certainly budding must involve additional steps some of which could be energy (ATP) dependent, hypoxia triggered, nutrient-related or density regulated. We plan to use our budding model to delineate these steps in future studies.
Conclusions
Our study therefore is the first study that observes and quantitates actual budding of tumor emboli in an IBC model both in vivo and in vitro which account for the markedly greater number of tumor emboli and distinctly smaller emboli whose numbers reflect a geometric or exponential process in IBC patients.
Blocking the calpain-mediated proteolysis of membrane E-cadherin by SC and SB mimicking decapeptides suggests that E-cad/NTF1 participates in both tight spheroidgenesis as well as budding. E-cad/NFT1 retains its p120ctn binding site but loses both the β-catenin and α-binding sites, facilitating its disassembly from traditional CAJs. E-cad/NFT1 can exhibit 360° mobility around the membrane and its vacillating levels would both initiate and subsequently consolidate the budding process (Fig. 7B). This insight could lead to therapies at inhibiting budding and embolic propagation, thereby decreasing skin recurrences in IBC [70].
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (AVI 8238 KB)
Supplementary file2 (MP4 5280 KB)
Acknowledgements
The authors wish to thank CUSM Instructional and Informational Technology Services for enabling videoconferencing coauthor communications during the COVID-19 pandemic. The authors further wish to thank Dean Burkin, PhD of the University of Nevada School of Medicine for advice concerning the oligopeptide studies.
Author Contributions
All authors made an intellectual contribution to the work. Arnav P. Modi, carried out the vast majority of the in vitro spheroidgenesis and budding experiments. Julie P.T. Nguyen conducted a critical interpretation of the data and further characterized the nature of the budding. Justin Wang supervised the xenograft experiments. Jonathan S. Ahn analyzed the immunofluorescence and immunocytochemical experiments and conducted additional in vitro budding experiments. William A. Libling troubleshot additional experiments designed to test the significance of the hypothesis. Jacob M. Klein and Preeanka Mazumder conducted a review of the relevant literature and suggested additional experiments. Sanford H. Barsky supervised all of the experiments and wrote and further modified the manuscript which was reviewed by all the authors.
Funding
This work was supported by the Department of Defense Breast Cancer Research Program Grants BC990959, BC024258, BC053405 and the Dr. Carolyn S. Glaubensklee Endowed Cancer Center Directorship.
Data Availability
Both Mary-X and Karen-X are available to any investigator upon request. Imaging algorithms used in the study are also available. All data sets generated and used in the study are available upon request.
Declarations
Competing Interests
The authors declare that they, at the present time, have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. None of the sources of support listed influenced the collection, analysis and interpretation of data, the generation of the hypothesis, the writing of the manuscript or the decision to submit the manuscript for publication.
Ethical Approval
Initial xenograft studies were conducted under the UCLA’s Human Subject Protection Committee and the Chancellor’s Animal Research Committee (Certification 95–127-11). Continuing animal studies were approved by The Ohio State University’s Animal Care and Use Committee (IACUC), protocol 2007A0218 and by The Ohio State University’s Institutional Biosafety Committee, protocol 2007R0057. Additional animal studies were approved by the University of Nevada’s School of Medicine and the Nevada Cancer Institute’s IACUC, protocols 00439 and 00440 when the corresponding author of this study was affiliated with these previous institutions. Final animal studies were conducted under an Interinstitutional Agreement between the California University of Science and Medicine and Anticancer, Inc. using the latter’s IACUC protocol D16-00503 and OLAW A3873-01. Collection and use of human tissues from patients with breast cancer including non-IBC as well as IBC cases, completely anonymized, was approved by The Ohio State University Cancer IRB under protocol 2006C0042.
Consent for Publication
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Dent R Trudeau M Pritchard KI Hanna WM Kahn HK Sawka CA Lickley LA Rawlinson E Sun P Narod SA Triple-negative breast cancer: Clinical features and patterns of recurrence Clin Cancer Res 2007 13 4429 4434 10.1158/1078-0432.CCR-06-3045 17671126
2. Brenton JD Carey LA Ahmed A Caldas C Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? J Clin Oncol 2005 23 7350 7360 10.1200/JCO.2005.03.3845 16145060
3. Cristofanilli M Buzdar AU Hortobágyi GN Update on the management of inflammatory breast cancer; update on the management of inflammatory breast cancer Oncologist 2003 8 141 148 10.1634/theoncologist.8-2-141 12697939
4. Kertmen N Babacan T Keskin O Solak M Sarici F Akin S Arik Z Asian A Ates O Aksoy S Ozisik Y Altundag K Molecular subtypes in patients with inflammatory breast cancer A single center experience J BUON 2015 20 35 39
5. Alpaugh ML Tomlinson JS Shao ZM Barsky SH A novel human xenograft model of inflammatory breast cancer Cancer Res 1999 59 5079 5084 10537277
6. Tomlinson JS Alpaugh ML Barsky SH An intact overexpressed E-cadherin/α, β-catenin axis characterizes the lymphovascular emboli of inflammatory breast carcinoma Cancer Res 2001 61 5231 5241 11431364
7. Alpaugh ML Tomlinson JS Ye Y Barsky SH Relationship of sialyl-Lewisx/a underexpression and E-cadherin overexpression in the lymphovascular embolus of inflammatory breast carcinoma Am J Pathol 2002 161 619 628 10.1016/S0002-9440(10)64217-4 12163386
8. Alpaugh ML Tomlinson JS Kasraeian S Barsky SH Cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in inflammatory breast carcinoma Oncogene 2002 21 3631 3643 10.1038/sj.onc.1205389 12032865
9. Eckhardt BL Gagliardi M Iles LK Evans K Ivan C Liu X Liu CG Souza G Rao A Meric-Bernstam F Ueno NT Bartholomeusz GA Clinically relevant inflammatory breast cancer patient-derived xenograft–derived ex vivo model for evaluation of tumor-specific therapies PLoS ONE 2018 13 1 23 10.1371/journal.pone.0195932
10. Colpaert CG Vermeulen PB Benoy I Soubry A Van Roy F Van Beest P Goovaerts G Dirix LY Van Dam P Fox SB Harris AL Van Marck EA Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression Br J Cancer 2003 88 718 725 10.1038/sj.bjc.6600807 12618881
11. Ye Y Tellez JD Durazo M Belcher M Yearsley K Barsky SH E-cadherin accumulation within the lymphovascular embolus of inflammatory breast cancer is due to altered trafficking Anticancer Res 2010 30 3903 3910 21036701
12. Alpaugh ML Barsky SH Reversible model of spheroid formation allows for high efficiency of gene delivery Ex Vivo and accurate gene assessment In Vivo Hum Gene Ther 2002 13 1245 1258 10.1089/104303402320139023 12133277
13. Kalluri R Weinberg RA The basics of epithelial-mesenchymal transition J Clin Invest 2009 119 1420 1428 10.1172/JCI39104 19487818
14. Thiery JP Acloque H Huang RYJ Nieto MA Epithelial-mesenchymal transitions in development and disease Cell 2009 139 871 890 10.1016/j.cell.2009.11.007 19945376
15. Zheng X Carstens JL Kim J Scheible M Kaye J Sugimoto H Wu C Lebleu VS Kalluri R Biology C EMT program is dispensable for metastasis but induces chemoresistance in pancreatic cancer Nature 2015 527 525 530 10.1038/nature16064 26560028
16. Fernandez SV Robertson FM Pei J Aburto-Chumpitaz L Mu Z Chu K Alpaugh RK Huang Y Cao Y Ye Z Cai KQ Boley KM Klein-Szanto AJ Devarajan K Addya S Cristofanilli M Inflammatory breast cancer (IBC): Clues for targeted therapies Breast Cancer Res Treat 2013 140 23 33 10.1007/s10549-013-2600-4 23784380
17. Robertson FM Bondy M Yang W Yamauchi H Wiggins S Kamrudin S Krishnamurthy S Le-Petross H Bidaut L Player AN Barsky SH Woodward WA Buchholz T Lucci A Ueno N Cristofanilli M Inflammatory breast cancer: the disease, the biology, the treatment CA Cancer J Clin 2010 60 351 375 10.3322/caac.20082 20959401
18. Cristofanilli M Valero V Buzdar AU Kau SW Broglio KR Gonzalez-Angulo AM Sneige N Islam R Ueno NT Buchholz TA Singletary SE Hortobagyi GN Inflammatory breast cancer (IBC) and patterns of recurrence: Understanding the biology of a unique disease Cancer 2007 110 1436 1444 10.1002/cncr.22927 17694554
19. Xiao Y Ye Y Yearsley K Jones S Barsky SH The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype Am J Pathol 2008 173 561 574 10.2353/ajpath.2008.071214 18599608
20. Xiao Y Ye Y Zou X Jones S Yearsley K Shetuni B Tellez J Barsky SH The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction Oncogene 2011 30 287 300 10.1038/onc.2010.405 20838375
21. Ye Y Tian H Lange AR Yearsley K Robertson FM Barsky SH The genesis and unique properties of the lymphovascular tumor embolus are because of calpain-regulated proteolysis of E-cadherin Oncogene 2013 32 1702 1713 10.1038/onc.2012.180 22580607
22. Sharangpani GM Joshi AS Porter K Deshpande AS Keyhani S Naik GA Gholap AS Barsky SH Semi-automated imaging system to quantitate estrogen and progesterone receptor immunoreactivity in human breast cancer J Microsc 2007 226 244 255 10.1111/j.1365-2818.2007.01772.x 17535263
23. Joshi AS Sharangpani GM Porter K Keyhani S Morrison C Basu AS Gholap GA Gholap AS Barsky SH Semi-automated imaging system to quantitate Her-2/neu membrane receptor immunoreactivity in human breast cancer Cytom Part A 2007 71A 273 285 10.1002/cyto.a.20374
24. Barsky SH Gentchev L Basu AS Jimenez RE Boussaid K Gholap AS Use and validation of epithelial recognition and fields of view algorithms on virtual slides to guide TMA construction Biotechniques 2009 47 927 938 10.2144/000113207 20041846
25. Mahooti S Porter K Alpaugh ML Ye Y Xiao Y Jones S Tellez JD Barsky SH Breast carcinomatous tumoral emboli can result from encircling lymphovasculogenesis rather than lymphovascular invasion Oncotarget 2010 1 131 147 10.18632/oncotarget.117 21297224
26. Gholap AS, Gholap GA, Rao CVK, Barsky SH, Vipra M, Patil SM, Jadhav P, Abhyankar J. Methods and system for morphology based mitoses identification and classification of digital images. U.S. Patent 7,979,212; July 12, 2–11.
27. Petrova SC Ahmad I Nguyen C Ferrell SD Jr Wilhelm SR Ye Y Barsky SH Regulation of breast cancer oncogenesis by the cell of origin's differentiation state Oncotarget 2020 11 43 3832 3848 10.18632/oncotarget.27783 33196707
28. https://ij.imjoy.io
29. Grover PK Cummins AG Price TJ Roberts-Thomson IC Hardingham JE Circulating tumour cells: The evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research Ann Oncol 2014 25 1506 1516 10.1093/annonc/mdu018 24651410
30. Ye Y Gao JX Tian H Yearsley K Lange AR Robertson FM Barsky SH Early to intermediate steps of tumor embolic formation involve specific proteolytic processing of E-cadherin regulated by Rab7 Mol Cancer Res 2012 10 6 713 726 10.1158/1541-7786.MCR-12-0009 22638108
31. Yamauchi H Woodward WA Valero V Alvarez RH Lucci A Buchholz TA Iwamoto T Krishnamurthy S Yang W Reuben JM Hortobágyi GN Ueno NT Inflammatory breast cancer: what we know and what we need to learn Oncologist 2012 17 891 899 10.1634/theoncologist.2012-0039 22584436
32. Patani N Mokbel K Oncological and aesthetic considerations of skin-sparing mastectomy Breast Cancer Res Treat 2008 111 391 403 10.1007/s10549-007-9801-7 17965954
33. Hoffman DI Santos PMG Goldbach M Keele LJ Taunk NK Bogen HS Burkbauer L Jankowitz RC Fosnot J Wu LC Freedman GM Tchou JC Immediate breast reconstruction for inflammatory breast cancer: trends in use and clinical outcomes 2004–2016 Ann Surg Oncol 2021 28 8789 8801 10.1245/s10434-021-10404-4 34269937
34. Norhisham NF Chong CY Safuan S Peritumoral lymphatic vessel density and invasion detected with immunohistochemical marker D240 is strongly associated with distant metastasis in breast carcinoma BMC Clin Pathol, BMC Clinical Pathology 2017 17 1 7
35. Kong L-L Yang N-Z Shi L-H Zhao G-H Zhou W Ding Q Wang M-H Zhang Y-S The optimum marker for the detection of lymphatic vessels Mol Clin Oncol 2017 7 515 520 10.3892/mco.2017.1356 28855985
36. Lozar T Gersak K Cemazar M Kuhar CG Jesenko T The biology and clinical potential of circulating tumor cells Radiol Oncol 2019 53 2 131 147 10.2478/raon-2019-0024 31104002
37. Wong SY Hynes RO Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide? Cell Cycle 2006 5 8 812 817 10.4161/cc.5.8.2646 16627996
38. Lambert AW Pattabiraman DR Weinberg RA Emerging biological principles of metastasis Cell 2017 168 4 670 691 10.1016/j.cell.2016.11.037 28187288
39. Hidalgo M Amant F Biankin AV Budinská E Byrne AT Caldas C Clarke RB de Jong S Jonkers J Mælandsmo GM Roman-Roman S Seoane J Trusolino L Villanueva A Patient-derived xenograft models: an emerging platform for translational cancer research Cancer Discov 2014 4 9 998 1013 10.1158/2159-8290.CD-14-0001 25185190
40. Yin L Wang XJ Chen DX Liu XN Wang XJ Humanized mouse model: a review on preclinical applications for cancer immunotherapy Am J Cancer Res 2020 10 12 4568 4584 33415020
41. Chernofsky MR Felix JC Muderspach LI Morrow CP Ye W Groshen SG Roman LD Influence of quantity of lymph vascular space invasion on time to recurrence in women with early-stage squamous cancer of the cervix Gynecol Oncol 2006 100 288 293 10.1016/j.ygyno.2005.08.019 16182347
42. Sykes P Allen D Cohen C Scurry J Yeo D Does the density of lymphatic vascular space invasion affect the prognosis of stage Ib and IIA node negative carcinoma of the cervix? Int J Gynecol Cancer 2003 13 313 316 10.1046/j.1525-1438.2003.13024.x 12801262
43. Roman LD Felix JC Muderspach LI Varkey T Burnett AF Qian D Morrow CP Influence of quantity of lymph-vascular space invasion on the risk of nodal metastases in women with early-stage squamous cancer of the cervix Gynecol Oncol 1998 68 220 225 10.1006/gyno.1998.4943 9570969
44. Scurry J Hacker NF Barlow E Friedlander M Jackson M Is quantification of lymphovascular space invasion useful in stage 1B2 cervical carcinomas? J Obstet Gynaecol (Lahore) 2015 35 377 381 10.3109/01443615.2014.958448
45. Jolly MK Boareto M Debeb BG Aceto N Farach-Carson MC Woodward WA Levine H Inflammatory breast cancer: A model for investigating cluster-based dissemination Breast Cancer 2017 3 1 7 10.1038/s41523-017-0023-9 28232952
46. Somarelli JA Schaeffer D Marengo MS Bepler T Rouse D Ware KE Hish AJ Zhao Y Buckley AF Epstein JI Armstrong AJ Virshup DM Garcia-Blanco MA Distinct routes to metastasis: Plasticity-dependent and plasticity-independent pathways Oncogene 2016 35 4302 4311 10.1038/onc.2015.497 26751776
47. Aceto N Bardia A Miyamoto DT Donaldson MC Wittner BS Spencer JA Yu M Pely A Engstrom A Zhu H Brannigan BW Kapur R Stott SL Shioda T Ramaswamy S Ting DT Lin CP Toner M Haber DA Maheswaran S Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis Cell 2014 158 1110 1122 10.1016/j.cell.2014.07.013 25171411
48. Cheung KJ Padmanaban V Silvestri V Schipper K Cohen JD Fairchild AN Gorin MA Verdone JE Pienta KJ Bader JS Ewald AJ Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters Proc Natl Acad Sci U S A 2016 113 E854 E863 10.1073/pnas.1508541113 26831077
49. Choi YJ Pinto MM Hao L Riba AK Interobserver variability and aberrant E-cadherin immunostaining of lobular neoplasia and infiltrating lobular carcinoma Mod Pathol 2008 21 1224 1237 10.1038/modpathol.2008.106 18587329
50. Palacios J Sarrió D García-Macias MC Bryant B Sobel ME Merino MJ Frequent E-cadherin gene inactivation by loss of heterozygosity in pleomorphic lobular carcinoma of the breast Mod Pathol 2003 16 674 678 10.1097/01.MP.0000073974.42583.F7 12861063
51. Weiswald LB Bellet D Dangles-Marie V Spherical cancer models in tumor biology Neoplasia (United States) 2015 17 1 15 10.1016/j.neo.2014.12.004
52. Zanoni M Piccinini F Arienti C Zamagni A Santi S Polico R Bevilacqua A Tesei A 3D tumor spheroid models for in vitro therapeutic screening: A systematic approach to enhance the biological relevance of data obtained Sci Rep 2016 6 1 11 10.1038/srep19103 28442746
53. Nath S Devi GR Three-dimensional culture systems in cancer research: Focus on tumor spheroid model Pharmacol Ther 2016 163 94 108 10.1016/j.pharmthera.2016.03.013 27063403
54. Young SR Saar M Santos J Nguyen HM Vessella RL Peehl DM Establishment and serial passage of cell cultures derived from LuCaP xenografts Prostate 2013 73 1251 1262 10.1002/pros.22610 23740600
55. Oktem G Sercan O Guven U Uslu R Uysal A Goksel G Ayla S Bilir A Cancer stem cell differentiation: TGFβ1 and versican may trigger molecules for the organization of tumor spheroids Oncol Rep 2014 32 641 649 10.3892/or.2014.3252 24927163
56. Froehlich K Haeger JD Heger J Pastuschek J Photini SM Yan Y Lupp A Pfarrer C Mrowka R Schleußner E Markert UR Schmidt A Generation of multicellular breast cancer tumor spheroids: comparison of different protocols J Mammary Gland Biol Neoplasia 2016 21 89 98 10.1007/s10911-016-9359-2 27518775
57. Arora J Sauer SJ Tarpley M Vermeulen P Rypens C Van LS Williams KP Devi GR Dewhirst MW Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: Use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies Oncotarget 2017 8 25226 25241 10.18632/oncotarget.15667 28423680
58. Kang HG Jenabi JM Zhang J Keshelava N Shimada H May WA Ng T Reynolds CP Triche TJ Sorensen PHB E-cadherin cell-cell adhesion in Ewing tumor cells mediates suppression of anoikis through activation of the ErbB4 tyrosine kinase Cancer Res 2007 67 3094 3105 10.1158/0008-5472.CAN-06-3259 17409416
59. Van Golen KL Wu ZF Xiao Tan Qiao, Li Wei Bao, Merajver SD: RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype Cancer Res 2000 60 5832 5838 11059780
60. Weiswald LB Richon S Massonnet G Guinebretière JM Vacher S Laurendeau I Cottu P Marangoni E Nemati F Validire P Bellet D Bièche I Dangles-Marie V A short-term colorectal cancer sphere culture as a relevant tool for human cancer biology investigation Br J Cancer 2013 108 1720 1731 10.1038/bjc.2013.132 23538387
61. Weiswald LB Richon S Validire P Briffod M Lai-Kuen R Cordelières FP Bertrand F Dargere D Massonnet G Marangoni E Gayet B Pocard M Bieche I Poupon MF Bellet D Dangles-Marie V Newly characterised ex vivo colospheres as a three-dimensional colon cancer cell model of tumour aggressiveness Br J Cancer 2009 101 473 482 10.1038/sj.bjc.6605173 19603013
62. Kondo J Endo H Okuyama H Ishikawa O Iishi H Tsujii M Ohue M Inoue M Retaining cell-cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer Proc Natl Acad Sci U S A 2011 108 6235 6240 10.1073/pnas.1015938108 21444794
63. Lehman HL Dashner EJ Lucey M Vermeulen P Dirix L Van LS Van Golen KL Modeling and characterization of inflammatory breast cancer emboli grown in vitro Int J Cancer 2013 132 2283 2294 10.1002/ijc.27928 23129218
64. Dawson H Lugli A Molecular and pathogenetic aspects of tumor budding in colorectal cancer Front Med 2015 2 11 10.3389/fmed.2015.00011
65. Man Y gao: Tumor cell budding from focally disrupted tumor capsules: A common pathway for all breast cancer subtype derived invasion J Cancer 2010 1 32 37 10.7150/jca.1.32 20842222
66. Pease JC Brewer M Tirnauer JS Spontaneous spheroid budding from monolayers: A potential contribution to ovarian cancer dissemination Biol Open 2012 1 622 628 10.1242/bio.2012653 23213456
67. Bronsert P Enderle-Ammour K Bader M Timme S Kuehs M Csanadi A Kayser G Kohler I Bausch D Hoeppner J Hopt UT Keck T Stickeler E Passlick B Schilling O Reiss CP Vashist Y Brabletz T Berger J Lotz J Olesch J Werner M Wellner UF Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface J Pathol 2014 234 410 422 10.1002/path.4416 25081610
68. Grigore A Jolly M Jia D Farach-Carson M Levine H Tumor budding: the name is EMT Partial EMT J Clin Med 2016 5 51 10.3390/jcm5050051 27136592
69. Boareto M Jolly MK Goldman A Pietilä M Mani SA Sengupta S Ben-Jacob E Levine H Onuchic JN Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype J R Soc Interface 2016 10.1098/rsif.2015.1106
70. Dobiasova B Mego M Biomarkers for inflammatory breast cancer: Diagnostic and therapeutic utility Breast Cancer Targets Ther 2020 12 153 163 10.2147/BCTT.S231502
71. Marambaud P Shioi J Serban G Georgakopoulos A Sarner S Nagy V Baki L Wen P Efthimiopoulos S Shao Z Wisniewski T Robakis NK A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions EMBO J 2002 21 8 1948 1956 10.1093/emboj/21.8.1948 11953314
| 36473978 | PMC9734724 | NO-CC CODE | 2022-12-14 23:28:30 | no | Breast Cancer Res Treat. 2022 Dec 6;:1-18 | utf-8 | Breast Cancer Res Treat | 2,022 | 10.1007/s10549-022-06819-6 | oa_other |
==== Front
Mol Cell Biochem
Mol Cell Biochem
Molecular and Cellular Biochemistry
0300-8177
1573-4919
Springer US New York
36471123
4621
10.1007/s11010-022-04621-y
Article
Facts and ideas on statins with respect to their lipophilicity: a focus on skeletal muscle cells and bone besides known cardioprotection
Svec Andrey [email protected]
1
http://orcid.org/0000-0002-9803-043X
Adameova Adriana [email protected]
23
1 grid.7634.6 0000000109409708 Faculty of Medicine, Department of Orthopaedics and Traumatology, Comenius University in Bratislava, Bratislava, Slovakia
2 grid.7634.6 0000000109409708 Faculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University in Bratislava, Bratislava, Slovakia
3 grid.419303.c 0000 0001 2180 9405 Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
5 12 2022
17
16 8 2022
28 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Statins are known to block cholesterol synthesis in the liver. They also exhibit non-lipid pleiotropic effects due to the inhibition of protein prenylation, thereby modulating various signaling pathways of cellular homeostasis and integrity. Both lipid control and pleiotropic action of statins are clinically used, mainly for treatment of hypercholesterolemia and primary and secondary prevention of cardiovascular diseases. Because the prescription of statins is increasing and statin therapy is often lifelong, in particular in patients with other risk factors, safety issues being associated with polymorbidity and polypragmasia as well as the persistence with and adherence to statins are specific points of attention of clinicians and clinical pharmacologists. Furthermore, because skeletal myocytes have a cholesterol inhibitory sensitivity greater than hepatocytes, a choice of an appropriate statin based on its lipophilicity and the associated likelihood of its side effects on skeletal muscle cells and bone is warranted in such polymorbid patients. These approaches can effectively modulate the risk: benefit ratio and highlight a need for personalized therapy as much as possible, thereby minimizing risk of discontinuation of therapy and poor compliance.
Keywords
Statins
Pleiotropic action
Side effects
Lipophilicity
Skeletal muscles
Bone
Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak RepublicVEGA 1/0016/20 Adameova Adriana The Slovak Research and Development AgencyAPVV-20-0242, APPV-15-0607 Adameova Adriana
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pmcIntroduction
Statins are the most used class of lipid-modifying agents. In the United States, nearly 30% of adults 40 years and older are on a statin. In the world, an estimated 145.8 million people took statins in 2018 and the consumption of statins increased by 3.99% from 2013 to 2018 [1]. It is predicted that statin use will have a growing trend worldwide, although some specifications related to region, subregion, and country are expected.
Statins are powerful hypolipidemic drugs and called as “new penicillin” and “new aspirin”
Different statins have distinct hypolipidemic properties, with pravastatin and simvastatin providing less LDL-lowering power (25–35% reduction in LDL at 20 mg dosing) than newer statins, like rosuvastatin and atorvastatin (40–50% reduction in LDL at 20 mg dosing) [2]. Based on across-dose analyses, rosuvastatin (10–80 mg) has shown the most potent hypolipidemic activity which is followed by atorvastatin (10–80 mg), simvastatin (10–80 mg) and pravastatin (10–40 mg) [3]. The reduction of LDL levels has been indicated to be independent of the patient characteristics and doubling the dose of any statin has been able to generate on average only a further 6% decrease in LDL cholesterol [2, 4]. In addition to the effects on LDL levels, statins also increase HDL cholesterol levels by 6–12% and lower triacylglycerol levels [3]. The mechanism of action of hypolipidemic effects of statins involves the inhibition of the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) with resultant feedback effects on the transcription factor SREBP-2 (sterol-regulatory-element-binding protein 2) promoting the synthesis of LDL receptors on the surface of hepatocytes [5, 6]. As a result, the circulating LDL lipopoproteins are cleared from the blood. Statins-mediated decrease in the production of apolipoprotein B, which is the major constituent of the atherogenic particles, and the increase in the production of apolipoprotein A, which is the major apolipoprotein of HDL particles, also contribute to the hypolipidemic effects of these drugs [7]. Due to these effects of statins on lipid metabolism, they arrest the atherosclerosis process, and prevent further atherosclerotic plaque formation. Thus, statins have been suggested to be to atherosclerosis what penicillin was to infectious diseases [8]. Furthermore, because they have been shown to reduce cardiovascular events, including myocardial infarction, stroke, and death, statins have also been named as “new aspirin” [9]. Indeed, it has been reported that lowering LDL cholesterol by 2 mmol/L with any effective statin regimen can prevent major vascular events in about 10% patients at high risk of heart attacks and strokes (secondary prevention) and in 5% patients at lower risk (primary prevention) [10, 11].
Pleiotropic action of statins
Lipid modification alone cannot explain all benefits of statins on the cardiovascular system and non-lipid pleiotropic effects of statins significantly contribute to their cardioprotection. Namely, the inhibition of the synthesis of isoprenoids through a common pathway as cholesterol biosynthesis, that prevents post-translational modification of small GTP-binding proteins of the Ras/Rho family (Ras, Rac and Rho), has been shown to affect endothelial function [12, 13], oxidative stress [14–16], inflammation [17, 18], and thrombogenesis [19, 20]. Thus, reduction of the cardiovascular mortality and morbidity due to statin therapy can be a result of vascular endothelial function-improving, anti-inflammatory, anti-oxidant, platelet aggregation-inhibiting effects and plaque-stabilizing effects besides lowering cholesterol levels. Some of these pleiotropic effects can also modulate the pathomechanisms of cerebrovascular diseases, such as stroke, Alzheimer's disease, and Parkinson’s disease. However, both scenarios—the improvement of cognitive impairment and reversible decline in cognitive function due to statin therapy have been documented in clinical trials [21–24]. A very recent meta-analysis has indicated the absence of statins-induced neurocognitive risk and highlighted that treatment with statins shall be considered and not discontinued in elderly patients for primary and secondary prevention of cardiovascular disease [25]. Furthermore, it has been shown that statins due to pleiotropic action make the cancer cells more prone to apoptosis, and that inhibit their growth and differentiation, thereby eliciting the antitumor effects [25–27]. However under ischemic conditions, statins have been reported rather to retard apoptotic cell death and thereby mitigate post-ischemic organ damage [16, 28, 29]. Moreover, potential beneficial effects of statins due to pleiotropy have also been studied in diabetes mellitus, HIV [30], and multiple sclerosis [31]. It should be, however, mentioned that there was an intensive debate on the statin-induced modulation of glucose metabolism as a new-onset diabetes had occurred [32, 33]. The effects of statins have also been a subject of investigation in patients with COVID-19 infection. It has been indicated that statin use reduces risk of progressing to severe illness and in-hospital death in COVID-19 patients due to suppressing viral entry and replication, anti-inflammatory, anti-oxidative and immunomodulatory, as well as anti-thrombotic effects [34–36].
Classification of statins as the over-the counter drugs
The impressive cardioprotective effects of statins have instigated discussion of the re-classification of low doses of these drugs as the over-the counter (OTC) products. The sponsors of the applications proposed that a single-dose OTC statin should be indicated for individuals (i) who qualify for primary prevention under the third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program, (ii) who are with multiple (≥ 2) risk factors and a 10-year coronary heart disease risk ≤ 20%, (iii) and who are with no contraindications to statins, and with no favorable likelihood of experiencing benefit versus risk [37, 38]. Initially, a low-dose of pravastatin and lovastatin had failed to secure OTC approval and a pharmaceutical company reapplied to the US Food and Drug Administration (FDA) for its non-prescription preparation in the United States. In 2004, a low-dose formulation of simvastatin (10-mg tablet) was approved as an OTC product in the United Kingdom. The anticipated effects of simvastatin 10 mg was a reduction of risk of a first major coronary event, such as non-fatal myocardial infarction or coronary artery disease death. It was estimated that by using such OTC products, an approximate 30% reduction in LDL cholesterol level results in an 11% diminution in risk of a major coronary artery disease event after 1 year of therapy, 24% after 2 years, and 33% after 3 years [39]. In spite of many positive ideas and ambitions for OTC classification of statins, various critical issues were raised. For instance, critics questioned the clinical efficacy of such a low dosage approved. Furthermore, the product marketing was challenged by the consumers groups. Lastly, it was retrospectively reported that OTC availability unlikely impacted on the level of general practice led management of patients at risk of coronary events. [40]. In addition to these factors, an increasing number of newly recognized adverse effects of statins forced the regulatory authorities to re-consider the OTC approval of statins and keep these hypolipidemic drugs as the prescription drugs in the majority of countries. In this regard, it can be mentioned that side effects of statins are usually considered as effects of a whole class while in certain cases they should be rather assigned to some types of statins only. In fact, side effects of an individual statin are determined by its pharmacokinetic properties and its chemical structure. This is of a particular importance in risk patients with other co-morbidities, in which the adherence to a certain statin over another one can be affected. In this paper, we address some side effects of statins on the skeletal muscle and bone and indicate their lipophilicity-associated individual differences. Furthermore, this review is also intended to help clinicians to manage patients on statins therapy in order to minimize the occurrence of side effects while not discontinuing the treatment of hypercholesterolemia and/or prevention of cardiovascular diseases.
Lipophilicity and chemical structure of statins
Dihydroxyheptanoic acid unit and a ring system with different side substituents are the two main structural components of statins. Within the former component, the modified hydroxyglutaric acid is similar to the endogenous substrate HMG-CoA and it is called the HMG-CoA analogue. The closed chain, which can be partially reduced naphthylene (like in lovastatin, simvastatin, and pravastatin), pyrrole (atorvastatin), indole (fluvastatin), pyrimidine (rosuvastatin), and quinoline (pitavastatin), is a part of the drug structure that binds to the target enzyme—HMG-CoA reductase [41]. Conversely, side chains determine the drug lipophilicity/hydrophilicity. Atorvastatin, fluvastatin, lovastatin and simvastatin are relatively lipophilic drugs, whereas pravastatin and rosuvastatin are more hydrophilic due to a polar hydroxyl and methylsulfonamide group [42, 43]. Cerivastatin was the most lipophilic statin—the statin with the highest oil:water ratio, while pravastatin is the most hydrophilic statin [44, 45]. Being aware of the complex physical and chemical properties of statins, which can affect the drug interaction with biological structures of cells (e.g., membrane diffusion, intracellular translocation, etc.), it is obvious that statins have different rate of drug absorption, organ penetration as well as action in a respective organ. Namely, hydrophilic statins require the carrier-mediated uptake into the liver, with the higher transport affinity and efficiency for rosuvastatin than that of pravastatin [46]. In contrast, lipophilic statins are capable of passive diffusion through the cell membrane indicating the decrease in their hepatoselectivity as they are also able to passively diffuse into other tissues [45]. Thus, lipophilicity/hydrophilicity is important for statin bioactivity as well as for bioavailability determined by drug metabolism, clearance and drug accumulation within the body. Pravastatin and rosuvastatin exhibit the efficacy and affinity mainly for the hepatic tissue, and a reduced potential for the uptake by peripheral cells. In contrast, non-hepatic cells are likely more exposed to simvastatin, atorvastatin, and fluvastatin than to hydrophilic statins. This paradigm can be adopted for both beneficial, therapeutic and adverse effects of statins. Beneficial non-lipid effects of statins due to affecting various cellular signaling pathways in non-hepatic tissues have been intensively studied and are nicely reviewed elsewhere [47–50]. In the following section of this manuscript, some side effects of statins on the skeletal muscle and bone, which are likely dependent on drug lipophilicity, are discussed. They are schematically drawn in Fig. 1.Fig. 1 A schematic picture indicating the increasing partition coefficients (water-octanol) at pH = 7.4 of some statins and highlighting the more incidence of side effects on the skeletal muscle and bone by taking lipophilic, rather than hydrophilic statins. Cerivastatin* was withdrawn from market in 2001
Some side effects of statins on skeletal muscle with respect to their lipophilicity
Statin muscle symptoms are well-known side effect of statins as the skeletal myocytes have cholesterol inhibitory sensitivity 40-times greater than hepatocytes [51]. A paper analyzing case reports of statin-induced rhabdomyolysis has indicated the cases associated mainly with simvastatin (40 mg/day) and atorvastatin therapy (10 mg/day). The majority of the statin-induced rhabdomyolysis cases occurred when simvastatin and atorvastatin were taken concomitantly with other medications, such as fibrates [52]. Cerivastatin is another statin known to produce various forms of myotoxicity ranging from mild forms, such as myopathy and myalgia, to fatal rhabdomyolysis. A combination therapy of cerivastatin with cyclosporine [53], bezafibrate [54], gemfibrozil [55, 56], influenza vaccine [54] as well as monotherapy of cerivastatin [57, 58] were reported to cause rhabdomyolysis. The incidence of cerivastatin-induced rhabdomyolysis appeared to be tenfold greater as compared to other statins [59]. About 100 rhabdomyolysis-related deaths were found to be associated with cerivastatin therapy till its deregistration by manufacturer in 2001. It can be, however, mentioned that cerivastatin exhibited remarkable hypolipidemic action. It was about 250-fold more potent than fluvastatin, 20-fold more potent than atorvastatin and 5.5-fold more potent than rosuvastatin. At a dose of 0.025 mg/day to 0.8 mg/day, cerivastatin caused LDL cholesterol decrease of 11.0–40.8%. These hypolipidemic effects were linear dose-related [60].
Clinical studies have inconsistently shown the association between statin use and risk of fracture. Both the prevention and higher probability of fractures due to statin therapy have been reported [61–67]. Patients taking high-potency statins, like atorvastatin and rosuvastatin, have been shown to be at a lower risk of developing osteoporotic fractures than those taking simvastatin [65]. In contrast, but in line with a concept presented in this paper referring to a higher probability of lipophilic statins to produce side effects on the non-hepatic tissue, it has been reported that females on lipophilic statins had statistically lower bone mineral density than those on hydrophilic statins. In addition, a high dose of atorvastatin reduced bone mineral density more than a low dose [68]. From our clinical experience, it is also apparent that atorvastatin and simvastatin increased the risk of fractures. Some studies have indicated no effects on the risk of fractures due to statin therapy [62, 63]. Contradictory to these observations, the increased increment in bone mineral density due to statin therapy has also been reported in some risk groups. In this regards, patients with osteoporosis and metabolic syndrome [66] and patients with diabetes mellitus would likely benefit from statin therapy [69]. Targeting cellular signaling pathways of inflammation and oxidative stress, which are common pathophysiological mechanisms for osteoporosis and metabolic syndrome and diabetes, can provide the rationale on multifactorial benefits in these specific subgroups of patients.
The above-discussed controversy on statins-mediated action on fractures could be explained by several factors. Firstly, many meta-analyses have been performed in elderly, and polymorbid patients. Thus, other co-existing risk factors, such as sedentary lifestyle, hypercholesterolaemia, disturbed calcium homeostasis, body mass index, age, gender, etc., in addition to polypragmasia could underlie heterogeneous and inconsistent data. A type of a statin, being either of the hydrophilic or lipophilic chemical structure, was also not specified in many of the above-discussed studies [61–66]. In fact, the enrollment of all statins irrespective of a type, and dose, instead of a comparative analysis among individual statins could also significantly affect findings.
Although side effects of statins on the skeletal muscles and bone can be a result of various above-discussed factors, lipophilicity and thereby non-selectively affecting non-hepatic tissues and increasing risk of toxicity in these tissues could play an important role. Thus, the administration of hydrophilic versus lipophilic statin should be carefully considered in this regard. This approach can also impact on the persistence with and adherence to statins, which are sex-dependent, and poor with a lower proportion for the primary prevention of cardiovascular diseases compared to secondary prevention populations [70–72].
Conclusion
In conclusion, statins-mediated pleiotropic effects largely account for clinical benefits. Because there is a growing need for statins to control high cholesterol and reduce the risk of cardiovascular disease a special attention is given on their safety in view of a short and long perspective. In addition, because there is the correlation between atherosclerosis and osteoporosis, independent of age, it is evident that many patients admitted to hospital at the orthopedics and traumatology department are on statin. Being mindful of all these facts, a personalized approach is highly warranted in the management of these patients. Besides generally known and advised methods, such as motivation and better communication between clinician and patient, the personalized intervention might include the recommendations which individual statin shall be used to achieve better compliance and not discontinuation of therapy.
Acknowledgements
The authors thank Dr. Horvath for his help with a graphical illustration.
Author contributions
Both authors contributed to the study conception and design and approved the final manuscript.
Funding
This study was supported by Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and The Slovak Research and Development Agency (APVV-20–0242, APPV-15–0607, VEGA 1/0016/20).
Data availability
Data availability statement is not applicable for this review.
Declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Ethical approval
This is a review article and ethical approval is not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Blais JE Wei Y Yap KKW Alwafi H Ma TT Brauer R Lau WCY Man KKC Siu CW Tan KCB Wong ICK Wei L Chan EW Trends in lipid-modifying agent use in 83 countries Atherosclerosis 2021 328 44 51 10.1016/j.atherosclerosis.2021.05.016 34091069
2. Law MR Wald NJ Rudnicka AR Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis BMJ 2003 326 1423 10.1136/bmj.326.7404.1423 12829554
3. Jones PH Davidson MH Stein EA Bays HE McKenney JM Miller E Cain VA Blasetto JW Group SS Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* trial) Am J Cardiol 2003 92 152 60 10.1016/s0002-9149(03)00530-7 12860216
4. Nicholls SJ Brandrup-Wognsen G Palmer M Barter PJ Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER) Am J Cardiol 2010 105 69 76 10.1016/j.amjcard.2009.08.651 20102893
5. Horton JD Goldstein JL Brown MS SREBPs: transcriptional mediators of lipid homeostasis Cold Spring Harb Symp Quant Biol 2002 67 491 498 10.1101/sqb.2002.67.491 12858575
6. Brown MS Goldstein JL The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor Cell 1997 89 331 340 10.1016/s0092-8674(00)80213-5 9150132
7. Vega GL Grundy SM Effect of statins on metabolism of apo-B-containing lipoproteins in hypertriglyceridemic men Am J Cardiol 1998 81 36B 42B 10.1016/s0002-9149(98)00036-8 9462603
8. Roberts WC The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infectious disease Am J Cardiol 1996 78 377 378 10.1016/s0002-9149(96)00441-9 8759827
9. Veillard NR Mach F Statins: the new aspirin? Cell Mol Life Sci 2002 59 1771 1786 10.1007/pl00012505 12530513
10. Collins R Reith C Emberson J Armitage J Baigent C Blackwell L Blumenthal R Danesh J Smith GD DeMets D Evans S Law M MacMahon S Martin S Neal B Poulter N Preiss D Ridker P Roberts I Rodgers A Sandercock P Schulz K Sever P Simes J Smeeth L Wald N Yusuf S Peto R Interpretation of the evidence for the efficacy and safety of statin therapy Lancet 2016 388 2532 2561 10.1016/S0140-6736(16)31357-5 27616593
11. Cholesterol Treatment Trialists C Baigent C Blackwell L Emberson J Holland LE Reith C Bhala N Peto R Barnes EH Keech A Simes J Collins R Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials Lancet 2010 376 1670 1681 10.1016/S0140-6736(10)61350-5 21067804
12. Feron O Dessy C Desager JP Balligand JL Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance Circulation 2001 103 113 118 10.1161/01.cir.103.1.113 11136695
13. Pelat M Dessy C Massion P Desager JP Feron O Balligand JL Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E-/- mice in vivo Circulation 2003 107 2480 2486 10.1161/01.CIR.0000065601.83526.3E 12719275
14. Wassmann S Laufs U Baumer AT Muller K Ahlbory K Linz W Itter G Rosen R Bohm M Nickenig G HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species Hypertension 2001 37 1450 1457 10.1161/01.hyp.37.6.1450 11408394
15. Wassmann S Laufs U Muller K Konkol C Ahlbory K Baumer AT Linz W Bohm M Nickenig G Cellular antioxidant effects of atorvastatin in vitro and in vivo Arterioscler Thromb Vasc Biol 2002 22 300 305 10.1161/hq0202.104081 11834532
16. Hsieh CC Li CY Hsu CH Chen HL Chen YH Liu YP Liu YR Kuo HF Liu PL Mitochondrial protection by simvastatin against angiotensin II-mediated heart failure Br J Pharmacol 2019 176 3791 3804 10.1111/bph.14781 31265743
17. Glynn RJ Koenig W Nordestgaard BG Shepherd J Ridker PM Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial Ann Intern Med 2010 152 488–96 W174 10.7326/0003-4819-152-8-201004200-00005 20404379
18. Egashira K Ni W Inoue S Kataoka C Kitamoto S Koyanagi M Takeshita A Pravastatin attenuates cardiovascular inflammatory and proliferative changes in a rat model of chronic inhibition of nitric oxide synthesis by its cholesterol-lowering independent actions Hypertens Res 2000 23 353 358 10.1291/hypres.23.353 10912772
19. Bourcier T Libby P HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells Arterioscler Thromb Vasc Biol 2000 20 556 562 10.1161/01.atv.20.2.556 10669656
20. Dujovne CA Harris WS Altman R Overhiser RW Black DM Effect of atorvastatin on hemorheologic-hemostatic parameters and serum fibrinogen levels in hyperlipidemic patients Am J Cardiol 2000 85 350 353 10.1016/s0002-9149(99)00745-6 11078305
21. Schultz BG Patten DK Berlau DJ The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms Transl Neurodegener 2018 7 5 10.1186/s40035-018-0110-3 29507718
22. Trompet S van Vliet P de Craen AJ Jolles J Buckley BM Murphy MB Ford I Macfarlane PW Sattar N Packard CJ Stott DJ Shepherd J Bollen EL Blauw GJ Jukema JW Westendorp RG Pravastatin and cognitive function in the elderly. Results of the PROSPER study J Neurol 2010 257 85 90 10.1007/s00415-009-5271-7 19653027
23. Shepherd J Blauw GJ Murphy MB Bollen EL Buckley BM Cobbe SM Ford I Gaw A Hyland M Jukema JW Kamper AM Macfarlane PW Meinders AE Norrie J Packard CJ Perry IJ Stott DJ Sweeney BJ Twomey C Westendorp RG PsgPSoPitEa R Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial Lancet 2002 360 1623 1630 10.1016/s0140-6736(02)11600-x 12457784
24. Evans MA Golomb BA Statin-associated adverse cognitive effects: survey results from 171 patients Pharmacotherapy 2009 29 800 811 10.1592/phco.29.7.800 19558254
25. Olmastroni E Molari G De Beni N Colpani O Galimberti F Gazzotti M Zambon A Catapano AL Casula M Statin use and risk of dementia or alzheimer's disease: a systematic review and meta-analysis of observational studies Eur J Prev Cardiol 2022 29 804 814 10.1093/eurjpc/zwab208 34871380
26. Wong WW Clendening JW Martirosyan A Boutros PC Bros C Khosravi F Jurisica I Stewart AK Bergsagel PL Penn LZ Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma Mol Cancer Ther 2007 6 1886 1897 10.1158/1535-7163.MCT-06-0745 17575117
27. Crescencio ME Rodriguez E Paez A Masso FA Montano LF Lopez-Marure R Statins inhibit the proliferation and induce cell death of human papilloma virus positive and negative cervical cancer cells Int J Biomed Sci 2009 5 411 420 23675166
28. Rajtik T Carnicka S Szobi A Mesarosova L Matus M Svec P Ravingerova T Adameova A Pleiotropic effects of simvastatin are associated with mitigation of apoptotic component of cell death upon lethal myocardial reperfusion-induced injury Physiol Res 2012 61 Suppl 2 S33 41 10.33549/physiolres.932420 23130901
29. Adameova A Harcarova A Matejikova J Pancza D Kuzelova M Carnicka S Svec P Bartekova M Styk J Ravingerova T Simvastatin alleviates myocardial contractile dysfunction and lethal ischemic injury in rat heart independent of cholesterol-lowering effects Physiol Res 2009 58 449 454 10.33549/physiolres.931751 19627175
30. Eckard AR McComsey GA The role of statins in the setting of HIV infection Curr HIV/AIDS Rep 2015 12 305 312 10.1007/s11904-015-0273-9 26126687
31. Pihl-Jensen G Tsakiri A Frederiksen JL Statin treatment in multiple sclerosis: a systematic review and meta-analysis CNS Drugs 2015 29 277 291 10.1007/s40263-015-0239-x 25795002
32. Zaharan NL Williams D Bennett K Statins and risk of treated incident diabetes in a primary care population Br J Clin Pharmacol 2013 75 1118 1124 10.1111/j.1365-2125.2012.04403.x 22845189
33. Carter AA Gomes T Camacho X Juurlink DN Shah BR Mamdani MM Risk of incident diabetes among patients treated with statins: population based study BMJ 2013 346 f2610 10.1136/bmj.f2610 23704171
34. Rossi R Talarico M Coppi F Boriani G Protective role of statins in COVID 19 patients: importance of pharmacokinetic characteristics rather than intensity of action Intern Emerg Med 2020 15 1573 1576 10.1007/s11739-020-02504-y 33011928
35. Song SL Hays SB Panton CE Mylona EK Kalligeros M Shehadeh F Mylonakis E Statin use is associated with decreased risk of invasive mechanical ventilation in COVID-19 patients: a preliminary study Pathogens 2020 10.3390/pathogens9090759
36. Zhang XJ Qin JJ Cheng X Shen L Zhao YC Yuan Y Lei F Chen MM Yang H Bai L Song X Lin L Xia M Zhou F Zhou J She ZG Zhu L Ma X Xu Q Ye P Chen G Liu L Mao W Yan Y Xiao B Lu Z Peng G Liu M Yang J Yang L Zhang C Lu H Xia X Wang D Liao X Wei X Zhang BH Zhang X Yang J Zhao GN Zhang P Liu PP Loomba R Ji YX Xia J Wang Y Cai J Guo J Li H In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19 Cell Metab 2020 32 176–187 e4 10.1016/j.cmet.2020.06.015
37. Gotto AM Jr Is it appropriate to make statins available over the counter? Over-the-counter statins are worth considering in primary prevention of cardiovascular disease Circulation 2006 114 1310 1314 10.1161/CIRCULATIONAHA.105.552257 16982952
38. Expert Panel on Detection E and Treatment of High Blood Cholesterol in A Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) JAMA 2001 285 2486 2497 10.1001/jama.285.19.2486 11368702
39. Nash DB Nash SA Reclassification of simvastatin to over-the-counter status in the United Kingdom: a primary prevention strategy Am J Cardiol 2004 94 35F 39F 10.1016/j.amjcard.2004.07.053 15219505
40. Paudyal V Hansford D Cunningham S Stewart D Pharmacists' perceived integration into practice of over-the-counter simvastatin five years post reclassification Int J Clin Pharm 2012 34 733 738 10.1007/s11096-012-9668-5 22740232
41. Istvan ES Deisenhofer J Structural mechanism for statin inhibition of HMG-CoA reductase Science 2001 292 1160 1164 10.1126/science.1059344 11349148
42. McTavish D Sorkin EM Pravastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia Drugs 1991 42 65 89 10.2165/00003495-199142010-00005 1718686
43. McTaggart F Buckett L Davidson R Holdgate G McCormick A Schneck D Smith G Warwick M Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Am J Cardiol 2001 87 28B 32B 10.1016/s0002-9149(01)01454-0 11137829
44. Corsini A Bellosta S Baetta R Fumagalli R Paoletti R Bernini F New insights into the pharmacodynamic and pharmacokinetic properties of statins Pharmacol Ther 1999 84 413 428 10.1016/s0163-7258(99)00045-5 10665838
45. Schachter M Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update Fundam Clin Pharmacol 2005 19 117 125 10.1111/j.1472-8206.2004.00299.x 15660968
46. Nezasa K Higaki K Takeuchi M Nakano M Koike M Uptake of rosuvastatin by isolated rat hepatocytes: comparison with pravastatin Xenobiotica 2003 33 379 388 10.1080/0049825031000066259 12745873
47. Bonetti PO Lerman LO Napoli C Lerman A Statin effects beyond lipid lowering–are they clinically relevant? Eur Heart J 2003 24 225 248 10.1016/s0195-668x(02)00419-0 12590901
48. Liao JK Laufs U Pleiotropic effects of statins Annu Rev Pharmacol Toxicol 2005 45 89 118 10.1146/annurev.pharmtox.45.120403.095748 15822172
49. Davignon J Beneficial cardiovascular pleiotropic effects of statins Circulation 2004 109 III39 43 10.1161/01.CIR.0000131517.20177.5a 15198965
50. Adameova A Xu YJ Duhamel TA Tappia PS Shan L Dhalla NS Anti-atherosclerotic molecules targeting oxidative stress and inflammation Curr Pharm Des 2009 15 3094 3107 10.2174/138161209789058048 19754384
51. Muntean DM Thompson PD Catapano AL Stasiolek M Fabis J Muntner P Serban MC Banach M Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms? Drug Discov Today 2017 22 85 96 10.1016/j.drudis.2016.09.001 27634340
52. Mendes P Robles PG Mathur S Statin-induced rhabdomyolysis: a comprehensive review of case reports Physiother Can 2014 66 124 132 10.3138/ptc.2012-65 24799748
53. Rodriguez ML Mora C Navarro JF Cerivastatin-induced rhabdomyolysis Ann Intern Med 2000 132 598 10.7326/0003-4819-132-7-200004040-00031
54. Plotkin E Bernheim J Ben-Chetrit S Mor A Korzets Z Influenza vaccine–a possible trigger of rhabdomyolysis induced acute renal failure due to the combined use of cerivastatin and bezafibrate Nephrol Dial Transplant 2000 15 740 741 10.1093/ndt/15.5.740 10809833
55. Pogson GW Kindred LH Carper BG Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy Am J Cardiol 1999 83 1146 10.1016/s0002-9149(99)00034-x 10190540
56. Alexandridis G Pappas GA Elisaf MS Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil Am J Med 2000 109 261 262 10.1016/s0002-9343(00)00514-3 11023440
57. Gemici G Toprak A Oktay A Rhabdomyolysis due to cerivastatin monotherapy Am J Med 2001 110 742 10.1016/s0002-9343(01)00730-6
58. Bakri R Wang J Wierzbicki AS Goldsmith D Cerivastatin monotherapy-induced muscle weakness, rhabdomyolysis and acute renal failure Int J Cardiol 2003 91 107 109 10.1016/s0167-5273(02)00581-8 12957739
59. Jamal SM Eisenberg MJ Christopoulos S Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors Am Heart J 2004 147 956 965 10.1016/j.ahj.2003.12.037 15199341
60. Adams SP Tiellet N Alaeiilkhchi N Wright JM Cerivastatin for lowering lipids Cochrane Database Syst Rev 2020 1 CD012501 10.1002/14651858.CD012501.pub2 31981471
61. Pena JM Aspberg S MacFadyen J Glynn RJ Solomon DH Ridker PM Statin therapy and risk of fracture: results from the JUPITER randomized clinical trial JAMA Intern Med 2015 175 171 177 10.1001/jamainternmed.2014.6388 25437881
62. LaCroix AZ Cauley JA Pettinger M Hsia J Bauer DC McGowan J Chen Z Lewis CE McNeeley SG Passaro MD Jackson RD Statin use, clinical fracture, and bone density in postmenopausal women: results from the women's health initiative observational study Ann Intern Med 2003 139 97 104 10.7326/0003-4819-139-2-200307150-00009 12859159
63. van Staa TP Wegman S de Vries F Leufkens B Cooper C Use of statins and risk of fractures JAMA 2001 285 1850 1855 10.1001/jama.285.14.1850 11308398
64. An T Hao J Sun S Li R Yang M Cheng G Zou M Efficacy of statins for osteoporosis: a systematic review and meta-analysis Osteoporos Int 2017 28 47 57 10.1007/s00198-016-3844-8 27888285
65. Lin TK Liou YS Lin CH Chou P Jong GP High-potency statins but not all statins decrease the risk of new-onset osteoporotic fractures: a nationwide population-based longitudinal cohort study Clin Epidemiol 2018 10 159 165 10.2147/CLEP.S145311 29403315
66. Kim KJ Choi J Kim JY Bae JH Kim KJ Kim HY Yoo HJ Seo JA Kim NH Choi KM Baik SH Kim SG Kim NH Statin therapy and the risk of osteoporotic fractures in patients with metabolic syndrome: a nested case-control study J Lipid Atheroscler 2021 10 322 333 10.12997/jla.2021.10.3.322 34621703
67. Del Chiaro A Marchetti S Parchi PD Caprili G Ipponi E Scaglione M Use of statins and hip fracture risk: a case-control study Acta Chir Orthop Traumatol Cech 2022 89 104 107 35621399
68. Antonenko A Leahy A Babenko M Lyons D Low dose hydrophilic statins are the preferred agents for females at risk of osteoporosis Bone Rep 2022 16 101152 10.1016/j.bonr.2021.101152 34934779
69. Chung YS Lee MD Lee SK Kim HM Fitzpatrick LA HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients J Clin Endocrinol Metab 2000 85 1137 1142 10.1210/jcem.85.3.6476 10720052
70. Olmastroni E Boccalari MT Tragni E Rea F Merlino L Corrao G Catapano AL Casula M Sex-differences in factors and outcomes associated with adherence to statin therapy in primary care: need for customisation strategies Pharmacol Res 2020 155 104514 10.1016/j.phrs.2019.104514 31678211
71. Hope HF Binkley GM Fenton S Kitas GD Verstappen SMM Symmons DPM Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease PLoS ONE 2019 14 e0201196 10.1371/journal.pone.0201196 30653535
72. Colantonio LD Rosenson RS Deng L Monda KL Dai Y Farkouh ME Safford MM Philip K Mues KE Muntner P Adherence to statin therapy among US adults between 2007 and 2014 J Am Heart Assoc 2019 8 e010376 10.1161/JAHA.118.010376 30616455
| 36471123 | PMC9734727 | NO-CC CODE | 2022-12-14 23:28:30 | no | Mol Cell Biochem. 2022 Dec 5;:1-7 | utf-8 | Mol Cell Biochem | 2,022 | 10.1007/s11010-022-04621-y | oa_other |
==== Front
Clin Oral Investig
Clin Oral Investig
Clinical Oral Investigations
1432-6981
1436-3771
Springer Berlin Heidelberg Berlin/Heidelberg
36460919
4815
10.1007/s00784-022-04815-0
Research
Selective removal to soft dentine or selective removal to firm dentine for deep caries lesions ın permanent posterior teeth: a randomized controlled clinical trial up to 2 years
Gözetici-Çil Burcu [email protected]
1
Erdem-Hepşenoğlu Yelda [email protected]
2
Tekin Alperen [email protected]
3
Özcan Mutlu [email protected]
4
1 grid.411781.a 0000 0004 0471 9346 Department of Restorative Dentistry, School of Dentistry, Istanbul Medipol University, Birlik Mah. Bahçeler Cad. No. 5, Esenler, Istanbul, Turkey
2 grid.411781.a 0000 0004 0471 9346 Department of Endodontics, School of Dentistry, Istanbul Medipol University, Birlik Mah. Bahçeler Cad. No. 5, Esenler, Istanbul, Turkey
3 grid.411781.a 0000 0004 0471 9346 Oral Diagnosis and Maxillofacial Radiology, School of Dentistry, Istanbul Medipol University, Birlik Mah. Bahçeler Cad. No. 5 Esenler, Istanbul, Turkey
4 grid.7400.3 0000 0004 1937 0650 Division of Dental Biomaterials, Clinic for Reconstructive Dentistry, Center of Dental Medicine, University of Zurich, Plattenstrasse 11, CH-8032 Zurich, Switzerland
3 12 2022
113
9 7 2022
27 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Objectives
The aim of this randomized clinical trial was to compare selective removal to soft dentin (SRSD) and selective removal to firm dentin (SRFD) in permanent teeth. The primary outcome of the study was to compare the success rates of the two caries removal techniques. The secondary outcome of the study was to investigate whether or not calcium silicate-based material (CS) had an effect on the success rate of the treatment.
Materials and methods
Between November 2018 and March 2020, patients with deep caries lesions were invited to participate in the study. Posterior teeth (N = 165) with primary caries lesion radiographically extending ¾ of dentin and positive response to cold test were randomly selected. A total of 134 participants meeting the inclusion criteria were randomized to SRSD and SRFD (control) groups. After the caries removal procedure, teeth with exposed pulps were assigned to the pulp exposure (PE) group, and the SRSD group was further divided into test 1 (with CS) and test 2 groups (without CS). Success was defined as a positive response to the cold test, a negative response to percussion, the absence of pain, an abscess, a fistula, and periapical alterations. Fisher–Freeman–Halton exact tests, Kaplan–Meier survival analysis, and the log-rank tests were performed for comparisons between groups.
Results
No statistically significant difference was found between the success rates of test 1 (100%) and test 2 (93.5%) groups, whereas the proportion of success in control (82.4%) and PE (84%) groups were significantly lower when compared with test groups (p = 0.024; p < 0.05) at the end of 2-year follow-up.
Conclusions
SRSD had a higher success rate when compared to SRFD to treat deep carious lesions after 2 years of follow-up. The use of CS material after SRSD as a liner had no effect on the treatment outcome.
Clinical relevance
SRSD with good coronal sealing might be recommended without CS application for the treatment of deep caries lesions in permanent teeth.
Trial registration
Clinical trial registration number NCT04052685 (08/09/2019).
Keywords
Selective caries removal
Dental materials
Permanent dentition
Calcium silicate cements
Clinical trial
==== Body
pmcIntroduction
In recent years, there has been a growing number of studies questioning conventional caries tissue removal, especially for deep caries lesions [1]. In the concept of conventional caries removal, “affected dentin” and “infected dentine” are widely used terms [2]. According to this concept, the removal of infected dentin contaminated with bacteria and remaining affected dentin detected as firm dictated the management of cavitated caries lesions. Recently, this removal technique has been termed “SRFD” and seems to increase the potential risk for loss of pulp vitality for deep caries lesions radiographically extending ¾ of dentin tissue [3].
The first treatment option proposed as an alternative to SRFD for deep caries lesions to reduce pulp exposure and preserve pulp vitality was the stepwise excavation method [4]. Stepwise removal is a 2-stage procedure in which incomplete removal of caries tissue is carried out in the first stage, and then the cavity is sealed with a temporary filling to promote tertiary dentin formation. In the second stage, the cavity is reopened, and the remaining demineralized dentin is removed [5]. Regarding the disadvantages of stepwise removal, including the requirement of two sessions for treatment completion and the probability of pulp exposure during the second procedure, partial caries removal in 1-stage was proposed later on [6]. Higher success rates were observed for partial caries removal in 1-stage versus stepwise excavation in a long-term randomized clinical trial [7]. Reduced frequency of pulp exposure has also been shown with partial caries excavation when compared with SRFD [8]. Recently, the used term for this 1-stage partial caries removal is SRSD which refers to the removal of peripheral carious tissue to hard dentin to provide hermetic sealing of the restoration and leaving behind a layer of soft carious tissue over the pulp to avoid pulpal exposure [9]. According to the report of the International Caries Consensus Collaboration (ICCC) group, SRSD is strongly recommended in deep cavitated lesions extending into ¾ of dentin tissue [1].
In the case of pulp exposure, direct pulp capping is the treatment of choice for a tooth with vital pulp and without any inflammation predictor. However, according to the results of a retrospective study evaluating the treatment outcome of direct pulp capping with calcium hydroxide, 44.5% in the 5-year group and 79.9% in the 10-year group had a postoperative root canal treatment or an extraction [10]. Similarly, another retrospective study showed that over the 1st year after direct pulp capping with calcium hydroxide, almost 10% and, after 5 years, nearly 20% of the teeth had an unfavorable treatment outcome [11]. Recently, Biodentine™ (Septodont, St Maur-des-Fosses, France), which is a calcium silicate-based material, has gained popularity for pulp capping treatment. The success rate of Biodentine™ was reported to be 91.7% after 3 years in a recent prospective longitudinal randomized controlled study of vital permanent teeth with deep caries [12].
In the literature, there are very few studies concerned with the clinical success of SRSD. In a recently published review, it has been reported that SRSD seems to be the best option for the treatment of deep caries lesions, and the remaining caries tissue close to the pulp seems not to interfere with the longevity of the restorations [13]. However, information on the clinical advantages or disadvantages of SRSD and SRFD excavation methods mostly relies on studies conducted for primary teeth [8, 14–16]. In the currently available literature, not much scientific evidence on the clinical success of SRSD and SRFD excavation methods for deep carious lesions in permanent teeth could be found. Moreover, clinical trials are needed to demonstrate the combined effect of various removal strategies and CS.
The aim of this study was to compare clinical success rates of SRSD and SRFD techniques in posterior deep caries lesions of permanent teeth. The primary outcome of the study was a comparison of the clinical success of SRSD and SRFD techniques by clinical and radiographic evaluation after 3 months, 6 months, 1 year, and 2 years. The secondary outcome of the study was to investigate whether or not CS had an effect on the success rate of the treatment. The hypothesis tested in this study was that SRSD preserves tooth vitality better than SRFD.
Materials and methods
Study design
The study was approved by the University Ethics Committee (the protocol number is given in the “Declarations” part of the manuscript). All participants provided written informed consent. Written information was given to each patient regarding the alternative treatment options. This study was carried out as a prospective randomized clinical trial and registered at clinicaltrials.gov (the registration no. was given on the “Abstract” part of the manuscript). Teeth (N = 259) were evaluated for eligibility to participate in this study between November 2018 and March 2020. Of these teeth, 94 were excluded because they did not meet the inclusion criteria. Thus, 165 teeth were included. The study had a double-blind design, as the observers who assessed outcomes and the patients were blinded to the interventions performed. Details of the study design can be seen in Fig. 1.Fig. 1 Study flowchart
The sample size calculation was based on the difference between success rates of partial caries removal after a 3-year period of 91% [6] and direct complete excavation after a 1-year follow-up period of 62.4% [17], at α = 5% with a power of 90%. This indicated the need for 33 restorations per treatment group. Taking into account a dropout rate of 50% after 2 years, the trial was planned to include at least 66 restorations. Unexpectedly, due to COVID-19 pandemic-related restrictions, a total number of 198 restorations could not be completed. Thus, enrollment in the study had to be finished by March 2020.
Potential patients attending the University Dental Clinics from both genders, with ages ranging from 13 to 65, in good general health, were invited to the study. To be included in the study patients were required to have at least one deep posterior primary caries lesion radiographically extending ¾ of dentin. Eligible lesions detected on panoramic X-ray radiography were further evaluated by measurement of the extent of the lesion on periapical and bite-wing radiography using the software (Kodak RVG 5200, Carestream Health, New York, USA). Additionally, teeth were required to present the absence of spontaneous pain, periradicular pathology, or non-carious lesions (attrition, abrasion, erosion, or abfraction). Teeth with untreated periodontal disease, positive response to percussion, and negative response to electrical and cold vitality tests were excluded. Patients were not included in the study in case of pregnancy, orthodontic treatment, prosthetic rehabilitation, and allergy to the ingredients of the study materials.
Study groups
The unit of randomization was the tooth. A randomization software (Excel, Microsoft Office 2016) was used for 2:1 block randomization of the teeth into SRSD and SRFD (control) groups. In the case of pulp exposure, pulp capping was performed for these teeth, and they were assigned to the “PE” group. The SRSD group was further divided into two subgroups: (1) SRSD with CS (test 1) and (2) SRSD without CS (test 2). In order to ensure allocation concealment, the operator was unaware of the subgroup until SRSD was completed. The operator received a sealed envelope for each tooth, previously prepared by an independent research coordinator who was responsible for block randomization of teeth in the SRSD group.
Clinical procedures
Clinical treatments were carried out by the operator (BGÇ), who has experience in restorative dentistry for more than 15 years since graduation. The operator was trained in all clinical procedures before the beginning of the study. All procedures were carried out under local anesthesia. The treatments were performed as follows:The level of preoperative sensitivity, tooth type, age and gender of the patient, ICDAS score, and radiographic depth of the lesions were assessed just before treatment. The patient’s description of sensitivity to thermal stimulus lasting up to 15–20 s was considered moderate, while increased pain for more than several minutes and needing painkillers was considered severe [18].
Dentinal carious lesions were accessed by the removal of surrounding unsupported enamel with a round diamond bur operated at high speed under water cooling.
Carious tissue was examined by the operator and the characteristics of the caries tissue were categorized as light yellow actively progressing (LYAP), light brown slowly progressing (LBSP), or dark brown slowly progressing (DBSP) and recorded [19].
Carious tissue at the lateral walls of cavities was removed to hard dentin using round tungsten carbide burs operated at low speed in all groups.
In SRSD groups, carious tissue in the pulpal aspect of the cavity was excavated by hand instruments to soft dentin. Only disorganized dentine was removed. A reasonable amount of soft carious tissue was left over the pulp.
In the SRFD group, carious tissue was completely removed to firm dentin using round tungsten carbide burs.
Following caries removal, a cotton pellet moistened with 5% sodium hypochlorite was placed into each cavity in all groups for 3 min [12].
In test 1 and control groups, after caries removal, CS was applied on the pulpal floor following the instructions of the manufacturer. CS (Biodentine™) was covered by resin-based lining material (Glass liner, Willmann & Pein GmbH, Barmstedt, Germany) after 12 min setting time.
In test 2 group, resin composite application procedure was followed after caries removal without CS placement.
If the excavations led to pulp exposure, the teeth were assessed for eligibility for pulp capping. Pulp-capping with CS was performed for teeth with normal bleeding. None of the teeth included in the study were referred for endodontic treatment due to prolonged bleeding for more than 3 min.
Matrix band (Adapt Super Cap Matrix, KerrHave SA, Bioggio, Switzerland) was used prior to restoration for ClI cavities.
Selective etching with 37% phosphoric acid (Total Etch—Ivoclar/Vivadent, Liechtenstein) was applied for 10 s in enamel. Cavities were rinsed for 10 s, and adhesive material (3 M Single Bond Universal Adhesive, 3M ESPE St Paul, USA) was applied with a micro brush in cavity walls rubbing for 20 s. After gentle air drying for approximately 5 s, a 1200 W/cm2 intensity LED light device (LED.B, Guilin Woodpecker Medical Instrument, Guilin, Guangxi, China) was used for 10 s light curing.
Clinical and radiographic evaluation
The patients were asked to make pain assessments at home daily for the 1st week after the treatments using a visual analog scale (VAS) printed on paper ranging from no pain to unbearable pain (1–10) and return the assessments by phone call.
The primary outcome was pulp vitality without apical radiolucency. Two blinded observers to the study who have experience in endodontics and oral diagnosis more than 10 years since graduation independently evaluated the following parameters for overall success:Positive response to cold test (– 50 °C spray; Roeko Endo-Frost, Coltene, Whaledent GmbH, Langeneu, Germany).
A negative response to percussion.
Absence of pain on palpation, abscess, or fistula.
Radiographically, absence of periapical pathology or alterations (absence of lamina dura, periodontal ligament space widening at least twice, root canal obliteration, internal and external resorption).
The radiographic examinations were performed before treatment, immediately after the treatment, and then during control visits. The examinations were standardized using film-holding instruments for bite-wing (Kwik-Bite, Kerr Corporation, Orange, CA, USA) and periapical (Super-Bite Senso, Kerr Corporation) radiography. All periapical radiographic procedures were based on the parallel capturing technique. Radiography was taken using Kodak RVG CS 5200 digital radiography system and intraoral x-ray unit CareStream CS2100 (Carestream Health) operating at 60 kVp, 7 mA, and 0.25 s. The object-to-focus distance was 30 cm. The images were stored in maximum-quality JPEG format. All the images of the same tooth were placed side by side on a black screen using software (Keynote, Apple Inc., Cupertino, CA, USA) for comparative evaluation of the radiographic changes through follow-ups according to baseline. Radiographically, interruption of the white line of the lamina dura, darkening around the roots, and abnormal radiolucency or radiopacity at the pulpal or root surfaces were considered a failure of the treatment.
Clinical performance of the resin composite restorations was evaluated at baseline and designated follow-ups according to FDI World Dental Federation criteria for surface luster, surface and marginal staining, color match and translucency, esthetic anatomical form, fracture and retention of the material, marginal adaptation, occlusal wear, approximal anatomic form, radiographic examination, and patient’s view [20].
Statistical analysis
Number Cruncher Statistical Systems (NCSS 2007, Kaysville, UT, USA) was used for statistical analysis. Distribution of quantitative data (age and postoperative pain scores) was rejected as being normally distributed (Shapiro–Wilk test), hence Mann–Whitney U and Kruskal–Wallis with Dunn–Bonferroni tests for inter-group comparisons were used. Qualitative data was compared with Pearson chi-square and Fisher–Freeman–Halton exact tests. Cox proportional hazard regression analyses were used to evaluate the univariate and multivariate influences of baseline variables on treatment success. Kaplan–Meier analysis was used to determine survival rates, and the log-rank test to find out the differences between the survival rates of the groups was used. The significance level was set at 5%, and the unit of analysis was the tooth.
Results
Out of 134 (77 female and 57 male) patients included in the study, approximately 80% received 1 treatment, 17% received 2 treatments, and 3% received 3 or more treatments. The participants were mainly young adults; the mean age was 24.14 (with a minimum age of 13 and a maximum age of 44 years), with a standard deviation of 8.30 years. All baseline characteristics are listed in Table 1. There was no statistically significant difference between the control and test groups with respect to age, gender, tooth, cavity type, radiographic depth, ICDAS scores, carious tissue characteristics, and preop sensitivity. In the PE group, the teeth with moderate preoperative sensitivity scores were higher and the teeth with no preoperative sensitivity were lower when compared to the control and test groups (p = 0.001; p < 0.01).Table 1 Description of baseline characteristics by type of treatment assigned
Variables Test 1
(nrestotarion = 45)
(npatient = 38) Test 2
(nrestotarion = 45)
(npatient = 33) Control
(nrestotarion = 46)
(npatient = 36) PE
(nrestotarion = 29)
(npatient = 27) p
Gender
Female n (%)
Male n (%)
21 (55.3)
17 (44.7)
20 (60.6)
13 (39.4)
21 (58.3)
15 (41.7)
15 (55.6)
12 (44.4)
a0.970
Age
Mean (SD)
Median (min–max)
23.95 (8.38)
23.5 (13–44)
23.42 (8.25)
22 (13–42)
25.64 (8.62)
25.5 (13–41)
23.30 (8.00)
23 (13–41)
b0.641
Tooth type
Molar n (%)
Premolar n (%)
28 (62.2)
17 (37.8)
31 (68.9)
14 (31.1)
22 (47.8)
24 (52.2)
17 (58.6)
12 (41.4)
a0.225
Cavity type
Cl I n (%)
Cl II n (%)
8 (17.8)
37 (82.2)
3 (6.7)
42 (93.3)
6 (13.0)
40 (87.0)
5 (17.2)
24 (82.8)
a0.384
Radyographic depth
> 3/4 n (%)
3/4 n (%)
35 (77.8)
10 (22.79
29 (64.4)
16 (35.6)
28 (62.2)
18 (37.8)
22 (75.9)
7 (24.1)
a0.309
ICDAS score
4 n (%)
5 n (%)
6 n (%)
16 (35.6)
28 (62.2)
1 (2.2)
18 (40.0)
27 (60.0)
0 (0.0)
19 (41.3)
26 (56.5)
1 (2.2)
5 (17.2)
20 (69.0)
4 (13.8)
a0.051
Caries tissue
LYAP n (%)
LBSP n (%)
DBSP n (%)
34 (75.6)
7 (15.6)
4 (8.9)
31 (68.9)
9 (20.0)
5 (11.1)
26 (56.5)
9 (19.6)
11 (23.9)
26 (89.7)
2 (6.9)
1 (3.4)
a0.068
Preop sensitivity
No n (%)
Moderate n (%)
Severe n (%)
39 (86.7)
6 (13.3)
0 (0.0)
37 (82.2)
8 (17.8)
0 (0.0)
41 (89.1)
4 (8.7)
1 (2.2)
13 (44.8)
15 (51.7)
1 (3.4)
a0.001**
aFisher Freeman Halton test; bKruskal–Wallis test; **p < 0.01
Postoperative pain within the 1st week following the interventions was evaluated. The change in the VAS scorings of the postoperative pain according to groups was given in Fig. 2. Postoperative pain was found to be significantly higher in the PE group when compared to test groups (p < 0.05). No significant difference was found between PE and control group (p > 0.05) except for the higher pain scores on day 1 in the PE group (p < 0.05).Fig. 2 The change in the VAS scorings of the postoperative pain within the 1st week
At the end of 2 years of follow-up, 125 restorations in 100 patients (76%) could be followed, and 40 restorations in 33 patients (24%) were lost to follow-up. The study flow is summarized in Fig. 1. Among the lost cases, 2 patients moved to another city, 10 patients could not be reached, and the remaining 21 patients could be reached but did not show up. No differences were observed between followed and unfollowed cases regarding age, gender, radiographic depth, ICDAS score, caries tissue, preoperative sensitivity, and tooth and cavity type (Table 2; p > 0.05).Table 2 Comparisons of baseline variables between followed and unfollowed treatments
Variables Followed Unfollowed P
Age Mean (SD) 24.44 (8.58) 23.26 (7.46) c0.566
Median (min–max) 23 (13–44) 23 (13–42)
Gender Female 59 18 d0.537
Male 41 16
Tooth type Molar 74 24 d0.929
Premolar 51 16
Cavity type Cl I 18 4 d0.476
Cl II 107 36
Radiographic depth 3/4 37 13 d0.751
More than 3/4 88 27
ICDAS score 4 39 19 d0.088
5 80 21
6 6 0
Caries tissue LYAP 86 31 a0.554
LBSP 21 6
DBSP 18 3
Preop sensitivity No 100 30 a0.448
Moderate 24 9
Severe 1 1
aFisher Freeman Halton test; cMann–Whitney U test; dPearson chi-square test
Success and failure rates according to groups after 2 years are given in Table 3. No statistically significant difference was found between the success rates of test 1 (100%) and test 2 (93.5%) groups, whereas the proportion of success in control (82.4%) and PE (84%) groups were significantly lower when compared to the test groups (p = 0.024; p < 0.05). No statistically significant difference was found for the incidence of vitality loss with apical radiolucency (p = 0.79; p > 0.05). The presence of irreversible pulpitis with pain at percussion and palpation was significantly lower in test 1 (0%) and test 2 (3.2%) groups when compared to the control (14.7%) and PE (12%) groups (p = 0.038; p < 0.05).Table 3 Primary outcome analysis of teeth at 2 years of follow-up
Analyzed (n = 125) Test 1
SRSD + CS
(n = 35) Test 2
SRSD − CS
(n = 31) Control
SRFD
(n = 34) PE
(n = 25) P
Overall success
Pulp vitality without apical radiolucency n (%) 35 (100) 29 (93.5) 28 (82.4) 21 (84.0) a0.024*
Overall failure
No pulp vitality with apical radiolucency n (%) 0 (0.0) 1 (3.2) 1 (2.9) 1 (4.0) a0.709
Irreversible pulpitis with pain at percussion and palpation n (%) 0 (0.0) 1 (3.2) 5 (14.7) 3 (12.0) a0.038*
aFisher Freeman Halton Test; *p < 0.05
Figure 3 shows the survival curves for the groups. Statistically significant difference was found in favor test groups versus control and PE groups using the log rank test (p=0.45; p<0.05). When all lost cases were considered as success the difference between the survival curves was still statistically significant (p=0.038; p<0.05). Representative radiography of the teeth in test 1 and test 2 groups assessed as having normal periapical structures at 2-year follow-up is presented in Figs. 4 and 5. One failure due to loss of vitality was observed in each group except the test 1 group (p = 0.709; p > 0.05). Representative radiography of these failures with apical radiolucency is given in Fig. 6 (a, b, e, and f). In total, 9 failures were detected due to irreversible pulpitis symptoms: 6 failures within 3 months, 2 failures at 6 months, and one at 1-year follow-up. Representative radiography of one of these failures can be seen in Fig. 6 c, d.Fig. 3 Survival curves of clinical and radiographic success over 2 years of Test 1 (SRSD with calcium silicate-based material), Test 2 (SRSD without calcium silicate-based material), Control (SRFD with calcium silicate-based material) and PE (Pulp exposure) groups
Fig. 4 Representative photo and radiography of one of the cases in Test 2 group (SRSD without calcium silicate-based material) group with vital pulp a) pre-op b) immediately after treatment c-d) after 2 years follow-up without any apical radiolucencyc
Fig. 5 Radiography of one case in Test 1 (SRSD with calcium silicate-based material) group with vital pulp and without apical radiolucency a) Pre-op b) immediately after treatment c) 2 years follow-up
The Cox proportional hazard regression analyses are displayed in Table 4. Borderline significance was obtained for univariate analysis of tooth type, radiographic depth, carious tissue, and preoperative sensitivity (Table 4; p < 0.200). Multivariate analyses with the backward elimination method were performed for these variables. Tooth type and radiographic depth showed some effect in this model, whereas carious tissue and preop sensitivity had no effect on the treatment outcome. No variable exhibited a statistically significant influence on the outcome of the interventions (Table 4; p < 0.05).Table 4 The Cox proportional hazard regression analyses of the influence of the baseline variables on the failure outcomes at 2 year follow-up
Variables Success Failure Univariate Multivariable
n n HR (95% CI) P HR (95% CI) P
Tooth type
Molar 64 10 Reference
Premolar 49 2 3.679 (0.806–16.795) 0.093 3.339 (0.729–15.292) 0.120
Radiographic depth
3/4 36 1 Reference
More than 3/4 77 11 5.041 (0.650–39.073) 0.122 4.416 (0.567–34.376) 0.156
Caries tissue
LYAP 80 6 Reference 0.152
LBSP 19 2 1.214 (0.245–6.030) 0.812
DBSP 14 4 3.417 (0.963–12.119) 0.057
Preop sensitivity
No 92 8 Reference
Modarete 20 4 2.347 (0.706–7.805) 0.164
CI, confidence interval; HR, hazard ratio
The pulp was exposed unintentionally in 11 and 18 teeth after SRSD and SRFD techniques, respectively (Fig. 1, Table 5). Pulp exposure rates according to groups and characteristics of the carious tissue were given in Table 5. Representative radiography of one of the teeth with unintentional pulp exposure in the SRSD group was given in Fig. 7. The risk of pulp exposure in the SRFD group was approximately 3 times higher than in the SRSD group, with a 95% CI of 1.396–7.342 (p = 0.005; p < 0.01).Table 5 Pulp exposure rates according to groups and characteristics of the carious tissue
Group SRSD (n = 101) Group SRFD (n = 64)
Pulp exposure No n (%) 90 (89.1) 46 (71.9)
LYAP LBSP DBSP LYAP LBSP DBSP
65 (87.8) 16 (94.1) 9 (90) 26 (60.5) 9 (90) 11 (100)
Yes n (%) 11 (10.9) 18 (28.1)
LYAP LBSP DBSP LYAP LBSP DBSP
9 (12.1) 1 (5.9) 1 (10) 17 (39.5) 1 (10) 0 (0)
LYAP, light yellow actively progressing; LBSP, light brown slowly progressing; DBSP, dark slowly progressing
Representative radiography for tertiary dentin formation in the PE group is given in Figs. 7 and 8. The highest rate of tertiary dentin formation was observed in the PE group (84%), when compared to the control (41.2%) and test groups after 2 years (p < 0.01). Tertiary dentin formation was also higher in the test 1 group (77.1%) when compared to the test 2 (22.6%) group after 2 years (p < 0.01).Fig. 6 a–d Radiography of one PE (pulp exposure) case with vital pulp and dentin bridge formation a preop b immediately after treatment c 2 years follow-up periapical radiography (cavity formation at distal side) d 2 years follow-up bite-wing radiography after the restoration of the cavitation
Discussion
In the present study, different treatment strategies for deep carious lesions were tested. After 2 years of follow-up, the results demonstrated that SRSD was more effective than SRFD in preserving pulp vitality in permanent teeth. A higher proportion of teeth with unexposed pulps (17.6%) in the SRFD group experienced pulp inflammation, whereas only 3.1% of teeth in the SRSD groups were referred to endodontic treatment. Moreover, significantly less pulp exposure was observed after SRSD (10.9%) than after SRFD (28.1%).
To our knowledge, the present study is the first longitudinal randomized clinical trial on permanent teeth compared to the clinical outcomes of the SRSD and SRFD techniques. In permanent teeth, uncompleted caries removal in combination with different base materials and resin composite restorations has previously been studied in two clinical trials [7, 21]. The first one was a single-arm clinical trial that evaluated SRSD in combination with calcium hydroxide cement [22]. The second one compared SRSD in combination with glass ionomer cement with stepwise caries removal [7]. High rates of overall success (90–91%) for SRSD were found in these clinical trials at 36 months after treatment [7, 21]. The observed success of SRSD with (100%) or without (93.5%) calcium silicate-based material in the present study corroborates the findings of these previous studies.
A longitudinal randomized clinical trial on primary teeth comparing SRSD and SRFD in combination with calcium hydroxide cement has also found high rates of success (92 and 96%, respectively) at 24 months after treatment [8]. In this study, no significant difference was observed between the success rates of the two caries removal techniques. This result was in accordance with the findings in clinical trials on primary teeth and young permanent teeth [23, 24]. However, in the present study, the success rate of SRSD was higher than the SRFD. Similarly, a recent systematic review and meta-analysis of clinical trials on permanent teeth demonstrated a statistically significant difference, favoring SRSD for the overall success of maintaining pulp vitality compared with the control group that was composed of stepwise caries removal, or SRFD [9]. Obviously, different results were obtained from permanent and primary teeth for the comparison of two caries removal techniques. It seems that the results of the studies conducted on primary dentition could not be extrapolated to permanent dentition, as suggested by Barros et al. [9], taking into account the difference in regeneration potential between the two different types of dentition.
The risk of pulp exposure in the present study was found to be approximately 3 times higher in SRFD when compared to SRSD. This was in accordance with the findings reported by Orhan et al. [25] in mixed dentition that pulp exposure was reduced with SRSD when compared with SRFD (6 and 22%, respectively). However, Franzon et al. [8] reported a lower risk ratio of pulp exposure for SRSD (2%) compared to SRFD (27.5%) on primary teeth. When interpreting these results, the depth of carious lesions should be taken into consideration. Notably, lesions radiographically extending ¾ of dentin were evaluated by Orhan et al. [25], which was similar to the depth of lesions in the present study, whereas the radiographic depth of the caries lesions was not clearly defined by Franzon et al. [8]. Additionally, the characteristics of the caries lesions might also have an influence on the frequency of pulp exposure. In the present study, 89.7% of the lesions were defined as LYAP according to the classification of Bjørndal et al. in the PE group [19]. The overall pulp exposure rate was higher during the removal of LYAP carious tissue (22%) when compared to LBSP (7%) and DBSP (4.7%), irrespective of the caries removal technique. Taking only the LYAP lesions into account, it seems that pulp exposure was still less likely with SRSD (12.1%) compared with SRFD (39.5%), whereas no difference for LBSP and DBSP lesions (Table 5).
The degree of excavation and excavation technique can also be argued that perhaps less pulp exposure would have been observed if more amount of soft caries tissue was left over the pulp. The use of a hand excavator for SRSD might have increased the risk of pulp exposure [26]. However, it is still unclear whether leaving more carious tissue is beneficial or harmful [9]. In the present study, carious removal was performed following the principles recommended by Schwendicke and Innes [27]. Understanding the terms soft, leathery, firm, and hard dentine was helpful for the standardization of the carious removal degree. The endpoint for caries excavation was in close proximity to the leathery dentin, and residual soft tissue was very thin and appeared dry after air drying. Leaving a thicker layer of carious tissue can be challenged in further randomized clinical trials.
Pulp exposure was not accepted as a failure in this clinical trial. Teeth with exposed pulps were assigned to the PE group, and 84% of the teeth that received pulp capping treatment had successfully sustained pulp vitality, with tertiary dentin formation and without apical radiolucency or unbearable pain at a 2-year follow-up. The overall survival rate of the teeth with exposed pulps at the 12-month follow-up (89%) in the current study was significantly different from the survival rate of teeth treated with calcium hydroxide cement (32.8%) but in accordance with the survival rate of the teeth treated with CS (96%) at the same follow-up period in permanent teeth [12, 17]. However, Brizuela et al. [28] reported higher success rates and no significant difference between calcium hydroxide cement (86.4%) and CS (100%) in young permanent teeth. The treatment outcome of pulp capping relies on the factors such as age, the capping material, preoperative condition of the pulp, use of rubber dam, and size of the pulp exposure [29, 30]. In the present study, one of the possible reasons for failures might be not using a rubber dam to provide asepsis. No prolonged bleeding, which is an indicator of pulp inflammation, was observed in any failed case. When the radiography of success (Fig. 7 and Fig. 8) and failure cases (Fig. 7.2 and 7.3) are compared, it can be underlined that the contact area between pulp tissue and CS is smaller in failed cases. One possible explanation can be offered concerning the bioactive effect of CS is that presence of a hard tissue barrier at the pulpal surface may prevent the healing potential of the material. Even though the lower success rate (77.8%) of indirect pulp capping with CS in permanent teeth after 2 years [18] when compared with the results obtained from previous direct pulp capping studies [12, 28] supports this view, no significant difference between SRFD and PE groups was found in the present study. Fig. 7 a–f Representative radiography of failed cases: a, b preop and 2 years follow-up with apical radiolucency in test 2 (SRSD without calcium silicate-based material) group c, d preop and immediately after treatment (failure after 1 week with unbearable pain and positive percussion) in PE (pulp exposure) group e, f preop and 2 years follow-up with a negative response to the cold test, absence of lamina dura and dentin bridge formation in PE group
Fig. 8 a–f Radiography of the tooth (#24) with preop severe sensitivity, dark brown slowly progressing carious tissue characteristics and pulp exposure during SRSD a preop b immediately after treatment c 3 months, d 6 months, e 1 year, and f 2 years follow-up with vital pulp, dentin bridge formation and without apical radiolucency
Age, gender, tooth, cavity type, radiographic depth, ICDAS scores, carious tissue characteristics, and preoperative sensitivity were not correlated with treatment success. These findings corroborate previous studies showing no significant influence of gender, tooth, and cavity type on treatment outcome [4, 6, 8]. However, Björndal et al. [30] compared stepwise caries removal with SRFD and found higher success rates for teeth without preoperative pain and lower success rates for patients older than 50 years old. These contradictory findings may be related to the difference in the precondition of the pulp and age of the population. In the present study, the study population consisted of younger patients, and the preoperative pain could be defined as moderate sensitivity. To the best of our knowledge, this is the first clinical study to assess whether radiographic depth, ICDAS scores, and carious tissue characteristics are associated with clinical and radiographic success or not.
Based on the clinical and radiographic observations reported from the present study, CS might be proposed to be a choice of base material for deep carious lesions with or without pulp exposure. CS seemed to have a positive influence on tertiary dentin formation and preservation of pulp vitality. However, long setting time and difficult handling properties were the main drawbacks to the application of CS in this clinical trial. It should also be noted that the application of a lining material was required to cover the CS prior to placement of the restoration. Otherwise, CS was easily removed during air drying, or the walls of the cavity were contaminated during the application of the adhesive system with a micro brush, despite the 12 min setting time recommended by the manufacturer being completed. Alternatively, the use of novel resin-based composite materials with self-adhesive properties might be preferred instead of conventional resin composites to eliminate these difficulties. However, there is a lack of long-term evidence on the clinical outcome of this simplified restoration concept.
In the case of pulp exposure, despite all of the disadvantages such as long chairside time and high cost, CS still might be the material of choice with its potential to prevent endodontic treatment procedures and related complications. However, the role of lining material in treatment success with SRSD can be questioned. Coralo and Maltz [31] compared the effects of calcium hydroxide, glass ionomer cement, and wax (inert material) on carious dentin after SRSD. In this randomized clinical trial, after a sealing period of 3–4 months, dentin hardening detected by clinical assessment and partial or total obliteration of tubules revealed by ultrastructural analysis indicated that liner itself did not play a role in the arrestment process of the remaining carious tissue [31]. It was emphasized that SRSD with good cavity sealing played a major role to the promote defense mechanisms of the pulpo-dentinal organ [31]. The effect of various lining materials on treatment outcomes with SRSD was also investigated in long-term clinical trials [4, 26]. Sign et al. [4] reported no significant difference between the success rates of calcium hydroxide (96.6%), resin-modified glass ionomer cement (96.5%), and direct composite (94.6%) in permanent teeth after 1 year. Falster et al. [26] reported a 96% success rate without placement of calcium hydroxide prior to direct composite in primary teeth after 2 years. Similar to the results of the abovementioned studies, no significant effect of CS on treatment success after SRSD was found in the present study. This is an important finding that further adds to the clinical evidence that only SRSD with good coronal sealing may be recommended without any liner application for the treatment of deep caries lesions. Nevertheless, longer-term evidence is required for a strong recommendation.
The high success rates in the present study may also be attributed to good coronal sealing, and all of the restorations were 100% acceptable according to FDI criteria. No restoration failure, such as fracture, secondary caries, or marginal gap that may promote detrimental effects of bacteria in the remaining caries tissue, was observed.
Randomization, single operator, standardized treatment, well-defined lesions, and no difference between the control and test groups with respect to the baseline characteristics were strengths of this study. One of the limitations of this study was that not all patients attended the follow-up appointments, which might affect the reported success rates. As a precaution against loss of contact, the phone number of the one to be called in an emergency situation, e-mail, and social media accounts of the patients were noted at the first session. Most of the patients reached out but did not want to show up, declaring any pain and disturbance. Additionally, the unbalanced distribution of sample size according to lesion characteristics could not be predicted at the beginning of the study. Thus, the stratified randomization technique was not used. This is one of the other limitations of the present study that no firm evidence could be provided for the influence of this parameter on pulp exposure. Therefore, future studies with a large sample permitting subgroup analysis of teeth with well-defined radiographic depths and carious tissue characteristics are required to find out whether or not these parameters have an effect on the incidence of pulp exposure.
Conclusions
From this study, it can be concluded that SRSD had a high success rate when compared to SRFD to treat deep carious lesions in permanent teeth after 2 years of follow-up. The use of calcium silicate-based material after SRSD had no effect on the treatment outcome.
Acknowledgements
The present work was supported by the Research Fund of Istanbul Medipol University with project no. 2019-01.
Author contribution
BGÇ and MÖ contributed to the conceptualization and methodology of the study. AT, YEH, and BGÇ performed the data curation. BGÇ performed the project administration, funding acquisition, literature research, interpretation of the data, and draft writing. The study and manuscript writing were supervised by MÖ. All authors revised, validated, and edited the work. All authors agree to be accountable for all aspects of the study design and its content. All authors approved the final submitted version.
Funding
The present work was supported by the Research Fund of Istanbul Medipol University (project no. 2019–01).
Declarations
Ethics approval
The study was approved by the University Ethics Committee with protocol no. 10840098–604.01.01-E.53565.
Consent to participate
All participants provided written informed consent.
Conflict of interest
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Schwendicke F Frencken JE Bjørndal L Managing carious lesions: consensus recommendations on carious tissue removal Adv Dent Res 2016 28 58 67 10.1177/0022034516639271 27099358
2. Massler M Pulpal reactions to dental caries Int Dent J 1967 17 441 460 5233875
3. Schwendicke F, Frencken J, Innes N (2018) Caries excavation: evolution of treating cavitated carious lesions. In Innes N (ed), Monographs in Oral Science, Karger, Basel, pp 82–91. 10.1159/000487822
4. Singh S Mittal S Tewari S Effect of different liners on pulpal outcome after partial caries removal: a preliminary 12 months randomised controlled trial Caries Res 2019 53 547 554 10.1159/000499131 31096259
5. Bjørndal L Thylstrup A A practice-based study on stepwise excavation of deep carious lesions in permanent teeth: a 1-year follow-up study Community Dent Oral Epidemiol 1998 26 122 128 10.1111/j.1600-0528.1998.tb01938.x 9645406
6. Maltz M Koppe B Jardim JJ Alves LS de Paula LM Yamaguti PM Almeida JCF Moura MS Mestrinho HD Partial caries removal in deep caries lesions: a 5-year multicenter randomized controlled trial Clin Oral Invest 2018 22 1337 1343 10.1007/s00784-017-2221-0
7. Maltz M Garcia R Jardim JJ de Paula LM Yamaguti PM Moura MS Garcia F Nascimento C Oliveira A Mestrinho HD Randomized trial of partial vs. stepwise caries removal: 3-year follow-up J Dent Res 2012 91 1026 1031 10.1177/0022034512460403 22983407
8. Franzon R Guimarães LF Magalhães CE Haas AN Araujo FB Outcomes of one-step incomplete and complete excavation in primary teeth: a 24-month randomized controlled trial Caries Res 2014 48 376 383 10.1159/000357628 24732081
9. Barros MMAF De Queiroz Rodrigues MI Muniz FWMG Rodrigues LKA Selective, stepwise, or nonselective removal of carious tissue: which technique offers lower risk for the treatment of dental caries in permanent teeth? A systematic review and meta-analysis Clin Oral Invest 2020 24 521 532 10.1007/s00784-019-03114-5
10. Barthel CR Rosenkranz B Leuenberg A Roulet JF Pulp capping of carious exposures: treatment outcome after 5 and 10 years: a retrospective study J Endod 2000 26 525 528 10.1097/00004770-200009000-00010 11199794
11. Dammaschke T Leidinger J Schäfer E Long-term evaluation of direct pulp capping—treatment outcomes over an average period of 6.1 years Clin Oral Invest 2010 14 559 567 10.1007/s00784-009-0326-9
12. Awawdeh L Al-Qudah A Hamouri H Chakra RJ Outcomes of vital pulp therapy using mineral trioxide aggregate or Biodentine: a prospective randomized clinical trial J Endod 2018 44 1603 1609 10.1016/j.joen.2018.08.004 30292451
13. Carvalho JC Dige I Machiulskiene V Qvist V Bakhshandeh A Fatturi-Parolo C Maltz M Occlusal caries: biological approach for its diagnosis and management Caries Res 2016 50 527 542 10.1159/000448662 27658123
14. Foley J Evans D Blackwell A Partial caries removal and cariostatic materials in carious primary molar teeth: a randomised controlled clinical trial Br Dent J 2004 197 11 697 701 10.1038/sj.bdj.4811865 15592552
15. Phonghanyudh A Phantumvanit P Songpaisan Y Petersen PE Clinical evaluation of three caries removal approaches in primary teeth: a randomised controlled trial Community Dent Health 2012 29 173 178 22779380
16. Schwendicke F Meyer-Lueckel H Dörfer C Paris S Failure of incompletely excavated teeth–a systematic review J Dent 2013 41 569 580 10.1016/j.jdent.2013.05.004 23685036
17. Bjørndal L Reit C Bruun G Markvart M Kjaeldgaard M Näsman P Thordrup M Dige I Nyvad B Fransson H Lager A Ericson D Petersson K Olsson J Santimano EM Wennström A Winkel P Gluud C Treatment of deep caries lesions in adults: randomized clinical trials comparing stepwise vs. direct complete excavation, and direct pulp capping vs. partial pulpotomy Eur J Oral Sci 2010 118 290 297 10.1111/j.1600-0722.2010.00731.x 20572864
18. Hashem D Mannocci F Patel S Manoharan A Watson TF Banerjee A Evaluation of the efficacy of calcium silicate vs. glass ionomer cement indirect pulp capping and restoration assessment criteria: a randomised controlled clinical trial-2 year results Clin Oral Invest 2019 23 1931 1939 10.1007/s00784-018-2638-0
19. Bjørndal L Demant S Dabelsteen S Depth and activity of carious lesions as indicators for the regenerative potential of dental pulp after intervention J Endod 2014 40 S76 81 10.1016/j.joen.2014.01.016 24698699
20. Hickel R Peschke A Tyas M Mjör I Bayne S Peters M Hiller KA Randall R Vanherle G Heintze SD FDI World Dental Federation - clinical criteria for the evaluation of direct and indirect restorations. Update and clinical examples J Adhes Dent 2010 12 259 272 10.3290/j.jad.a19262 20847997
21. Maltz M Alves LS Jardim JJ Moura Mdos S de Oliveira EF Incomplete caries removal in deep lesions: a 10-year prospective study Am J Dent 2011 24 211 214 22016914
22. Maltz M Oliveira EF Fontanella V Carminatti G Deep caries lesions after incomplete dentine caries removal: 40-month follow-up study Caries Res 2007 41 493 496 10.1159/000109349 17921671
23. Li T Zhai X Song F Zhu H Selective versus non-selective removal for dental caries: a systematic review and meta-analysis Acta Odontol Scand 2018 76 135 140 10.1080/00016357.2017.1392602 29073814
24. Casagrande L Seminario AT Correa MB Werle SB Maltz M Demarco FF Araujo FB Longevity and associated risk factors in adhesive restorations of young permanent teeth after complete and selective caries removal: a retrospective study Clin Oral Invest 2017 21 847 855 10.1007/s00784-016-1832-1
25. Orhan AI Oz FT Orhan K Pulp exposure occurrence and outcomes after 1- or 2-visit indirect pulp therapy vs complete caries removal in primary and permanent molars Pediatr Dent 2010 32 347 355 20836956
26. Falster CA Araujo FB Straffon LH Nör JE Indirect pulp treatment: in vivo outcomes of an adhesive resin system vs calcium hydroxide for protection of the dentin-pulp complex Pediatr Dent 2002 24 241 248 12064499
27. Schwendicke F, Innes N (2018) Removal strategies for carious tissues in deep lesions: management of deep carious lesions. In Schwendicke F (ed), Springer, Cham, pp 15–35. 10.1007/978-3-319-61370-3_2
28. Brizuela C Ormeño A Cabrera C Cabezas R Silva CI Ramírez V Mercade M Direct pulp capping with calcium hydroxide, mineral trioxide aggregate, and Biodentine in permanent young teeth with caries: a randomized clinical trial J Endod 2017 43 1776 1780 10.1016/j.joen.2017.06.031 28917577
29. Chailertvanitkul P Paphangkorakit J Sooksantisakoonchai N Pumas N Pairojamornyoot W Leela-Apiradee N Abbott PV Randomized control trial comparing calcium hydroxide and mineral trioxide aggregate for partial pulpotomies in cariously exposed pulps of permanent molars Int Endod J 2014 47 835 842 10.1111/iej.12225 24299006
30. Bjørndal L Fransson H Bruun G Markvart M Kjældgaard M Näsman P Hedenbjörk-Lager A Dige I Thordrup M Randomized clinical trials on deep carious lesions: 5-year follow-up J Dent Res 2017 96 747 753 10.1177/0022034517702620 28410008
31. Corralo DJ Maltz M Clinical and ultrastructural effects of different liners/restorative materials on deep carious dentin: a randomized clinical trial Caries Res 2013 47 243 250 10.1159/000345648 23343804
| 36460919 | PMC9734731 | NO-CC CODE | 2022-12-14 23:28:30 | no | Clin Oral Investig. 2022 Dec 3;:1-13 | utf-8 | Clin Oral Investig | 2,022 | 10.1007/s00784-022-04815-0 | oa_other |
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Nat Rev Endocrinol
Nat Rev Endocrinol
Nature Reviews. Endocrinology
1759-5029
1759-5037
Nature Publishing Group UK London
780
10.1038/s41574-022-00780-6
Review Article
Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?
Lott Nicola 12
Gebhard Caroline E. 3
Bengs Susan 12
http://orcid.org/0000-0002-5204-4473
Haider Ahmed 45
Kuster Gabriela M. 6
http://orcid.org/0000-0002-3566-3467
Regitz-Zagrosek Vera 78
http://orcid.org/0000-0001-7240-5822
Gebhard Catherine [email protected]
129
1 grid.412004.3 0000 0004 0478 9977 Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
2 grid.7400.3 0000 0004 1937 0650 Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
3 grid.410567.1 Intensive Care Unit, University Hospital Basel, Basel, Switzerland
4 grid.32224.35 0000 0004 0386 9924 Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Boston, MA USA
5 grid.38142.3c 000000041936754X Department of Radiology, Harvard Medical School, Boston, MA USA
6 grid.6612.3 0000 0004 1937 0642 Department of Cardiology and Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
7 grid.6363.0 0000 0001 2218 4662 Charité, Universitätsmedizin Berlin, Berlin, Germany
8 grid.452396.f 0000 0004 5937 5237 DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
9 grid.411656.1 0000 0004 0479 0855 Department of Cardiology, Inselspital Bern University Hospital, Bern, Switzerland
9 12 2022
115
10 11 2022
© Springer Nature Limited 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.
There is growing awareness of differences in susceptibility to SARS-CoV-2 infection and COVID-19 severity between men and women. This Review assesses the evidence for this disparity and its potential causes, with a focus on the role of sex hormones.
Key points
There is currently no clear evidence that a sex-specific expression of virus entry receptors accounts for some of the sex discordances observed in coronavirus disease 2019 (COVID-19).
Studies on the effects of oestrogen, progesterone and testosterone on the course of COVID-19 have provided inconsistent results, and current data do not support the administration of oestradiol or deprivation of androgens in COVID-19 treatment.
Much more research is needed to clarify the potential therapeutic value of endogenous or exogenous sex hormones in COVID-19.
Subject terms
Infectious diseases
Gonadal disorders
Infectious diseases
==== Body
pmcIntroduction
The coronavirus disease 2019 (COVID-19) pandemic has become one of the greatest public health challenges in modern times. Male sex, cardiovascular disease, diabetes mellitus and advanced age (>65 years) are predominant risk factors for a severe course and poor prognosis of COVID-19 (ref.1). Accordingly, men with COVID-19 die at twice the rate of women with COVID-19 (ref.2). Conversely, increasing evidence suggests that cis women (hereafter referred to as women) are at higher risk of developing long-term sequelae of the disease3 (Fig. 1). Given this disparity in clinical outcomes of COVID-19 between men and women, several theories have been proposed to explain this difference. Sociocultural (gender) differences in risk behaviours, such as smoking, hand-washing or delayed health-care seeking, have been suggested to contribute to this sex disparity as have male-specific comorbid conditions, including cardiometabolic disease. Additionally, biological (sex) differences in immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or expression levels of virus entry receptors have also been suggested to contribute to the differential outcomes of women and cis men (hereafter referred to as men)4.Fig. 1 Sex differences in virus entry protein expression and clinical outcomes of COVID-19.
ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; RAAS, renin–angiotensin–aldosterone system.
The differential outcomes between women and men have raised great interest in the role of androgens in driving a less favourable prognosis of COVID-19 in men as compared with women and children. Higher androgen levels in men and the impact of androgens on genes encoding the SARS-CoV-2 entry receptors angiotensin-converting enzyme 2 (ACE2) receptor and cell surface transmembrane protease serine 2 (TMPRSS2) have been suggested to partially account for the higher risk of adverse outcomes observed in men with acute SARS-CoV-2 infection4. While these concepts are intriguing as they might offer potential antiviral strategies, many controversies regarding the impact of sex and sex hormones on the clinical course of COVID-19 remain. Consequently, research from the past year has questioned whether biological sex differences have a major effect on COVID-19 outcomes5,6, and it has been hypothesized that non-biological aspects of being a man or a woman (such as institutionalized gender and culturally entrenched roles and norms) could provide a better explanation for the observed sex dysbalance in disease outcomes7–9.
This Review summarizes the current understanding of the role of androgens, oestrogens and progesterone in ACE2 and TMPPRSS2 regulation and progression of COVID-19 as well as the therapeutic value of these hormones by discussing the latest data from both experimental and clinical studies.
ACE2 and TMPRSS2
The role of ACE2 in SARS-CoV-2 infection
SARS-CoV-2 preferentially infects type II alveolar cells (AT2) as opposed to type I alveolar cells (AT1) in the human lung. The virus enters AT2 cells by recognizing and attaching its spike glycoprotein to the membrane-bound ACE2 after the spike protein is cleaved and activated by TMPRSS2 (refs.10–14). The SARS-CoV-2 spike protein has two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to ACE2 or other cellular receptors while the S2 subunit undergoes priming and cleavage by TMPRSS2, thereby enabling S2 to mediate the fusion of the virus with the cellular membrane10. Accordingly, higher ACE2 expression correlates with increased viral load in human respiratory cells15. ACE2 is ubiquitously expressed in the endothelium, with highest levels being detected in the vasculature of the cardiovascular system, intestinal tract, kidneys and lungs16. Within the pulmonary tissue, ACE2 is abundantly expressed in bronchial transient secretory cells or AT2 cells, the main cellular target of SARS-CoV-2 (ref.17). Accordingly, a hexapeptide inhibiting the association between the S1 subunit and ACE2 was shown last year to reduce fever, inflammation and lung injury in SARS-CoV-2 spike S1-intoxicated mice18. Similarly, in a 2020 study, higher levels of ACE2 expression were detected in lung samples from patients with comorbidities that predispose them to severe COVID-19 as compared with healthy controls19. Based on these reports, it was concluded that overexpression of ACE2 might facilitate virus penetration and, hence, organ damage during SARS-CoV-2 infection. Accordingly, children, who appear to be less susceptible to SARS-CoV-2 infection than adults, were shown to express lower levels of ACE2 (refs.20,21). However, owing to its role as a key player in the renin–angiotensin–aldosterone system (RAAS), where ACE2 opposes the vasoconstrictor actions of angiotensin II by converting angiotensin II to vasodilatory angiotensin 1–7, the involvement of ACE2 in COVID-19 seems to be more complex than initially thought. In addition, ACE2 also plays a role in both innate and adaptive immune responses by regulating T lymphocyte responses and secretion of pro-inflammatory cytokines, resulting in anti-inflammatory effects as well as in inhibition of cancer cell growth and tumour angiogenesis22,23. Finally, the ability of SARS-CoV-2 to downregulate ACE2 expression in infected cells adds further complexity to the role of ACE2 in COVID-19. The downregulation of membrane-bound ACE2 results from endocytosis of the receptor into endosomes alongside viral particles and from the enhanced activity of disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). ADAM17 activity leads to shedding of ACE2, release of soluble ACE2 (sACE2) and accumulation of vasoconstrictive angiotensin II. Angiotensin II then stimulates the release of pro-inflammatory cytokines via liberation of membrane-bound precursors of tumour necrosis factor, IFNγ and IL-4, resulting in detrimental effects, including enhanced vascular permeability, multiorgan inflammation, and pulmonary and/or myocardial injury24. sACE2 is enzymatically active and seems to exert moderate antiviral activity25; however, it is currently unclear whether its protective antiviral activities predominate in COVID-19.
Taken together, the bivalent role of ACE2 hampers research efforts exploring its therapeutic utility in SARS-CoV-2 infection. However, two trials are currently testing the use of human recombinant sACE2, administered either as an aerosol26 or intravenously, for COVID-19 (refs.27,28). One of them, a clinical phase II trial testing the ability of intravenous recombinant human ACE2 to sequester SARS-CoV-2 particles in the circulation while activating the protective axis of the RAAS, was completed in 2021 (NCT04335136)28. Preliminary data published by the sponsor (Apeiron Biologics) in March 2021 show an improvement in mechanical ventilator-free days and a reduction in viral RNA load as compared with the placebo group; however, no further results have since been published29.
The role of TMPRSS2 in SARS-CoV-2 infection
TMPRSS2 is abundantly expressed in the prostate epithelium and its expression in the prostate increases in response to androgens through direct transcriptional regulation by the androgen receptor30. TMPRSS2 is one of the most dysregulated genes in prostate cancer. Recurrent gene fusions of the 5′ untranslated region of TMPRSS2 to the transcription factor ERG (encoding transcriptional regulator ERG) is the most frequent genomic alteration in early-stage and late-stage prostate cancer and results in overexpression of ERG31. TMPRSS2 is also detected in epithelial cells throughout the entire respiratory tract, including the lungs, bronchi, larynx, trachea, nasal mucosa and respiratory sinus, where its normal physiological function remains unknown17. Evidence of TMPRSS2 expression was found in different cells of the lung and bronchial branches17,32, with higher levels of TMPRSS2 being detected in AT2 cells as compared with AT1 cells17. Consistent with an involvement of TMPRSS2 in viral spike protein priming, a case-control study conducted in 2021 has demonstrated that the ratio of TMPRSS2 to ACE2 mRNA but not the level of TMPRSS2 mRNA alone outperforms ACE2 mRNA expression as a predictor for COVID-19 respiratory outcomes. This finding indicates that the functional activity of TMPRSS2 on viral fusion depends on ACE2 (ref.33). Accordingly, TMPRSS2 inhibitors have been shown to block entry of SARS-CoV-2 in vitro34–36. In mice sensitized to SARS-CoV-2 infection, treatment with the serine protease inhibitor nafamostate before or shortly after infection resulted in lower viral replication and mortality compared with untreated mice37. Likewise, patients with mild COVID-19 treated with the serine protease inhibitor camostat mesylate over 7 days had a more rapid resolution of COVID-19 symptoms and amelioration of the loss of taste and smell than patients in the placebo group in a clinical trial currently published as a preprint38. Conversely, results from a phase II trial conducted in 2021 show that addition of nafamostate to standard of care did not change time to clinical improvement in the overall population of 104 patients and led to faster recovery only in a small subset of 36 patients with COVID-19 at high risk and requiring oxygen treatment39.
Sex-specific expression of ACE2
It has been hypothesized that women have higher levels of cell-bound ACE2 than men, and thus have a potentially larger reservoir for the maintenance of RAAS equilibrium and tissue protection after viral entry of SARS-CoV-2. Indeed, genes coding for ACE2 and angiotensin II receptor 2 are located on the X chromosome. Although one of the two X chromosomes in females is transcriptionally silenced during late blastocyst stage to ensure a balanced gene expression between sexes, approximately 15–30% of X-linked genes escape the inactivation40. Given that the majority of genes escaping X inactivation are located on the short arm (p) of the X chromosome and ACE2 maps at band p22.2 (ref.41), it has been suggested that a higher expression of ACE2 occurs in women compared with men. Conversely, the SRY gene family located on the male Y chromosome has been shown to upregulate the activity of components of RAAS that decrease ACE2 promoter activity42 (Fig. 1). In addition, gender-specific environmental factors might influence epigenetic mechanisms such as DNA methylation by DNA methyltransferases at the CpG sites, resulting in altered ACE2 gene expression in women and men43.
Tissue expression of ACE2
Studies assessing pulmonary ACE2 expression in humans and experimental models have yielded highly conflicting results (Table 1). In fact, an analysis conducted in 2020 comparing expression levels of ACE2 RNA across 31 human tissues found no statistically significant sex difference44. Likewise, other studies report similar expression levels of ACE2 in women and men in a variety of tissues17,45,46. Conversely, a large meta-analysis comprising 31 single-cell RNA sequencing studies revealed a cell type-specific association between sex, age and smoking status, with higher ACE2 expression levels in AT2 cells being associated with male sex and increasing age47. A higher ACE2 gene expression in lung epithelial cells and airway smooth muscle cells was also found in men as compared with women in previous investigations48,49. Single-cell RNA sequencing of ACE2 in the adult human heart demonstrated a higher myocardial ACE2 RNA expression in women as compared with men50. On the contrary, several preclinical studies in mice agree that ACE2 activity as well as expression is increased in males as compared to females in different tissues, mainly under pathological conditions51–54 (Fig. 1). Overall, these conflicting data make it difficult to draw any conclusion regarding a sexual dimorphism in ACE2 expression. Species differences, difficulties in precisely measuring ACE2 expression at the tissue level, confounding variables, such as smoking, obesity and pre-existing cardiac conditions, as well as counter-regulatory effects of oestrogens on RAAS could account for the high variability of reported data.Table 1 Sex-specific pulmonary ACE2 expression
ACE2 Species Sample Ref.
Increased expression in men or male animals Human Airway secretory, AT1 and AT2 cells (single-cell meta-analysis) 47
Lung tissue (RNA and protein) 32
Lung epithelial cells (RNA) 48
Lung tissue (GTEx data) 60
Airway epithelial cells (RNA) 158
Primary isolated airway smooth muscle cells (protein) 49
Mouse Lung tissue (RNA and protein) 32
Increased expression in women Human Lung tissue (RNA) 159
No sex difference Human Lung tissue (RNA) 17
Bronchial epithelial cells
Lung and associated respiratory tissues (GEO data) 32
Lung tissue (GTEx data) 45
Lung tissue (RNA and protein) 46
Lung tissue (GTEx and TCGA data) 44
Bronchial brushing and bronchial biopsies (RNA) 160
Lung tissue (GEO data) 161
Lung tissue (GTEx data) 162
Bronchial epithelial cells (GEO data)
Lung tissue from organ donors (RNA) 163
Lung tissue (GTEx data)
Lung tissue (TCGA data)
Upper respiratory cilia (protein) 164
Primary lung epithelial cell cultures (RNA) 165
Lung tissue (GTEx data) 166
Mouse Lung tissue (RNA and protein) 46
Lung tissue (protein) 62
Lung tissue (RNA) 163
Rat Lung tissue (RNA)
ACE2, angiotensin-converting enzyme 2; AT1, type I alveolar cells; AT2, type II alveolar cells; GEO, Genomic Expression Omnibus; GTEx, Genotype-Tissue Expression Project; TCGA, The Cancer Genome Atlas.
Soluble ACE2
Older women show higher sACE2 serum activity than younger women55, and a longitudinal study conducted in 2020 demonstrated that serum levels of sACE2 protein increases more in boys than in girls, resulting in sex differences in adulthood56. Accordingly, a genome-wide association study identified three loci associated with increased plasma concentrations of sACE2 in men but not in women57, and higher circulating levels of ACE2 have been described in men with type 1 diabetes mellitus compared with healthy men and healthy women as well as in men with renal disease as compared with women with renal disease58. Finally, in women and men with type 1 diabetes mellitus, circulating sACE2 activity increases with increasing vascular tone and in the presence of microvascular or macrovascular atherosclerotic disease59.
Overall, male sex and certain disease states seem to have an enhancing effect on sACE2 levels (Fig. 1). However, numerous questions remain unresolved regarding the equilibrium of membrane-bound ACE2 and sACE2 during SARS-CoV-2 infection. In fact, current evidence suggests that the role of RAAS-associated molecules changes dynamically during the course of COVID-19 and cannot be seen as straightforwardly positive or negative. As such, it is likely that serum levels of sACE2 mirror increased endocytosis of ACE2 by SARS-CoV-2 and disruption of the RAAS equilibrium, which, in turn, is associated with an attenuation of immune responses and an increased risk of multiorgan injury. On the other hand, increased sACE2 activity might protect against the high levels of inflammation associated with a cytokine storm. The role of sex and sex hormones in ACE2 endocytosis and shedding is currently unknown and will have to be explored by further studies.
Regulation of ACE2 by sex hormones
In humans, oestradiol, in combination with androgen deprivation therapy (ADT), resulted in an increase in ACE2 expression and a higher amount of ACE2-expressing Sertoli cells in trans women60, while an oestrogen and progesterone combination statistically significantly reduced ACE2 expression in testicular tissue in this population as compared with cis men61. In an experimental study, however, ACE2 expression in various tissues remained unaltered in multiparous 12-month-old mice, which displayed statistically significantly higher progesterone levels as compared to nulliparous mice62. Additionally, stimulation of the androgen receptor resulted in upregulation of ACE2 in mouse lung epithelial cells, and exposure to testosterone for 24 h increased ACE2 expression in isolated male and female human airway smooth muscle cells46,49. Accordingly, a moderate decrease of pulmonary ACE2 expression was observed in mice after administration of the androgen receptor antagonist enzalutamide32. Treatment with anti-androgenic drugs reduced ACE2 expression in human embryonic stem cell-derived cardiac cells and protected human embryonic stem cell-derived lung organoids against SARS-CoV-2 infection63.
Experimental data indicate that oestrogens can disrupt glycan–glycan and glycan–protein interactions between ACE2 and SARS-CoV-2, thereby blocking alveolar uptake of the SARS-CoV-2 spike protein64. However, the interaction between oestrogen and ACE2 is complex and seems to be organ and/or context specific. While oestrogen appears to reduce myocardial and renal ACE2 expression in vivo65, no alteration of ACE2 mRNA was found in VERO E6 cells, an in vitro model for SARS-CoV-2 infection, following 17β-oestradiol treatment66. Analysis of public genomic data showed that oestrogen upregulates ACE2 in mouse thymus and human lung epithelial adenocarcinoma cells20,60. In contrast, in bronchial epithelial cells and airway smooth muscle cells, ACE2 seems to be moderately downregulated by 17β-oestradiol49,67.
Taken together, sex hormones seem to modulate ACE2 expression, with an upregulation of ACE2 by testosterone being consistently shown by several studies (Fig. 2). More research effort is needed to clarify the effect of oestradiol on ACE2 expression.Fig. 2 Effects of sex steroid hormones on SARS-CoV-2 susceptibility.
Effect of testosterone (upper part), progesterone (middle part) and oestradiol (lower part) on virus entry receptors (left), immune responses (middle) and coronavirus disease 2019 (COVID-19) course (right). ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2; TH, T helper cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Sex-specific expression of TMPRSS2
The androgen-dependent regulation of TMPRSS2 and its involvement in SARS-CoV-2 spike protein priming has led researchers to suspect that TMPRSS2 has a potential detrimental role in COVID-19 outcomes in men. Consistent with this hypothesis, oral epithelial cells in men had higher expression levels of TMPRSS2 compared with oral epithelial cells in women68. Along that line, a meta-analysis conducted in 2021 based on human single-cell RNA sequencing data revealed higher levels of TMPRSS2 expression in AT1 cells in men as compared with AT1 cells in women47. However, the authors did not detect any sex differences in TMPRSS2 gene expression in AT2 cells, the main cellular target of SARS-CoV-2 (ref.47). In addition, further studies reported similar levels of TMPRSS2 in lung tissue of women and men based on single-cell transcriptomics and protein expression data derived from the Genotype-Tissue Expression (GTEx) project and the Human Protein Atlas GTEx data, respectively45,69. These findings were confirmed in a study conducted in 2021, which reported no sex difference in TMPRSS2 protein expression in alveolar epithelial cells32.
In conclusion, there is currently only weak evidence for an increased expression of TMPRSS2 in the male lung with no data supporting sex discordance of TMPRSS2 expression in AT2 cells. Table 2 lists studies reporting sex-disaggregated data of TMPRSS2 expression.Table 2 Sex-specific pulmonary TMPRSS2 expression
TMPRSS2 Species Sample Ref.
Increased expression in men and male animals Human Airway secretory cells, AT1 cells (single-cell meta-analysis) 47
Bronchial brushing and bronchial biopsies (RNA) 160
Lung tissue (GEO data) 161
Bronchial epithelial cells (GEO data) 162
Mouse Lung tissue (RNA) 159
No sex difference Human AT2 cells (single-cell meta-analysis) 47
Lung and associated respiratory tissues (GEO data) 32
Lung tissue (protein and RNA) 32
Lung tissue (GTEx data) 45
Lung epithelial cells (RNA) 48
Lung tissue (RNA and protein) 46
Lung tissue (GTEx and GEO data) 167
Lung tissue (GTEx data) 162
Mouse Lung tissue (RNA and protein) 32
Lung tissue (protein) 62
Lung tissue (RNA and protein) 46
AT1, type I alveolar cells; AT2, type II alveolar cells; GEO, Genomic Expression Omnibus; GTEx, Genotype-Tissue Expression Project; TMPRSS2, transmembrane protease serine 2.
Regulation of TMPRSS2 by sex hormones
The androgen-mediated regulation of TMPRSS2 and the higher case fatality rates seen in men infected with SARS-CoV-2 than in women has brought questions to the forefront about the role of sex hormones in COVID-19 severity and whether their modulation could serve as a treatment option for SARS-CoV-2 infection. As previously outlined, TMPRSS2 transcription in the prostate gland is regulated by androgenic ligands and an androgen receptor-binding element in the promoter31. Accordingly, an increased expression of TMPRSS2 was observed following androgen treatment in a human lung adenocarcinoma-derived cell line70 (Fig. 2). Similarly, androgen receptor antagonism by enzalutamide downregulated TMPRSS2 and reduced cell entry of SARS-CoV-2 in multiple human lung cell lines as well as in mouse lung epithelial cells71. Further, androgen deprivation by gonadectomy or treatment with anti-androgens attenuated spike-mediated cellular entry of SARS-CoV-2 in mice72. If this link proves correct, it could pave the way to novel strategies for the treatment of COVID-19. Therefore, these strategies are the subject of several clinical trials (listed in Supplementary Table 1); to date, however, many of these trials have been withdrawn due to lower-than-planned accrual or limited resources, and those who have been published report mixed results (Table 3). Additionally, more recent studies offer little hope that repurposing of androgen synthesis inhibitors or androgen receptor antagonists will become a valuable treatment option in COVID-19. TMPRSS2 expression in lung cancer cell lines, mouse lung tissue and human lung organoids remained unaltered following treatment with enzalutamide, suggesting that TMPRSS2 regulation in the lung differs from the clear androgen-dependent regulation in prostatic tissues32,73.Table 3 Overview of ongoing and completed randomized controlled clinical trials assessing the safety and efficacy of treatments targeting sex hormone pathways on COVID-19 outcomes
Trial title (trial registration number) Status as of October 2022 Phase Recruitment status and/or sample size Study drug Primary outcome and/or findings Refs.
A phase 2 randomized, double-blinded, placebo-controlled, multicentre trial evaluating the efficacy and safety of raloxifene for patients with mild to moderate COVID-19 (NCT05172050) Published II 61 participants Raloxifene 60 mg, raloxifene 120 mg The proportion of participants with undetectable SARS-CoV-2 after 7 days of treatment with raloxifene 60 mg and 120 mg was higher than in patients treated with placebo 93
Progesterone in addition to standard of care vs standard of care alone in the treatment of men hospitalized with moderate to severe COVID-19: a randomized, controlled pilot trial (NCT04365127) Published I 42 men Progesterone 20 mg (s.c.) Overall improvement in median clinical status score from baseline to day 7 in the progesterone group vs placebo 148
Early antiandrogen therapy with dutasteride reduces viral shedding, inflammatory responses and time-to-remission in males with COVID-19: a randomized, double-blind, placebo-controlled interventional trial (EAT-DUTA AndroCoV Trial – Biochemical) (NCT04729491) Published II 87 men Dutasteride 0.5 mg per day for 30 days Dutasteride reduces viral shedding and inflammatory markers in men with mild COVID-19 symptoms treated with dutasteride vs placebo 99
Proxalutamide significantly accelerates viral clearance and reduces time to clinical remission in patients with mild to moderate COVID-19: results from a randomized, double-blinded, placebo-controlled trial Publisheda III 236 participants Proxalutamide 200 mg per day for 7 days On day 7, SARS-CoV-2 became non-detectable with rtPCR (Ct >40) in 82% of the participants in the proxalutamide group vs 31% in the placebo group (P <0.001) 100
Hormonal intervention for the treatment in veterans with COVID-19 requiring hospitalization (HITCH); a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial (NCT04397718) Published II 96 men Degarelix 40 mg/ml (s.c.) Androgen suppression by degarelix did not result in amelioration of COVID-19 severity 118,168
A phase 2 trial of the effect of antiandrogen therapy on COVID-19 outcome: no evidence of benefit, supported by epidemiology and in vitro data Published II 42 participants Enzalutamide 160 mg per day (p.o.) for 5 days Patients treated with enzalutamide required longer hospitalization than patients in the placebo group, and the trial was terminated early 119
Final results of a randomized, placebo-controlled, two-arm, parallel clinical trial of proxalutamide for hospitalized COVID-19 patients: a multiregional, joint analysis of the proxa-rescue AndroCoV trial Published (study has been criticized for methodological issues)a III 778 participants (comprising 645 and 133 participants from NCT04728802 and NCT05126628, respectively) Proxalutamide 300 mg per day for 14 days Recovery rate was 121% higher and all-cause mortality rate was 80% lower in the proxalutamide group than in the placebo group on day 14; men and women presented similar results in all outcomes 112
Proxalutamide reduces the rate of hospitalization for COVID-19 male outpatients: a randomized double-blinded placebo-controlled trial (NCT04446429) Publication retracteda NA 268 men Proxalutamide 200 mg per day Hospitalization rate in men treated with proxalutamide reduced by 91% compared with placebo 115
Proxalutamide (GT0918) reduces the rate of hospitalization in mild-to-moderate COVID-19 female patients: a randomized double-blinded placebo-controlled two-arm parallel trial (NCT04853134) Published (preprint)a III 177 women Proxalutamide 200 mg per day (p.o.) for 7 days 30-day hospitalization rate was 2.7% in the proxalutamide arm and 18.6% in the placebo arm (P <0.001); no safety concerns 107
Efficacy of proxalutamide treatment for hospitalized COVID-19 patients: a randomized, double-blind, placebo-controlled, parallel-design clinical trial (NCT04728802) Published (preprint)a III 645 participants Proxalutamide 300 mg per day for 14 days Hospitalized patients with COVID-19 receiving proxalutamide had a 128% higher recovery rate than those treated with placebo; all-cause mortality was reduced by 77.7% over 28 days 108
Proxalutamide improves inflammatory, immunologic, and thrombogenic markers in mild-to-moderate COVID-19 males and females: an exploratory analysis of a randomized, double-blinded, placebo-controlled trial early antiandrogen therapy (EAT) with proxalutamide (The EAT-Proxa Biochemical AndroCoV-Trial) (NCT04853134 and NCT04446429) Published (preprint)a III 445 participants Proxalutamide 200 mg per day for 7 days Improvements observed in immunological, inflammatory and thrombotic markers as well as in oxygen saturation with proxalutamide compared with placebo 109
Proxalutamide treatment for hospitalized COVID-19 patients in southern Brazil: the south arm of a randomized, double-blind, placebo-controlled, parallel clinical trial — The South Proxa-Rescue AndroCoV Trial (NCT05126628) Published (preprint)a III 133 participants Proxalutamide 300 mg per day for 14 days Proxalutamide reduced mortality, increased recovery speed, reduced hospital stay, reduced levels of abnormal hsCRP and D-dimers, and reduced the need for broad-spectrum antibiotics in hospitalized patients with COVID-19 112
Proxalutamide reduction of mortality rate in hospitalized COVID-19 patients depends on treatment duration – an exploratory analysis of the Proxa-Rescue AndroCoV Trial (NCT04728802) Published (preprint)a III 580 participants Proxalutamide 300 mg per day for 14 days The 28-day COVID-19 mortality rate was 4.2% in the proxalutamide group and 49.0% in the placebo group 110
Proxalutamide improves lung injury in hospitalized COVID-19 patients – an analysis of the radiological findings of the Proxa-Rescue AndroCoV trial (NCT04728802) Published (preprint)a III 246 participants Proxalutamide 300 mg per day for 14 days Proxalutamide improves lung opacities in hospitalized patients with COVID-19 when compared with placebo 111
Acute estradiol and progesterone therapy in hospitalised adults to reduce COVID-19 severity: a randomised control trial (NCT04865029) Completed (only 10 patients recruited), study protocol published II 10 (120 planned) Oestradiol cypionate 5 mg/ml (i.m.) and micronized progesterone 200 mg (p.o.) Proportion of patients improving to scores 1 or 2 on the WHO scale169 through day 28 170
Estrogen therapy in non-severe COVID-19 patients (NCT04539626) Active, not recruiting (last update 07/2022) N/A 44 men Combination norelgestromin 6 mg and ethinyl oestradiol 0.60 mg skin patches (weekly over 21 days) Clinical improvement with oestrogen therapy in patients with non-severe COVID-19 171
A prospective, multicenter, randomized phase II clinical trial of enzalutamide treatment to decrease the morbidity in patients with corona virus disease 2019 (COVID-19) (NCT04475601) Terminated (stopped early) II 42 participants Enzalutamide 40 mg per day (p.o.) Time to worsening of disease 172
Camostat with bicalutamide for COVID-19 (COMBO) (NCT04652765) Terminated (new accrual) I 6 participants Bicalutamide 150 mg per day (p.o.) and camostat 4 × 600 mg per day (p.o.) for 7 days Number of participants requiring hospitalization 173
Phase II clinical trial of oestradiol to reduce severity of COVID19 infection in COVID19+ and presumptive COVID19+ patients (NCT04359329) Terminated (poor accrual) II 2 participants Climara 25 cm2 oestrogen patch (single use) Rate of hospitalization 174
Trial to promote recovery from COVID-19 with endocrine therapy (RECOVER) (NCT04374279) Withdrawn (limited resources) II 0 participants Bicalutamide 150 mg per day (p.o.) Percentage of participants who have clinical improvement at day 7 after randomization 175
Randomized trial of bicalutamide to block TMPRSS2 in males with COVID-19 infection (NCT04509999) Withdrawn III 0 participants Bicalutamide 150 mg per day (p.o.) Proportion of patients with improved COVID-19 symptoms within 28 days 176
Proxalutamide treatment for COVID-19 patients in intensive care unit (NCT04853927) Withdrawna III 0 participants Proxalutamide 300 mg day Proportion of death 177
The impact of oestrogen administration on COVID-19 disease (NCT04853069) Not recruiting (last update 04/2021) II 0 (planned 2,000) Transdermal 17β-oestradiol gel (3 mg) for 10 days Proportion hospitalized within 28 days 178
Efficacy of aerosol combination therapy of 13 Cis retinoic acid and captopril for treating COVID-19 patients via indirect inhibition of Transmembrane Protease, Serine 2 (TMPRSS2) (NCT04578236) Not recruiting (last update 10/2020) II 0 (planned 360) Aerosolized 13-cis-retinoic acid and nebulized captopril Lung injury score 179
Clinical role of testosterone and dihydrotestosterone and which of them should be inhibited in COVID-19 patients — a double-edged sword? (NCT04623385) Not recruiting (last update 11/2020) IIII 0 (planned 1,000) Aerosolized 13-cis-retinoic acid and testosterone for 14 days Lung injury score 180
Raloxifene, selective oestrogen receptor modulator; enzalutamide, non-steroidal anti-androgen; dutasteride, 5α-reductase inhibitor; proxalutamide, androgen receptor antagonist; bicalutamide, non-steroidal anti-androgen; degarelix, luteinizing hormone-releasing hormone antagonist; 13-cis-retinoic acid, inhibitor of dihydrotestosterone. Ct, cycle threshold; hsCRP, high-sensitivity C-reactive protein; rtPCR, real-time PCR; i.m., intramuscular; NA, not available; p.o., per os (by mouth); s.c., subcutaneously. aStudies published by the same authors and data derived from one cohort (AndroCoV Trial).
Notably, there is a lack of data regarding the effect of progesterone on TMPRSS2 signalling, and only few studies have assessed an association between oestrogen levels and TMPRSS2 expression. In fact, two reports indicate that prostate cancer cells expressing the TMPRSS2:ERG fusion gene might be responsive to oestrogen signalling30,74. Consistent with this observation, treatment with 17β-oestradiol resulted in a reduction in TMPRSS2 mRNA in VERO E6 cells66 (Fig. 2).
Sex steroids and immune responses
Both, innate and adaptive immune responses differ between men and women. Women and female animals usually mount stronger immune responses against pathogens than men and male animals as the number of innate immune cells, including monocytes, macrophages and dendritic cells, is higher in females75–77. Women also exhibit higher cytotoxic T cell activity78, higher immunoglobulin levels (both at baseline and following infection or vaccination79,80), higher CD3+ and CD4+ cell counts, and more robust T helper (TH) cell activation than men81–84. Several mechanisms could account for these sex differences, including an imbalance in the expression of genes encoded on the X and Y chromosomes85, polymorphism in autosomal genes86, epigenetic modifications87, and direct effects of sex hormones on immunological pathways. Indeed, sex steroids, particularly testosterone, oestradiol and progesterone, have all been shown to influence the function of immune cells by binding to their specific receptors, which are expressed in various lymphoid tissue cells as well as in circulating lymphocytes, macrophages and dendritic cells88 (Fig. 2). Testosterone is known to suppress TH2 and TH17 cell function89,90 and to alter the production of cytokines, including IFNγ91. Additionally, many pro-inflammatory and antiviral genes have oestrogen response elements in their promoters78, and immune responses to viruses have been shown to vary depending on female hormone status (for example, menopause, pregnancy, contraception and hormone replacement therapy (HRT))92. Accordingly, treatment with raloxifene, a selective oestrogen receptor modulator, resulted in an increase in white blood cell numbers alongside an accelerated viral clearance in patients with SARS-CoV-2 infection in a clinical trial conducted in 202293 (n = 61; Table 3).
Although stronger cytokine responses to viral infections are usually seen in women, higher levels of pro-inflammatory cytokines, such as IL‐8 and IL‐18, have been observed in men infected with SARS-CoV-2 compared with infected women94. These higher pro-inflammatory cytokine levels are seen in individuals with severe COVID-19 culminating in a systemic inflammatory syndrome and lung injury95. Poorer COVID-19 outcomes are also seen in people with weak T cell activation, which was more commonly observed in men than in women94. Men with COVID‐19 also have a lower lymphocyte count and higher neutrophil‐to‐lymphocyte ratios and serum concentrations of C‐reactive protein as compared with women, all of which have been associated with a poor prognosis in COVID-19 (ref.96). Conversely, women seem to clear the SARS-CoV-2 virus faster than men given that the virus is detected for a longer period in men than in women97,98. In support of this observation, clinical trials testing the anti-androgenic drugs dutasteride (a 5α-reductase inhibitor used to treat benign prostatic hyperplasia and male pattern hair loss) and proxalutamide (an androgen receptor antagonist) have reported an accelerated viral clearance, reduced viral shedding and reduced C-reactive protein levels as compared with placebo in patients with mild to moderate COVID-1999,100 (n = 87 and n = 236, respectively; Table 3).
Impact of androgens on COVID-19 severity
Consistent with a detrimental role of androgens in immune responses to viral infections, several studies conducted during the early phase of the pandemic reported a link between the androgen-mediated phenotype of androgenetic alopecia and COVID-19 severity101,102. Although these studies were lacking a control group, and hair loss can be the consequence of physical shock or treatment side effects, these studies have strengthened the hypothesis of a potential role of male sex hormones in COVID-19. This hypothesis was further supported by observational studies reporting reduced COVID-19 incidence and case fatality rates in patients with prostate cancer receiving ADT103,104. Likewise, men exposed to 5α-reductase inhibitors were less likely to develop severe COVID-19 as observed in two studies from 2021, one of which is a clinical trial conducted in 87 men99,105 (Table 3). Similarly, a study conducted in 2021 in individuals with gender dysphoria described that the risk of contracting COVID-19 was 3.46 times higher in individuals with female-to-male gender dysphoria (who had received testosterone therapy) than in individuals with male-to-female gender dysphoria (who received oestrogen and anti-androgen therapy)106. However, it should be noted that there is substantial risk that the effect size reported in this study is overestimated and that undetected confounders might have influenced the study results given its small sample size and large confidence intervals (1.01–11.84)106.
Finally, the results of several clinical trials testing proxalutamide in women and men with COVID-19, which are currently available as preprints, suggest that clinical endpoints as well as inflammatory and immunological markers are improved in the treatment arm107–112 (Table 3). However, of note, these trials have all been conducted by the same authors and have recently been criticized for irregularities113,114 (Table 3). Additionally, a clinical trial in 268 men infected with SARS-CoV-2, which reported reduced hospitalization rates by 91% in the proxalutamide arm, was retracted last year115. The same compound administered at a higher dose (300 mg) and for a longer treatment duration (14 days) resulted in a 121% higher recovery rate and a reduction of all-cause mortality by 80% in 778 men and women with COVID-19 (ref.112). However, this trial has also been criticized for methodological issues (Table 3).
Additionally, more recent observational studies from last year have refuted an association between increased androgen activity and COVID-19 outcomes116,117. Moreover, a clinical trial in 96 hospitalized patients with COVID-19 testing the anti-androgenic compound degarelix demonstrated that androgen suppression did not result in amelioration of COVID-19 severity118, and a trial testing the androgen receptor antagonist enzalutamide in a small cohort of 42 patients was terminated early because patients treated with enzalutamide required longer hospitalization than patients in the placebo group119. These trial data were supported by epidemiological data from 7,894 patients with prostate cancer where no preventive effects of ADT on COVID-19 outcomes was observed119. Similarly, in women with conditions that are associated with androgen excess (polycystic ovarian syndrome, acne cystica and hirsutism), no excess morbidity related to COVID-19 was reported120. Moreover, testosterone replacement therapies were not associated with worse disease outcomes in men infected with SARS-CoV-2 in an observational study conducted in 2020 (ref.121). Given these inconsistencies, it is important to note that testosterone levels might change during acute illness and that the relationship between circulating androgen levels, androgen sensitivity and COVID-19 severity is not straightforward122 (Fig. 2). Indeed, low serum levels of testosterone characterize the hormonal milieu in seriously ill individuals and predict organ injury and poor prognosis in men infected with SARS-CoV-2 (refs.123–130).
As outlined previously, increasing evidence also suggests that a blunted immune response in men with normal testicular function can occur during the early phase of infection, resulting in low viral clearance and a high risk of systemic illness97,98. On the other hand, lower androgen activity, frequently seen in critically ill older men with hypogonadism, might negatively affect endothelial cell functioning and increase the risk of an aggressive inflammatory response with the release of large amounts of pro-inflammatory cytokines, known as a ‘cytokine storm’131,132. A cytokine storm is associated with an increased risk of severe lung injury, multiorgan failure and an overall unfavourable prognosis133 (Fig. 1). Consistent with this hypothesis, an association between COVID-19 complications and androgen imbalance, defined as high serum levels of luteinizing hormone, low levels of testosterone and/or increased levels of oestradiol, has been shown in men infected with SARS-CoV-2 (refs.63,127,134). Accordingly, we have shown, in 2022, that a higher ratio of testosterone to oestradiol was linked to a favourable prognosis in hospitalized patients with COVID-19 (ref.135).
Taken together, the multifactorial nature of COVID-19 infection and hormonal regulation in men does not currently allow us to draw any definitive conclusions. However, existing data emphasize that consideration of sex, reproductive age, disease state and comorbidities seem to be crucial when exploring the effect of androgens on COVID-19 outcomes. Indeed, the health status of individuals infected with SARS-CoV-2 is often complex, and the effect of these comorbidities on hypogonadism, treatment responses and outcomes should be given special attention. While many clinical trials have been initiated to assess the effect of sex steroids on clinical outcomes of COVID-19, many of those trials have never been completed, most probably reflecting the complexity of this research field and the lack of a clear mechanism as well as the challenges associated with drug repurposing for COVID-19 treatments (Table 3). An overview of studies addressing the different roles of androgens in COVID-19 prognosis is given in Supplementary Table 1. The complex impact of age on COVID-19, sex hormones, virus entry proteins and disease outcomes is summarized in Fig. 3.Fig. 3 Alterations of hormone levels, immune responses, virus entry protein expression and clinical outcomes according to age in men.
This figure depicts the relationship between increasing age and testosterone levels during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, cardiovascular risk factors, the risk of critical illness and viral clearance during SARS-CoV-2 infection (upper part). The risk of a cytokine storm according to age and testosterone levels is also shown (middle). There is only a weak association between age and pulmonary angiotensin-converting enzyme 2 (ACE2) expression and no clear association between age and testosterone-dependent regulation of transmembrane protease serine 2 (TMPRSS2) expression in the lung (lower part).
Female sex steroids and COVID-19 severity
Oestradiol and progesterone play distinct roles in modulating innate and adaptive immunity and have been associated with an attenuated inflammatory response during acute infection136,137. Moreover, a protective role of oestrogen against SARS infection in mice has been previously reported, highlighting the potential for oestrogens to modulate COVID-19 susceptibility and progression138. Accordingly, two studies reported higher SARS-CoV-2 infection rates139 and longer hospital stays140 in women in postmenopause as compared with women in premenopause. The same authors found that circulating levels of 17β-oestradiol and anti-Müllerian hormone, a marker for ovarian reserve, were higher in women with mild COVID-19 disease course than those with a more severe disease course140. A cohort study comprising 68,466 people infected with SARS-CoV-2 reported a reduction of fatality risk by 50% in women aged >50 years receiving postmenopausal HRT (n = 439)141. These results were confirmed by preliminary data from a study conducted in 2022 that described a lower likelihood of COVID-19-related mortality in women using HRT than in women not using HRT in a sample of 1,863,478 women142. In addition, the fact that women with hormone-driven cancers, who are often treated with anti-oestrogen therapies, seem to encounter an increased risk of SARS-CoV-2 infection and critical illness than women without these cancers suggests a protective role of oestrogens in COVID-19 (ref.143).
However, more recent studies from 2021 on the impact of oestrogen on COVID-19 outcomes have provided highly controversial results: while both the ablation of oestrogens by selective oestrogen receptor modulators in women with breast or ovarian cancers143 and the use of exogenous oestrogen in the form of the combined oral contraceptive pill139 was associated with a reduced incidence of COVID-19 in women, HRT in women in postmenopause did not show consistent correlations with COVID-19 incidence and disease severity139. Additionally, no statistically significant differences in sex hormone levels were detected in women critically ill with COVID-19 as compared to women with mild disease127. The lack of information on hormone treatment type, route of administration, duration of treatment and potential confounders, such as comorbidities, most likely accounts for the current controversies regarding the effect of female sex steroids on SARS-CoV-2 infection. In addition, the variation of endogenous oestrogen levels and the predominance of different oestrogen subtypes depending on age and reproductive status further complicates assessment of its role in COVID-19144 (Fig. 2).
Finally, progesterone has been shown to exert broad anti-inflammatory effects by decreasing leukocyte activation and production of pro-inflammatory mediators through inhibition of NF-κB145,146 (Fig. 2). Due to its multifaceted function, progesterone has been suggested to play a potential beneficial role in SARS-CoV-2 infection in the events of immune dysregulation147. Accordingly, in a pilot trial conducted in 2021, it was demonstrated that subcutaneous administration of progesterone improved the clinical status of 20 critically ill men infected with SARS-CoV-2 (ref.148). Although this preliminary work suggests that progesterone could be beneficial in patients with COVID-19 with pathophysiological indications of immune dysregulation, severe symptoms and critical illness, the small sample size of the trial along with marginal P values does not permit any definite conclusions to be drawn. Further studies in larger populations are warranted to confirm these findings.
Importantly, progesterone levels fluctuate throughout the cycle and reach high levels during pregnancy. Hence, pregnant women and those in premenopause in the mid-luteal phase of the cycle display the highest progesterone levels149. Although several small studies reported no adverse outcomes of pregnancy and/or COVID-19 in pregnant women infected with SARS-CoV-2 (refs.150,151), surveillance data from 8,207 pregnant women published by the US Centers for Disease Control and Prevention (CDC) showed an increased risk of hospitalizations, intensive care unit admissions and mechanical ventilation in this population152. Further, increased risks of pre-eclampsia, preterm birth and other adverse pregnancy outcomes were reported by a large meta-analysis comprising 42 studies involving 438,548 pregnant women153. Further data from China demonstrated that most severe cases in pregnant women occurred after delivery154, when progesterone levels rapidly decline. However, it should be noted that pregnancy complications related to COVID-19 might occur for reasons other than hormonal changes as a direct link between female sex steroids and pregnancy complications in women positive for SARS-CoV-2 has never been established. In conclusion, further mechanistic studies are warranted to corroborate or refute the protective effect of progesterone in men and women with COVID-19 and potentially establish a mechanistic link between progesterone and molecular key variables such as TMPRSS2 or ACE2.
Post-COVID-19 syndrome
Increasing evidence suggests that SARS-CoV-2 causes a protracted disease course beyond acute illness. Several studies from different populations indicate that the prevalence of this ‘post-COVID-19 syndrome’ and the number of persistent symptoms is higher in women than in men3 (Fig. 1). Given that the largest group of patients with post-COVID-19 syndrome appears to be in their early 50s3, an age at which menopause occurs, a link between alterations in ovarian steroid hormone production and post-COVID-19 syndrome has been hypothesized155. An alternative explanation for the higher incidence of post-COVID-19 syndrome in women involves sex differences in immunomodulation. Indeed, a specific immune signature, which has been previously observed following viral infections, has been suggested to account for the persistence of fatigue following acute COVID-19 (ref.156), and preliminary data (currently available as a preprint) indicate that dysfunctional immune cells with an autoimmune phenotype are present in patients with post-COVID-19 syndrome157. Thus, the higher prevalence of autoimmune disorders in the female population as well as known sex differences in immune responses to SARS-CoV-2 (ref.94) might predispose women to a potential long-term hyper-inflammatory state. Further, preliminary data from Newson et al. indicate that 74% of women with post-COVID-19 syndrome report changes in their menstrual cycle as well as worsening of symptoms during menstruation when hormone levels are at their lowest155. The authors suggest that involvement of the angiotensin–(1–7)–Mas receptor–ACE2 axis in follicle maturation and disturbance of ovarian steroid hormone production following SARS-CoV-2 infection might account for these associations155.
Conclusions
Despite intense research efforts, there is currently no consensus on whether sex differences in ACE2 and TMPRSS2 expression drive the higher disease burden of COVID-19 among men than in women and children. Additionally, the precise mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity remain unknown. Conflicting data have been reported regarding pulmonary ACE2 and TMPRSS2 expression in humans, making it difficult to draw conclusions regarding the sexual dimorphism of the two receptors. Clinical studies exploring the effect of sex hormones on COVID-19 outcomes report inconsistent effects of androgens and oestrogen in COVID-19, and there is currently no evidence supporting the administration of oestradiol or deprivation of androgens in patients with COVID-19. Thus, although variation in sex steroid levels in men and women might, to some extent, explain the sex disparities in susceptibility to SARS-CoV-2, the underlying mechanisms are still open to speculation. Current evidence is hampered by the lack of mechanistic studies as well as the lack of clinical trials reporting sex-disaggregated data. Finally, there is strong evidence that sociocultural gender influences a person’s lived experience and, therefore, exposure to SARS-CoV-2 and access to care7–9. Hence, investigating the influence of both biological (sex) and sociocultural (gender) differences on COVID-19 manifestations will be necessary to understand and manage this pandemic.
Supplementary information
Supplementary Information
Supplementary information
The online version contains supplementary material available at 10.1038/s41574-022-00780-6.
Author contributions
C.G. and N.L. researched data for the article, wrote the article, contributed substantially to the discussion of content and reviewed/edited the manuscript before submission. C.E.G. wrote the article and reviewed/edited the manuscript before submission. S.B. researched data for the article and reviewed/edited the manuscript before submission. A.H. and G.M.K. contributed substantially to the discussion of content and reviewed/edited the manuscript before submission. V.R.Z. wrote the article, contributed substantially to the discussion of content and reviewed/edited the manuscript before submission.
Peer review
Peer review information
Nature Reviews Endocrinology thanks Elena Ortona, who co-reviewed with Daniela Perruzzu, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Competing interests
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Ma Q Hao ZW Wang YF The effect of estrogen in coronavirus disease 2019 (COVID-19) Am. J. Physiol. Lung Cell Mol. Physiol. 2021 321 L219 L227 10.1152/ajplung.00332.2020 33949212
2. Green MS Nitzan D Schwartz N Niv Y Peer V Sex differences in the case-fatality rates for COVID-19 — A comparison of the age-related differences and consistency over seven countries PLoS One 2021 16 e0250523 10.1371/journal.pone.0250523 33914806
3. Sudre CH Attributes and predictors of long COVID Nat. Med. 2021 27 626 631 10.1038/s41591-021-01292-y 33692530
4. Gebhard C Regitz-Zagrosek V Neuhauser HK Morgan R Klein SL Impact of sex and gender on COVID-19 outcomes in Europe Biol. Sex. Differ. 2020 11 29 10.1186/s13293-020-00304-9 32450906
5. Danielsen AC Sex disparities in COVID-19 outcomes in the United States: quantifying and contextualizing variation Soc. Sci. Med. 2022 294 114716 10.1016/j.socscimed.2022.114716 35042136
6. Shattuck-Heidorn H A finding of sex similarities rather than differences in COVID-19 outcomes Nature 2021 597 E7 E9 10.1038/s41586-021-03644-7 34552251
7. Galasso V Gender differences in COVID-19 attitudes and behavior: panel evidence from eight countries Proc. Natl Acad. Sci. USA 2020 117 27285 27291 10.1073/pnas.2012520117 33060298
8. The Lancet. The gendered dimensions of COVID-19 Lancet 2020 395 1168 10.1016/S0140-6736(20)30823-0
9. Tadiri CP The influence of sex and gender domains on COVID-19 cases and mortality Can. Med. Assoc. J. 2020 192 E1041 E1045 10.1503/cmaj.200971 32900766
10. Hoffmann M SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 2020 181 271 280.e8 10.1016/j.cell.2020.02.052 32142651
11. Walls AC Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein Cell 2020 181 281 292.e6 10.1016/j.cell.2020.02.058 32155444
12. Hikmet F The protein expression profile of ACE2 in human tissues Mol. Syst. Biol. 2020 16 e9610 10.15252/msb.20209610 32715618
13. Ryu G Shin HW SARS-CoV-2 infection of airway epithelial cells Immune Netw. 2021 21 e3 10.4110/in.2021.21.e3 33728096
14. Hou YJ SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract Cell 2020 182 429 446.e414 10.1016/j.cell.2020.05.042 32526206
15. Gutiérrez-Chamorro L SARS-CoV-2 infection modulates ACE2 function and subsequent inflammatory responses in swabs and plasma of COVID-19 patients Viruses 2021 13 1715 10.3390/v13091715 34578296
16. Hamming I Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis J. Pathol. 2004 203 631 637 10.1002/path.1570 15141377
17. Lukassen S SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells EMBO J. 2020 39 e105114 10.15252/embj.2020105114 32246845
18. Paidi RK ACE-2-interacting domain of SARS-CoV-2 (AIDS) peptide suppresses inflammation to reduce fever and protect lungs and heart in mice: implications for COVID-19 Therapy J. Neuroimmune Pharmacol. 2021 16 59 70 10.1007/s11481-020-09979-8 33426604
19. Pinto BGG ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19 J. Infect. Dis. 2020 222 556 563 10.1093/infdis/jiaa332 32526012
20. Bunyavanich S Do A Vicencio A Nasal gene expression of angiotensin-converting enzyme 2 in children and adults JAMA 2020 323 2427 2429 10.1001/jama.2020.8707 32432657
21. Saheb Sharif-Askari N Airways expression of SARS-CoV-2 receptor, ACE2, and TMPRSS2 is lower in children than adults and increases with smoking and COPD Mol. Ther. Methods Clin. Dev. 2020 18 1 6 10.1016/j.omtm.2020.05.013 32537478
22. Imai Y Angiotensin-converting enzyme 2 protects from severe acute lung failure Nature 2005 436 112 116 10.1038/nature03712 16001071
23. Cantero-Navarro E Renin-angiotensin system and inflammation update Mol. Cell. Endocrinol. 2021 529 111254 10.1016/j.mce.2021.111254 33798633
24. Wang K Gheblawi M Oudit GY Angiotensin converting enzyme 2: a double-edged sword Circulation 2020 142 426 428 10.1161/CIRCULATIONAHA.120.047049 32213097
25. Jia HP Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia Am. J. Physiol. Lung Cell Mol. Physiol. 2009 297 L84 L96 10.1152/ajplung.00071.2009 19411314
26. Shoemaker RH Development of an aerosol intervention for COVID-19 disease: Tolerability of soluble ACE2 (APN01) administered via nebulizer PLoS One 2022 17 e0271066 10.1371/journal.pone.0271066 35816490
27. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05065645 (2022).
28. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04335136 (2021).
29. Apeiron Biologics. APEIRON’s APN01 Shows Clinical Benefits for Severely Ill COVID-19 Patients in Phase 2 Trial https://www.apeiron-biologics.com/apeirons-apn01-shows-clinical-benefits-for-severely-ill-covid-19-patients-in-phase-2-trial/ (2021).
30. Lucas J The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis Cancer Discov. 2014 4 1310 1325 10.1158/2159-8290.CD-13-1010 25122198
31. Tomlins SA Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer Science 2005 310 644 648 10.1126/science.1117679 16254181
32. Baratchian M Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes Sci. Rep. 2021 11 11130 10.1038/s41598-021-90491-1 34045511
33. Rossi AD Araujo JLFd Almeida TBD Ribereiro-Alves M Association between ACE2 and TMPRSS2 nasopharyngeal expression and COVID-19 respiratory distress Sci. Rep. 2021 6 9658 10.1038/s41598-021-88944-8
34. Hoffmann M Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity EBioMedicine 2021 65 103255 10.1016/j.ebiom.2021.103255 33676899
35. Hoffmann M Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19 Antimicrob. Agents Chemother. 2020 64 e00754-20 10.1128/AAC.00754-20 32312781
36. Mahoney M A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells Proc. Natl Acad. Sci. USA 2021 118 e2108728118 10.1073/pnas.2108728118 34635581
37. Li K Meyerholz DK Bartlett JA McCray PB Jr The TMPRSS2 inhibitor nafamostat reduces SARS-CoV-2 pulmonary infection in mouse models of COVID-19 mBio 2021 12 e0097021 10.1128/mBio.00970-21 34340553
38. Chupp G A phase 2 randomized, double-blind, placebo-controlled trial of oral camostat mesylate for early treatment of COVID-19 outpatients showed shorter illness course and attenuation of loss of smell and taste medRxiv 2022 10.1101/2022.01.28.22270035
39. Zhuravel SV Khmelnitskiy OK Birlaka OO Gritsan AI Goloshchekin BM Nafamostat in hospitalized patients with moderate to severe COVID-19 pneumonia: a randomised Phase II clinical trial EClinicalMedicine 2021 41 101169 10.1016/j.eclinm.2021.101169 34723164
40. Berletch JB Yang F Xu J Carrel L Disteche CM Genes that escape from X inactivation Hum. Genet. 2011 130 237 245 10.1007/s00439-011-1011-z 21614513
41. Tukiainen T Landscape of X chromosome inactivation across human tissues Nature 2017 550 244 248 10.1038/nature24265 29022598
42. Milsted A Regulation of multiple renin-angiotensin system genes by Sry J. Hypertens. 2010 28 59 64 10.1097/HJH.0b013e328332b88d 19809364
43. Fan R Preliminary analysis of the association between methylation of the ACE2 promoter and essential hypertension Mol. Med. Rep. 2017 15 3905 3911 10.3892/mmr.2017.6460 28440441
44. Li MY Li L Zhang Y Wang XS Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues Infect. Dis. Poverty 2020 9 45 10.1186/s40249-020-00662-x 32345362
45. Baughn LB Targeting TMPRSS2 in SARS-CoV-2 Infection Mayo Clin. Proc. 2020 95 1989 1999 10.1016/j.mayocp.2020.06.018 32861340
46. Qiao Y Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2 Proc. Natl Acad. Sci. 2021 118 e2021450118 10.1073/pnas.2021450118 33310900
47. Muus C Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics Nat. Med. 2021 27 546 559 10.1038/s41591-020-01227-z 33654293
48. Song H Seddighzadeh B Cooperberg MR Huang FW Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells Eur. Urol. 2020 78 296 298 10.1016/j.eururo.2020.04.065 32418620
49. Kalidhindi RSR Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19? Am. J. Physiol. Lung Cell. Mol. Physiol. 2020 319 L843 L847 10.1152/ajplung.00391.2020 32996784
50. Liu H Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart Cardiovasc. Res. 2020 116 1733 1741 10.1093/cvr/cvaa191 32638018
51. Chappell MC Marshall AC Alzayadneh EM Shaltout HA Diz DI Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways Front. Endocrinol. 2014 4 201 10.3389/fendo.2013.00201
52. White MC Fleeman R Arnold AC Sex differences in the metabolic effects of the renin-angiotensin system Biol. Sex. Dif. 2019 10 31 10.1186/s13293-019-0247-5
53. Liu J Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17beta-oestradiol-dependent and sex chromosome-independent Biol. Sex. Differ. 2010 1 6 10.1186/2042-6410-1-6 21208466
54. Gupte M Angiotensin converting enzyme 2 contributes to sex differences in the development of obesity hypertension in C57BL/6 mice Arterioscler. Thromb. Vasc. Biol. 2012 32 1392 1399 10.1161/ATVBAHA.112.248559 22460555
55. Fernandez-Atucha A Sex differences in the aging pattern of renin-angiotensin system serum peptidases Biol. Sex. Differ. 2017 8 5 10.1186/s13293-017-0128-8 28174624
56. Swärd P Age and sex differences in soluble ACE2 may give insights for COVID-19 Crit. Care 2020 24 221 10.1186/s13054-020-02942-2 32410690
57. Nelson CP Genetic associations with plasma angiotensin converting enzyme 2 concentration Circulation 2020 142 1117 1119 10.1161/CIRCULATIONAHA.120.049007 32795093
58. Patel SK Velkoska E Burrell LM Emerging markers in cardiovascular disease: where does angiotensin-converting enzyme 2 fit in Clin. Exp. Pharmacol. Physiol. 2013 40 551 559 10.1111/1440-1681.12069 23432153
59. Soro-Paavonen A Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications J. Hypertens. 2012 30 375 383 10.1097/HJH.0b013e32834f04b6 22179088
60. Chen J Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation Aging Cell 2020 19 e13168 10.1111/acel.13168 32558150
61. Masteron JM Feminising hormone therapy reduces testicular ACE-2 receptor expression: implications for treatment or prevention of COVID-19 infection in men Andrologica 2021 53 e14186
62. Bengs S Immunoreactivity of the SARS-CoV-2 entry proteins ACE-2 and TMPRSS-2 in murine models of hormonal manipulation, ageing, and cardiac injury Sci. Rep. 2021 11 23993 10.1038/s41598-021-03181-3 34907257
63. Samuel RM Androgen signaling regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men Cell Stem Cell 2020 27 876 889.e812 10.1016/j.stem.2020.11.009 33232663
64. Aguilar-Pineda JA Structural and functional analysis of female sex hormones against SARS-CoV-2 cell entry Int. J. Mol. Sci. 2021 22 11508 10.3390/ijms222111508 34768939
65. Fischer M Baessler A Schunkert H Renin angiotensin system and gender differences in the cardiovascular system Cardiovasc. Res. 2002 53 672 677 10.1016/S0008-6363(01)00479-5 11861038
66. Lemes RMR 17β-estradiol reduces SARS-CoV-2 infection in vitro Physiol. Rep. 2021 9 e14707 10.14814/phy2.14707 33463909
67. Stelzig KE Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells Am. J. Physiol. Lung Cell Mol. Physiol. 2020 318 L1280 L1281 10.1152/ajplung.00153.2020 32432918
68. Peng J Age and gender differences in ACE2 and TMPRSS2 expressions in oral epithelial cells J. Transl. Med. 2021 19 358 10.1186/s12967-021-03037-4 34412632
69. Song J Systematic analysis of ACE2 and TMPRSS2 expression in salivary glands reveals underlying transmission mechanism caused by SARS-CoV-2 J. Med. Virol. 2020 92 2556 2566 10.1002/jmv.26045 32441816
70. Mikkonen L Pihlajamaa P Sahu B Zhang FP Jänne OA Androgen receptor and androgen-dependent gene expression in lung Mol. Cell Endocrinol. 2010 317 14 24 10.1016/j.mce.2009.12.022 20035825
71. Leach DA The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells Nat. Commun. 2021 12 4068 10.1038/s41467-021-24342-y 34210968
72. Deng Q Rasool RU Russell RM Natesan R Asangani IA Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19 iScience 2021 24 102254 10.1016/j.isci.2021.102254 33681723
73. Li F Han M Dai P He J Tao X Distinct mechanisms for TMPRSS2 expressionexplain organ-specific inhibition of SARS-CoV-2infection by enzalutamide Nat. Commun. 2021 12 866 10.1038/s41467-021-21171-x 33558541
74. Setlur SR Estrogen-dependent signaling in the molecularrly distinct subclass of agressive prostate cancer J. Natl Cancer Inst. 2008 100 815 825 10.1093/jnci/djn150 18505969
75. Boissier J Chlichlia K Digon Y Ruppel A Mone H Preliminary study on sex-related inflammatory reactions in mice infected with Schistosoma mansoni Parasitol. Res. 2003 91 144 150 10.1007/s00436-003-0943-1 12910415
76. Xia HJ Zhang GH Wang RR Zheng YT The influence of age and sex on the cell counts of peripheral blood leukocyte subpopulations in Chinese rhesus macaques Cell Mol. Immunol. 2009 6 433 440 10.1038/cmi.2009.55 20003819
77. Melgert BN Macrophages: regulators of sex differences in asthma? Am. J. Respir. Cell Mol. Biol. 2010 42 595 603 10.1165/rcmb.2009-0016OC 19574533
78. Hewagama A Patel D Yarlagadda S Strickland FM Richardson BC Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis Genes. Immun. 2009 10 509 516 10.1038/gene.2009.12 19279650
79. Butterworth M McClellan B Allansmith M Influence of sex in immunoglobulin levels Nature 1967 214 1224 1225 10.1038/2141224a0 4169229
80. Cook IF Sexual dimorphism of humoral immunity with human vaccines Vaccine 2008 26 3551 3555 10.1016/j.vaccine.2008.04.054 18524433
81. Wikby A Mansson IA Johansson B Strindhall J Nilsson SE The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20-100 years of age Biogerontology 2008 9 299 308 10.1007/s10522-008-9138-6 18369735
82. Villacres MC Longmate J Auge C Diamond DJ Predominant type 1 CMV-specific memory T-helper response in humans: evidence for gender differences in cytokine secretion Hum. immunol. 2004 65 476 485 10.1016/j.humimm.2004.02.021 15172447
83. Amadori A Genetic control of the CD4/CD8 T-cell ratio in humans Nat. Med. 1995 1 1279 1283 10.1038/nm1295-1279 7489409
84. Das BR Reference ranges for lymphocyte subsets in adults from western India: influence of sex, age and method of enumeration Indian J. Med. Sci. 2008 62 397 406 10.4103/0019-5359.42725 19008613
85. Arnold AP Chen X What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front. Neuroendocrinol. 2009 30 1 9 10.1016/j.yfrne.2008.11.001 19028515
86. Poland GA Ovsyannikova IG Jacobson RM Personalized vaccines: the emerging field of vaccinomics Expert Opin. Biol. Ther. 2008 8 1659 1667 10.1517/14712598.8.11.1659 18847302
87. Márquez EJ Sexual-dimorphism in human immune system aging Nat. Commun. 2020 11 751 10.1038/s41467-020-14396-9 32029736
88. Kovats, S., Carreras, E. & Agrawal, H. In Sex Hormones and Immunity to Infection (eds Klein, S. L. & Roberts, C. W.) 53–92 (Springer-Verlag, 2010).
89. Roved J Westerdahl H Hasselquist D Sex differences in immune responses: hormonal effects, antagonistic selection, and evolutionary consequences Horm. Behav. 2017 88 95 105 10.1016/j.yhbeh.2016.11.017 27956226
90. Trigunaite A Dimo J Joergensen TN Suppressive effects of androgens on the immune system Cell Immunol. 2015 294 87 94 10.1016/j.cellimm.2015.02.004 25708485
91. Kadel S Kovats S Sex hormones regulate innate immune cells and promote sex differences in respiratory virus infection Front. Immunol. 2018 9 1653 10.3389/fimmu.2018.01653 30079065
92. Klein, S. L. In Sex and Gender Differences in Pharmacology (ed Regitz-Zagrosek, V.) (Springer, 2012).
93. Nicastri E A phase 2 randomized, double-blinded, placebo-controlled, multicenter trial evaluating the efficacy and safety of raloxifene for patients with mild to moderate COVID-19 EClinicalMedicine 2022 48 101450 10.1016/j.eclinm.2022.101450 35582123
94. Takahashi T Sex differences in immune responses that underlie COVID-19 disease outcomes Nature 2020 588 315 320 10.1038/s41586-020-2700-3 32846427
95. Lucas C Longitudinal analyses reveal immunological misfiring in severe COVID-19 Nature 2020 584 463 469 10.1038/s41586-020-2588-y 32717743
96. Meng Y Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: a retrospective study of 168 severe patients PLoS Pathog. 2020 16 e1008520 10.1371/journal.ppat.1008520 32343745
97. Xu K Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19) Clin. Infect. Dis. 2020 71 799 806 10.1093/cid/ciaa351 32271376
98. Zheng S Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study BMJ 2020 369 m1443 10.1136/bmj.m1443 32317267
99. Cadegiani FA McCoy J Gustavo Wambier C Goren A Early antiandrogen therapy with dutasteride reduces viral shedding, inflammatory responses, and time-to-remission in males with COVID-19: a randomized, double-blind, placebo-controlled interventional trial (EAT-DUTA AndroCoV Trial – Biochemical) Cureus 2021 13 e13047 33643746
100. Cadegiani FA Proxalutamide significantly accelerates viral clearance and reduces time to clinical remission in patients with mild to moderate COVID-19: results from a randomized, double-blinded, placebo-controlled trial Cureus 2021 13 e13492 33633920
101. Goren A A preliminary observation: male pattern hair loss among hospitalized COVID-19 patients in Spain - A potential clue to the role of androgens in COVID-19 severity J. Cosmet. Dermatol. 2020 19 1545 1547 10.1111/jocd.13443 32301221
102. Wambier CG Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: The “Gabrin sign” J. Am. Acad. Dermatol. 2020 83 680 682 10.1016/j.jaad.2020.05.079 32446821
103. Montopoli M Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532) Ann. Oncol. 2020 31 1040 1045 10.1016/j.annonc.2020.04.479 32387456
104. Patel VG Does androgen deprivation therapy protect against severe complications from COVID-19? Ann. Oncol. 2020 31 1419 1420 10.1016/j.annonc.2020.06.023 32653425
105. Lazzeri M Impact of chronic exposure to 5-α reductase inhibitors on the risk of hospitalization for COVID-19: a case-control study in male population from two COVID-19 regional centers of Lombardy (Italy) Minerva Urol. Nefrol. 2021 74 77 84
106. Durcan E TransCOVID: does gender-affirming hormone therapy play a role in contracting COVID-19? J. Sex. Marital. Ther. 2021 48 415 426 10.1080/0092623X.2021.2000535 34806552
107. Cadegiani FA Proxalutamide (GT0918) reduces the rate of hospitalization in mild-to-moderate COVID-19 female patients: a randomized double-blinded Placebo-controlled two-arm parallel trial medRxiv 2021 10.1101/2021.07.06.21260086
108. Cadegiani FA Efficacy of proxalutamide in hospitalized COVID-19 patients: a randomized, double-blind, Placebo-controlled, parallel-design clinical trial medRxiv 2021 10.1101/2021.06.22.21259318
109. Cadegiani FA Goren A Wambier CG Zimerman RA Proxalutamide improves inflammatory, immunologic, and thrombogenic markers in mild-to-moderate COVID-19 males and females: an exploratory analysis of a randomized, double-blinded, placebo-controlled trial early antiandrogen therapy (EAT) with proxalutamide (The EAT-Proxa Biochemical AndroCoV-Trial) medRxiv 2021 10.1101/2021.07.24.21261047
110. Zimerman RA Proxalutamide reduction of mortality rate in hospitalized COVID-19 patients depends on treatment duration – an exploratory analysis of the proxa-rescue AndroCoV trial medRxiv 2021 10.1101/2021.06.28.21259661
111. Cadegiani FA Proxalutamide improves lung injury in hospitalized COVID-19 patients – an analysis of the radiological findings of the proxa-rescue AndroCoV trial medRxiv 2021 10.1101/2021.07.01.21259656
112. Cadegiani FA Final results of a randomized, placebo-controlled, two-arm, parallel clinical trial of proxalutamide for hospitalized COVID-19 patients: a multiregional, joint analysis of the proxa-rescue AndroCoV trial Cureus 2021 13 e20691 34976549
113. Service, R. S. Too Good to be True: Doubts Swirl Around Trial that Saw 77% Reduction in COVID-19 Mortality https://www.science.org/content/article/too-good-be-true-doubts-swirl-around-trial-saw-77-reduction-covid-19-mortality (2021).
114. Taylor L Covid-19: Trial of experimental “covid cure” is among worst medical ethics violations in Brazil’s history, says regulator BMJ 2021 375 n2819 10.1136/bmj.n2819 34789508
115. McCoy J Proxalutamide reduces the rate of hospitalization for COVID-19 male outpatients: a randomized double-blinded placebo-controlled trial Front. Med. 2021 8 668698 10.3389/fmed.2021.668698
116. Klein EA Androgen deprivation therapy in men with prostate cancer does not affect risk of infection with SARS-CoV-2 J. Urol. 2021 205 441 443 10.1097/JU.0000000000001338 32897764
117. Bringel M Duarte O Leal F Argenton JLP Carvalheira JBC Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: a propensity score-based analysis Infect. Agents Cancer 2021 16 66 10.1186/s13027-021-00406-y
118. Nickols NG Effect of androgen suppression on clinical outcomes in hospitalized men with COVID-19: the HITCH randomized clinical trial JAMA Netw. Open 2022 5 e227852 10.1001/jamanetworkopen.2022.7852 35438754
119. Welén K A phase 2 trial of the effect of antiandrogen therapy on COVID-19 outcome: no evidence of benefit, supported by epidemiology and in vitro data Eur. Urol. 2022 81 285 293 10.1016/j.eururo.2021.12.013 34980495
120. Yale K Androgens and women: COVID-19 outcomes in women with acne vulgaris, polycystic ovarian syndrome, and hirsutism Int. J. Dermatol. 2021 60 e267 e268 10.1111/ijd.15473 33650165
121. Rambhatla A COVID-19 infection in men on testosterone replacement therapy J. Sex. Med. 2020 18 215 218 10.1016/j.jsxm.2020.09.013 33191186
122. Pozzilli P Lenzi A Commentary: testosterone, a key hormone in the context of COVID-19 pandemic Metabolism 2020 108 154252 10.1016/j.metabol.2020.154252 32353355
123. Rastrelli G Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients Andrology 2021 9 88 98 10.1111/andr.12821 32436355
124. Rowland SP O’Brien Bergin E Screening for low testosterone is needed for early identification and treatment of men at high risk of mortality from Covid-19 Crit. Care 2020 24 367 10.1186/s13054-020-03086-z 32560707
125. Dhindsa S Zhang N McPhaul MJ Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19 Diabetes Endocrinol. 2021 4 e2111398
126. Giagulli VA Worse progression of COVID-19 in men: is testosterone a key factor? Andrology 2021 9 53 64 10.1111/andr.12836 32524732
127. Schroeder M High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study Emerg. Microbes Infect. 2021 10 1807 1818 10.1080/22221751.2021.1969869 34402750
128. van Zeggeren IE Sex steroid hormones are associated with mortality in COVID-19 patients: Level of sex hormones in severe COVID-19 Medicine 2021 100 e27072 10.1097/MD.0000000000027072 34449505
129. Camici M Role of testosterone in SARS-CoV-2 infection: a key pathogenic factor and a biomarker for severe pneumonia Int. J. Infect. Dis. 2021 108 244 251 10.1016/j.ijid.2021.05.042 34023492
130. Pagano MT Predicting respiratory failure in patients infected by SARS-CoV-2 by admission sex-specific biomarkers Biol. Sex. Dif. 2021 12 63 10.1186/s13293-021-00407-x
131. Salciccia S Giudice FD Eisenberg ML Mastroianni CM Testosterone target therapy: focus on immune response, controversies and clinical implications in patients with COVID-19 infection Ther. Adv. Endocrinol. Metab. 2021 12 1 8 10.1177/20420188211010105
132. Younis YS Skorecki K Abassi Z The double edge sword of testosterone´s role in the COVID-19 pandemic Front. Endocrinol. 2021 12 607179 10.3389/fendo.2021.607179
133. Huang C Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 497 506 10.1016/S0140-6736(20)30183-5 31986264
134. Ma L Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients J. Med. Virol. 2021 93 456 462 10.1002/jmv.26259 32621617
135. Gebhard CE Hamouda N Gebert P Regitz-Zagrosek V Gebhard C Sex versus gender-related characteristics: which predicts clinical outcomes of acute COVID-19? Intensive Care Med. 2022 48 1652 1655 10.1007/s00134-022-06836-5 35943570
136. Klein SL Flanagan KL Sex differences in the immune response Nat. Rev. Immunol. 2016 16 626 638 10.1038/nri.2016.90 27546235
137. Szekeres-Bartho J Faust Z Varga P Szereday L Kelemen K The immunological pregnancy protective effect of progesterone is manifested via controlling cytokine production Am. J. Reprod. Immunol. 1996 35 348 351 10.1111/j.1600-0897.1996.tb00492.x 8739452
138. Channappanavar R Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection J. Immunol. 2017 198 4046 4053 10.4049/jimmunol.1601896 28373583
139. Costeira R Estrogen and COVID-19 symptoms: associations in women from the COVID symptom study PLoS One 2021 16 e0257051 10.1371/journal.pone.0257051 34506535
140. Ding T Potential influence of menstrual status and sex hormones on female SARS-CoV-2 infection: a cross-sectional study from multicentre in Wuhan, China Clin. Infect. Dis. 2020 72 e240 e248 10.1093/cid/ciaa1022
141. Seeland U Evidence for treatment with estradiol for women with SARS-CoV-2 infection BMC Med. 2020 18 369 10.1186/s12916-020-01851-z 33234138
142. Dambha-Miller H Mortality in COVID-19 among women on hormone replacement therapy: a retrospective cohort study Fam. Pract. 2022 10.1093/fampra/cmac041
143. Montopoli M Clinical outcome of SARS-CoV-2 infection in breast and ovarian cancer patients who underwent antiestrogenic therapy Ann. Oncol. 2021 32 676 677 10.1016/j.annonc.2021.01.069 33524477
144. Baker ME What are the physiological estrogens? Steroids 2013 78 337 340 10.1016/j.steroids.2012.12.011 23313336
145. Bereshchenko O Bruscoli S Riccardi C Glucocorticoids, sex hormones, and immunity Front. Immunol. 2018 9 1332 10.3389/fimmu.2018.01332 29946321
146. Goddard LM Ton AN Org T Mikkola HK Iruela-Arispe ML Selective suppression of endothelial cytokine production by progesterone receptor Vasc. Pharmacol. 2013 59 36 43 10.1016/j.vph.2013.06.001
147. Shah SB COVID-19 and progesterone: part 1. SARS-CoV-2, progesterone and its potential clinical use Endocr. Metab. Sci. 2021 5 100109 10.1016/j.endmts.2021.100109 34396353
148. Ghandehari S Matusov Y Pepkowitz S Stein D Kaderi T Progesterone in addition to standard of care alone in the treatment of men hospitalized with moderate to severe COVID-19: a randomized, controlled, pilot trial Chest Infect. 2021 160 74 84 10.1016/j.chest.2021.02.024
149. Wood P Groom G Moore A Ratcliffe W Selby C Progesterone assays: guidelines for the provision of a clinical biochemistry service Ann. Clin. Biochem. 1985 22 1 24 10.1177/000456328502200101 3885833
150. Qiancheng X Jian S Lingling P Coronavirus disease 2019 in pregnancy Int. J. Infect. Dis. 2020 95 376 383 10.1016/j.ijid.2020.04.065 32353549
151. Knight M Bunch K Kaler J Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study BMJ 2020 369 m2107 10.1136/bmj.m2107 32513659
152. Ellington S Characteristics of women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status - United States, January 22-June 7, 2020 Morb. Mortal. Wkly. Rep. 2020 69 769 775 10.15585/mmwr.mm6925a1
153. Wei SQ Bilodeau-Bertrand M Liu S Auger N The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis Can. Med. Assoc. J. 2021 193 E540 E548 10.1503/cmaj.202604 33741725
154. Chen L Clinical characteristics of pregnant women with Covid-19 in Wuhan, China N. Engl. J. Med. 2020 382 e100 10.1056/NEJMc2009226 32302077
155. Newson L Sensitive to infection but strong in defense — female sex and the power of oestradiol in the COVID-19 pandemic Front. Glob. Womens Health 2021 2 651752 10.3389/fgwh.2021.651752 34816207
156. Natelson BH Haghighi MH Ponzio NM Evidence for the presence of immune dysfunction in chronic fatigue syndrome Clin. Vaccine Immunol. 2002 9 747 752 10.1128/CDLI.9.4.747-752.2002
157. Mishra PK Vaccination boosts protective responses and counters SARS-CoV-2-induced pathogenic memory B cells medRxiv 2021 10.1101/2021.04.11.21255153
158. Wark PA ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma Respirology 2021 5 442 451 10.1111/resp.14003
159. Sarver DC Wong GW Obesity alters Ace2 and Tmprss2 expression in lung, trachea, and esophagus in a sex-dependent manner: Implications for COVID-19 Biochem. Biophys. Res. Commun. 2020 538 92 96 10.1016/j.bbrc.2020.10.066 33168188
160. Kermani NZ Song WJ Badi Y Versi A Guo Y Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma Respri. Res. 2021 22 10 10.1186/s12931-020-01605-8
161. Okuwan-Duodu D Lim EC You S Engman DM TMPRSS2 activity may mediate sex differences in COVID-19 severity Signal. Transduct. Target. Ther. 2021 6 100 10.1038/s41392-021-00513-7 33649313
162. Asselta R Paraboschi EM ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy Aging 2020 12 10087 10098 10.18632/aging.103415 32501810
163. Smith JC Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev. Cell 2020 53 514 529 10.1016/j.devcel.2020.05.012 32425701
164. Lee IT ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs Nat. Commun. 2020 11 5453 10.1038/s41467-020-19145-6 33116139
165. Li K Wohlford-Lenane C Bartlett JA McCray PB Inter-subject variation in ACE2 protein expression in human airway epithelia and its relationship to severe acute respiratory syndrome coronavirus 2 J. Infect. Dis. 2021 224 1357 1361 10.1093/infdis/jiab383 34289058
166. Barker H Parkkila S Bioinformatic characterization of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2 PLoS One 2020 15 e0240647 10.1371/journal.pone.0240647 33112891
167. Piva F Sabanovic B Cecati M Giulietti M Expression and co-expression analyses of TMPRSS2, a key element in COVID-19 Eur. J. Clin. Microbiol. Infect. Dis. 2021 40 451 455 10.1007/s10096-020-04089-y 33245471
168. Nickols NG Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial Trials 2021 22 431 10.1186/s13063-021-05389-0 34225789
169. WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect. Dis. 2020 20 e192 e197 10.1016/S1473-3099(20)30483-7 32539990
170. Lovre D Acute estradiol and progesterone therapy in hospitalised adults to reduce COVID-19 severity: a randomised control trial BMJ Open 2021 11 e053684 10.1136/bmjopen-2021-053684
171. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04539626 (2022).
172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04475601 (2021).
173. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04652765 (2021).
174. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04359329 (2020).
175. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/study/NCT04374279 (2021).
176. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04509999 (2021).
177. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04853927 (2022).
178. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04853069 (2021).
179. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04578236 (2020).
180. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04623385 (2020).
| 36494595 | PMC9734735 | NO-CC CODE | 2022-12-14 23:28:30 | no | Nat Rev Endocrinol. 2022 Dec 9;:1-15 | utf-8 | Nat Rev Endocrinol | 2,022 | 10.1038/s41574-022-00780-6 | oa_other |
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Hydrobiologia
Hydrobiologia
Hydrobiologia
0018-8158
1573-5117
Springer International Publishing Cham
5086
10.1007/s10750-022-05086-2
Trends in Aquatic Ecology IV
Are stable isotopes an efficient tool for tracking the effect of anthropogenic activities on mangrove food web structure and function?
http://orcid.org/0000-0002-4156-0755
Medina-Contreras Diana [email protected]
Arenas Fernando
grid.418275.d 0000 0001 2165 8782 Centro Interdisciplinario de Ciencias Marinas, Instituto Politécnico Nacional, Av. Instituto Politécnico Nacional S/N Col. Playa Palo de Santa Rita, Código Postal 23096 La Paz, B.C.S México
Guest editors: Koen Martens, Sidinei M. Thomaz, Diego Fontaneto & Luigi Naselli-Flores / Emerging Trends in Aquatic Ecology IV
8 12 2022
113
7 5 2022
1 11 2022
8 11 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Understanding and connecting the impact of anthropogenic activities on mangrove food webs is a research challenge. Has research on the subject been able to find answers using stable isotopes? The present opinion paper analyzed the utility of stable isotopes in tracing the impact of anthropogenic activities on mangrove food webs and if the research questions raised could be answered using these chemical markers. Representative research papers (16) focused on the use of stable isotopes (δ13C, δ15N, δ34S, δ2H, δD,206Pb/207Pb, and 208Pb/207Pb) to evaluate the effect of anthropogenic activities (Sewage discharge, timber harvesting–deforestation, metallurgical activities, hydrological disruption, aquaculture ponds, and urban development) on mangrove food webs were selected. Each article included at least one group of consumers (invertebrate or fish). Publications only focused on water quality or primary producers were not included. Most studies managed to determine the effect of the anthropogenic activities on the food web’s stable isotope values. Based on the above, we concluded that these markers are an effective tool to determine affectation patterns on the structure and function of mangrove food webs. The results obtained herein facilitate the correct management of mangroves and their derived resources.
Keywords
Isotopic modeling
Ecosystem management
Trophic ecology
Mangrove trophic flows
Ministerio de Ciencia Tecnología e Innovación71323 http://dx.doi.org/10.13039/501100003069 Instituto Politécnico Nacional SIP 20210421 - SIP 20195113 - SIP 20200708 BEIFI 2022 Medina-Contreras Diana CONSEJO NACIONAL DE CIENCIA Y TECNOLOGÍA (CONACYT)734084 DOCTORAL SCHOLARSHIP Medina-Contreras Diana Arenas Fernando
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pmcIntroduction
Mangrove forests are recognized for their important functional and structural characteristics. It is widely documented that these ecosystems are exporters or carbon sequesters, nursery areas, shoreline protectors, land builders, and climate change mitigators (Nagelkerken et al., 2008; Lee et al., 2014; Adame et al., 2021) among other vital ecosystem services for human communities (Palacios & Cantera, 2017). In coastal areas anthropogenic activities converge at various levels (subsistence, artisanal, and industrial), affecting mangrove function (Erazo & Bowman, 2021) and reducing their area (Wolanski et al., 2000). These activities include sewage discharges, timber extraction, aquaculture, agriculture, infrastructure construction, fishing, and tourism, among others (Valiela et al., 2001; Adame et al., 2021).
In the last decades, high levels of degradation and loss of mangrove ecosystems have occurred due to anthropogenic activities, especially in tropical regions. Between 1980 and 2000, at least 35% of global mangrove cover has been lost, equating to more than that of tropical forests and coral reefs (Valiela et al., 2001). Due to pond culture, 58% of mangrove cover in the Philippines were lost, 50% in Thailand (Primavera, 1993) and 50–80% in Southeast Asia (Wolanski et al., 2000). Due to shrimp farming, 28–40% of mangrove cover was lost in Ecuador between 1970 and 2006 (Ashton, 2008). Moreover, it is estimated that by the end of the century (2010–2100), the main causes of degradation and loss of mangrove function will be agriculture and aquaculture in Tropical Eastern Pacific, Temperate South America, and Central Indo-Pacific regions; erosion in Western and Central Indo-Pacific and Tropical Atlantic, clearing in Temperate Australasia, Central and Western Indo-Pacific, and Tropical Atlantic; and climate events in Temperate Australasia (Adame et al., 2021).
Anthropogenic modification of mangrove ecosystems contribute to decreased habitat quality, potentially affecting food web structure and function (Taylor et al., 2007; Bui & Lee, 2014; López-Rasgado et al., 2016; Medina-Contreras et al., 2021). Stable isotopes have been used for 4 decades to study mangrove food webs. The analysis of these markers (δ13C and δ15N) allows for the identification of primary producer sources and foods for consumers and has been extensively used as a tool for assessing ecological trophic relationships (Bouillon et al., 2011; Layman et al., 2012).
Initially, the studies determined the importance of mangrove carbon for consumers of tropical and subtropical systems (Rodelli et al., 1984; Zieman et al., 1984), principally species of fishery importance (Stoner & Zimmerman, 1988; Harrigan et al., 1989). The number of publications that study mangrove food webs using these chemical markers increased considerably, becoming relatively numerous during the previous 4 decades (> 80). The most recurrent research questions are which autotrophic sources sustain mangroves food webs? (Nyunja et al., 2009; Sepúlveda-Lozada et al., 2015; Medina-Contreras et al., 2018); how important is mangrove-derived carbon to certain species, groups, or assemblages? (Abrantes et al., 2015); and what is the spatial scope of mangrove organic carbon as a food source for consumers of estuarine food webs? (Rodelli et al., 1984; Mendoza-Carranza et al., 2010; Claudino et al., 2015).
Studies of the effect of anthropogenic activities on mangrove food webs through the use of stable isotopes has been limited (Hadwen & Arthington, 2007), with most of the research developed from 2010, but is becoming a subject of growing interest. The main objective of these studies has been to examine nitrogen and carbon flow patterns through the mangrove food webs with some anthropogenic alteration; for example, deforestation (Viana et al., 2015; Then et al., 2020), sewage inputs (Hadwen & Arthington, 2007; Medina-Contreras et al., 2021), and hydrological disruption (López-Rasgado et al., 2016), among others. These studies hypothesized that anthropogenic habitat modification leads to differences in niche and trophic structure of mangrove communities and hence trophic function.
In this opinion paper, representative research papers from different oceanic regions (Spalding et al., 2007) focused on the use of multiple stable isotopes (δ13C, δ15N, δ34S, δ2H, δD, 206Pb/207Pb, and 208Pb/207Pb) to evaluate the effect of anthropogenic activities on mangrove food webs were selected and reviewed. With the objectives of (1) analyzing if stable isotopes are effective tracers to evaluate the effect of anthropogenic activities on mangrove food webs and (2) conclude whether stable isotopes were useful to answer the research questions and to evaluate raised hypotheses.
Why use stable isotopes to track the effect of anthropogenic activities on mangrove food webs?
As will be discussed throughout this opinion paper, isotopic composition, trophic position, isotopic niche, and food web pathways may vary depending not only on mangrove environmental settings (Abrantes et al., 2015) but also on human modification of the habitat. For example, striking differences in the isotopic composition and niche of dominant fish communities of tropical and subtropical mangroves with different levels of anthropic intervention have been found (López-Rasgado et al., 2016; Mwandya, 2019; Medina-Contreras et al., 2021). The conservation status of mangroves could also have an effect on the connectivity between ecosystems (coral/rocky reefs), affecting ontogenetic fish movements between them (López-Rasgado et al., 2016; Medina-Contreras et al., 2021). Moreover, large-scale mangrove forest clearing may impact estuarine food webs, with potential consequences to nearby coastal ecosystems (Fraga et al., 2018).
According to this, stable isotopes principally δ15N and δ13C values potentially could track the anthropogenic effects on mangrove food webs. Regarding δ15N, this parameter could be an indicator of the alteration of water quality. In general, higher concentrations of 15 N are usually found in intervened mangrove systems compared to moderate or non-intervened mangroves (Hadwen & Arthington, 2007; Souza et al., 2018; Medina-Contreras et al., 2021), possibly due to the influence of waters loaded with nitrites, nitrates, and ammonium from various anthropic activities developed in bays, estuaries, and creeks associated to mangroves.
The δ13C values are widely used as indicators of differences in the sources of organic carbon used by consumers. Patterns of 13C enrichment/impoverishment and its relation to anthropogenic activities are not entirely clear (Medina-Contreras et al., 2021). For example, mangroves systems subject to hydrological restriction and deforestation exhibit different 13C values compared to non-intervened mangroves (López-Rasgado et al., 2016; Mwandya, 2019); however, the magnitude and tendency of these differences are particular for every study case as will be discussed later.
Papers selection criteria
A search was made in different databases of scientific citations, specifically Google Scholar and Scopus. The search keywords were mangrove anthropogenic intervention, stable isotopes, trophic structure of intervened mangroves, and stable isotope models in disturbed mangroves. The time range of the search was from 1980 to 2021. The selected papers had the following characteristics: (1) their main objective had to be to evaluate or understand the effect of anthropogenic activities on mangrove food webs. (2) They had to include at least one group of primary or secondary consumers (macroinvertebrates or fish, not bacteria or fungi). (3) They should include isotopic values and analysis of mangrove leaves. (4) Articles that only analyzed primary sources or basal resources (i.e., Particulate organic matter, Mangroves, Algae) were not included, even if they sought to identify contamination using stable isotopes, since the main objective of this opinion paper was not to analyze the efficiency of stable isotopes to track mangrove water quality or nutrient levels. (5) Only in situ research was included, not experiments. (6) The studies had to be carried out in mangrove creeks and not in large estuaries far from mangrove areas.
Anthropogenic actions evaluated
The following anthropogenic activities affecting mangrove food webs were evaluated in the selected papers (Fig. 1): sewage discharges, timber harvesting and/or deforestation, hydrological disruption, urban development, waste deposition from metallurgical activities, and aquaculture ponds (Table 1). Others were listed as part of the anthropogenic activities developed in anthropogenically intervened systems which potentially affect the structure and function of mangrove food webs. For example, tourism, shell harvesting, fishing, solid waste deposition, and recreation among others. However, its effect on mangrove food webs was not particularly evaluated.Fig. 1 Geographical location of selected research that has analyzed the effect of anthropogenic activities on mangrove food webs. The numbers correspond to studies from the oldest (1) to the most recent (16). (1): Tallow and Belongil Creeks, Australia (Hadwen & Arthington, 2007); (2): Annandale Wetland, Australia (Sheaves et al., 2007); (3) Moreton Bay, Australia (Pitt et al., 2009); (4) Botany and Homebush Bays, Australia (Mazumder et al., 2015); (5) Chiriquí Gulf, Panamá (Viana et al., 2015); (6): La Paz Bay, México (López-Rasgado et al., 2016), (7) Puloh River, Malaysia (Zulkifli et al., 2016); (8) Dulce Gulf, Costa Rica (Samper-Villarreal et al., 2018), (9) Vitória and Santa Cruz Bays, Brasil (Souza et al. 2018); (10) Piraquê-Açu-Mirim Estuary, Brasil (Fraga et al., 2018), (11) Makoba and Chwaka Bays, Tanzania (Mwandya, 2019), (12) Mantang mangrove forest reserve, Peninsular Malaysia (Then et al., 2020), (13) Buenaventura and Málaga Estuaries, Colombia (Medina-Contreras et al., 2021), (14) Vitória and Santa Cruz Bays, Brasil (Souza et al., 2021), (15) Dar es Salaam and Pawani mangroves, Tanzania (Lugendo & Kimirei, 2021), and (16) Qinglan Mangrove Nature Reserve, China (Herbeck et al., 2021). World mangroves distribution (Giri et al., 2010) and oceanic regions (Spalding et al., 2007)
Table 1 Selected research evaluating the effect of anthropogenic activities on mangrove food webs, using stable isotopes
Oceanic Region Country Locality Primary anthropogenic activity evaluated Stable isotopes used to evaluate the effect of anthropogenic activities on mangroves food webs References
Indo-Pacific Australia Tallow and Belongil Creeks Sewage discharged δ13C and δ15N Hadwen & Arthington (2007)
Indo-Pacific Australia Annandale wetland Urban development δ13C and δ15N Sheaves et al. (2007) Sheaves et al. (2007
Indo-Pacific Australia Moreton bay Sewage discharged δ15N Pitt et al. (2009)
Indo-Pacific Australia Brisbane water; botany and homebush bays Sewage discharged δ13C and δ15N Mazumder et al. (2015)
Eastern Pacific Panamá Chiriquí gulf Deforestation δ13C and δ15N Viana et al. (2015)
Eastern Pacific México California gulf Hydrological disruption δ13C and δ15N López-Rasgado et al. (2016)
Eastern Pacific Costa Rica Dulce gulf Sewage discharged δ13C and δ15N Samper-Villarreal et al. (2018)
Eastern Pacific Colombia Bahía Málaga and Buenaventura Bays Timber harvesting δ13C and δ15N Medina-Contreras et al. (2021)
Sewage discharged
Western Atlantic Brasil Vitória and Santa Cruz Bays Metallurgical activities δ13C, δ15N, 206Pb/207Pb, 208Pb/207Pb Souza et al. (2018)
Sewage discharged
Western Atlantic Brasil Piraquê-Açu-Mirim Estuary Deforestation δ13C Fraga et al. (2018)
Western Atlantic Brasil Vitória and Santa Cruz Bays Metallurgical activities δ15N Souza et al. (2021)
Indian Ocean Malaysia Puloh River Sewage discharged δ13C and δ15N Zulkifli et al. (2016)
Indian Ocean Tanzania Makoba and Chwaka Bays Deforestation δ13C and δ15N Mwandya (2019)
Aquaculture ponds
Indian Ocean Malaysia Matang Mangrove Forest Reserve Timber harvesting δD, δ13C, δ15N Then et al. (2020)
Indian Ocean Tanzania Dar es Salaam and Pawani mangroves Sewage discharged δ15N Lugendo & Kimirei (2021)
Indian Ocean China Qinglan Mangrove Nature Reserve Aquaculture ponds δ15N Herbeck et al. (2021)
Sewage discharge
The studies that evaluated the effect of sewage discharges on mangrove food webs hypothesized that the δ15N values in food web components (primary producers and consumers) are higher in mangroves with sewage inputs compared to those without them (Hadwen & Arthington, 2007; Pitt et al., 2009; Mazumder et al., 2015; Zulkifli et al., 2016; Samper-Villarreal et al., 2018; Souza et al., 2018; Lugendo & Kimirei, 2021; Medina-Contreras et al., 2021). The elevation of nitrogen levels has the potential to alter the structure and function of mangrove ecosystems. As a result, stable nitrogen isotope analysis (δ15N) has emerged as an effective way of exploring the effects of anthropogenic N uptake by mangrove food webs (Mazumder et al., 2015). These studies through δ15N values indicate that sites with sewage discharges present 15 N enrichment in sediments, primary producers (algae and mangroves), and consumers (invertebrates and fish). This pattern of 15 N enrichment can also be observed by comparing sites categorized as non-polluted and moderate, indicating that δ15N is highly sensitive to the increase in N of anthropogenic origin in mangroves and creeks (Lugendo & Kimirei, 2021). Moreover, Mazumder et al., (2015) demonstrated the decrease of food-chain length in sites with sewage discharges identifying one of the effects of nitrogen elevation on the structure of the food webs.
Another study suggests that sewage-derived nitrogen had been widely assimilated by producers and had been transferred through all trophic levels of the food web (Hadwen & Arthington, 2007). In this study, the authors also attribute 15 N enrichment to the hydrological conditions of the systems, which are intermittently open with a restricted circulation of water, indicating that the food webs of mangroves with this partial circulation setting are highly vulnerable to the effects of sewage discharges. This work presented strong evidence of the assimilation and trophic transfer of nitrogen effluent throughout the food web to the top consumers. Enrichment in 15 N (~ 1–3%) was also detected in tropical mangrove fish tissues, characterized by high anthropogenic impact, including sewage discharges, in contrast to a relatively pristine system (Medina-Contreras et al., 2021).
Other studies (Samper-Villarreal et al., 2018; Souza et al., 2018) also indicated 15N enrichment in primary producers’ tissues. For example, in Costa Rica (Samper-Villareal et al., 2018), mangrove leaf isotopic values showed enriched 15N at nutrient-loaded mangroves, whereas algae and bivalves showed a small variation between reference and nutrient-loaded mangroves. In Brazil (Souza et al., 2018), the results indicated that the lower components of the food web, especially mangroves exhibited enriched 15N in nutrient-loaded mangroves, which are more affected than organisms of higher trophic positions (crabs, oysters, shrimps, and fish). These studies also indicate that along with sewage discharges, the hydrological and geomorphological characteristics of the mangrove system also influence the assimilation of nitrogen from anthropogenic sources throughout the food web (Medina-Contreras et al., 2021). Similar to the mangrove systems in Australia (Hadwen & Arthington, 2007), the results of Samper-Villarreal et al., (2018) in Costa Rica were obtained in a system of long water residence time, contrasting a deep system with a fjord‐like bathymetry and naturally low nutrient levels. The results obtained in Costa Rica provide isotopic evidence of subtle nutrient enrichment in these mangrove habitats, despite limited evidence of nutrient loading from water quality analyses. These findings are suggestive of chronic low‐level nutrient loading in the study area.
In Brazil, Souza et al. (2018) found differences in the primary producers that support fish and oysters from mangroves with sewage discharge and without them. They also found 15 N enrichment in mangrove tissues from the site with sewage discharges. The authors suggest that these results are not only due to differences in anthropogenic pressures but also to the hydrological characteristics of each site under study, since one has greater influence from marine water, which in turn reduces the suspended sediment load, directly affecting the food source of Oysters. These results are evidence that studies that aim to determine the effect of sewage discharges on the mangrove food web should involve or consider the hydrology and geomorphology of the systems.
The previous studies showed that systems with less circulation (intermittently open) incorporate nitrogen from sewage discharges along the entire food web (Hadwen & Arthinton, 2007). Deep (Samper-Villarreal et al., 2018) or open circulation sites (Souza et al., 2018) will initially exhibit 15 N enrichment in their primary producers and with time anthropogenic nitrogen will also be incorporated into other food web constituents, including top consumers (Samper-Villarreal et al., 2018). According to this, Pitt et al. (2009) studied the effects of wastewater treatment plant upgrades on the utilization of sewage-N by mangrove–estuarine primary producers (filamentous algae and mangrove leaves) and consumers (shore crabs) using δ15N values. The authors concluded that although the total N discharged into the study sites decreased by more than 80% after the upgrades had occurred, the δ15N values of mangrove leaves remained elevated in all rivers, indicating that sewage-N remained a major source for mangroves, either from sewage discharges or from N accumulated in the sediments over many years.
The mobility of toxic trace elements (Cr, As, Cd, and Pb) from sewage discharges via terrestrial and marine anthropogenic activities and its relationship with δ15N was studied on mangrove food webs of Puloh River in Malaysia (Zulkifli et al., 2016). Through the study of the giant mudskipper [Periophthalmodon schlosseri (Pallas, 1770)], a carnivorous fish living in mudflats and mangrove ecosystems, the authors used δ15N values to assess the impact of biomagnification of toxic trace elements in food webs of mangrove creeks. The authors suggested that biomagnification was possibly occurring due to the increase of trophic levels and compared the δ15N values with the concentration of selected toxic trace elements of each biological sample. The study concluded that the mobility of toxic trace elements is strongly related with δ15N values. The significant relationship between both parameters served as a tool to prove that biomagnification occurs in the mangrove forest under study.
The results of the previous studies suggest that δ15N values are good indicators of changes in mangrove ecosystem water quality, since nutrient enrichment can lead to elevated 15N. Therefore, this parameter can be used to distinguish between clean and polluted mangrove aquatic systems. By demonstrating that the highest δ15N values in a mangrove ecosystem are associated with anthropogenic discharges, the effect of these on the trophic dynamics of the ecosystem can be evaluated with such markers. Mangroves of impacted systems incorporate anthropogenic nitrogen of higher δ15N values into their tissues, therefore these plants could be used to distinguish between clean and polluted mangrove estuaries. Sewage discharges modify the structure of mangrove food webs, deteriorating their food web’s function and ecosystem services. For a better understanding of the effect of sewage discharges on mangrove food webs, it is necessary to develop studies in mangroves from different regions around the globe, including diverse patterns of geomorphology and environmental settings and involving seasonal variations.
Timber harvesting and deforestation
Within selected papers, studies evaluating the effect of timber harvesting and/or deforestation on mangrove food webs using stable isotopes were less compared to those that evaluated sewage discharges (Viana et al., 2015; Fraga et al., 2018; Mwandya, 2019; Then et al., 2020; Medina-Contreras et al., 2021). Some specifically analyzed the effect of deforestation and timber harvesting on the structure of mangrove food webs (Viana et al., 2015; Fraga et al., 2018; Mwandya, 2019; Then et al., 2020), while others list timber harvesting as one of the anthropogenic activities that characterize a highly impacted mangrove (Medina-Contreras et al. 2021) in a comparison of their aquatic communities’ trophic structure with that of less affected mangrove systems.
In the Pacific of Panama the effect of watershed deforestation on food webs within the receiving mangrove estuaries was evaluated (Viana et al., 2015). This study was developed in eight tropical mangroves that received inputs from watersheds with different percentages of deforestation (23%, 29%, 47%, 73%, 91%, and 92%) where the isotopic values (δ13C and δ15N) of consumers (fish and invertebrates) were compared. The results suggest that δ13C and δ15N values of consumers tissues collected from the estuaries with different percentages of deforestation were remarkably similar. Although a subtle difference in stable isotopic values of some consumers was found, the links to watershed deforestation were not evident. Due to the components of the food web being collected at the mouth of the mangrove estuaries, their isotopic signals were not affected by the degree of deforestation of the contributing watershed.
However, the authors point out that although the effect of deforestation could not be evidenced in the consumers’ isotopic composition, the impact of these ecosystems by deforestation cannot be ignored. In these same Panamanian estuaries, the deforestation degree significantly affected amounts of dissolved and particulate materials released into the fresh reaches. It appears that the biogeochemical transformations taking place within mangrove estuaries are powerful enough to erase the footprint of the contributing watershed during the transit of waters and materials downstream (Viana et al., 2015). The analysis of consumers from the mudflats and forests may have evidence of the effect of deforestation on the mangroves’ food webs.
The other study directly focused on timber harvesting–deforestation and used a multi-isotope approach (δ13C, δ15N, and δD) to trace ecosystem responses to forest clearing and replanting in a tropical mangrove forest reserve at Matang, Malaysia (Then et al., 2020). This study sampled four macroinvertebrate taxa (barnacles, prawns, gastropods, and crabs) in mangrove forests of different ages, including a reference site that has experienced little harvesting. The objectives were to determine whether a multi-isotope approach could track ecological changes of mangrove functional support of food webs and determine the timing of isotopic shifts that signal critical transitions in restoration success.
Unlike research in Panamá, this study (Then et al., 2020) could determine differences in the food web due to a deforestation gradient of 70 years. A functional food web recovery was indicated by a decrease in δ13C and δ15N, as well as an increase in δD for gastropods and crabs in older forests. For the benthic mangrove food webs, the δ13C and δD values were practical for tracking changes in forest floor resources. For example, the open younger forests (0–5 years) received high sunlight exposure which likely promoted benthic microalgae growth and increased utilization of microalgal food sources (including phytoplankton) caused higher δ13C and lower δD values in tissues of gastropods and crabs. The study also concluded that the time of a mangrove food web recovery is between 5- and 15-year post-clearing of mangroves.
In another study, changes in benthic macrofaunal assemblages and food webs at a deforested mangrove and natural site in a tropical estuary in Eastern Brazil were evaluated (Fraga et al., 2018) using δ13C values. The results suggested that benthic assemblage composition, infaunal δ13C signatures, and food web diversity markedly differed at the impacted site being strongly related to sedimentary changes. The authors concluded that large-scale mangrove forest clearing may impact estuarine food webs, with potential consequences to nearby coastal ecosystems.
Finally, δ13C and δ15N values from undisturbed mangrove creeks were compared with clear-cut areas of mangroves to understand the effects of deforestation on trophic structure of mangrove-associated fish species, in Makoba and Chwaka Bays, Tanzania (Mwandya, 2019). Results suggest that stable isotope values (δ13C and δ15N) in fish muscles indicated significant diet shifts between undisturbed and disturbed mangrove creeks, although the effects were species specific. For example, Mugil cephalus Linnaeus, 1758 collected from unforested mangroves had significantly lower 15 N values than individuals collected in forested mangroves, due to a change in diet from omnivore to herbivore. Similarly, lower 15N values in samples of Gerres oyena (Forsskål, 1775) from disturbed creeks indicate a change from a fish-based diet to increased benthos. In accordance with Medina-Contreras et al. (2021) and Then et al. (2020), the results obtained (Mwandya, 2019) indicated that mangrove deforestation has a greater impact on the trophic structure of mangrove creeks’ fish communities. The authors also suggest that in conjunction with land-use changes, the effects of deforestation on the trophic structure of mangrove fish communities is exacerbated (Mwandya, 2019). According to the previous papers, isotopic values of consumers’ tissues are functional indicators of ecosystem changes occurring in food webs, vegetation cover, and soils.
Metallurgical activities
The effect of the deposition of residues from metallurgical activities on mangrove food webs through stable isotopes was analyzed through two studies (Souza et al., 2018, 2021) from Brazil. The articles hypothesized that the evaluation of multiple stable isotopes in mangrove ecosystems allows for linking anthropogenic activity to different levels and sources of contamination. The authors employed volatile stable isotopes (δ13C, δ15N) which are commonly used for the evaluation of pollutant plumes in groundwater and non-volatile stable isotopes (87Sr/86Sr, 206Pb/207Pb and 208Pb/207Pb) which used less frequently. These isotopes were measured in sediments, mangroves, plankton, shrimps, crabs, oysters, and fish from three mangrove areas with different levels of anthropogenic impact and sources of contamination. According to this research (Souza et al., 2018), the combined use of both volatile and non-volatile stable isotopes is uncommon but highly valuable for identifying sources of environmental contaminants in estuarine mangrove systems affected by anthropogenic and industrial pollution (Souza et al. 2018).
The analysis of 206Pb/207Pb and 208Pb/207Pb ratios confirmed that the Pb isotope values in all sampling sites were similar to sites with typical metallurgical activities (Souza et al., 2018, 2021). The authors suggest that this result is due to the presence of anthropogenic aerosols containing Pb from industrial sources, such as mining, smelting, coal burning, crushing, grinding, separation, refining, and residue management. One of the three study sites exhibited the highest Pb isotopic ratios (206Pb/207Pb and 208Pb/207Pb) for sediment, mangroves, and crabs due to the presence of solid waste from metallurgical activities, affecting mainly sediments and the benthic components of the food web. Finally, the study concludes that three out of five measured isotopic ratios (206Pb/207Pb; δ15N and 87Sr/86Sr) were sufficient to indicate differences between the studied areas, and as metal/metalloid contamination can originate from several sources, stable isotope ratios have been used to identify the origin (source) of metals and metalloids in the mangrove food webs (Souza et al., 2018).
Additionally, most metals were biomagnified through the mangrove food web and were found in all trophic levels (Souza et al., 2021). Due to the similar trophodynamics of non-polluted and polluted mangroves and the unequal transfer patterns in other cases, the effectiveness of 15N to study food webs with aquatic biota affected by anthropogenic contaminants is questionable.
Hydrological disruption
The effects of hydrological disruption caused by anthropogenic activities on mangrove food webs using stable isotopes were analyzed in a single study (López-Rasgado et al., 2016) in the Gulf of California, where mangrove systems are under serious threat due to the construction of shrimp farms and tourism development. Here the authors examine the relationship between the degree of anthropogenic modification of three mangrove systems and the isotopic trophic structure of the dominant fish community. The study areas included a natural system that has not been subject to habitat modification, a slightly impacted mangrove by possible urban expansion, and a highly impacted mangrove with a severe limitation of water exchange with the adjacent bay due to road construction and heavily modified by anthropogenic activities.
The results indicate that δ13C values of most fish caught within the highly impacted mangrove were greater than those in systems impacted at a lesser degree (López-Rasgado et al., 2016). The hydrological disruption may lead to a high dependence of the fish community on autochthonous carbon. As indicative of high functional trophic redundancy and a more compact food web, the fish community collected in the most pristine mangrove system exhibited the smallest isotopic niche space. In contrast, the highest niche space was found in the mangrove with hydrological disruption, the broadest functional trophic diversity, and lowest trophic redundancy (López-Rasgado et al., 2016). This result coincides with what was found in tropical mangroves, where the largest fish isotopic niche was also found in the mangrove system with greater intervention in contrast to less impacted systems (Medina-Contreras et al., 2021).
In contrast to most of the studies reviewed in the present paper (Hadwen & Arthington, 2007; Samper-Villarreal et al., 2018; Souza et al., 2018; Medina-Contreras et al., 2021), the δ15N isotopic values found in fish tissues from highly impacted mangroves exhibited relatively low nitrogen isotope ratios compared with those from the less impacted mangroves. δ15N values reflect only the input of fixed nitrogen into the system, which is consistent with the presence of cyanobacteria. According to the authors (López-Rasgado et al., 2016), hydrologic restrictions between mangrove systems and the ocean lead to the decline in the abundance of flora (macroalgae) that provide important habitat for marine fauna and alters the dynamics of prey populations, larvae, and juveniles. The lower structural diversity of the fish community sampled in the hydrologically disrupted mangrove was associated with a broader isotopic niche space and less trophic redundancy (López-Rasgado et al., 2016).
Finally, the authors (López-Rasgado et al., 2016) concluded that anthropogenic degradation of mangrove habitat generates fundamental changes in food web structure. The anthropogenic activities that impact fish habitat quality and their functional trophic diversity in mangroves should be assessed using stable isotopes. These markers may also be useful for monitoring ecological recovery after habitat restoration (López-Rasgado et al., 2016).
Aquaculture ponds
Coastal aquaculture expansion resulted in mangrove area loss and ecosystem degradation in past decades. But, what about its effects on mangrove food web structure and function? The use of stable isotopes to evaluate the effects of aquaculture ponds on mangrove food webs is analyzed in this opinion paper through two research papers: one from Tanzania (Mwandya, 2019) and one from China (Herbeck et al., 2021). In the study carried out in China, the effects of aquaculture ponds were evaluated in different sections of an estuarine system. Mangroves were mostly associated to the river and inner estuary, where in general higher 15N values were found in comparison to those of the outer estuary where the authors suggest that the effect of aquaculture nitrogen discharges is less detectable (Herbeck et al., 2021). However, 15N is significantly higher in all areas of the estuary, but the highest increase was found between the river site and the inner bay. In general, δ15N values of all trophic levels were strikingly high and located at the higher end of the worldwide range for estuaries, indicating that the aquaculture-derived nitrogen is then transferred through the entire planktonic and benthic estuarine food web (Herbeck et al., 2021). Authors finally concluded that δ15N is a useful indicator to assess the cumulative effects of aquaculture sewage on a mangrove–estuarine food web scale.
The Tanzania study does not specify the effects of aquaculture ponds on the food web studied, since the work focused on the effect of deforestation. However, the authors reported a dietary shift related to a change in the availability of food sources due to mangrove creek disturbance (see Timber harvesting and deforestation section). This evident impact on the mangroves’ trophic dynamics is exacerbated by the change of land use to aquaculture ponds, indicating that a combination of mangrove deforestation and construction of fish farms negatively affects fish assemblages and functional groups. Moreover, the recovery of mangrove food web attributes is less likely when these two human activities are combined.
Urban development
The effects of urban development on mangrove food webs were evaluated through the study of juvenile penaeid shrimp abundance and their dietary dependence (mangrove plant-based pathways vs. marine pathways) in two locations (mangrove and a non-mangrove pools) adjacent to an urban development using stable isotopes (δ13C and δ15N) (Sheaves et al., 2007). Urban development in these areas is generally associated to harvesting of fish and shrimp, regular grass fires, and the development of an extensive trail network. Based on the abundance results, this paper concluded that although situated in a highly urbanized area, the wetland under study provides an important habitat for juvenile penaeid shrimps, including 5 commercial penaeids species, highlighting the functionality of mangroves, even those that are highly impacted by human activities. Based on δ13C values both marine and wetland primary producers were important to the nutrition of juvenile shrimps. The substantial differences in nitrogen sources in the study pools indicated by different δ15N values may be signs of increasing anthropogenic nutrient inputs. This paper provides an initial step for the assessment of the ecological value of urbanized tropical coastal littoral wetlands as habitats of juvenile commercial penaeid shrimps and highlights their increasing value.
Conclusion
Based on the results of the studies reviewed in this article and the conclusions given by the authors, stable isotopes are useful tools to address research that aims to evaluate the effect of different anthropogenic activities on the structure and function of mangrove food webs.
Anthropogenic influences on nutrient inputs into mangrove creeks and estuaries, specifically the elevation of nitrogen levels, could potentially alter the structure and function of mangrove food webs. The nitrogen isotope (δ15N) analysis has emerged as an effective way of exploring the uptake of anthropogenic N in mangrove ecosystems. According to the papers reviewed here, it was useful in identifying systems subject to contamination by sewage discharges, in some cases enriching the nitrogen isotopic signal in various constituents of the food web and along the different trophic levels and in other cases only at the level of primary producers. Furthermore, the identification of nutrient enrichment is needed for the management of mangrove systems. Its identification along the food web can assist in the evaluation of the ecological responses to anthropogenic sources of nutrients. The use of sessile invertebrates and fish species with a small home range could be more suitable to study this topic, combining isotopic measurements (δ15N) with traditional nutrient and water transparency measurements.
The results of the studies analyzed suggest that the natural hydrology of mangrove systems could determine if anthropogenic nitrogen will be assimilated throughout the food web or only at a primary producers’ level. As demonstrated in the reviewed research, mangrove systems with naturally restricted water circulation are more susceptible to the incorporation of anthropogenic nitrogen along all the constituents of their food webs, evidenced by the enriched values of 15 N in their tissues. It is also important to consider the natural abundance of the nitrogen isotope in a system with pristine conditions, which is why researchers compare systems affected by sewage discharges with similar systems that have not been affected by sewage discharges. This is because nitrogen baselines vary depending on the environmental characteristics of each mangrove system. It is important to clarify that although several studies use δ15N as a tool to evaluate water quality, few studies have investigated the uptake and assimilation of 15 N-enriched sewage effluents through the entire food web.
A direct proportional strong relationship between the biomagnification of toxic trace elements (Cr, As, Cd, and Pb) from sewage discharges via land and sea human activities and δ15N was identified in one of the reviewed studies. For further evidence, more studies are required, as well as the comparison with sites not impacted by wastewater discharges. However, it indicates to another potential variable of which δ15N could be a useful marker.
Not in all cases, mangroves highly affected by anthropogenic activities will exhibit enrichment of 15 N in the tissues of food web constituents. For example, in the study that evaluated the effect of hydrological disruption on mangrove food webs, a decrease in δ15N was evidenced due to the restriction of water flow, because the predominant primary producers were autochthonous and corresponded mainly to cyanobacteria. It is important to consider that there are mangrove systems naturally enriched or depleted in 15 N, therefore this condition as well as the composition of predominant primary producers will determine δ15N baseline values in case of a hydrological disruption. Also, in another study that evaluated the effect of deforestation, individuals of Mugil cephalus collected from deforested mangrove sites had significantly lower 15 N values than those collected in near-pristine mangrove forests, due to a change in diet from omnivore to herbivore. Similarly, lower 15 N values in samples of Gerres oyena from disturbed creeks suggest a change from a fish diet to a benthos diet. The previous results indicate a dietary shift related to a change in the availability of food sources due to mangrove creeks disturbance.
Isotopic carbon values (δ13C) provide evidence of differential use of basal resources by anthropogenically impacted mangrove consumers and their counterparts. For example, in a mangrove with hydrological disruption, fish tissues were 13C enriched compared with mangroves without hydrological disruption, indicating the consumption of autochthonous sources (cyanobacteria) and without differences between climatic seasons. In tropical mangroves of Colombia, fish tissues from a mangrove system impacted by timber harvesting were 13C enriched compared to those from less impacted systems, due to greater consumption of benthic microalgae. Similarly, in Malaysia, δ13C was an indicator of the gradient of temporal deforestation as mollusk and crustacean tissues were enriched in 13C due to the consumption of benthic microalgae, which proliferate in highly fragmented systems compared to systems less impacted by timber harvesting. Additionally, based on δ13C values, one of the studies concluded that large-scale mangrove forest clearing may impact estuarine food webs, with potential consequences to nearby coastal ecosystems. This conclusion extends the scope of the interpretation of the results obtained with this marker.
The deuterium isotope (δD) presented the contrary pattern with 13C-enriched values in consumers from less fragmented forests. The authors of the papers reviewed agree that the carbon isotope is useful for understanding how anthropogenic activities affect consumption patterns of primary sources by different consumers. These results are useful for the management of resources of fishing importance in mangrove areas impacted by human activities, capable of indicating shifts in food web isotopic signals can also be determined based on the deforestation of the forest.
Concerning the effect of waste from metallurgical activities, Pb isotopic ratios (206Pb/207Pb) were sufficient to identify the origin of metal/metalloid contamination in mangrove food webs. However, this topic requires further investigation. Moreover, one conclusion addressing metallurgical activities is highlighted: a combination of techniques and components could be used as a comprehensive toolkit for the study of mangrove systems affected by anthropogenic pollution (See Souza et al., 2018).
Finally based on their size, most fish (See López-Rasgado et al., 2016; Mwandya, 2019; Medina-Contreras et al., 2021) and shrimps (See Sheaves et al., 2007) caught in the mangrove systems under study were juveniles, regardless of the anthropogenic intervention level. This result suggests that despite the modification of structure patterns and function in mangrove food webs by anthropogenic intervention, their nursery function is still maintained, indicating the high resilience of these ecosystems and highlights the ecological importance of such habitats. Finally, most of the mangrove areas studied in the reviewed papers are important fishing areas, offering food security and livelihood for human local communities. Therefore, impacts on their food web functions and structure endangers their role as a food providers.
Acknowledgements
Financial and logistic support for this study have been given by the projects: Aporte de la diversidad funcional de los ecosistemas de manglar al bienestar humano en las costas Caribe y Pacífico, de Colombia: Una mirada desde el enfoque de los servicios ecosistémicos (code 71323), from the program Evaluación comparativa de servicios ecosistémicos proporcionados por diferentes tipos de manglar en Colombia (code 110685270796) accomplished by Universidad del Valle and co-funded by Ministerio de Ciencia Tecnología e Inno- vación through the call number: 852-2019. And the projects: Variabilidad espacio-temporal del nitrógeno utilizando bioindicadores y nutrientes en ambientes mari- nos transicionales (codes SIP 20195113, 20200708), Influencia de los Arribazones de Sargassum spp. como fuente de Nitrógeno en la costa de Caribe Mexicano (code SIP 20210421). Project SIP 20221362, Resilience of the Mexican Fish Sector to the Effects of the Covid-19 Pandemic, CICIMAR. DMC and FA were supported by a doctoral scholarship funded by Consejo Nacional de Ciencia y Tecnología (CONACYT) México and ‘‘Beca de estímulo Institucional de Formación de Investigadores BEIFI’’ fellowship from Instituto Politécnico Nacional, México. The author gratefully acknowledge the very valuable help of Zenia Perez Falls for mapping the study areas. In dedication to DMC father's memory.
Funding
This study was supported by Ministerio de Ciencia Tecnología e Innovación (Project: Aporte a la diversidad funcional de los ecosistemas de manglar al bienestar humano en las costas Caribe y Pacífico de Colombia: Una mirada a los Servicios Ecosistémicos, Grant No. 71323) from the program: “Evaluación comparativa de los servicios ecosistémicos proporcionados por diferentes tipos de manglar en Colombia” Code. 110685270796, Instituto Politécnico Nacional Projects 20210421-SIP, 20195113-SIP, 20200708-SIP (Grant No. BEIFI 2022) and CONSEJO NACIONAL DE CIENCIA Y TECNOLOGÍA (CONACYT) (Grant No. 734084, DMC DOCTORAL SCHOLARSHIP and CUV No. 1031683, FA Doctoral Scholarship).
Data availability
Manuscript does not have original data.
Declarations
Conflict of interest
This paper does not present social, political, or economic conflicts of interests. The Opinion paper does not have original data.
Ethical approval
The manuscript does not involve animal experimentation or human participants.
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References
Abrantes KG Johnston R Connolly RM Sheaves M Importance of Mangrove carbon for aquatic food webs in wet-dry tropical estuaries Estuaries and Coasts 2015 38 383 399 10.1007/s12237-014-9817-2
Adame MF Connolly RM Turschwell MP Lovelock CE Fatoyinbo T Lagomasino D Goldberg LA Holdorf J Friess DA Sasmito SD Sanderman J Sievers M Buelow C Bryan- JBKD Brown BCJ Future carbon emissions from global mangrove forest loss Global Change Biology 2021 00 1 11
Ashton EC The impact of shrimp farming on mangrove ecosystems CAB Reviews 2008 10.1079/PAVSNNR20083003
Bouillon S Connolly RM Gillikin DP Use of stable isotopes to understand food webs and ecosystem functioning in estuaries Treatise on Estuarine and Coastal Science 2011 10.1016/B978-0-12-374711-2.00711-7
Bui THH Lee SY Does ‘You Are What You Eat’ apply to mangrove grapsid crabs? PLoS ONE 2014 9 2 89074 10.1371/journal.pone.0089074
Claudino MC Luiz A Pessanha M Araújo FG Garcia AM Trophic connectivity and basal food sources sustaining tropical aquatic consumers along a mangrove to ocean gradient Estuarine, Coastal and Shelf Science Elsevier Ltd 2015 167 part A 45 55 10.1016/j.ecss.2015.07.005
Erazo NG Bowman JS iScience ll Sensitivity of the mangrove-estuarine microbial community to aquaculture effluent iScience 2021 24 1 16 10.1016/j.isci.2021.102204
Fraga A Eduardo L Gomes DO Louise H Andrades R Barreto L Mangrove clearing impacts on macrofaunal assemblages and benthic food webs in a tropical estuary Marine Pollution Bulletin 2018 126 228 235 10.1016/j.marpolbul.2017.11.008 29421092
Giri C Ochieng E Tieszen LL Zhu Z Singh A Loveland T Masek J Duke N Status and distribution of mangrove forests of the world using earth Global Ecology Biogeography 2010 10.1111/j.1466-8238.2010.00584.x
Hadwen WL Arthington AH N-enriched sewage effluent Estuarine, Coastal and Shelf Science 2007 71 347 358 10.1016/j.ecss.2006.08.017
Harrigan P Zieman J Macko SA The base of nutritional support for the gray snapper (Lutjanus Griseus): an evaluation based on a combined stomach content and stable isotope analysis Bulletin of Marine Science 1989 44 65 77
Herbeck LS Krumme U Nordhaus I Jennerjahn TC Pond aquaculture effluents feed an anthropogenic nitrogen loop in a SE Asian estuary Science of the Total Environment 2021 756 144083 10.1016/j.scitotenv.2020.144083 33280879
Layman CA Boucek R Hammerschlag-peyer CM Applying stable isotopes to examine food-web structure : an overview of analytical tools Biological Reviews 2012 87 542 562 10.1111/j.1469-185X.2011.00208.x
Lee SY Primavera JH Dahdouh-guebas F Mckee K Bosire JO Cannicci S Diele K Fromard F Koedam N Marchand C Mendelssohn I Ecological role and services of tropical mangrove ecosystems : a reassessment Global Ecology and Biogeography 2014 23 726 743 10.1111/geb.12155
López-Rasgado F Luch-Cota S Balart E Herzka S Variation in isotopic trophic structure and fish diversity in mangrove systems subject to different levels of habitat modification in the Gulf of California, Mexico Bulletin of Marine Science-Miamy 2016 92 4 399 422 10.5343/bms.2015.1100
Lugendo BR Kimirei IA Anthropogenic nitrogen pollution in mangrove ecosystems along Dares Salaam and Bagamoyo coasts in Tanzania Marine Pollution Bulletin Elsevier Ltd 2021 168 112415 10.1016/j.marpolbul.2021.112415
Mazumder D Saintilan N Alderson B Hollins S Inputs of anthropogenic nitrogen in fluence isotopic composition and trophic structure in SE Australian estuaries Marine Pollution Bulletin 2015 100 217 223 10.1016/j.marpolbul.2015.08.047 26371847
Medina-Contreras D Cantera-Kintz J Sánchez-González A Mancera JE Food web structure and trophic relations in a riverine mangrove system of the tropical eastern pacific, central coast of Colombia Estuaries and Coasts 2018 41 1511 1521 10.1007/s12237-017-0350-y
Medina-Contreras D Cantera J Sánchez A Trophic structure of fish communities in mangrove systems subject to different levels of anthropogenic intervention, tropical eastern pacific, Colombia Environmental Science and Pollution Research Springer, Berlin Heidelberg 2021 10.1007/s11356-021-16814-x
Mendoza-Carranza M Hoeinghaus DJ Garcia AM Aquatic food webs in mangrove and seagrass habitats of Centla wetland, a biosphere reserve in Southeastern Mexico Neotropical Ichthyology 2010 8 171 178 10.1590/S1679-62252010000100020
Mwandya AW Influence of mangrove deforestation and land use change on trophic organization of fish assemblages in creek systems African Journal of Biological Sciences 2019 1 42 57 10.33472/AFJBS.1.4.2019.42-57
Nagelkerken I Blaber SJM Bouillon S Green P Haywood M Kirton LG Meynecke J Pawlik J Penrose HM Sasekumar A Somerfield PJ The habitat function of mangroves for terrestrial and marine fauna : a review Aquatic Botany 2008 89 155 185 10.1016/j.aquabot.2007.12.007
Nyunja J Ntiba M Onyari J Mavuti K Soetaert K Bouillon S Carbon sources supporting a diverse fish community in a tropical coastal ecosystem (Gazi Bay, Kenya ) Estuarine, Coastal and Shelf Science Elsevier Ltd 2009 83 333 341 10.1016/j.ecss.2009.01.009
Palacios ML Cantera JR Mangrove timber use as an ecosystem service in the Colombian Pacific Hydrobiologia Springer International Publishing 2017 803 345 358
Pitt KA Connolly RM Maxwell P Redistribution of sewage-nitrogen in estuarine food webs following sewage treatment upgrades Marine Pollution Bulletin Elsevier Ltd 2009 58 573 580 10.1016/j.marpolbul.2008.11.016
Primavera JH Reviews in fisheries science a critical review of shrimp pond culture in the a critical review of shrimp pond culture in the Philippines Reviews in Fisheries Science 1993 1 151 201 10.1080/10641269309388539
Rodelli MR Gearing JN Gearing PJ Marshall N Sasekumar A Stable isotope ratio as a tracer of mangrove carbon in Malaysian ecosystems Oecologia 1984 10.1007/BF00379629
Samper-Villarreal J Cortés J Polunin N Isotopic evidence of subtle nutrient enrichment in mangrove habitats of Golfo Dulce, Costa Rica Hydrological Processes 2018 32 1956 1964 10.1002/hyp.13133
Sepúlveda-Lozada A Mendoza-Carranza M Wolff M Saint-Paul U Ponce-Mendoza A Differences in food web structure of mangroves and freshwater marshes: evidence from stable isotope studies in the Southern Gulf of Mexico Wetlands Ecology and Management 2015 23 293 314 10.1007/s11273-014-9382-2
Sheaves M Abrantes K Johnston R Nursery ground value of an endangered wetland to juvenile shrimps Wetlands Ecol Manage 2007 15 311 327 10.1007/s11273-006-9031-5
Souza C Arrivabene HP Craig C Midwood AJ Thornton B Matsumoto ST Elliott M Wunderlin DA Monferrán MV Fernandes MN Science of the total environment interrogating pollution sources in a mangrove food web using multiple stable isotopes Science of the Total Environment 2018 640–641 501 511 10.1016/j.scitotenv.2018.05.302
Souza C Arrivabene HP Azevedo VC Duarte ID Rocha LD Matsumoto ST Franco A Elliott M Wunderlin DA Monferrán MV Fernandes MN Different trophodynamics between two proximate estuaries with differing degrees of pollution Science of the Total Environment 2021 770 144651 10.1016/j.scitotenv.2020.144651 33736395
Spalding MD TN ConservancyFox H NG SocietyDavidson NC ND Environmental, & T. N. Conservancy Marine ecoregions of the world: a bioregionalization of coastal and shelf areas BioScience 2007 57 573 10.1641/B570707
Stoner A Zimmerman R Food pathways associated with penaeid shrimps in a mangrove-fringed estuary Fishery Bulletin 1988 86 543 551
Taylor DS Reyier EA Davis WP Mcivor CC Mangrove removal in the Belize cays : Effects on mangrove-associated fish assemblages in the intertidal and subtidal Bulletin of Marine Science 2007 80 879 890
Then AY Adame MF Fry B Chong VC Riekenberg PM Zakaria RM Lee SY Stable isotopes clearly track mangrove inputs and food web changes along a reforestation gradient Ecosystems Springer, US, 2020 10.1007/s10021-020-00561-0
Valiela I Bowen JL York JK Mangrove forests : one of the world ’ s threatened major tropical environments BioScience 2001 51 807 814 10.1641/0006-3568(2001)051[0807:MFOOTW]2.0.CO;2
Viana IG Valiela I Martinetto P Monteiro Pierce R Fox SE Viana G Valiela I Martinetto P Monteiro R Fox SE Isotopic studies in Pacific Panama mangrove estuaries reveal lack of effect of watershed deforestation on food webs In e Marine Environmental Research 2015 103 95 102 10.1016/j.marenvres.2014.10.003 25481652
Wolanski E Spagnol S Thomas S Moore K Alongi DM Trott L Davidson A Modelling and visualizing the fate of shrimp pond effluent in a mangrove-fringed tidal creek Estuarine Coastal and Shelf Science 2000 50 85 97 10.1006/ecss.1999.0535
Zieman J Macko S Mills L Role of seagrasses and mangroves in estuarine food webs : temporal and spatial changes in stable isotope composition and amino acid content during decomposition Bulletin of Marine Science 1984 35 380 392
Zulkifli S Mohamat-yusuff F Mukhtar A Ismail A Biomagnification of selected toxic trace elements ( Cr, As, Cd, Pb ) in a mangrove ecosystem : insights from stable isotope analysis Pollution Research 2016 35 211 219
| 0 | PMC9734736 | NO-CC CODE | 2022-12-14 23:28:30 | no | Hydrobiologia. 2022 Dec 8;:1-13 | utf-8 | Hydrobiologia | 2,022 | 10.1007/s10750-022-05086-2 | oa_other |
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Surg Today
Surg Today
Surgery Today
0941-1291
1436-2813
Springer Nature Singapore Singapore
36462056
2626
10.1007/s00595-022-02626-0
Original Article
The impact of preclinical clerkship in general surgery on medical students’ attitude to a surgical career
Shimada Ayako
Itano Osamu [email protected]
Ishida Takashi
Tamura Takuya
Minagawa Takuya
Hirano Yuki
Tsuruta Masashi
Oyama Takashi
Hoshimoto Sojun
Shinoda Masahiro
grid.411731.1 0000 0004 0531 3030 Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, International University of Health and Welfare School of Medicine, 852, Hatakeda, Narita, Chiba 286-8520 Japan
3 12 2022
116
17 8 2022
9 11 2022
© The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose
With the advent of a new program for postgraduate medical students in 2004, the number of applicants choosing surgical careers in Japan has been declining. We conducted this study to evaluate the impact of preclinical clerkship and how it affects students’ attitudes toward a surgical career.
Methods
The subjects of our study were fifth-year medical students who participated in a clinical clerkship in general surgery in our department between April 2021 and March 2022. We conducted pre- and post-preclinical clerkship surveys to assess the perceived image of surgeons and the impact of clerkship on surgical career interest.
Results
Among 132 medical students (77 men and 55 women) who rotated through preclinical clerkship in our department, 125 participated in the survey and 66% expressed interest in a surgical career. In the post-clerkship survey, an increased interest in a surgical career was expressed by 79% of the students; notably, including those who initially expressed interest. Approximately 77% of students were satisfied with the practical skill training they received.
Conclusion
Engaging medical students early in surgical experience through a preclinical clerkship for general surgery appears to promote their interest in a surgical career.
Keywords
Surgery
Medical students
Education
Pre-clinical clerkship
Career
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pmcIntroduction
Since the introduction of the new postgraduate medical education system in Japan in 2004, the number of applicants for surgical residency programs has declined [1]. In Japan, medical school graduates are mandated to rotate through several departments during their first 2 years [2]. Once they have successfully completed the clinical resident training system, they enter a residency program based on their preferred specialty [2]. In recent years, there has been a worldwide trend of declining numbers of applicants for surgical residency programs [3–6]. According to the National Resident Matching Program in the United States, the match rate in general surgery categorical residents has declined by 13% since 1994 [5].
Several factors may account for the declining interest in general surgery, such as a lack of mentorship, hostile work environment, gender differences, and the duration of mandatory training to become independent surgeons [4]. Varghese et al. reported that increased exposure to surgical experience during a student’s preclinical years may encourage medical students by inducing a greater interest in general surgery [7]. Therefore, efforts should be made to involve medical students early in interesting surgical programs [8].
There have been several methods reported to provide medical students with early surgical experience [9, 10]. Alkatout et al. reported that the early involvement of medical students in a scientific congress had a positive impact on learning motivation and decision-making for a career in surgery [9]. Participating in a laparoscopic surgery training course was also reported to cultivate an interest in surgery [10]. On the other hand, some studies have shown that stereotypes and misconceptions may negatively influence students’ career choices [11]. Stereotypes of the culture related to surgery, such as its competitiveness, male dominance, and the need for self-sacrifice, as well as the perceived self-confidence of surgeons and their intimidating demeanor may prevent graduates from seeking a career in surgery [11]. However, it has also been reported that once students encounter surgeons with whom they are able to discuss their professional and personal lives favorably, their perception of the surgical profession may be enlightened [12].
We hypothesized that an interesting surgical preclinical clerkship program could effectively cultivate medical students’ interest in a surgical career. The aim of this study is to investigate how medical students perceive surgeons, and to evaluate the effect of a surgical preclinical clerkship program. This is the first report on students’ perception of surgeons and the effect of preclinical surgical experience on medical students in Japan.
Methods
Participants and surgical clerkship program
Our institution, the International University of Health and Welfare (IUHW), Narita Hospital, is the newest university hospital in Japan, having opened in April 2020. The International University of Health and Welfare medical school was established before the hospital in 2017. Our university is unique in that it provides an unprecedented style of medical education, with emphasis on internationalism. Every year, we welcome approximately 140 medical students, consisting of 120 selected students from Japan and 20 international students recommended by their governments, mainly from East Asian countries. All international students studying medicine in Japan aim to become doctors by passing the Japanese national examination. All students are trained using active learning systems including English lectures, which may differ from the traditional Japanese educational system.
All undergraduate medical students start preclinical clerkships in their fourth year, at several affiliated hospitals. During their fifth year, they are required to participate in clinical clerkships at our institution’s gastrointestinal surgery department. All students who participated in the clerkship in our department between April 2021 and March 2022 were included in this study.
Students were divided into small groups of six to eight and rotated through every department during the year. During the 2 week clerkship (10 days), we included a training program for surgical sutures, laparoscopic surgery, and robot-assisted surgery. We assigned all students to oversee a single patient’s care and to accompany the attending physician during daily treatment of the patient, including surgery. At various operations, they performed skin closure and some other procedures involving surgical skills. Although the clerkship was held during the COVID-19 pandemic, it was conducted in person with adequate preventive measures in place under hospital guidelines.
Study design
We conducted a survey using a paper-based questionnaire in Japanese, distributed before and after the clinical clerkship. On the first day of the clinical clerkship, a single mentor explained the curriculum of the clerkship and asked all students to complete the three-part survey. The mentor explained that the aim of the survey was to assess their perception of issues related to surgeons, and evaluate the contents of clerkship for further improvement and creation of attractive programs. The mentor collected Section 1 of the survey on the second day of the clerkship, and Section 2 and 3 on the last day.
Our questionnaire comprised three sections (see the English version in Table 1). Sections 1–1 and 1–2 aimed to assess the students’ interest in surgery and their perception of surgeons, prior to starting the clinical clerkship, and Section 1–3 assessed their previous experience of performing medical or surgical procedures. Section 2 required a record of scores received by the student during the training program. Section 3 aimed to assess the students’ perceived level of achievement for each surgical procedure learned during the clerkship and evaluate any change in their opinion of surgeons. We included several questions for each section followed by blank sections for the students to express their opinions. This was our first survey of medical students, and we included 17 questions to evaluate their perceptions of surgery including working environment, training, personal characteristics, and lifestyle. Sex distinction was required for all parts of the survey, and the students were given the option to provide anonymous feedback by omitting their name from the questionnaire if they preferred, except in Section 1–3, 2, and 3–1, where we asked for an account of their individual experience of surgical procedures. We used a 5-scale score (5, strongly agree; 4, agree; 3, neutral; 2, somewhat disagree; 1, disagree) for Sections 1–2 and 3, and another 5-scale score (5, more than 5 times; 4, more than 3 times; 3, once or twice; 2, have seen this procedure before; 1, never) for Section 1–3 when answering the questionnaire. In Section 1–1, we asked students about their level of interest using a 5-scale score (5, extremely interested; 4, interested; 3, neutral; 2, not highly interested; 1, not interested at all). We considered students who answered with a score of 4 or 5 to the question about the level of interest in surgery in the survey to be interested in surgery. We compared the questionnaire results between students who were interested in surgery (interested group) and those who were not (non-interested group). We also compared results between sexes and between international students and Japanese students. Furthermore, we investigated if initial skill levels or the timing of rotation in our department affected the students’ perception of surgery and the extent of satisfaction.Table 1 Original questionnaire translated from Japanese to English
In the surgical suture program, students learned interrupted suturing and demonstrated their skill. A single mentor evaluated their skills on a scale of 1 to 5 at the beginning and end of the program. Our evaluation criteria were defined as follows: 1, no previous experience and required instruction for the entire procedure; 2, unable to perform the entire procedure independently; 3, able to perform more than half of the procedure independently with little instruction; 4, able to perform almost all of the procedure independently; 5, able to perform the entire procedure independently with a high level of skill. In the laparoscopic surgery training program, students performed laparoscopic cholecystectomy using the LAP Mentor™ III (Surgical System, Drakegatan, Sweden). In the robotic surgery training program, students were subdivided into two groups of three to four and after the mentor provided instructions on using the DaVinci surgical system, they were asked to demonstrate tasks using the DaVinci surgical system. We asked students to perform the robotic surgery task several times and to record their scores each time they finished. The first task was Seaspikes, in which students would perform the task by transferring rings to each triangular corn. After repeating this task several times, they could select any task they liked. All practical training was scheduled in 1 h sessions with a single mentor teaching and providing advice. Figure 1 shows the scheme of our clerkship.Fig. 1 Scheme of the timeline of our clinical clerkship
Study approval was obtained by the Ethics Committee of the International University of Health and Welfare, Narita Hospital, Japan, before the commencement of this study (Institutional Review Board number 21-Nr-010).
Statistical analysis
Statistical analyses were done using SPSS Statistics, version 25 (IBM Corporation, Armonk, NY, USA). We used the Student’s t test and χ2 test to analyze continuous variables, and Fisher’s exact tests for categorical variables. We used a paired t-test or one-way analysis of variance (ANOVA) test to compare difference in scores at the commencement and on completion of the surgical training program. Differences were considered significant at a P value of < 0.05.
Results
A total of 132 medical students participated in clinical clerkships in our department between April 2021 and March 2022. They comprised 117 Japanese and 17 international students, 66% of whom expressed an interest in a career related to surgery, with no significant difference in sex distribution (male 67%: female 65%, P = 0.847; Fig. 2). A total of 125 students (93%) completed Sect. 1 of the survey which assessed their perception of surgeons. Hepato-Biliary-Pancreatic & Gastrointestinal Surgery was the most selected field among all departmentsas a possible future career (28%), followed by Cardiology (23%), then Orthopedics (20%) (Fig. 3). Many students were interested specifically in clerkship programs related to surgery (53%), suture training (80%), and simulator training (74%) (Fig. 4).Fig. 2 Amount of interest in surgery among male and female medical students
Fig. 3 Student interest in medical fields for their future career
Fig. 4 Responses from the pre-clerkship survey about what students wish to learn through their clinical clerkship
The most dominant concerns about becoming a surgeon were the muscle strength required and the challenges of life-work balance (Fig. 5a). Students described the necessary support for a good life–work balance of a surgeon to be a flexible working arrangement, a substantial system for major life events, and a system for reinstatement in work after leave (Fig. 5b). Despite having negative images of a surgeon’s working environment, they had a positive view of the future demands of surgeons and their prospects. Table 2 summarizes the results of the perception of surgeons according to the levels of interest in surgery. The interested group considered significantly more often than the less interested group that surgeons experience a sense of accomplishment (P = 0.015). Table 3 shows how male and female students perceived surgeons. Female students often expressed concerns about how gender differences may impact on becoming a surgeon (P = 0.001). Female students also expressed a preference for earlier training programs, starting before graduation (P = 0.032), and they considered significantly more often that surgeons need to have good judgment (P = 0.020), and experience a lot of emergency work (P = 0.010). We also divided the 115 students who provided their name on the survey into groups of international students (14 students) and Japanese students (101 students) and compared the results. The vast majority (93%) of international students expressed an interest in surgery. The general perception about surgeons was similar among international students and Japanese students, and our results revealed that international students significantly more often prioritized the importance of surgical skill (P = 0.038, Table 4).Fig. 5 a Responses from the pre-clerkship survey about student concerns regarding becoming surgeons. b Responses from the pre-clerkship survey about necessary support for a versatile work–life balance in a career in surgery
Table 2 Results of the pre-clerkship survey: the interested group vs. the non-interested group
Total (n = 125) Interested group (n = 86) Non-interested group (n = 39) P value
Characteristics of the surgeons’ job
Surgeons must work long hours 4.23 ± 0.71 4.16 ± 0.71 4.36 ± 0.58 0.137
Surgeons need a long time to become independent 4.47 ± 0.59 4.47 ± 0.57 4.46 ± 0.64 0.975
Surgeons need to have physical strength 4.57 ± 0.54 4.57 ± 0.54 4.56 ± 0.55 0.957
The work of surgeons can be dangerous 4.13 ± 0.71 4.12 ± 0.64 4.00 ± 0.83 0.174
Surgeons need to be skillful 4.12 ± 0.63 4.06 ± 0.64 4.23 ± 0.58 0.153
Surgeons need to have good judgment 4.40 ± 0.55 4.40 ± 0.56 4.41 ± 0.55 0.890
Surgeons have a lot of emergency work 3.94 ± 0.78 3.95 ± 0.80 3.90 ± 0.75 0.711
Surgeons need to have off-the job training 4.42 ± 0.60 4.45 ± 0.61 4.36 ± 0.58 0.450
Working environment of surgeons
Surgeons are well supported for lifestyle events 2.67 ± 0.73 2.73 ± 0.69 2.51 ± 0.79 0.119
There is no gender difference to becoming a surgeon 3.18 ± 0.96 3.16 ± 0.92 3.23 ± 1.06 0.716
You may have objection from your family to become a surgeon 2.47 ± 1.00 2.37 ± 0.99 2.64 ± 0.99 0.173
Motivation of surgeons
Surgeons love surgery 4.36 ± 0.65 4.38 ± 0.60 4.28 ± 0.76 0.421
Surgeons feel accomplishment in work 4.51 ± 0.53 4.58 ± 0.52 4.33 ± 0.53 0.015*
Surgeons dislike teaching juniors 2.10 ± 0.82 2.06 ± 0.71 2.21 ± 1.03 0.356
Surgeons have future demands 3.41 ± 0.76 3.37 ± 0.80 3.51 ± 0.68 0.342
Surgeons have future prospects 3.83 ± 0.65 3.87 ± 0.67 3.74 ± 0.59 0.303
Learning surgical skills from the time of being a medical student is effective for a future surgical career 4.13 ± 0.77 4.20 ± 0.79 3.97 ± 0.71 0.135
Results are reported as means ± standard deviation of a 5-point scale defined as: 1 = Disagree, 2 = Somewhat disagree 3 = Neutral, 4 = Agree, 5 = Strongly agree
Table 3 Results of the pre-clerkship survey: male vs. female students
Total (n = 125) Male group (n = 72) Female group (n = 53) P value
Characteristics of surgeons’ role
Surgeons have to work long hours 4.23 ± 0.71 4.18 ± 0.72 4.30 ± 0.63 0.349
Surgeons need a long time to become independent 4.47 ± 0.59 4.47 ± 0.60 4.46 ± 0.57 0.931
Surgeons need to have physical strength 4.57 ± 0.54 4.53 ± 0.58 4.63 ± 0.49 0.287
The work of surgeons can be dangerous 4.13 ± 0.71 4.06 ± 0.79 4.24 ± 0.58 0.147
Surgeons need to be skillful 4.12 ± 0.63 4.03 ± 0.65 4.24 ± 0.58 0.059
Surgeons need to have good judgment 4.40 ± 0.55 4.31 ± 0.57 4.54 ± 0.50 0.020*
Surgeons have a lot of emergency work 3.94 ± 0.78 3.79 ± 0.80 4.15 ± 0.71 0.010*
Surgeons need to have off-the job training 4.42 ± 0.60 4.49 ± 0.56 4.34 ± 0.65 0.178
Working environment of surgeons
Surgeons are well supported for lifestyle events 2.67 ± 0.73 2.65 ± 0.73 2.68 ± 0.72 0.805
There is no gender difference to becoming a surgeon 3.18 ± 0.96 3.43 ± 0.96 2.85 ± 0.86 0.001*
You may have objection from your family to become a surgeon 2.47 ± 1.00 2.41 ± 1.10 2.54 ± 0.86 0.492
Motivation of surgeons
Surgeons love surgery 4.36 ± 0.65 4.36 ± 0.74 4.35 ± 0.52 0.934
Surgeons feel accomplishment in work 4.51 ± 0.53 4.53 ± 0.50 4.48 ± 0.57 0.638
Surgeons dislike teaching juniors 2.10 ± 0.82 2.19 ± 0.88 1.98 ± 0.71 0.137
Surgeons have future demands 3.41 ± 0.76 3.36 ± 0.77 3.48 ± 0.75 0.382
Surgeons have future prospects 3.83 ± 0.65 3.75 ± 0.71 3.93 ± 0.54 0.117
Learning surgical skills from the time of being a medical student is effective for a future surgical career 4.13 ± 0.77 4.00 ± 0.86 4.30 ± 0.60 0.032*
Results are reported as means ± standard deviation of a 5-point scale defined as: 1 = Disagree, 2 = Somewhat disagree 3 = Neutral, 4 = Agree, 5 = Strongly agree
Table 4 Results of the pre-clerkship survey: international vs. Japanese medical students
Total (n = 115) International students (n = 14) Japanese students (n = 101) P value
Characteristics of surgeons’ role
Surgeons must work long hours 4.22 ± 0.69 4.14 ± 0.66 4.23 ± 0.69 0.666
Surgeons need a long time to become independent 4.45 ± 0.58 4.43 ± 0.65 4.46 ± 0.57 0.872
Surgeons need to have physical strength 4.56 ± 0.55 4.38 ± 0.50 4.58 ± 0.55 0.148
The work of surgeons can be dangerous 4.10 ± 0.72 4.29 ± 0.47 4.08 ± 0.74 0.315
Surgeons need to be skillful 4.10 ± 0.63 4.43 ± 0.51 4.06 ± 0.63 0.038*
Surgeons need to have good judgment 4.40 ± 0.56 4.36 ± 0.63 4.41 ± 0.63 0.761
Surgeons have a lot of emergency work 3.93 ± 0.78 3.93 ± 1.00 3.93 ± 0.75 0.994
Surgeons need to have off-the job training 4.44 ± 0.58 4.36 ± 0.50 4.45 ± 0.59 0.577
Working environment of surgeons
Surgeons are well supported for lifestyle events 2.67 ± 0.73 2.86 ± 0.86 2.64 ± 0.72 0.310
There is no gender difference to becoming a surgeon 3.17 ± 0.96 3.29 ± 0.91 3.16 ± 0.97 0.643
You may have objection from your family to become a surgeon 2.43 ± 1.00 2.43 ± 1.02 2.44 ± 1.00 0.980
Motivation of surgeons
Surgeons love surgery 4.35 ± 0.65 4.50 ± 0.52 4.33 ± 0.66 0.352
Surgeons feel accomplishment in work 4.53 ± 0.52 4.57 ± 0.51 4.52 ± 0.52 0.754
Surgeons dislike teaching juniors 2.11 ± 0.84 2.29 ± 0.91 2.09 ± 0.83 0.412
Surgeons have future demands 3.38 ± 0.77 3.50 ± 1.02 3.37 ± 0.73 0.544
Surgeons have future prospects 3.83 ± 0.68 3.86 ± 0.53 3.82 ± 0.68 0.853
Learning surgical skills from the time of being a medical student is effective for a future surgical career 4.17 ± 0.78 4.21 ± 0.70 4.16 ± 0.80 0.804
Results are reported as means ± standard deviation of a 5-point scale defined as: 1 = Disagree, 2 = Somewhat disagree 3 = Neutral, 4 = Agree, 5 = Strongly agree
Table 5 summarizes the results of the survey asking about the students’ previous experience. Almost all the students lacked experience in simulator training. The students who showed interest in a surgical career had significantly more experience in the daily care of surgical patients. The results of the survey investigating the effect of the clerkship on each procedure showed high satisfaction with training related to surgical skills in both the interested and non-interested groups (Table 6). We also compared the results among the former, middle, latter groups (47, 40, and 39 students respectively) divided based on the timing of those students being rotated to our department. No significant difference was found in their initial interest in surgery (P = 0.574) or the degree of changes through our clerkship (P = 0.157), or in perceptions (P = 0.608) among these groups after completing the clerkship program.Table 5 Self-reported results from the clerkship survey assessing previous experience of surgical procedures
Total (n = 124) Interested group (n = 86) Non-interested group (n = 38) P value
Insertion of urethral catheter 3.27 ± 0.92 3.35 ± 0.96 3.08 ± 0.82 0.112
Disinfection of surgical field 3.41 ± 1.02 3.50 ± 0.98 3.21 ± 1.10 0.137
Scrubbing for surgery 4.87 ± 0.36 4.88 ± 0.36 4.85 ± 0.37 0.589
Suturing of the wound 3.33 ± 1.04 3.41 ± 1.00 3.15 ± 1.11 0.208
Being a scopist in surgery 2.58 ± 0.84 2.65 ± 0.81 2.44 ± 0.91 0.188
Applying a wound dressing after finishing surgery 2.86 ± 1.06 3.00 ± 1.06 2.56 ± 0.99 0.033*
Daily wound dressings 2.62 ± 0.94 2.73 ± 0.94 2.37 ± 0.88 0.048*
Removing a drain 2.55 ± 0,73 2.65 ± 0.76 2.32 ± 0.57 0.008*
Knot-tying 3.60 ± 0.96 3.70 ± 0.96 3.37 ± 0.94 0.079
Instrument knotting 3.07 ± 1.15 3.16 ± 1.18 2.86 ± 1.06 0.187
Training in using a DaVinci simulator 1.91 ± 0.86 1.91 ± 0.86 1.92 ± 0.85 0.933
Training in using a laparoscopic simulator 1.77 ± 0.82 1.78 ± 0.86 1.76 ± 0.75 0.922
Results are reported as means ± standard deviation of a 5-point scale defined as: 1 = Never, 2 = Have seen this procedure before 3 = Once or twice, 4 = More than 3 times, 5 = More than 5 times
Table 6 Effect of clerkship on proficiency in each surgical procedure
Total (n = 112) Interested group (n = 78) Non-interested group (n = 34) P value
Insertion of urethral catheter 3.76 ± 1.12 3.71 ± 1.15 3.94 ± 0.95 0.262
Disinfection of surgical field 4.19 ± 1.04 4.17 ± 1.07 4.29 ± 0.84 0.540
Scrubbing in for surgery 4.47 ± 0.61 4.53 ± 0.57 4.35 ± 0.69 0.173
Suturing of the wound 4.50 ± 0.67 4.55 ± 0.68 4.47 ± 0.61 0.583
Being a scopist in surgery 3,36 ± 1.02 3.46 ± 1.01 3.18 ± 0.97 0.178
Applying wound dressing after finishing surgery 4.12 ± 0.92 4.35 ± 0.88 3.85 ± 0.99 0.038*
Daily wound dressings 3.50 ± 1.06 3.65 ± 1.04 3.26 ± 1.02 0.071
Removing a drain 3.43 ± 1.22 3.68 ± 1.17 3.03 ± 1.17 0.008*
Knot-tying 4.42 ± 0.72 4.49 ± 0.72 4.32 ± 0.73 0.271
Instrument knotting 4.66 ± 0.50 4.73 ± 0.45 4.56 ± 0.50 0.091
Training in using a DaVinci simulator 4.57 ± 0.62 4.64 ± 0.63 4.44 ± 0.61 0.131
Training in using a laparoscopic simulator 4.48 ± 0.67 4.53 ± 0.70 4.38 ± 0.61 0.289
Results are reported as means ± standard deviation of a 5-point scale defined as: 1 = Disagree, 2 = Somewhat disagree 3 = Neutral, 4 = Agree, 5 = Strongly agree
Figure 6 shows the results of the practical training. Only 58% of the students were ranked higher than 3 in suturing technique by a 5-scaled evaluation at the beginning of the training; however, almost all the students ranked higher than 3 by the completion of the training, with a significant improvement noted in all groups (Fig. 6a). There was also a significant difference in the evaluation scale initially, between the interested and non-interested groups. The percentages of participants who scored higher than 3 on a 5-point scale in the interested group and non-interested groups were 60% and 53%, respectively; P = 0.042; Fig. 6b-1; however, there was no significant difference in the evaluation of achievement score at the completion of the training class (interested group 98% vs. non-interested group 100%, P = 0.213; Fig. 6b-2).Fig. 6 Results of the suture training program. a For all students, the first time and on completion of the program. b-1 For the interested group and non-interested group, the first time. b-2 For the interested group and non-interested group, on completion of the program. c-1 For male and female students, the first time. c-2 For male and female students, on completion of the program
During robotic surgery training, the advantage score of the tasks increased significantly for all groups with the number of times the tasks were repeated (Fig. 7). Initially, the scores of the tasks tended to be higher for students in the interested group and for male students (Fig. 4a-1, b-1); however, there was no significant difference in the average highest score between the two groups (Fig. 7a-2, b-2).Fig. 7 Results of the robotic surgery training program. a Results of the robotic surgery training program comparing the interested group and the non-interested group. a-1 Initial scores in the interested group and the non-interested group. a-2 Highest score in the interested group and the non-interested group. Results of the robotic surgery training program comparing male and female students. b-1 Initial scores of the male and female students. b-2 Highest scores of the male and female students
A satisfaction survey performed at the end of the clinical clerkship showed that 79% of the students had become more interested in a surgical career, especially those who initially showed interest in a surgical career (P = 0.026) (Fig. 8a). On answering the question, “What you think was beneficial in the clerkship,” approximately 77% of students wrote in the blank space for comments that surgical training programs were most beneficial in our clinical clerkship. Some also commented that our clerkship was beneficial to promote a favorable attitude (8%) or to acquire knowledge of surgery (4%). More than 70% of the students expressed that they were able to acquire surgical skills through the clinical clerkship (Fig. 8b), and 37% reported change in their perception of surgeons, with a high tendency in the non-interested group (P = 0.052) (Fig. 8c). Fifteen students gave us reasons for their changes in perception, mentioning changes in their view of surgeons (n = 4) or what is involved in the work of a surgeon (n = 4), and some mentioned that they liked the atmosphere of our department (n = 8). We also compared the degree of satisfaction based on the first scores of suture training (first score ≥ 3 or ≤ 2) and robotic surgery training (first score ≥ 45 or < 45). The results revealed changes in the perception of surgeons by students with initially lower scores in suture training program (Fig. 9).Fig. 8 Results of the post-clerkship survey. a Answers to the question asking about whether, “The clerkship made me more interested in surgery.” b Answers to the question asking about whether, “The clerkship taught me surgical procedures.” c Answers to the question asking about whether, “The clerkship made me change my perception of surgeons and surgery.”
Fig. 9 Results of the post-clerkship survey according to the first score in the training program. a Answers to the question asking about whether “The clerkship made me more interested in surgery.” b Answers to the question asking about whether “The clerkship taught me surgical procedures.” c Answers to the question asking about whether “The clerkship made me change my perception of surgeons and surgery.”
Discussion
In Japan, graduates of the 6-year medical course are eligible to take the National Medical Practitioners Qualifying Examination, under the jurisdiction of the Ministry of Health, Labor and Welfare. Those who pass this examination are qualified to begin clinical resident training [2]. The first 2 years of training may be equivalent to the internship year of American medical graduates or the foundation programs in the UK. It is a serious concern that the number of new graduates choosing a surgical career in Japan has declined in the past 20 years [13]. To resolve this problem, we must identify an effective way to promote their interest in a surgical career. Previous studies have demonstrated that medical students’ interest in surgery can be stimulated by increased clinical involvement in surgery [8, 11]. All medical students are required to attend preclinical clerkship programs in surgery; thus, providing an interesting program could positively influence their attitude toward surgical careers.
More than 60% of the students in this study expressed interest in a surgical career. Overall, the interested and non-interested groups had similar perceptions about the future or characteristics of surgeons. When comparing male and female students, female students seemed to be more anxious about the negative effect of gender differences on becoming surgeons. In the surgical skill training program, students in both the interested and non-interested groups achieved an average level by the end of the class. The final satisfaction survey performed revealed the positive impact of clinical surgical clerkship for all students, especially those who were initially interested in surgery. Our survey identified a positive impact on the perception of surgeons, especially by students with lower scores at the commencement of the training program. Furthermore, among those who initially did not show any interest in surgery, a positive change was noted in their perception of a career in surgery. The responses of students showed the strong impact of clinical experience with surgical skills and practice on their attitudes.
Even though our curriculum was limited to 2 weeks, it had a positive effect on all students, motivating them to pursue a surgical career. Moreover, it is possible that the curriculum itself triggered an interest in surgery. On the other hand, most of our students had a negative perception about the surgeon’s environment. These perceptions may act as a barrier when they consider a surgical career in future. A previous report identified that many factors need to be improved in relation to the working environment for surgeons in Japan [13]. Efforts must be made to promote a better environment for surgeons by providing additional staff and reducing administration tasks [13].
The findings of our study also showed the possible impact of gender difference on the determination of surgical careers, especially for female students. In our study, many female students thought that surgeons need to have good judgment and that they have a high workload of emergency cases. These results may be related to a perception of the world of surgeons, including the effects of gender difference, which may make them deliberate more about becoming a surgeon. According to the results of a survey conducted by the Japan Surgical Society, there is still a significant difference in working styles between men and women working as surgeons in Japan [14, 15]. Many medical students responded to their experience of gender discrimination or gender privilege [16]. It has been reported that initiatives to promote awareness through “diversity and inclusion” lectures, were successful in fostering a better understanding [16]. In addition to developing an appealing program to promote future careers in surgery, we should devout ourselves to develop a more sustainable working environment for surgeons with a wide variety of styles. A 2-week clerkship cannot provide sufficient opportunity for students to understand everything involved in a career as a surgeon. To address their many concerns, including those related to gender difference or lack of support, we may give them some concrete examples or feedback such as the countermeasures we adopt, and our efforts toward further improvement. If we could provide more concrete experiences and examples of a surgical career, they may feel reassured to consider pursuing a surgical career.
Our future study will focus on how we can maintain students’ interest or motivation in pursuing surgical careers, until they become doctors. Although many medical students showed interest in the beginning, it is still unclear how many will eventually choose surgical careers in future. It may be effective for us to provide regular classes or lectures related to surgery, so that they can always feel connected and assigned to a surgical field. We will continue tracking the careers of all these students and clarify how early exposure programs impact students seeking surgical careers after they graduate.
Some of our students were very curious about a surgical career. Previous studies have shown that early intervention in surgical skills training has been effective [3, 17, 18]. Although we ran some sessions on suture training before starting the clinical clerkship, earlier introduction of laparoscopic or robotic surgery training may be attractive for some students. For those with a strong interest in surgery, we can provide them not only with exposure to surgical skills, but also an early-oriented training program, which would be helpful to their careers. In our study, most female students showed a preference for an earlier training program. Early intervention can also enable them to learn and become independent faster, which may support a versatile career style in future. However, at present, only a few systematic programs are targeting medical students. Our further aim is to establish a systematic surgical training program that commences in the undergraduate period. This program itself can also be effective in constantly stimulating interest in surgery among students until they make their final career choice.
This study has some limitations. First, it was performed only on a single-year level of medical students. It is possible that the opinions may not sufficiently reflect those of all medical students in Japan. Nevertheless, we consider our results to be meaningful in revealing the possible impact of clinical clerkship on the perceptions of medical students. Second, this study was performed at only one point for each student. To identify the effect of surgical clerkship, it will be necessary for us to follow these students until they select their final specialty in future. However, this was a unique study that demonstrated the perception of surgeons among medical students and evaluated the short-term impact of clinical clerkship in Japan. Many medical students have a potential interest in surgery; therefore, we are responsible for making all possible efforts to provide medical students with an interesting program to foster their interest and motivation toward a career in surgery.
In conclusion, we can provide a positive image of surgical careers through an attractive preclinical clerkship program that focuses on experience of surgical skills. Efforts should be made to cultivate medical students’ interest in surgery to encourage them to consider choosing a career in surgery in future.
Acknowledgements
We thank all the medical students for their participation in our study.
Funding
Not applicable.
Declarations
Conflict of interest
We have no conflicts of interest to declare.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Tomizawa Y Women in surgery: little change in gender equality in Japanese medical societies over the past 3 years Surg Today 2013 43 1202 1205 10.1007/s00595-012-0447-7 23224261
2. Kurashima Y Watanabe Y Ebihara Y Murakami S Shichinohe T Hirano S Where do we start? The first survey of surgical residency education in Japan Am J Surg 2016 211 405 410 10.1016/j.amjsurg.2015.09.004 26576684
3. Shelton J Obregon M Luo J Feldman-Schultz O MacDowell M Factors influencing a medical student’s decision to pursue surgery as a career World J Surg 2019 43 2986 2993 10.1007/s00268-019-05167-9 31506712
4. Peel JK Schlachta CM Alkhamesi NA A systematic review of the factors affecting choice of surgery as a career Can J Surg 2018 61 58 67 10.1503/cjs.008217 29368678
5. Are C Stoddard H Carpenter LA O’Holleran B Thompson JS Trends in the match rate and composition of candidates matching into categorical general surgery residency positions in the United States Am J Surg 2017 213 187 194 10.1016/j.amjsurg.2016.03.015 27492588
6. Grigg M Arora M Diwan AD Australian medical students and their choice of surgery as a career: a review ANZ J Surg 2014 84 653 655 10.1111/ans.12389 24103025
7. Varghese TK Jr Mokadam NA Verrier ED Wallyce D Wood DE Motivations and demographics of I-6 and traditional 5+2 cardiothoracic surgery resident applicants: insights from an academic training program Ann Thorac Surg 2014 98 877 883 10.1016/j.athoracsur.2014.04.120 25085556
8. Are C Stoddard HA Nelson KL Huggett K Carpenter L Thompson JS The influence of medical school on career choice: a longitudinal study of students’ attitudes toward a career in general surgery Am J Surg 2018 216 1215 1222 10.1016/j.amjsurg.2018.10.036 30415928
9. Alkatout I Günther V Brügge S Ackermann J Krüger M Bauerschlag D Involvement of medical students in a surgery congress: impact on learning motivation, decision-making for a career in surgery, and educational curriculum Wien Med Wochenschr 2021 171 182 193 10.1007/s10354-020-00802-w 33443613
10. Madan AK Frantzides CT Tebbit C Quiros RM Participants’ opinions of laparoscopic training devices after a basic laparoscopic training course Am J Surg 2005 189 758 761 10.1016/j.amjsurg.2005.03.022 15910733
11. Schmidt LE Cooper CA Guo WA Factors influencing US medical students’ decision to pursue surgery J Surg Res 2016 203 64 74 10.1016/j.jss.2016.03.054 27338536
12. Kozar RA Lucci A Miller CC Azizzadeh A Cocanour CS Potts JR Brief intervention by surgeons can influence students toward a career in surgery J Surg Res 2003 111 166 169 10.1016/S0022-4804(03)00104-5 12842462
13. Hanazaki K Tominaga R Nio M Iwanaka T Okoshi K Kaneko K Report from the committee for improving the work environment of Japanese surgeons: survey on effects of the fee revision for medical services provided by surgeons Surg Today 2013 43 1209 1218 10.1007/s00595-013-0691-5 24006126
14. Kawase K Nomura K Tominaga R Iwase H Ogawa T Shibasaki I Analysis of gender-based differences among surgeons in Japan: results of a survey conducted by the Japan surgical society. Part. 2: personal life Surg Today 2018 48 308 319 10.1007/s00595-017-1586-7 28921482
15. Kawase K Nomura K Tominaga R Iwase H Ogawa T Shibasaki I Analysis of gender-based differences among surgeons in Japan: results of a survey conducted by the Japan surgical society. Part 1: Working style Surg Today 2018 48 33 43 10.1007/s00595-017-1556-0 28634729
16. Takasu C Kono E Morine Y Yoshikawa K Tokunaga T Nishi M A ‘diversity and inclusion’ lecture for promoting self-awareness among medical students Surg Today 2022 52 964 970 10.1007/s00595-021-02424-0 35001195
17. Tang B Zhang L Alijani A Evidence to support the early introduction of laparoscopic suturing skills into the surgical training curriculum BMC Med Educ 2020 20 70 10.1186/s12909-020-1986-z 32143709
18. Sellers T Ghannam M Asantey K Klei J Olive E Roach VA An early introduction to surgical skills: validating a low-cost laparoscopic skill training program purpose built for undergraduate medical education Am J Surg 2021 221 95 100 10.1016/j.amjsurg.2020.07.003 32888629
| 36462056 | PMC9734737 | NO-CC CODE | 2022-12-14 23:28:30 | no | Surg Today. 2022 Dec 3;:1-16 | utf-8 | Surg Today | 2,022 | 10.1007/s00595-022-02626-0 | oa_other |
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Ir J Med Sci
Ir J Med Sci
Irish Journal of Medical Science
0021-1265
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Springer International Publishing Cham
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3228
10.1007/s11845-022-03228-y
Article
Abstracts from the 47th Sir Peter Freyer Surgical Symposium 2022
6 12 2022
2022
191 Suppl 6 none 187237
© The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
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SESSION 1: BREAST
1. Axillary Clearance For Cn0 Breast Cancer When Z011 Criteria Are Not Met - Is It Worth It?
Colm Neary, Nicola Raftery, Anna Heeney, Maurice Stokes, John Mitchel Barry, Malcolm Kell, Siun Walsh
Oncoplastic Breast Surgery, Mater Misericordiae Hospital, Eccles St., Dublin, Ireland
Introduction
For women who do not meet Z0011 criteria, axillary lymph node dissection (ALND) is recommended. A proportion of this population may harbor no residual metastatic disease, and thus the benefit of ALND is questionable.
Aim
This study aims to identify risk factors for further nodal disease and determine the benefit of ALND in this group.
Methods
All patients who had sentinel lymph node biopsy (SLNB) followed by ALND from 2010–2015 in our unit were included. Those who has neoadjuvant treatment were excluded. Regression analysis was performed to identify pre-operative variables associated with further nodal burden, and predictors of distant recurrence free survival (DRFS) and overall survival (OS).
Results
Among 67 patients who met inclusion criteria, 44 (65.7%) had no additional positive nodes. Mastectomy (50.7%) followed by extra-nodal extension (37.3%) were the most common reasons Z0011 criteria were not met. On multivariable analysis only extranodal extension was predictive of further nodal metastases (HR 3.74 {CI 1.17 – 11.9}, p = .02). The presence of additional positive nodes on ALND was not associated with decreased DRFS (HR 1.76 {CI 0.47 – 6.5}, p = .39) or OS (HR 0.46 {CI 0.48 – 4.4}, p = .46).
Conclusion
The majority of patients who did not meet Z0011 criteria had no additional nodal burden. Moreover, additional positive nodes on ALND was not independently associated with DRFS or OS on multivariate analysis, meaning it is rarely clinically useful. Further research is warranted to develop tools which predict risk of further disease, potentially sparing many the morbidity of ALND.
2. Published.
https://www.breastsurgeons.org/meeting/2022/docs/2022_Official_Proceedings_ASBrS.pdf
3. The Incidence and Significance of Breast Lesions Identified Incidentally on Non-Dedicated Computed Tomography in a Tertiary Referral Centre
Ryan Donnelly, Markus K Kostka, Shane Keogh, Aisling Fawaz, Jason Mahony, Gerry O'Donoghue
Breast and General Surgery, University Hospital Waterford, Ireland
Introduction
Despite computed tomography (CT) not being the primary screening tool for breast evaluation it does incorporate the whole breast tissue and its increased use in clinical practice is leading to an increased incidence of ‘incidental’ breast lesions.
Aim
Incompletely assessed lesions can result in missed malignancy therefore an understanding of the significance of these CT findings is important for clinical decision making.
Method
A retrospective analysis of breast lesions detected incidentally on CT scans between January 2016 and September 2021 was conducted.Patients with known breast cancer or undergoing CT for staging and surveillance were excluded. Clinical correlation and follow-up investigations, including histopathology, were reviewed from the electronic radiology and pathology reporting system.
Results
Out of 3367 screened CT’s, 257 satisfied the inclusion criteria. Of these, 113 contained concerning incidental breast findings or clinical correlation was advised. 54 of these 113 (48%) patients underwent mammographic screening investigation. Of these 54 cases, 17 (31%) had a ultrasound guided core needle biopsy. Of these 17 biopsied patients, 9 (53%) had malignant lesions. All were Grade 1–3 Ductal cancers. Overall, 13 benign breast abnormalities were detected amongst the 113 (11.5%) (5 fibroadenoma, 4 cysts, 3 unspecific fibrous change, 1 myofibroblastoma).
The overall malignancy rate in all patients with an incidental breast finding on CT was 9 out of 113 (7.9%).
Conclusion
Increased radiological awareness and prompt specialised breast unit follow up is important to improve diagnostic efficacy but the overall incidence of malignant histological findings is very low.
4. Qualitative Study of Therapeutic Mammoplasty as Surgical Treatment for Breast Cancer by One Surgeon at a District Hospital
Tessa Walton, Manvydas Varzgalis
General Surgery, Letterkenny University Hospital, Letterkenny, Ireland
Introduction
Wide local excision followed by radiotherapy is the accepted surgical management of breast cancer, however, patients with large ptotic breasts, large tumours, multifocal or multicentric disease often have poor cosmetic outcomes or require mastectomy. Therapeutic mammoplasty is an option for such patients with the aim to avoid mastectomy and achieve good oncological and cosmetic outcomes.
Aim
To demonstrate that therapeutic mammoplasty is an acceptable and safe alternative to wide local excision in select patients with breast cancer.
Method
Retrospective analysis was performed on patients who underwent therapeutic mammoplasty for breast cancer between 2017–2021. Cases were assessed for cancer subtypes and radiological and histological cancer size. Prospective analysis of wound complications, cosmetic outcome and cancer recurrence was performed. Cosmetic outcomes were assessed using the BREAST-Q questionnaire.
Results
Ten patients underwent therapeutic mammoplasty during the specified time frame. The average radiological cancer size was 51.7 mm (SD 39.1) and the average histological cancer size 50.5 mm (SD 40.1). The average specimen weight was 511 g (SD 287.2). All the patients underwent adjuvant treatment as per breast cancer MDT advice. There were no immediate or delayed surgical complications, with most patients experiencing mild side effects of radiotherapy. One patient had axillary recurrence and is undergoing treatment for it. Good cosmetic outcome was reported by all patients.
Conclusion
Our review demonstrates that therapeutic mammoplasty offers an acceptable and safe alternative to wide local excision as surgical treatment for selected patients. Our data is in keeping with similar studies showing low surgical complications and patient satisfaction.
5. Outcomes of Older Patients with Non-Metastatic Breast Cancer Treated with Primary Hormonal Therapy
SW Koh, M Morrogh, M Corrigan, L Kelly, MJ O'Sullivan, EM Quinn
Breast Surgery, Cork University Hospital, Wilton Manor, Cork, Ireland
Introduction
Women over 70 years of age with oestrogen-receptive positive breast cancer may be less likely to be offered primary surgery, without a formal assessment of their frailty.1
Aim
The aim of this study was to assess outcomes of older patients with non-metastatic breast cancer treated with primary hormonal therapy.
Methods
All patients over the age of 70 diagnosed with oestrogen-receptor positive breast cancer in 2019 at our unit, who were not offered surgery as their primary treatment, were included in the study. Patients with metastatic disease at diagnosis were excluded. Patient charts were reviewed and data collected in relation to patient demographics, disease characteristics, comorbidities, formal frailty assessment, treatment prescribed, disease progression and survival.
Results
A total of 49 patients were included. Complete data is currently available for 20 patients. Patients had a mean of 3.9 documented comorbidities (range 1–5). However, no patient had a formal clinical frailty score or performance status score recorded. Mean follow-up was 29.2 months. In this timeframe, 2 patients (10%) required treatment changes due to disease progression. Fourteen patients (70%) remain alive.
Conclusion
Primary hormonal therapy can provide effective cancer treatment in patients who are too frail or who do not wish for surgery. However, high survival rates and the potential development of treatment resistance suggest formal frailty assessments could help subselect a cohort of older patients for whom surgery could be offered as primary treatment.
6. Published.
https://link.springer.com/article/10.1007/s11845-022-02966-3
7. Published.
https://academic.oup.com/bjsopen/article/6/2/zrac022/6563503
8. Evaluating the Necessity of Routine Sentinel Lymph Node Biopsy in Postmenopausal Patients being Treated for Clinically Node Negative Breast Cancer the Era of RxPONDER
Eoin Kerin 1 , Matthew Davey 1 , Ray McLaughlin 2 , Karl Sweeney 2 , Michael Barry 2 , Carmel Malone 2 , Aoife Lowery 1,2 , Michael Kerin 1,2
1. Surgery, Lambe Institute for Translational Research, University of Galway, Ireland;
2. Surgery, Galway University Hospitals, Galway, Ireland
Introduction
Traditionally, sentinel lymph node biopsy (SLNB) was performed to inform adjuvant chemotherapy (AC) prescription in breast cancer. Following RxPONDER, the OncotypeDX Recurrence Score (RS) now guides adjuvant chemotherapy prescription for all postmenopausal patients with estrogen receptor positive, human epidermal growth factor receptor-2 negative (ER+/HER2-) breast cancer with 0–3 positive lymph nodes (0-3+LN).
Aims
To establish the oncological safety of omitting SLNB in postmenopausal patients with ER+/HER2- breast cancer with clinically negative axillae (cLN-) and to evaluate the primary determinants of AC prescription in these patients.
Methods
A single centre, retrospective cohort study was undertaken. Cox regression and Kaplan Meier analyses were performed. Data analytics was performed using SPSS v26.0.
Results
687 patients were included (mean age: 66.5 years, range: 45–96). The median follow-up was 97.2 months (range: 3.0–181.6). Of the 575 patients undergoing SLNB (83.7%), just 12 patients had positive nodes (SLNB+) (2.1%). Using Cox regression analysis, SLNB+ independently predicted poorer disease-free survival (hazard ratio: 1.000, 95% confidence interval (95% CI): 1.000–1.001, P = 0.029). However, using Kaplan Meier analyses, SLNB+ failed to impact recurrence (P = 0.766) or mortality (P = 0.310). Finally, logistic regression analysis identified RS as the sole independent predictor of AC prescription (OR: 1.171, 95% CI: 1.097–1.250, P < 0.001).
Conclusion
These provisional results suggest omitting SLNB may be safe and justifiable in postmenopausal patients with ER+/HER2-cLN- breast cancer. Following RxPONDER, RS is the most important guide of AC use in those with 0-3+LN and SLNB may be less important than previously perceived. Nevertheless, prospective, randomised clinical trials are required to fully establish the oncological safety of omitting SLNB in this setting.
9. Gynacomastia Referral to Breast Clinics: Do We Need Triple Assessment?
R Kaminskas 1 , A Johnston 2,3 , M Varzgalis 3
1. National University of Ireland Galway, University Rd, Galway
2. Donegal Clinical Research Academy, Letterkenny University Hospital, Letterkenny, Co. Donegal, Ireland
3. Breast Surgery, Letterkenny University Hospital, Letterkenny, Co. Donegal, Ireland
Introduction
Male Breast Cancer (MBC) has an incidence of < 1% of breast cancers. Gynecomastia, the most common male benign condition seen in symptomatic breast units (SBUs) does not require all aspects of triple assessment (TA). Investigative processes vary across SBUs.
Aims
To appraise the requirement of TA and assess the value of clinical examination (CE) on male breast patients referred to our SBU.
Methods
An ethically approved study of all males undergoing assessment from 2010 to 2020 was undertaken. Demographics, TA and incidence of malignancy data was collected from Dendrite Clinical Systems Ltd. Clinical, radiological and pathological findings were compared using a standardized SRB grading system to assess diagnostic accuracy.
Results
A total of 20,289 patients, 649 (3.2%) male underwent TA with mean age 49.6 (11–92), SD 21.5. Male referral numbers trended upwards ranging from 59 (2010) to 83 (2020). 400/640 (62.4%) had radiology, 76/400 (19%) had clinical and radiological findings confirmed by biopsy with 5 cancers (0.78%) diagnosed. All clinically benign cases that were biopsied were histologically benign. No statistically significant difference noted between clinical and radiological diagnostic methods (p = 0.317).
Table 1 Sensitivities and specificities for components of TA
Clinical Examination Mammogram Ultrasound
Sensitivity (95% CI) 80% (28.36–99.49) 100% (39.76- 100.00) 100% (47.82–100.00)
Specificity (95% CI) 97.18% (90.19–99.66) 95.56% (84.85–99.46) 96.92% (89.32–99.63)
% (39.76–100.00) 100% (47.82–100.00)
Conclusion
CE is a reliable diagnostic tool in detecting lumps requiring further investigation by TA. Local guidelines need review. Imaging is warranted with a suspicious lump. Routine imaging for benign clinical findings should be discouraged.
SESSION 2: VASCULAR AND CARDITHORACIC SURGERY
10. Published.
https://www.summit-ctap.com/2022/eposter/eposter_abstract_view.php?code=ABS20211125_0013
11. Patients’ and Clinicians’ Perspectives on Virtual Phone Consultation in Vascular Surgery
Muhammad Syafwan Yahya 1 , Lilian Tang 1 , Malihah Mohamad 2 , Donagh Healy 3
1. Foundation Year, NIMDTA, Beechill House/42 Beechill Rd, Belfast BT8 7RL, United Kingdom;
2. Internal Medicine Training, NIMDTA, Beechill House/42 Beechill Rd, Belfast BT8 7RL, United Kingdom;
3. Vascular Surgery, Belfast Health and Social Care Trust, 51 Lisburn Road, Belfast; United Kingdom
Introduction
We started a virtual phone consultation (VPC) program at the start of the pandemic. A survey were done to evaluate further improvements.
Aim
To evaluate patients’ and clinicians’ perspectives on our VPC and to identify areas for improvement.
Methods
100 patients and 11 clinicians were surveyed between December 2021 and February 2022. We included questions on practical aspects of our VPC and on how it could be improved. Our results were presented as proportions and mean scores from 5-point Likert scales with standard deviation (SD).
Results
The average satisfaction score for patients’ most recent VPC was 4.42/5 (SD 0.90). The main benefits of VPC from patients’ perspectives were lower infection risk, lack of need to travel and increased efficiency. Many patients did not know that face to face (F2F) review could be requested instead of VPC.
Conclusions
Clinicians felt that the benefits of VPC were increased efficiency, lower infection risk and reduced cost. Clinicians felt that patients with normal scan results and patients unable to travel were most suitable for VPC. The main disadvantage of VPC that was identified by clinicians was the inability to do physical examination and the clinicians felt that this might delay diagnoses and treatments. Furthermore, clinicians felt that giving patients a written summary of the VPC would be beneficial.
12. Monitoring of Cholesterol in Patients Undergoing Lower Limb Revascularization Surgery
Yen Xian Lee, Syasya Mohd, Nathalie Doolan
Vascular Surgery, Galway University Hospital Galway, Ireland
Introduction
Hyperlipidaemia is one of the modifiable risk factors for peripheral vascular disease. Clinical practice guidelines for both peripheral and coronary artery disease recommend primary and secondary prevention with a lipid-lowering agent. The results of fasting serum lipid profiles should be considered by both GPs and Vascular Surgeons to ensure patients are benefiting from best medical therapy.
Aim
Not all of our PVD patients will have had their cholesterol levels checked as an inpatient as it requires a fasting sample. This audit is to investigate clinician practice regarding the monitoring of cholesterol levels in patients with peripheral vascular disease who have undergone lower limb revascularization surgery.
Method
A retrospective review of charts were done within the year of 2019. 65 cases included all patients with peripheral vascular disease who had any lower limb revascularization surgery performed in 2019.
Results
Data analysis showed that there was evidence of an inpatient fasting lipid profile obtained between 2018–2020 in 52.3% (n = 34).
Conclusion
Only half of our inpatients undergoing lower limb revascularization surgery in 2019 had fasting lipid profiles checked prior to or after their procedure.
We theorise that there are likely two main obstacles to obtaining lipid profiles in our patient cohort:
1) Fasting bloods are required for lipid profiles, and;
2) Lack of a formal pathway on admission that includes relevant bloodwork.
We have developed a formal pathway to obtain relevant bloodwork on inpatients with PVD. This will be re-audited in 4 months time.
13. Published.
https://www.cureus.com/articles/79988-two-decades-of-experience-with-chronic-mesenteric-ischaemia-and-median-arcuate-ligament-syndrome-in-a-tertiary-referral-centre-a-parallel-longitudinal-comparative-study
14. An Audit of Primary Care Referral for Peripheral Arterial Disease—A Missed Opportunity for Early Intervention
Megan Power Foley 1 , Riya Varman 1 , Nathalie Doolan 1 , Stewart Walsh 2 , Muhammad Tubassam 1
1. Vascular Surgery, University College Hospital Galway, Ireland,
2. Surgery, University of Galway, Ireland
Introduction:
Symptomatic peripheral arterial disease (PAD), either claudication or chronic limb-threatening ischaemia (CLTI), is a common cause for vascular surgery referral. Best medical therapy (BMT), encompassing anti-platelet therapy, statins, smoking cessation, blood pressure and glycaemic control, is a cornerstone of PAD management. We have noticed these easily-modifiable risk factors are often left unaddressed by GPs at time of referral.
Methods:
A random selection of electronic referrals by GPs to the vascular department for symptomatic PAD between between July 2021-March 2022 were audited prospectively. Referrals were individually reviewed for demographic characteristics, referral indication, medical history, smoking status and current medications. Data was analysed using Microsoft Excel.
Results:
One-hundred-and-sixteen referrals were analysed. The mean age was 69.0 years (range 35–94) and 67% (n = 78) were male. The typical vasculopath comorbidity profile was noted. Fifty-one percent (n = 59) were referred with claudication-type pain and 24% (n = 28) with CLTI, respectively. Seventy-nine percent of referrals (n = 92) included peripheral pulse examination findings. Twenty-eight percent (n = 33) of new referrals were active smokers, while 31% (n = 36) had no smoking status documented. Regarding BMT, only 34.5% (n = 40) and 52% (n = 60) were on anti-platelets and statins, respectively. Overall, only eleven referral letters specifically mentioned discussing risk factor optimisation with patients during the consultation.
Conclusions:
Our first-cycle results demonstrate a significant number of new PAD referrals were not receiving BMT in the community. For our intervention, we need to communicate how optimal PAD management begins in primary care and ensure GPs have sufficient knowledge to tackle these challenging, high-risk patients.
15. Published.
https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0042-1750956
16. Published.
https://www.frontiersin.org/articles/10.3389/fsurg.2022.946675/full
17. Published.
https://cslide.ctimeetingtech.com/cirse2021/attendee/confcal_1/show/session/207
18. Factors That Predict Postoperative Atrial Fibrillation with a Particular Emphasis on Body Mass Index in Patients Undergoing Cabg and/or Avr
James Butler 1 , John Hinchion 2
1. General Surgery, St Vincent’s University Hospital, Old Blackrock Road, Cork City, Ireland;
2. Cardiothoracic Surgery, Cork University Hospital, Wilton, Cork City, Ireland
Introduction
Post-operative Atrial Fibrillation (POAF) is a frequent complication of cardiac surgery and associated with significant morbidity and mortality. Identifying predictors that contribute to its occurrence may help to reduce the incidence of this common arrhythmia.
Aims
Our aim is to identify peri-operative variables that contribute to POAF propagation and determine if there is an association between BMI and POAF.
Methods
The data of 683 patients who underwent cardiac surgery in CUH and had no prior history of AFIB were included. Two groups were formed, the POAF Group and Non POAF group. Their demographics and clinical characteristics were analysed to determine what factors contributed to POAF.
Results
The overall incidence of POAF was 19.2%. Results of first Multivariate regression analysis found advancing age (OR 1.088, 95% CI: 1.058–1.118 p = 0.0001), prolonged cross clamp time (OR 1.014, 95% CI: 1.003–1.025 p = 0.012), prolonged stay in days (OR 1.017,95% CI: 1.001–1.033 p = 0.040) and body mass index as a continuous variable (OR 1.057, 95% CI:1.014–1.102) p = 0.037 to be predictors of POAF.
Results of Second multivariate regression analysis found BMI as a categorical value to not be significant, however the other predictors were matching with those found in the first regression model: advancing age (OR 1.088, 95% CI 1.057–1.119 p = < 0.0001), cumulative cross clamp time (OR 1.014, 95% CI 1.003–1.026 p = 0.015) and prolonged stay in days (OR 1.014, 95% CI .998–1.031 p = 0.040).
Conclusion
We found advancing age, prolonged cross clamp time, prolonged hospital stay in days and BMI as a continuous variable to be independent predictors of POAF.
SESSION 3: GASTROINTESTINAL SURGERY
19. Factors Associated With Treatment Allocation and Oncologic Outcome among Patients with Oesophageal Squamous Cell Carcinoma
Caitlyn J Loo 1 , Jessie A Elliott 1 , Mohammed Alazzawi 1 , Orla Brett 1 , Ghazi Ismael 1 , Brian DP O'Neill 2 , Mayilone Arumugasamy 1 , William B Robb 1
1. Upper GI Surgery, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland;
2. Radiation Oncology, St Luke's Radiation Oncology Network, Dublin, Ireland
Introduction:
The optimal strategy for management of localised squamous cell carcinoma (SCC) of middle and lower oesophagus is uncertain.
Aim:
The study aimed to determine current practice and outcomes with respect to curative management of oesophageal SCC.
Methods:
Consecutive patients diagnosed with non-metastatic SCC of the middle and lower oesophagus between January 2013 and December 2018 were studied. Clinicopathologic, treatment, and survival data were collected. Univariable and multivariable logistic and Cox proportional hazards regression analysis were undertaken to analyse factors predictive of treatment allocation and overall survival (OS).
Results:
123 patients were included (middle third, n = 83; locally advanced cT3/T4, n = 91; cN1-3, n = 61). Treatment with curative-intent was possible in 76 (61.8%), of whom 2 underwent endoscopic resection, 7 primary surgery, 24 neoadjuvant chemoradiotherapy and surgery (nCRT-S), and 43 definitive chemoradiation (dCRT). 6 patients treated with dCRT subsequently proceeded to salvage oesophagectomy, 2 of whom have unresectable disease. Younger age (P < 0.001) and localised T stage (P = 0.011) were independently predictive of allocation to curative-intent treatment. Median OS for patients treated with primary surgery was 63.4 months. There was no significant difference in OS among patients treated with dCRT versus nCRT-S on univariable (median OS, not reached versus 44.5 months, P = 0.337) or multivariable analysis (P = 0.159).
Conclusion:
Treatment with nCRT-S resulted in similar outcomes to dCRT and salvage surgery among patients with oesophageal SCC in this series. Further studies should examine the differential impact of treatment approach on health-related quality of life, treatment-associated morbidity, and suitability of surgical resection in older patients.
20. Quality Standards in Oesophagogastroduodenoscopy, A Critical Review
Eoghan Burke, Matthew Kelly, Achilles Mastrosimone, Mayilone Arumugasamy
Connolly Hospital, Blanchardstown, Dublin, Ireland
Introduction
Oesophagogastroduodenoscopy (OGD) remains the gold standard in diagnosing many upper gastrointestinal (UGI) pathologies. In 2017 the British society of gastroenterology (BSG) released a position statement on quality standards in OGD. These standards include guidelines on anatomical landmark photo-documentation, biopsy protocol to diagnose eosinophilic oesophagitis, biopsy protocol for workup of iron-deficiency anaemia and the approach to documentation and biopsy of gastric polyps.
Aim
To assess our units adherence to the guidelines set out by BSG for quality standards in OGD.
Methods
Retrospective review of OGD reports as stored on Endorad from elective non-therapeutic OGDs performed from 19/2/21.
Results
180 consecutive elective, non-therapeutic OGDs were reviewed. The most common indication was reflux (26%). The most common pathological finding was gastritis (32%). 2% of the OGDs had adequate photo-documentation of the recommended anatomical landmarks. The most poorly documented landmark was the gastric body (17%). Correct biopsy protocol for eosinophilic oesophagitis, anaemia workup and polyp evaluation was followed in 38%, 65% and 86% of OGDs respectively. 17% of OGDs were reported as normal yet of these only 3% had adequate objective photodocumentation.
Conclusion
We believe a national audit of the quality standards of OGD should be undertaken with a view to updating the current key performance indicators for OGD.
21. A Systematic Review and Network Meta-analysis of the Role of Antibiotics and Mechanical Bowel Preparation in Elective Colorectal Surgery
Jonavan Ming Yao Tan 1 , Éanna J. Ryan 1 , Fiachra T. McHugh 1 , Matthew G. Davey 2 , Ben Creavin 1 , Maria C. Whelan 1 , Michael E. Kelly 1 , Paul C. Neary 1 , Dara O. Kavanagh 1 , James M. O’Riordan 1
(1) Colorectal Surgery, Tallaght University Hospital, The Meath foundation, Tallaght, Ireland;
(2) Surgery, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland
Introduction
Use of intravenous(IV) antibiotics at anaesthetic induction is well known to reduce surgical site infection(SSI) rates in colorectal surgery and has long been standard of care. However, the role of mechanical bowel preparation(MBP), enemas(EN), oral antibiotics(OAB), and their effect on SSI, anastomotic leak(AL) rates and other perioperative outcomes remains controversial.
Aim
To determine the optimal preoperative bowel preparation strategy in elective colorectal surgery.
Methods
A systematic review and network meta-analysis(NMA) of randomised controlled trials(RCTs) was performed from inception to December 2021. Primary outcomes included SSI and AL. Secondary outcomes included 30-day mortality, ileus, length of stay, return to theatre, other infections, and preparation adverse effects.
Results
Fifty-six RCTs involving 15,159 patients were included in final analysis– 2941(19.4%) had IV antibiotics, 5255(34.7%) had IV+MBP, 1147(7.57%) had IV+OAB, 4143(27.3%) had IV+OAB+MBP, 262(1.72%) had IV+EN and 1411(9.31%) had OAB+MBP. Using the group receiving solely IV antibiotics as a baseline comparator, NMA demonstrated significant reduction in risk of SSI with IV+OAB(OR:0.45; 95% CI:0.27, 0.75) and IV+OAB+MBP(OR:0.55; 95% CI:0.38, 0.81). OAB+MBP had higher SSI rates compared to IV alone(OR:2.10; 95% CI:1.30, 3.39). AL rates were lower with IV+OAB(OR:0.56;95%CI:0.32,0.97) and IV+OAB+MBP(OR:0.63%;95%CI:0.41,0.98) compared to IV alone. There was minimal difference in outcomes with MBP in the absence of IV and OAB. There were minimal differences in secondary outcomes.
Conclusions
This NMA suggests that intestinal microbiome plays an important role in anastomotic wound healing and provides high-level evidence that combination preoperative IV+OAB reduces SSI and AL rates. Combined OAB and IV antibiotic bowel preparation should therefore represent the standard of care for elective colorectal surgery.
22. Application of Artificial Intelligence Methods for Transanal Minimally Invasive Surgery (TAMIS) of Significant Rectal Lesions
Niall P Hardy 1 , Jeffrey Dalli 1 , Mohammad Faraz Khan 2 , Jonathan Epperlein 3 , Pól Mac Aonghusa 3 , Johanna Joosten 4 , Roel Hompes 4 , Peter Neary 5 , Ronan Cahill 1
1. Surgery, UCD Centre for Precision Surgery, Eccles Street, Dublin 7, Ireland;
2. Surgery, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland;
3. IBM Research Europe, Dublin, Ireland;
4. Surgery, Amsterdam University Medical Centres, Amsterdam, Netherlands;
5. Surgery, University College Cork, University Hospital Waterford, Ireland
Introduction
Transanal minimally invasive surgery (TAMIS) can cure large benign tumours and earliest stage cancers of the rectum. Despite equipment and training improvements, its application is limited by the current state of the art re patient selection (preoperative imaging and colonoscopic biopsy are frequently inaccurate in lesions > 2 cm). We sought to digitally characterise rectal lesions in patients potentially amenable to local resection as cancer or benign at endoscopy/TAMIS using dynamic fluorescence perfusion detailing with machine learning (ML) assessment to potentially solve this issue.
Methods
Forty consecutive patients with rectal tumours undergoing diagnostic and therapeutic procedures at three university hospitals were imaged transanally for up to 10 continuous minutes following ICG administration (0.25 mg/kg) using a commercially available near infra-red imaging system (Pinpoint, Stryker, NCT04220242). Time-fluorescence profiles from lesion and healthy control visual regions were extracted from each video for algorithmic analysis in comparison to operator and final pathological assessment (benign vs malignant) as well as 2D heatmap representation.
Results
ML characterisation was > 95% accurate when compared to final pathology in this clinical series whereas the initial clinical/radiological impression (benign or malignant) was either uncertain or ultimately incorrect in 14 (35%). Eight (20%) patients with benign/non-diagnostic biopsies at initial lesion sampling were correctly predicted by ML to have invasive cancer. Full 2D lesional representation provided similar characterisation without the need for user-supervision/interaction.
Conclusion
Objective digital perfusion signalling can non-invasively characterise and delineate malignancy in significant rectal polyps and tumours clinically in a manner that is more accurate than conventional standard of care.
Funding Statement
This work was funded through the Disruptive Technologies Innovation Fund (DTIF) as part of a project entitled ‘The Future of Colorectal Cancer Diagnosis and Treatment: Combining Tissue Responsive Probes, AI and Machine Learning to Transform Medical Care’. The DTIF is administered by Enterprise Ireland on behalf of the Department of Enterprise, Trade and Employment.
23. Development of Augmented Reality Colonic Transection Recommendation via Quantitative ICGFA Guidance
Jeffrey Dalli 1 , Jonathan Epperlein 2 , Niall P Hardy 1 , Mohammad Faraz Khan 1 , Sergiy Zhuk 2 , Pol G Mac Aonghusa 2 , Ronan A Cahill 1
1. UCD Centre for Precision Surgery, University College Dublin, Catherine McAuley Centre, 21 Nelson St, Phibsborough, Dublin 7, Ireland;
2. IBM Research Europe, Dublin, Ireland
Introduction
ICGFA (Indocyanine Green Fluorescence Angiography) allows operative colonic perfusion assessment with the goal of diminishing malperfusion-related anastomotic leakage. However, its interpretation has been shown to be inconsistent especially without experience and computational methodology could enable automation of this intraoperative decision.
Aim
We have thus developed computational methods of simple and complex quantitative ICGFA analysis representation via image augmentation applicable to in-surgery deployment.
Method
Within a clinical trial (IRB 1/378/2092) patients undergoing elective colorectal resections received ICG(0.1 mg/kg) following mesentery preparation for ICGFA using a commercially available near-infrared laparoscopic stack (PINPOINT, Stryker). Video recordings were stabilised, and time fluorescence plots generated on a per pixel basis. Computationally generated metadata for the centre of mass, Fmax (peak intensity), Tmax (Time to Fmax) and T1/2(time to half Fmax):Tmax ratio were overlayed on the displayed image via colour gradients, producing an augmented display (heatmap).
Results
Heatmap imagery was obtained for 16 patients (mean age 66.5 years, 13 men, 11 with colorectal cancer) undergoing left (n = 10) and right (n = 6) sided resections with anastomosis being performed in 15 (one with end colostomy). Recording, tracking and per pixel quantification was performed at 30 frames/second. Motion and instrument intrusion compromised image stabilisation while prolonged recordings degraded images.
Conclusion
Full field of view analysis allows the augmentation of surgical imagery chronologically summarising simple (Fmax and Tmax) and complex (T1/2/Tmax and Centre of Mass) quantitative data. Image stabilisation and computational visual augmentation allows data-overlay onto imagery from commercially available systems with the scope of guiding colonic transection.
Trial registry
ClinicalTrials.gov Identifier: NCT04220242
Funding
This research is funded by the DTIF(Disruptive Technologies Innovation Fund), Republic of Ireland and Dr Jeffrey Dalli is a recipient of the TESS scholarship, Malta.
24. Published.
https://link.springer.com/article/10.1007/s10151-022-02629-6
25. Five-Year Institutional Experience of Patients Undergoing Colectomy for Ulcerative Colitis
Lucy Burns, Brenda Murphy , Naomi Shannon, Emma Comerford, Ciaran Reinhardt, Niamh McCawley, Deborah McNamara, John Burke
Surgery, Beaumont Hospital, Dublin, Ireland
Introduction
Despite medical therapies, up to 30% of patients with Ulcerative Colitis (UC) will require a colectomy. We present a five-year institutional experience of colectomies performed.
Methods
Patient demographics were obtained from an electronic patient record system and clinical notes were reviewed. All data were anonymised and analysed using GraphPad Prism v9.2.
Results
From January 2016 to December 2020, 83 colectomies (emergency 48, elective 35) were performed (M = 51, F = 32). Median age of all patients was 33 (17–79) for elective cases and 44 (17–76) for emergencies. Median length of stay was 9 days for elective and 20 days for emergency. 13 patients had an elective panproctocolectomy with 6 IPAAs fashioned immediately and a further 5 as a second stage procedure. 45 patients underwent an emergency subtotal colectomy of which 14 subsequently had a completion proctectomy with 8 IPAAs fashioned as a second stage procedure. 77% of patients undergoing elective surgery had received steroids within 12 weeks of surgery with 51% having received biologics. For emergency resections, this was 93% and 80%, respectively. 60 surgeries (72%) were performed laparoscopically. 30-day morbidity was 19% for emergency cases and 7% for elective. Morbidities included post-operative ileus (n = 3), surgical site infection (n = 6), blood transfusions (n = 2). No patients required a return to theatre on the same admission. There were no mortalities.
Conclusions
Our practice reflects the evolution of surgery for UC and changing trends in modern management, reinforcing that optimally timed operative intervention leads to favourable peri-operative and long-term outcomes.
26. Impact of Colorectal Cancer Screening Programme on Colonic Cancer Surgery Outcomes in our Institution
Mohamed Salama 1 , Wael Shabo 1 , Ahmed Salamna 2
1. General Surgery, Our Lady of Lourdes Hospital, Drogheda, Co. Louth, Ireland;
2. School of Medicine, University of Galway, Galway, Ireland
Introduction
Colorectal Cancer (CRC) cases have significantly increased in Ireland. The CRC screening programme was implemented in our institution in 2013. Despite considerable improvement in CRC management, there is a great variation of outcomes among different hospitals.
Aim
To evaluate the impact of CRC screening programme on patient outcomes after CRC surgery in our institution.
Method
A retrospective study of CRC patients treated at our institution between 2013 and 2018. These were classified into 3 subgroups: 1) Age ≤ 50 years, 2) Age > 50 and < 75 years, 3) Age ≥ 75 years. Data collected: age, gender, location, and staging.
Results
Total number: 342, age range: 30–96y. Group 1: 29, Group 2: 177, Group 3: 136. 4 patients underwent palliative treatment (3 advanced stage, 1 elderly). 29 patients (8.5%) underwent emergency surgery secondary to obstruction or perforation. With respect to tumour stage, 93% of Group 1, 91% of Group 2 and 86% of Group 3 presented with stage 3 or more. The total mortality rate of 25.4% (Group 1: 10.3%, Group 2: 27.1% and Group 3: 26.4%).
Conclusion
In our study, most cases were diagnosed late (Stage 3 and 4). It is probably due to comprehensive investigations in the perioperative period, causing a shift in stage allocation from stages 1 and 2 to stages 3 and 4. The bowel screening programme includes individuals aged 60 to 69 years. This narrow age range means that the potential benefits of screening are unlikely to be achieved in the short term.
27. Association of Programmed Death Ligand 1 (PDL1) with Neoadjuvant Treatment Response in Rectal Cancer- A Systematic Review and Meta-Analysis
G Feeney 1,2 , EJ Ryan 1 , M Davey 1,2 , N Miller 2 , M Joyce 1 , M Kerin 2
1. General Surgery, Galway University Hospital, Galway, Ireland
2. Surgery, Lambe Institute for Translational Research, University of Galway, Galway, Ireland
Introduction
PDL-1 plays an integral role in the immune systems response to neoplastic cells. Increased PD-1 has been recognised to be associated with reduced survival outcomes. Conversely, tumours with elevated PD-1 have been more sensitive to neoadjuvant therapy.
Aim
To examine potential association between elevated PDL1 expression in tumour tissue and incidence of complete pathological response to neoadjuvant therapy in locally advanced rectal cancer.
Methods
Systematic review was performed in accordance with PRISMA guidelines. Primary endpoint was defined as pathological complete response (pCR). Secondary endpoints included extramural venous invasion (EMVI), nodal metastases and local recurrence. Statistical analysis was performed with RevMan software.
Results
Overall, 7 studies involving 861 patients were included for analysis. PDL-1 was quantified via immunohistochemistry in all cases with elevated expression documented in 298 (34.6%) patients. pCR was recorded in 114 (13.2%) cases. Of these, 46.5% demonstrated elevated PDL-1 (OR = 0.79, CI 0.5–1.27, p = 0.34). Of the secondary endpoints, reduced PDL-1 expression was associated with EMVI positivity (OR 2.6, CI 1.26–5.37, p = 0.009) and Overall Survival (OR1.79, CI 1.03–3.11, p = 0.04). No significant associations were found between PDL-1 expression and Nodal Metastases, Advanced Stage or Local Recurrence.
Conclusion
Our study has demonstrated an association between increased PDL-1 expression and measures of response to NA therapy in locally advanced rectal cancer. This was not found to be statistically significant. We have also outlined that reduced PDL-1 expression is associated with EMVI positivity and improved OS rates in our study. These findings are in keeping with previously published literature on PDL-1.
28. The Introduction of Complete Mesocolic Excision / Central Vascular Ligation for Right-Sided Cancer Cases in a University Teaching Hospital
Emma Kearns (1), Sneha Singh (2), Katherine McDonald (2), Jessica O'Reilly (2), Faraz Khan (1), Jurgen Mulsow (2), Conor Shields (2), Ann Brannigan (2), Ronan Cahill (1)
1. UCD Centre for Precision Surgery, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland;
2. Surgery, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland
Introduction
Complete mesocolic excision with central vascular ligation for right colon cancer remains controversial despite evidence of superior oncological outcomes compared with standard resection due to concerns re safety and technical complexity.
Aims
To compare perioperative outcomes between CME/CVL cases and a control group.
Methods
Consecutive laparoscopic right hemicolectomy cases (December 2019-January 2022) where CME/CVL was performed with the use of personalized 3-D reconstructive images were audited against a control group of laparoscopic right hemicolectomies via standard resection in terms of perioperative outcomes.
Results
Twenty-two patients were included in the CME/CVL group and twenty in the control group. There were no significant differences in terms of age (71.55 ± 11 vs 70.1 ± 10.4, p = 0.33), gender (50% versus 45% males, p = 0.38), cancer stage (T1(n = 1):T2(n = 6):T3(n = 6):T4(n = 5) versus T1(n = 3):T2(n = 2):T3(n = 9):T4(n = 2), p = 0.07) between CME/CVL group and control group, respectively. There were no intraoperative complications in the CME/CVL group and one conversion to open for bowel ischaemia in the control group. There was no significant increase in early post operative morbidity (18% versus 30%, p = 0.19), length of hospital stay (8 days ± 3 versus 11 days ± 13, p = 0.18), 30-day readmission rates (5% versus 9%, p = 0.3), between the CME/CVL group and control group, respectively, while 30-day reoperation rates were lower in the CME/CVL group (0% versus 15% (n = 3), p = 0.04). Intraoperative time was found to be significantly longer in the CME/CVL group (208 ± 42.9 min versus 152 ± 66.9, p = 0.002), however, operative times for CME/CVL decreased significantly over the study timeframe.
Conclusion
Implementation of CME/CVL for right-sided colorectal cancer was safe in our institution without an increased rate of intraoperative or postoperative complication.
SESSION 4: BREAST RESEARCH
29. Balancing Risk of Haematoma and Venous Thrombosis in VTE Prophylaxis for Breast Cancer Surgery: A Meta-Analysis and Systematic Review
Amenah Dhannoon, Ishwarya Balasubramanian, Arnold Hill
Surgery, Beaumont University Hospital, Ireland
Introduction
Venous thromboembolism (VTE) is a largely preventable cause of morbidity and mortality in post-operative patients. Guidelines for VTE prophylaxis in breast cancer surgery are not well-established.
Methods
A comprehensive search was undertaken of all studies that described the role of VTE prophylaxis in breast cancer surgery. Comparative studies that reported on postoperative outcomes between patients who received VTE prophylaxis (prophylaxis) and those who did not (no prophylaxis) were included in the analysis. A meta-analysis using random-effects model was used to analyze key outcomes, with data presented as odds ratio (OR).
Results
A total of 2470 patients from 6 studies were included in this study. Of these patient, 60.9% (n: 1504) received prophylaxis. The haematoma rate in this study is 0.05% (n: 133). The incidence of haematoma was significantly associated with the use of prophylaxis (6.85% versus 3.11%, p: 0.001). Surgical intervention for haematomas was also significantly associated in this group (3.15% versus 0.83%, p: 0.004). However there was no difference in VTE events between both groups (0.26% versus 0.36%, p: 0.88).
Conclusion
The use of VTE prophylaxis in breast cancer surgery is associated with increased haematomas without any benefit in preventing venous thromboembolic events. Further studies that examine the use of risk assessment tools for VTE prophylaxis in high risk patients may be beneficial.
30. Characterisation of Patient-Derived Tumour Stromal Cell Signature
Luma AlDabel 1 , Ciara O’Neill 2 , Dómhnall O’Conno 2 Barry Digby 3 , Michael J Kerin 2 , Laura R. Barkley 2
1. School of Medicine, University of Galway, Ireland;
2. Surgery, Lambe Institute for Transitional Research, University of Galway, Ireland;
3. School of Mathematics, Statistics & Applied Mathematics, University of Galway, Ireland
Introduction
Tumour stromal cells (TSCs) are an important population of cells within the tumour microenvironment (TME) that play a major role in tumour formation, immunosuppression, and chemo-resistance. Stromal cells are also present at metastatic lesions (MET) making the site receptive to tumour cell engraftment and growth. Identifying and targeting these TSCs may impact breast cancer therapeutics and improve prognosis.
Aim
To evaluate a predertemined TSC gene signature in a breast cancer patient cohort to differentiate gene expression between TSCs, metastatic lesions, and tumour associated normal (TAN) stromal cells isolated from the same patient.
Methods
TSCs, TANs and MET stromal cells were isolated from breast cancer patients (n = 5) at Galway University Hospital. Cells were cultured and grown in incubation, then counted. Soluble and insoluble protein samples were prepared to carry out immunoblot (Western) analysis. RNA samples were isolated to perform RT-qPCR and validate TSC gene signature.
Results
SLC7A2, GPR116, PCDH10, WT-1 and GPR37 gene expression were upregulated in TSCs compared to TANs in 2 out of 3 of the patients. These genes were also upregulated in stromal cells isolated from a metastatic lesion compared to normal stromal cells.
Conclusion
These provisional results illustrated the importance of this gene signature in identifying TSCs within the TME, acting as potential therapeutic targets as well as predictors of metastasis. Further preclinical research is required to further establish the role of this genetic signature in breast cancer.
This work was supported by a HRB summer scholarship (SS-2021–004) and NBCRI.
31. Evaluating Clinical, Cardiovascular, and Survival Outcomes of Patients Treated for Estrogen Receptor Positive Breast Cancer in the West of Ireland
Aoife Nohilly, Matthew Davey, Ray McLaughlin, Karl Sweeney, Carmel Malone, Michael Barry, Aoife Lowery, Michael Kerin
Surgery, The Lambe Institute for Translational Research, University of Galway, Ireland
Introduction
Estrogen receptor positive (ER+) breast cancer makes up 70–80% of breast cancer diagnoses. Assessment of clinicopathological data, cardiovascular disease (CVD), and survival outcomes within this subgroup are important to improve patient prognosis.
Aims
To establish the oncological, cardiovascular, and survival outcomes of patients treated with ER+ breast cancer in a large European tertiary referral centre.
Methods
A single centre, retrospective cohort study was undertaken. All patients with ER+ breast cancer patients diagnosed between January 2005 and December 2015 were included. Descriptive data was performed to inform patient outcomes. Analysis will be performed using SPSS v26.
Results
2660 patients were included with median age of 59.6 ± 13.3 years (21–99). At median follow-up of 97.2 months (3.0–181.2), 12.4% of patients suffered a recurrence (450/2660): 2.1% of patients suffered a locoregional recurrence (56/2660) and 10.3% patients suffered distant recurrence (394/2660). The median time to relapse for patients suffering locoregional recurrence was 53.1 months versus 48.1 months for those suffering distant recurrence. Of those suffering disease recurrence or death, bone was the most common initial site of distant recurrence (18.7%, 74/394), followed by liver (18.1%, 71/394) followed by lung recurrences (5.3%, 21/394) and then brain recurrences (5.1%, 20/394). In total, 0.6% patients suffered CVD related-death (16/2,660) with a mean time to CVD-related death of 59.6 months (16.3 – 132.2 months).
Conclusion
Oncological and survival outcomes are favourable in ER+ breast cancer. Further evaluation of CVD-related death within cancer patients is required.
32. The Impact of Chemotherapy Prescription on Long-Term Survival Outcomes in Early-Stage Invasive Lobular Carcinoma – A Systematic Review and Meta-Analysis
Luis Bouz Mkabaah, Matthew Davey, Stephen Keelan, Aoife Lowery, Michael Kerin
Surgery, Lambe Institute for Translational Research, University of Galway, Ireland
Introduction:
Invasive lobular carcinoma (ILCs) are typically endocrine responsive breast cancers which respond poorly to chemotherapy. The long-term survival advantage of prescribing chemotherapy in such cases remains unclear.
Aims:
To perform a systematic review and meta-analysis assessing the impact of prescribing chemotherapy in such patients on long-term disease-free (DFS) and overall (OS) survival outcomes.
Methods:
A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. 10-year DFS and OS were pooled as odds ratios (ORs) with 95% confidence intervals (CI) using the Mantel–Haenszel method. Time-to-effect modelling was performed using the generic inverse variance method.
Results:
Overall, 9 studies including 28,218 patients were included. The mean follow-up was 74 months (range: 0 – 150 months) and mean age was 60 years (range: 22 – 90 years). Of these, 34.7% received chemotherapy (9,797/28,218) and 66.3% did not receive chemotherapy (18,421/28,218). Chemotherapy prescription failed to improve 10-year DFS (OR: 0.89, 95% CI: 0.65 – 1.23) and OS (OR: 0.92, 95% CI: 0.72 – 1.18). When using time-to-effect modelling, chemotherapy prescription failed to improve DFS (hazard ratio (HR): 1.01, 95% CI: 0.78 – 1.31) and OS (HR: 1.07, 95% CI: 0.89 – 1.27, I2 = 67%).
Conclusion:
This meta-analysis illustrates no long-term survival advantage associated with chemotherapy prescription in the setting of early-stage ILC. In the absence of well-designed, prospective clinical trials evaluating the impact of chemotherapy on long-term outcomes in ILC, these results should be considered by the multidisciplinary team when deciding on the value of systemic chemotherapy prescription in ILC.
33. Oncological Safety of Active Surveillance for Low-Risk Ductal Carcinoma In-Situ – A Systematic Review and Meta-Analysis
Aoife Nohilly, Matthew G. Davey, Aoife J. Lowery, Michael J. Kerin
Surgery, The Lambe Institute for Translational Research, University of Galway, Ireland
Introduction
Current standard of care for patients diagnosed with ‘low-risk’ ductal carcinoma in-situ (DCIS) involves surgical resection. Ongoing phase III clinical trials are hoping to establish the oncological safety of active surveillance (AS) in managing ‘low-risk’ DCIS.
Aims
To evaluate the oncological safety of AS versus surgery for ‘low-risk’ DCIS.
Methods
A systematic review was performed in accordance with PRISMA guidelines. Survival outcomes were expressed as dichotomous variables and reported as odds ratios (OR) with 95% confidence intervals (95%CI) using the Mantel–Haenszel method.
Results
4 studies including 9,626 patients were included, 3.9% of which were managed using AS (374/9,626) and 96.1% with surgery (9,252/9,626). The mean age of included patients was 50.3 years (range: 30–99 years) and mean follow-up was 6.1 years. Invasive cancer detection after surgery and AS were similar (OR: 0.93, 95% CI: 0.41–2.11, P = 0.860, heterogeneity (I2) = 0%). At 5-years, BCSS (surgery - 99.5% vs. AS - 98.7%, P = 0.116) and OS (surgery - 95.8% vs. AS - 95.7%, P = 0.876) were similar for both groups. At 10-years, BCSS (surgery - 98.7% vs. AS - 98.6%, P = 0.789) and OS (surgery - 87.9% vs. AS - 90.9%, P = 0.183) were similar for both groups. Overall, 10-year OS outcomes were similar for both management strategies (OR:0.32, 95% CI: 0.02–6.42, P = 0.460, I2 = 69%).
Conclusion
This study outlines the provisional oncological safety of AS for cases of ‘low-risk’ DCIS. While survival outcomes were comparable for both management strategies, ratification of these results in the ongoing phase III clinical trials is still required prior to changes to current management strategies.
34. Published.
https://www.sciencedirect.com/science/article/pii/S0960977621003982?via%3Dihub
35. Published.
https://doaj.org/article/b593074ff6694140a3278072c11969e5
36. Published.
https://journals.sagepub.com/doi/10.1177/11782234221086684
37. Published.
https://www.thebreastonline.com/article/S0960-9776(21)00999-1
SESSION 5: GENERAL SURGERY
38. Comparison of Colitis Reported on Computerised Tomography with Laboratory and Endoscopic Findings
Amy Edwards Murphy, Helen Earley, Ben Creavin, Fiachra Cooke, Peter McCullough, Peter Neary
Colorectal Surgery, University Hospital Waterford, Waterford, Ireland
Introduction
The aetiology of colitis is diagnosed using clinical, laboratory, colonoscopy and biopsy findings. A cohort of patients have incidental findings suggestive of colitis on computerised tomography (CT), without clinical suspicion.
Aim
The aim of the study was to stratify appropriate investigations for these patients to determine aetiology.
Methods
A search of all abdominal imaging performed from 01/08/2017–31/12/2020 with an incidental CT finding of colitis or features suggestive of colitis was performed. Exclusion criteria included prior known diagnosis of colitis or inflammatory bowel disease.
Results
201 patients were eligible for inclusion. Mean age was 60 years was years (16–94). 9.5% of reports were suggestive of IBD, typhlitis, pancolitis and enterocolitis (n = 11, n = 2, n = 4, n = 2). The remainder reported a specific location of colitis but no suggested aetiology. Stool cultures for clostridium difficile were performed in 57% (n = 114). Of those screened, 7.8% (n = 9) were positive. Molecular Enteric Screening was performed in 56% in whom 8% were positive. 40% of the cohort proceeded to endoscopy, of whom 46.9% had positive relevant findings. 14% of scopes were macroscopically and microscopically normal (n = 12).
Conclusion
As the number of CTs performed increases, it is necessary to rationalise use of further investigations for incidental findings of colitis. Stools cultures proved to be a high yield investigation and should be performed as a first line investigation for all incidental findings suggestive of colitis. Access to endoscopy is a limited resource and should be reserved for those in whom no other cause for colitis is found.
39. IR Cholecystostomy intThe Recent Era with Advanced Laparoscopy and Radiology Intervention – A Single Irish Centre Experience and Literature Review
Mohamed Salama 1 , Wael Shabo 1 , Mahmoud Salama 2
1. General Surgery, Our Lady of Lourdes Hospital, Drogheda, Co. Louth, Ireland;
2. School of Medicine, Trinity College Dublin, Co. Dublin, Ireland
Introduction
Laparoscopic cholecystectomy is the gold standard treatment for acute cholecystitis. The role of percutaneous cholecystostomy (PC) as an alternative treatment in high surgical risk patients remains debatable.
Aims
-To evaluate the role of PC in the management of acute cholecystitis in high surgical risk patients not responding to conservative treatment.
-To establish how PCs are inserted and managed in our department.
Methods
All patients that underwent PC in our unit between 2010 and 2021 were retrospectively reviewed. Data was collected from HIPE, NIMIS and Medical charts.
Results
During this period, 6026 were admitted to our hospital with cholecystitis. 2414 of them had cholecystectomy and 49 underwent PC (Transhepatic: 15, Transperitoneal: 34).
PC indications: Cholecystitis in unfit patients: 36, GB Perforation: 8, Empyema: 5. Out of PC group, 19 had interval laparoscopic cholecystectomy. PC complications: 15 (7 dislodged tubes, 2 liver abscesses, 2 minimal bleeding, 2 pneumonias and 2 sub hepatic collections).
Average time between PC and laparoscopic cholecystectomy: 154.7 days and the average time the drain stayed was 78.4 days. We had 5 mortalities post-PC due to old age and multiple comorbidities. No mortality was directly related to PC complication.
Conclusions
Laparoscopic cholecystectomy is the gold standard treatment for acute cholecystitis.
PC is a feasible and safe intervention for critically ill and elderly patients. Some patients who are too ill to receive interval cholecystectomy can only live with gallstones while others who recover from acute phase can undergo interval cholecystectomy. There is no standardised strategy for PC catheter management.
40. Neutrophil–Lymphocyte-Ratio and Platelet-Lymphocyte-Ratio Novel as Biomarkers for Diagnosis, Disease Severity and Length of Stay for Paediatric Acute Appendicitis
Markus K Kostka, Ryan Donnelly, Shane Keogh, Gerry O'Donoghue
Breast and General Surgery, University Hospital Waterford, Waterford, Ireland
Introduction
Paediatric acute appendicitis is one of the most common surgical presentations to emergency departments (ED) worldwide. Timely diagnosis and appendectomy prevents complications, improves outcomes and reduces length of hospital stay (LOS). Despite well known signs and symptoms, and assessing the risk of complicated appendicitis (CA) vs. uncomplicated appendicitis (UA) is challenging.
Aim
Biochemical ratios such a neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) may have utility for the diagnosis of acute appendicitis and assessing disease activity.
Method
A retrospective study of paediatric patients who underwent a laparoscopic appendectomy, between 2018–2021 was preformed. NLR, PLR, C-reactive protein (CRP), WCC, LOS and histology where examined and diagnostic accuracy of each biomarker was assessed.
Results
A total of 329 patients with a mean age of 12.2 years were identified. 69.9% had a histological diagnosis of AA, of these 77.4% UA and 22.6% CA. 31.1% had a normal appendix. The mean NLR value (9,42) was higher in the AA group compared to normal (4.03). Within the AA group the NLR was higher in the CA compared to UA (11.8 vs. 6.62). LOS was higher in the CA group (4.79 vs. 2.17 days). NLR and CRP are correlated with LOS. NLR had the greatest accuracy of the biomarker ratios in predicting CA.
Conclusion
NLR levels on admission predicted the presence of CA and a longer LOS. NLR is a useful adjunct in stratifying paediatric patients with AA. PLR did not identify AA within this paediatric population.
41. Percutaneous Drainage vs Antibiotics Alone in the Treatment of Diverticular Abscesses
Brian Murphy 1 , Stephanie O’ Connor 1 , Helen Earley 1 , Ben Creavin 1 , Ian Crosbie 2 , Peter McCullough 1 , Fiachra Cooke 1 , Peter Neary 3
1. General and Colorectal Surgery, University Hospital Waterford, Waterford, Ireland;
2. Radiology, University Hospital Waterford, Waterford, Ireland;
3. Academic Surgery, University College Cork, Cork, Ireland
Introduction
Diverticular abscesses account for a significant proportion of emergency surgical presentations. Recently, placement of image-guided guided percutaneous drains (PD) has an increasing role in the management these patients. NICE guidelines suggest that abscesses above 4 cm should be considered for PD.
Aim
To quantify the use of PD in the management of diverticular abscess at an Irish University Hospital.
To compare the outcomes of those treated with image-guided percutaneous drainage and antibiotics (PD Group) to those who had antibiotics alone (AA Group),
Method
A retrospective observational study of patients treated with AA or PD or over a ten-year period from 2011 to 2020 was carried out. Data were obtained from NIMIS imaging and patient records. Inclusion criteria included: Acute diverticulitis diagnosed on CT, with associated measurable abscess or collection – Modified Hinchey Stage 1b or 2. Exclusion criteria included: Post-operative collections, malignancy, or fistula.
Results
67 met the criteria, 7 of these underwent PD. Mean abscess size in the PD group was 9 cm compared to 4.6 cm in the AA group. When groups were size-matched, length of stay was 15 days in the PD group and 25 days in the size-matched AA group. Failure of initial management was 50% in the AA group vs 14% in the PD group. 28% had future emergency or elective surgery in the PD group vs 25% in the AA group.
Conclusion
At this institution PD use is limited and reserved for larger abscesses, highlighting potential for increased use of PD in these patients.
42. Wound Irrigation in the Prevention of Surgical Site Infection in Elective Colorectal Surgery – A Retrospective Cohort Study
Sahil Shet, Helen Earley, Ben Creavin, Cliona Nic Gabhann, Peter Neary
General and Colorectal Surgery, University Hospital Waterford, Waterford, Ireland
Introduction
Surgical site infection (SSI) in colorectal surgery is associated with significant cost and increased length of hospital stay. Recently, there has been interest in the use of pulsed-lavage to reduce the risk of SSI in wounds. In orthopaedic surgery, pulsed-lavage and has been shown to reduce concentration of debris in the surgical field, and reduce bacterial load. However, it’s effectiveness in colorectal surgery has been poorly documented.
Aim
To investigate the incidence of SSI within 30 days of elective colorectal surgery in patients who underwent wound irrigation with pulse lavage vs standard closure.
Methods
A retrospective study was conducted at a University Hospital over a two-year period between January 2020 and December 2021. All patients who underwent elective colorectal surgery were included. Standard closure was defined as PDS and clips to the skin. The intervention group underwent pulse lavage using and closure with PDS and 2-0 vicryl and 4-0 monocryl.
Results
222 patients were analysed. 39 SSIs were reported (17.6%). 76 patients underwent pulse-lavage while 146 underwent standard closure. Infection rates in the pulse-lavage group were lower at 13% compared to 20% in the standard closure group, however on statistical analysis using the Chi-sqaure test, the difference in infection rates did not reach significance (P = 0.213).
Conclusion
These data demonstrated a reduction in the incidence of SSI in patients who underwent pulse-lavage. Although it did not reach statistical significance, it warrants further investigation in the setting of colorectal surgery. Observed infection rates were in keeping with the literature.
43. An Observational Cohort Study of Percutaneous Cholecystostomy Use in an Irish University Hospital
Amy Edwards Murphy 1 , Helen Earley 2 , Ben Creavin 2 , Fiachra Cooke 2 , Peter McCullough 2 , Peter Neary 2
1. Colorectal Surgery, University Hospital Waterford, Waterford, Ireland;
2. Colorectal and General Surgery, University Hospital Waterford, Waterford, Ireland
Introduction:
Cholecystostomy tube (CCT) insertion is an accepted treatment for cholecystitis where cholecystectomy is not immediately appropriate. It is an adjunct to antimicrobial therapy in achieving source control of sepsis, particularly in comorbid patients. However, concern exists that cholecystostomy use may result in a more complex operative course at subsequent cholecystectomy.
Aim:
1. To evaluate trends in the current use of cholecystostomy 2. Determine outcomes including length of stay (LOS), mortality, subsequent definitive management or need for hepatobiliary specialist intervention.
Methods:
A retrospective, observational cohort study of all percutaneous CCT insertions at a University Hospital was conducted between January 2021 and January 2022.
Results:
12 patients underwent CCT insertion during the study period. All were transhepatic cholecystostomy drains. The mean age was 64 years (33–88), 58% male. All patients had cross-sectional imaging. 33% had no comorbidities. 50% had cardiovascular comorbidities, hypertension, atrial fibrillation, ischaemic heart disease, congestive cardiac failure. The average length of stay was 15 days. 3 patients (25%) required ICU admission. One patient died following prolonged ICU admission. 25% had the cholecystostomy removed as an outpatient and elected for no further intervention given comorbidities and age. 25% proceeded to elective laparoscopic cholecystectomy in the index hospital within 3 months of CCT insertion. 41% were referred to a hepatobiliary service for definitive management.
Conclusions:
These data support a role for CCT as a useful adjunct in management of cholecystitis, particularly in high-risk surgical candidates. This patient cohort are high risk for ICU admission or requirement for hepatobiliary opinion.
44. The Surgical Admission Proforma: Improving Quality and Completeness of Documentation at University Hospital Waterford
Youssef Al Mukhaizeem, Amro Osman, Jessica Ryan, Gerry O’Donoghue
General Surgery, University Hospital Waterford, Blackrock, Dublin, Ireland
Introduction
Accurate and complete documentation is essential and frequently referred to during handover of care. The current outdated proforma used to admit the acute general surgical take being four pages in length, with 168 different data points was in need of change. Due to the cubersome nature of documentation, key patient details were often omitted.
Aim
Introduction of an updated and simplified surgical admission proforma with the aim of improving standard of documentation for patients admitted under the acute general surgical service at University Hospital Waterford.
Method
Admission proformas for patitents admitted via the emergency department were analysed prospectively over a two-week period in April 2021 and in December 2021 following the introduction of the new proforma. Data were collected for 32 criteria taken from the Royal College of Surgeons of England guidelines for Clinicians on Medical Records and Notes (1994).
Results
A total of 47 admission proformas were analysed during the first audit cycle and 56 in the second cyle. An improvement of a total of 27 out of 32 criteria were observed following the introduction of the new proforma. Twenty criteria had more than or equal to 75% completeness in the new proforma versus 6 in the old proforma. The greatest improvement was documentation of grade of clerking doctor (96.4% vs 4.3% P < 0.001) and time seen by doctor (94.6% vs 4.3% P < 0.001).
Conclusion
This audit had demonstrated that significant improvements in documentation can be achieved through simple interventions. The updated proforma has ensured quality of our documentation.
45. An Audit of Intraoperative Analgesia in Appendicectomy
Conor Sheahan 1 , Andrew McGuire 2 , Arnold Hill 2
1. Medicine, RCSI, 123 St Stephen's Green, Dublin 2, Ireland;
2. General Surgery, Beaumont Hospital, Beaumont, Dublin, Ireland
Introduction
Appendicitis is the most common cause of the acute abdomen and emergency surgery. A hospital wide randomised controlled trial to compare Laparoscopic Transversus Abdominis Plane Block (LTAP Block) for appendicectomy versus standard treatment to standard port sites (control group) is being carried out later this year. Prior to commencement of LTAP block trial an audit of the current analgesic practices used in appendicectomy in the hospital was carried out.
Aim
Determine types of analgesia given intraoperatively and postoperatively during appendicectomy.
Determine if there is variation in the analgesia administered compared to a protocol developed for LTAP block study.
Methods
Clinical audit including patients who underwent appendicectomy for the management of acute appendicitis. Patients were identified using a combination of operating theatre lists and theatre log books.
Results
29 patients (14 male 15 female) were identified. Median age of both groups was older than described in the literature. Compliance with Paracetamol intraoperative protocol was 68.9% and 100% post-operatively. Ketorolac had the poorest compliance of the intraoperative regime with 0% compliance over collection period. Compliance with Ibuprofen was 3.4% of patients receiving as per the analgesic protocol. Poor compliance intraoperative Oxycodone with only 34.5% of patients receiving the drug per the protocol. In the post-operative period 27.6% of patients. In the post-operative period 48.3% of patients were prescribed over the protocol of Oxycodone.
Conclusions
There is under prescribing of NSAID's and overprescribing of opioids. Highlights the need to make the LTAP block protocol known prior to the study commencing.
46. Systematic Review and Meta-Analysis Comparing Minimally Invasive Surgical and Open Approaches to Pelvic Exenteration for Locally Advanced or Recurrent Pelvic Malignancies
Odhrán Ryan 1 , Katie Doogan 1 , Éanna Ryan 1 , Ian Reynolds 1 , Ben Creavin 1 , Matthew Davey 2 , Rory Kennelly 1 , Ann Hanly 1 , Seán Martin 1 , Des Winter 1
1. Surgery, St Vincent’s University Hospital, Elm Park, Dublin, Ireland
2. Surgery, Lambe Institute for Translational Research, University of Galway, Ireland
Introduction
Pelvic exenteration is a complex multivisceral surgical procedure that poses significant technical challenges. Developments in minimally invasive surgical (MIS) approaches and enhanced peri-operative care have facilitated improved long term outcomes, however, the optimum approach to pelvic exenteration remains controversial.
Aim
To compare MIS approaches versus the open approach for pelvic exenteration for locally advanced or recurrent pelvic malignancies.
Methods
A systematic literature search was conducted in accordance with PRISMA guidelines to identify studies comparing MIS (robotic or laparoscopic) approaches for pelvic exenteration versus the open approach, and a meta-analysis was conducted.
Results
10 studies were identified for inclusion. This included 1865 patients, of whom 204 (11%) underwent MIS pelvic exenteration approaches. The open approach showed increased lymph node yield (Weighted Mean Difference [WMD] 3.69, 95% Confidence Interval [95% CI] 1.91, 5.48, p,0.0001), however this did not impact the quality of R0 resections. The MIS group had a trend towards improved survival and recurrence outcomes, although, this did not reach statistical significance. MIS was associated with prolonged operating times (WMD 106.28, 95% CI 83.34, 129.23, p < 0.00001), however, this correlated with less intra-operative blood loss, less blood transfusions, and a shorter length of post-operative stay (WMD -3.45, 95% CI -4.39, -2.51, p < 0.00001). Readmission rates were higher with MIS, although, post-operative morbidity and mortality were comparable between both groups.
Conclusion
MIS approaches are a safe and feasible option for pelvic exenteration, with no differences in survival or recurrence outcomes compared to the open approach. MIS also reduced the length of post-operative stay and decreased blood loss, offset by increased operating time.
SESSION 6: UROLOGY
47. A Look at the Urological Burden on General Surgical Call When No Urology Service is Available
Irfan Qadir Afridi, Paul Ryan, Caroline Kelly, Aisling Fawaz, Mohammed Aboelmagd, John Keane, Padraig Daly
Urology, University Hospital Waterford, Waterford, Ireland
Introduction
Urology on-call services are available in most teaching hospitals. Some hospitals handover these services to the surgical team overnight. This can compromise the urgent management of patients and may result in unnecessary admission of others, due to the lack of a senior urology decision maker.
Aim
To audit the number of urology patients arriving through our emergency department out of hours over an 8-month period.
Methods
A retrospective review of a surgical admission logbook was performed for urology admissions between July 2021 and March 2022. The chief complaint of each patient was recorded. The theatre logbook was retrospectively evaluated for all emergency urology procedures carried out over the same period.
Results
A total of 260 patients were referred to the surgical on-call team with urological issues over this period. 161 of these patients were admitted for review. Mean length-of-stay was 4.27 days (range 1 – 23 days). 17 emergency urological procedures were performed by the general surgical team. 5 patients required urgent transfer to a neighboring hospital for specialist urology intervention by an on-call urology service.
Conclusion
Out of hours urology activity constitutes a significant burden on the workload of the general surgical team whilst also restricting essential training opportunities for urology trainees. Limiting urology cover can delay the treatment of urological emergencies and therefore compromise patient safety, whilst also resulting in the admission of patients who may otherwise have been discharged by a senior urology decision maker, therefore, adding to the burden on bed capacity at our institution.
48. Early Outcomes in a Robotic Upper Tract Reconstruction Series
Ailish Naughton, Mark Broe, Barry McGuire
Department of Urology, St. Vincent’s University Hospital, Dublin 4, Ireland
Introduction
The scope of robotic surgery has expanded to include reconstructive procedures, offering an alternative to the traditional approaches.
Aim
To assess perioperative and postoperative outcomes for patients undergoing robotic upper urinary tract reconstruction.
Methods
A prospective database of patients attending SVUH for robotic upper urinary tract reconstructive procedures was established in April 2018. Data recorded included patient demographics, intra-operative findings, post-operative recovery, and long-term outcomes. All procedures were performed by a single surgeon.
Results
74 patients to date have undergone robot-assisted reconstructive procedures for a range of underlying pathologies. Average patient age was 43.8 years (range 16–73). The most performed procedure was robotic pyeloplasty (n = 47). 9 buccal mucosa ureteroplasties were performed. 9 patients underwent ureteric reimplantation (7 with psoas hitch, 3 with Boari flap). Other reconstructive operations included appendix onlay ureteroplasty, non-transecting ureteric reimplantation (n = 2), ureterocalycostomy (n = 3), Uretero-uretero anastomosis (n = 2). Mean operation time was 2 h 49 min. Mean blood loss was 69.8mls. All patients followed an ERAS protocol. Median length of stay was 2 days. Mean length of follow up was 21.7 months (range 2 – 48). 4% of patients (n = 3) required a further procedure. There were two failures which were converted to Memokath nitinol stent successfully.
Conclusion
Robotic-assisted reconstruction of the upper urinary tract is a safe and feasible approach even in complex reconstructive cases with satisfactory short-term and long-term outcomes.
49. Standard Transurethral Resection versus Laser Surgery for Bladder Cancer: A Systematic Review and Meta-Analysis
Niall O Sullivan 1 , Eoin MacCraith 1 , Hugo Temperley 2 , Ailish Naughton 3 , James Forde 4 , Niall Davis 5
1. Urology, Tallaght University Hospital, Tallaght, Dublin 24, Ireland;
2. Surgery, St. James's Hospital, Dublin 8, Ireland;
3. Urology, St. Vincent's Hospital, Dublin, Ireland;
4. Urology, Blackrock Clinic, Dublin, Ireland;
5. Urology, Beaumont Hospital, Dublin, Ireland
Introduction
Transurethral resection of bladder tumour (TURBT) remains the gold standard method of diagnosing and treating non-muscle invasive bladder cancer. Laser resection has been demonstrated as a safe and efficacious alternative, however its mainstream use remains limited.
Aim
The aim of this review is to comparatively evaluate clinical outcomes of TURBT and laser resection of bladder tumour (LRBT) for bladder cancer.
Methods
A systematic review of the literature was performed for studies comparing TURBT and LRBT for bladder cancer. Outcome measurements were recurrence rates, complication rates, patient demographics, operative duration and inpatient stay. Meta-analysis was performed using Review Manager 5.
Results
Recurrence rates were similar between TURBT and LRBT (29.1% versus 28.2%%, p = 0.12). TURBT had a significantly greater obturator kick rate (11.5% versus 0.4%, p < 0.0001) and perforation rate (3.7% versus 0.009%, p = < 0.0001). In the six studies which reported on presence of detrusor muscle in the specimen, it was significantly greater in the LRBT group (96.6% versus 88.1%, p = 0.01). There was no significant different in operative time between the two groups. TURBT was associated with a significantly longer catheter duration (MD 0.98 days shorter in LBRT group; 95% CI, -1.45 to -0.5, p = < 0.00001), and length of stay (MD 1.12 days shorter in LRBT group, 95% CI; -1.7 to -0.54, p = 0.0001).
Conclusions
LRBT for bladder cancer has the benefit of reduced catheter duration, length of stay and perforation without impacting negatively on operation duration, recurrence rates or specimen quality.
50. The Inpatient Financial Burden of Radiation Cystitis
Brian Gilmartin, Sorcha O’Meara, Frank T D'Arcy, Catherine M Dowling
Urology, University Hospital Galway, Galway, Ireland
Introduction
Radiotherapy can be utilised as a treatment modality for pelvic malignancies. Complications of radiotherapy can lead to chronic management challenges. Radiation cystitis may result from radiotherapy for pelvic malignancies. Radiation cystitis develops in a small but significant proportion of the treated population with frequencies in the region of 5% to 10%1.
Aim
To establish the economic cost burden for inpatient care associated with radiation cystitis over a two-year period in University Hospital Galway.
Method
HIPE data was collated for patients with the diagnostic codes haematuria and radiation cystitis in 2018 and 2019. A retrospective review of electronic patient charts was performed to exclude patients presenting for reasons other than radiation cystitis. Costs were estimated in consultation with the hospital finance department and using HSE data on average inpatient bed day costs2, 3.
Results
A total of 23 individual patients were identified over a 2-year period. 96% male, 4% female. Mean age was 77 years. Radiation cystitis accounted for 621 inpatient bed days. Twelve patients required a flexible cystoscopy on the day ward. Seven patients required investigation and treatment in theatre under anaesthetic. Nine CT urograms and 10 Ultrasound kidneys were performed. The average running cost of an inpatient hospital bed is €878 per night3. Therefore, inpatient care cost was approximately €545,238, with a mean of €23,706 per patient.
Conclusions
Radiation cystitis accounts for a significant amount of inpatient bed days. A conservative estimate of cost was €23,706 per patient for inpatient care over the study period.
51. Published.
https://www.sciencedirect.com/science/article/abs/pii/S1477513122000961?via%3Dihub
52. The Psychological Impact of Adverse Events on Urology Trainees
Sorcha. O’Meara, Frank D’Arcy, Catherine Dowling, 1 Killian Walsh
Urology, University College Hospital Galway, Galway, Ireland
Introduction
Adverse events (AE) are an inevitable reality in healthcare, with an incidence of 12.6% in Irish hospital admissions.1 AEs have been recognised to cause psychological and emotional distress in healthcare workers, with surgical trainees being particularly susceptible.2,3 We report the first Irish data on experience of surgical trainees when dealing with AEs.
Methods
We distributed a web-based survey to all urology trainees in the Republic of Ireland. The questionnaire focused on trainees’ personal account of AEs within the previous six months, their emotional response, perceived contributing factors, and perceived benefit of support systems. The primary care PTSD screen (PC-PTSD-V) assessed for PTSD.
Results
A total of 16 responses were received from 12 (75%) registrars and 4 (25%) SHOs. Of the AEs reported, 12 (75%) were ≥ clavien-dindo 3b. Contributing factors identified included lapse of judgement (n = 6, 37.5%), risk of procedure (n = 7, 43%), lack of experience (n = 4, 25%). Anxiety (n = 8, 50%), guilt (n = 7, 44%) and sleep problems (n = 4, 25%) were the most reported emotional responses. Physical symptoms were reported in 2 (12%) trainees. A PC-PTSD-V score ≥ 3 was reported in 2 (12%) trainees. Most trainees (n = 13, 81%) reported talking to someone following the event with most (n = 12, 93%) talking to a consultant or NCHD colleague. Most trainees (n = 14, 87%) surveyed agreed that their training could better prepare them for the personal impact of AEs.
Conclusion
Urology trainees report negative psychological and emotional responses in the aftermath of an AE in keeping with international data. Those surveyed felt that their training could better prepare them for the personal impact of such events.
References
1. Rafter N, Hickey A, Conroy RM, et al. The Irish National Adverse Events Study (INAES): the frequency and nature of adverse events in Irish hospitals—a retrospective record review study. BMJ Quality & Safety 2017;26:111–119.
2. Han K, Bohnen JD, Peponis T, Martinez M, Nandan A, Yeh DD, Lee J, Demoya M, Velmahos G, Kaafarani HMA. The Surgeon as the Second Victim? Results of the Boston Intraoperative Adverse Events Surgeons' Attitude (BISA) Study. J Am Coll Surg. 2017 Jun;224(6):1048–1056. https://doi.org/10.1016/j.jamcollsurg.2016.12.039. Epub 2017 Jan 16. PMID: 28,093,300.
3. West CP, Huschka MM, Novotny PJ, et al. Association of Perceived Medical Errors With Resident Distress and Empathy: A Prospective Longitudinal Study. JAMA. 2006;296(9):1071–1078. https://doi.org/10.1001/jama.296.9.1071
53. Published.
https://link.springer.com/article/10.1007/s11845-022-02919-w
54. Surgical Versus Medical Castration for Metastatic Prostate Cancer; A Systematic Review And Meta-Analysis
Niall J. O’Sullivan, Hugo Temperley, Ailish Naughton, Rowan G. Casey
Urology, Tallaght University Hospital, Dublin 24, Ireland
Introduction
Metastatic disease is found in up to 20% of prostate cancer cases at diagnosis. Since their introduction in the 1980s, long acting gonadotropin releasing hormone (GnRH) analogues, administered subcutaneously or intramuscularly every one to six months have widely replaced bilateral orchidectomy as the method of castration for this cohort of patients. Recent evidence suggests that surgical castration confers a superior side effect profile and cost. We aimed to perform a systematic review and meta-analysis to compare these two treatment methods particularly in terms of survival, side effect profile and cost-effectiveness.
Methods
A systematic review of the literature was performed for studies comparing medical and surgical castration for metastatic prostate cancer. Outcome measurements included overall survival, side effect profile and cost.
Results
Fourteen studies on 38,877 participants (n = 35,584 for medical and n = 3,293 for surgical) met inclusion criteria. Our analysis demonstrated a significant difference in overall survival rates in favour of surgical castration (hazard ratio 0.81, 95% CI, 0.67 – 0.98, p = 0.03), less cardiovascular risk factors in the surgical group (OR 0.79, 95% CI, 0.62 – 1.00, p = 0.05) and nadir PSA levels in favour of medical castration (MD PSA 1.17 less in medical castration group, 95% CI, 0.67 – 1.67, p = < 0.00001).
Conclusion
Surgical castration appears to be a safe, feasible and efficacious alternative to medical castration, with evidence to suggest a potential survival benefit and limited evidence of a financial benefit in the treatment of men with metastatic prostate cancer. Further studies are required to further quantify the financial burden of one method over another, as well as to identify which subgroup of patients respond best to each method of castration.
55. Nephrectomy with Vena Caval Thrombectomy: Insights from a Single-Centre Series
Patrick Collins 1 , Matthew Gibbons 1 , Mohammed Hegazy 1 , Jonathan McGuinness 2 , John Conneely 3 , Stephen Connolly 1
1. Urology, Mater Misercordiae University Hospital, Dublin, Ireland
2. Cardiothoracic Surgery, Mater Misercordiae University Hospital, Dublin, Ireland
3. Upper Gastrointestinal and Hepatobiliary Surgery, Mater Misercordiae University Hospital, Dublin, Ireland
Introduction
Despite its technical complexity, surgical resection remains the mainstay treatment for locally-advanced kidney cancer. The aim of this study was to report on our centre’s contemporary experience with radical nephrectomy and inferior vena caval (IVC) thrombectomy.
Methods
Consecutive patients undergoing nephrectomy with IVC thrombectomy from 2016 to 2022 were retrospectively identified from a prospectively maintained operative database. Clinicopathological characteristics, operative details, and outcome were recorded.
Results
Twenty-four patients were included, with mean age 67.2 years. Half of patients were female. Most patients (78.3%) had right-sided tumours, with mean maximum tumour dimension of 93 mm. At presentation, 1 patient had known metastatic disease. Mean (SD) operative duration was 307.4(76.3) minutes. Level 1, 2, 3 and 4 thrombus was identified in 7(29%), 11(46%), 4(17%), and 2(8%) patients respectively. Cardiopulmonary bypass was required in 1 case. Graft reconstruction of the IVC was required in 2 cases. Most patients (91.7%) were initially managed in the high-dependency unit post-operatively. Median (IQR) overall length of stay was 10.5(7) days. Five patients experienced a grade 3 or greater complication. One patient died within 30 days of surgery. The most common (66.7%) histopathological finding was of clear cell renal cell carcinoma. Disease recurrence was observed in 50%, median (IQR) time to which was 11(10) months. However, three-year overall survival was 79.9 ± 9.2%.
Conclusion
We report on the feasibility and acceptable surgical morbidity profile of resection of locally advanced kidney cancer. These rare cases display aggressive tumour biology, and present a unique operative challenge, often requiring multi-specialty involvement.
References
1. Kaag MG, Toyen C, Russo P, et al. Radical nephrectomy with vena caval thrombectomy: a contemporary experience. BJU international. 2011;107(9):1386–1393.
SESSION 9: PLENARY SESSION
56. Anticoagulation for DVT Post-Endovascular ablation of Varicose Veins: Network Meta-analysis
Daniel Westby, Mohamed Elsharkawi, Fiona Nolan, Nathalie Doolan, Megan Power-Foley, Stewart Walsh
Vascular and Endovascular Surgery, Galway University Hospital, Galway, Ireland
Introduction
Deep vein thrombosis (DVT) is an established risk associated with endovascular ablation for varicose veins, < 1%. Anticoagulantion is the mainstay of treatment in the event of a DVT. Several anticoagulants ar available to choose from. This network meta-analysis compares anticoagulation regimes used in patients who develop a DVT post endovascular ablation for varicose veins.
Aim
Primary aim is to compare anticoagulation therapies and duration used in the event of DVT post endovascular ablation of varicose veins. Secondary aim to quantify the extent of secondary bleeding due to anticoagulation.
Methods
Medline, Embase, CINAHL and Cochrane Library databases were searched using appropriate terms for all studies reporting on DVT post endovascular ablation for varicose veins. Methodological quality of included studies was quantified using the Downs and Black checklist.
Results
407 articles were identified from preliminary searches with 22 studies satisfying the inclusion criteria. The analysis consisted of 63,076 patients with post-ablative DVT occurring in 358 patients. The anticoagulation regime was left to the treating physician in majority of cases. Agents commonly used were low-molecular weight heparin (LMWH), warfarin, a combination of both or direct oral anticoagulants (DOAC). Duration of therapy varied considerably among studies. Bleeding events related to anticoagulation are low and the need for intervention is lower again.
Conclusion
Although there has been a move towards DOAC in recent years, LMWH appears to remain the agent of choice for patients with post ablative DVT. The consensus for the duration of treatment is yet to be determined.
57. Surveillance, Oncologic Outcome and Health-Related Quality of Life: A Report from the ENSURE Study
Jessie A Elliott 1 , Sheraz R Markar 2 , George B Hanna 2 , John V Reynolds 1 , ENSURE Study Group 1 , Fredrik Klevebro 3 , Asif Johar 3 , Lucas Goense 4 , Pernilla Lagergren 3 , Giovanni Zaninotto 2 , Richard van Hillegersberg 4 , Mark Ivan Berge Henegouwen 5 , Magnus Nilsson 3
1. Surgery, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland;
2. Surgery and Cancer, Imperial College London, United Kingdom;
3. Karolinska Institutet, Department of Molecular Medicine and Surgery, Sweden;
4. Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands;
5. Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Netherlands
Introduction
Established and emerging therapies for recurrent oesophageal cancer may impact survival and health-related quality-of-life (HRQL), however surveillance protocols after primary curative treatment are inconsistent.
Methods
ENSURE was an international multicenter observational study of consecutive patients undergoing curative-intent surgery for oesophageal and junctional cancers (2009–2015) across 20 European and North American centers (NCT03461341). The initial report from ENSURE assessed the impact of intensive imaging surveillance on the primary outcome measure of overall survival (OS); secondary outcomes included treatment, disease-specific survival, recurrence pattern, and HRQL. In the present study, multivariable linear, logistic and Cox proportional hazards regression analyses were performed to determine the independent impact of surveillance modalities on oncologic outcome.
Results
4,682 patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy). Routine biochemistry, nutritional profiling, tumor markers, endoscopy and flexible nasolaryngoscopy were assessed in 37, 33, 15, 19 and 7% of Centers, respectively. Among all patients, endoscopic surveillance was independently associated with increased probability of isolated local or anastomotic recurrence (OR1.49 [1.05–2.14]), but not with improved OS. Endoscopic surveillance was associated with improved OS (HR0.73 [0.55–0.98]) among patients with Barrett’s oesophagus, while flexible nasolaryngoscopy was associated with improved OS among patients with SCC (HR0.19 [0.05–0.80]). On multivariable analysis, nutritional surveillance was associated with increased tumor-directed therapy, improved HRQL (P = 0.015) and OS (HR0.89 [0.80–0.99]), while a multimodal surveillance approach was also associated with improved OS (HR0.83 [0.72–0.95]) among all patients.
Conclusion
These data suggest that a multimodal and tailored surveillance approach may improve oncologic outcomes following curative-intent surgery for oesophageal cancer.
58. Surgical Approach for Partial Nephrectomy in the Management of Small Renal Masses: A Systematic Review and Network Meta-Analysis
Ailish Naughton 1 , Eanna Ryan 2 , Robert Keenan 3 , Arun Thomas 1 , Lisa Smyth 1 , Rustom Manecksha 1 , Robert Flynn 1 , Rowan Casey 1
1. Urology, Tallaght University Hospital, Tallaght, Dublin 24, Ireland;
2. Surgery, Tallaght University Hospital, Dublin 24, Ireland;
3. Urology, University Hospital Limerick, Co. Limerick, Ireland
Introduction
A variety of surgical and non-surgical management options for small renal masses (SRMs) exist. Surgery, in the form of partial nephrectomy (PN) has three different approaches. It is unclear which partial nephrectomy approach, if any, offers superior clinical outcomes.
Aim
To compare outcomes in patients with SRMs less than 4 cm undergoing PN via open (OPN), laparoscopic (LPN) or robotic (RPN) approach, and to establish the advantages and disadvantages of the various approaches.
Methods
A systematic literature search was conducted for studies comparing at least two of the above techniques. 18 studies and 17,013 patients were included in our study. A network meta-analysis with a frequentist framework was performed. OPN was used as the baseline comparator. The pre-specified primary outcome was R0 resection rates. Secondary outcomes included operating time, ischaemia time, blood loss, transfusion rates, urine leak rates, significant morbidity, length of stay and recurrence.
Results
There was no significant difference between the techniques in terms of R0 rates, tumour recurrence, urine leak rates, renal function and > 3a Clavien-Dindo complications. LPN had a longer ischaemic time and operating time. OPN had a longer length of stay and higher average intraoperative blood loss. RPN had lower blood transfusion rates.
Conclusion
All approaches are acceptable from an oncological perspective. The minimally invasive approach (i.e.RPN and LPN) offer advantages in terms of morbidity; however, LPN may increase ischaemic time and operative duration. Variations between perioperative outcomes may influence choice of approach on a case-by-case and institutional basis.
59. Published.
https://journals.sagepub.com/doi/10.1177/11782234221086684
60. Published.
https://www.mdpi.com/2075-4418/12/4/794
61. Endocytosis Regulates Uptake of Indocyanine Green in an In Vitro Spheroid Model of Colorectal Cancer
Anwesha Sarkar 1 , Niall Hardy 2 , Donal O'Shea 3 , Stephen Thorpe 4 , Ronan Cahill 2
1. UCD School of Medicine, UCD Precision Medicine, UCD Conway Institute, University College Dublin, Dublin 4, Ireland;
2. Surgery, UCD Precision Surgery, Mater Misericordiae University Hospital, Dublin 7, Ireland;
3. Chemistry, Royal College of Surgeons in Ireland, Dublin 2, Ireland;
4. UCD School of Medicine, UCD Conway Institute, University College Dublin, Dublin 4, Ireland
Introduction
Surgical resection plays an important role in the treatment of colorectal cancer. Fluorescence guidance utilising the intravenously delivered fluorophore indocyanine green (ICG) is commonly used to identify intestinal perfusion following tumour resection. ICG accumulates in colorectal tumour tissue and methods have been developed to identify cancerous lesions based on the dynamics of ICG retention in vivo. Understanding the mechanism through which ICG accumulates is important.
Aim
This study aims to investigate cellular uptake mechanisms of ICG using both 2D and 3D spheroids model of colorectal cancer as in vitro representations of both malignant cell and tissues.
Methods
Assessment of active cellular processes potentially driving ICG uptake in HT-29 adenocarcinoma cells cultured in both 2D (with both low and high density plating) and 3D cultures. FFPE sections were made for characterisation of spheroids, followed by H&E staining. ICG treated spheroid cryosections were made for imaging. Analysis was done with near infrared fluorescence imaging digital scanner and an epifluorescent microscope.
Results
ICG uptake was dependent on the media ICG concentration (5–50 µg/mL). Cells cultured at 4 °C had reduced ICG uptake in both 2D and 3D cultures (p < 0.001). Inhibition of clathrin-mediated endocytosis with an inhibitor (Pitstop2) reduced ICG uptake in both 2D and 3D cultures at 50 µg/mL ICG (p < 0.001) but not at the more clinically relevant concentration of 5 µg/mL ICG. ICG uptake however increased with tight junction absence (p = 0.007).
Conclusion
Tight junction-related uptake is more likely then clathrin-mediated endocytosis to drive tumoral ICG uptake at clinically relevant concentrations.
62. Optimisation of a Peptide Hydrogel-Based Model for Pancreatic Cancer
Ciara Doyle 1 , Ella Kearns 1 , Elena Mangul 2 , Stephen Thorpe 1
1. School of Medicine, University College Dublin, Conway institute, Belfield, Dublin 4, Ireland;
2. School of Mechanical and Materials Engineering, University College Dublin, Belfield, Dublin 4, Ireland
Introduction
Pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) being the most common form, has one of the lowest survival rates of all cancers worldwide at 4–9%. PDAC is a dense hypovascular tumour, which shields it from traditional therapy such as chemotherapy. Personalised medicine such as immunotherapy offers potential to improve mortality rates. Patient-derived organoids are cell cultures derived from tumour biopsies in a 3D matrix, providing an ex vivo mimic of tumour structure and function.
Aim
Currently organoids are derived in Matrigel, a solubilised basement membrane. Disadvantages of Matrigel include batch-to-batch variability, its xenogeneic nature given its mouse origin, and it is difficult to control its physical or biochemical properties. Synthetic hydrogels offer advantages including control over growth conditions in a xenogeneic-free scenario to better replicate the stiff PDAC microenvironment.
Method
To optimise peptide hydrogels to model PDAC, three peptide sequences (Manchester BIOGEL) with varying concentration (stiffness) were used. Cell types included a metastatic PDAC cell line, SUIT2, a non-metastatic PDAC cell line, BxPC3 and primary human pancreatic stellate cells (hPSCs) as a cancer associated fibroblast source. Hydrogel architecture was assessed using scanning electron microscopy (SEM). Live-Dead staining and Cell Titre-Glo 3D were used to assess cell viability and proliferation. Cell morphology was assessed using fluorescent microscopy.
Results
Results indicate both cancer cells and hPSCs can be cultured successfully in peptide hydrogels without any extracellular matrix (ECM) addition.
Conclusion
Ongoing work will assess whether it is necessary to incorporate ECM or ECM-mimicking peptide sequences to derive patient organoids with application in personalised medicine.
63. Assessing the Relevance of Circulating MicroRNAs as Prognostic Biomarkers in Breast Cancer
Matthew Davey 1 , Andrew McGuire 1 , Maire Caitlin Casey 1 , Ronan Waldron 1 , Maxwell Paganga 2 , Emma Holian 2 , John Newell 2 , Helen Heneghan 1 , Ailbhe McDermott 1 , Maccon Keane 3 , Aoife Lowery 1 , Nicola Miller 1 , Michael Kerin 1,4
1. Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, Ireland;
2. School of Mathematics, Statistics and Applied Mathematics, University of Galway, Ireland
3. Medical Oncology, Galway University Hospital, Galway, Ireland
4. Cancer Trials Ireland, Innovation House, Dublin, Ireland
Introduction
Deciphering patients who are likely to experience breast cancer relapse remains challenging to the multidisciplinary team. MiRNAs are small non-coding RNA which act at a post-transcriptional level influence protein synthesis by binding to messenger RNA. Their relevance in predicting breast cancer recurrence is uncertain.
Aim
To assess the value of circulating miRNAs in predict breast cancer recurrence.
Methods
ICORG10/11 was a prospective, multicenter trial which recruited patients undergoing neoadjuvant chemotherapy in 8 Irish hospitals. A miRNA panel were quantified from bloods at diagnosis and during neoadjuvant chemotherapy using RQ-PCR. MiRNA profiles were correlated with recurrence-free (RFS) and disease-free (DFS) survival. Data analytics was performed using R 3.2.3.
Results
124 patients with a median tumour size of 38.0 mm and follow-up of 8.6 years were recruited. Increased miR-145 expression predicted RFS (Hazard Ratio (HR): 0.00, 95% confidence interval (CI): 0.00–0.99, P = 0.05) with a relative cut-off of ≤ 0.2 for predicting an increased risk of recurrence using survival regression tree analysis (P = 0.04). Increased miR-145 expression trended towards predicting DFS (HR: 0.00, 95%CI: 0.00–1.42, P = 0.07) with a relative cut-off of ≤ 0.2 for predicting an increased risk of recurrence, new cancers, or death (P = 0.01).
Conclusion
This analysis illustrates the importance of using miRNAs as circulatory biomarkers capable of predicting recurrence in breast cancer patients. Validation of these findings is mandatory before the translation of these results into clinical practice.
SATURDAY, 3 RD SEPTEMBER 2022
SESSION 10: TRAINING AND EDUCATION
64. Assessment of the Use of Blood Cultures in the Detection of Bacteraemia: Phase 2 of an Experimental
Vianka Marcelino 1 , Dermot Hehir 1 , Sean Johnston 2
1. School of Medicine, University of Limerick, Castletroy, Limerick, Ireland;
2. Surgery, Midland Regional Hospital Tullamore, Offaly, Ireland
Introduction
Blood stream infection is one of the highest ranked problems in patient care due to its association with morbidity and mortality. The only consistent guideline for taking blood cultures (BCx) Ireland is the Sepsis 6 criteria. Research has shown that this approach yields a low rate of true positive samples, leading to misdiagnoses and delayed or over treatment. A prospective cohort study was undertaken in Midland Regional Hospital Tullamore (MRHT) from October to December 2020 to determine the number of true positive BCx, indicators prompting the BCx investigation and rate of contamination. A true positive rate of 8% and a contamination rate of 4% was found.
Aim
The aim of this study was to i) define indications for taking BCx; ii) reduce contamination rates following the implementation of novel interventions.
Method
A bespoke protocol for MRHT was drafted and circulated to all incoming non consultant hospital doctors (NCHD). Data from all BCx collected from July 10 2021 – July 31 2021 was studied prospectively.
Results
The key indicators identified were: pyrexia, tachycardia, tachypnoea, leucocytosis, neutrophilia, hyperlactataemia and raised CRP.
Blood Culture Results: 156 BCx Taken
Conclusion
The findings show no improvement in true positive rates or a decrease in contamination rates following the implementation of the bespoke protocol. This is possibly due to a significantly smaller population, non-compliance or inadequate distribution of the protocol. We recommend ( i) that this study be continued with an appropriate sample size over a longer period of time(ii) redistribution of the protocol to all staff along with a tutorial.
65. Generating A Prioritised List of Operative Procedures for Simulation-Based Assessment Using A Modified Copenhagen Needs Assessment Framework
Conor Toale, Marie Morris, Adam Roche, Leonie Heskin, Dara Kavanagh
Surgical Affairs, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
Introduction
From August 2021, surgical training in Ireland has become explicitly outcomes based. The implementation of such competency-based training programs requires robust methods of summative assessment.
Aim
This study sought to outline a consensus on the general surgery procedures appropriate for use in simulation-based operative competency assessments for general surgery trainees at two stages of progression identified by the ISCP curriculum 2021: phase 2 (indicative time 4 years post- core surgical training) and phase 3 (end of training certification).
Methods
A modified Copenhagen Needs Assessment Framework utilising an iterative survey process was used to generate a prioritised list of procedures, using responses from a group of surgical trainers and a steering committee of five surgical education researchers. The 'impact', 'frequency', and 'risk' of a pre-defined procedure list was ranked. The steering group further ranked each procedure using three feasibility metrics. The provisional list of procedures was then returned to surgical trainers for re-ranking and consensus on final inclusion.
Results
Thirty surgical trainers were presented with 90 procedures derived from the JCST/ ISCP competency expectations. Seventeen procedures were subsequently included on recommendation of included participants. After iterative ranking, a provisional prioritised list of 30 procedures for each stage of training was produced. Appendicectomy was the top ranked procedure for operative competence assessments at ST6 (score 4.23/5.00), while cholecystectomy was the top ranked procedure for assessments at ST8 (score 4.35/5).
Conclusion
This study generated a prioritised list of procedures for use in simulation-based operative assessments, aligned with JCST expectations.
66. Published.
https://www.sciencedirect.com/science/article/abs/pii/S0748798322000695?via%3Dihub
67. A Blended Learning Approach to Surgical Teaching; What We Can Learn From The Student Experience
Darren Mc Cormack 1 , Jamie Martin-Smith 1 , Peter Cantillon 2
1. Plastic Surgery, Beaumont Hospital, Beaumont, Dublin, Ireland;
2. Clinical Education, University of Galway, Ireland
Introduction:
There is a growing trend of shifting medical education towards an online and simulation-based approach. The traditional hands on or experimental approach to medical education, is becoming less acceptable due to a myriad of legal and ethical issues. The shift to virtual delivery of content has been accelerated due to the covid 19 pandemic. Medical students have been propelled into this form of learning and this represents a paradigm shift in medical training and assessment. From informal discussions with undergraduate medical students, there is discontent with the move towards a blended approach with a variable amount of physical clinical exposure. This shift has also commenced despite a very poor evidence base to support this move. I was intrigued by the experiences the students were having and wanted to explore what they felt they were missing when the content was delivered online and if we can learn from them, as to how we can improve the delivery of surgical teaching with a blended delivery approach.
Aims:
Understand the student experiences that influence effective delivery of surgical clinical skills through a blended learning approach.
Methods:
Qualitative data collection will be carried from video analysis. From this data we will try to determine the factors involved in the student experience or clinical skills and what elements of the hidden curriculum are essential in delivering an effective surgical skills session.
Sampling method:
Final year medical students currently on placement in Beaumont hospital who have volunteered to take part after invitation.
68. Trends in Irish Surgical Research
Nathalie Doolan 1 , Stewart Walsh 2
1. Vascular Surgery, University Hospital Galway, Galway, Ireland;
2. National Surgical Research Support Centre, RCSI, Dublin, Ireland
Introduction
Participation in high quality surgical research is important for surgeons in training and those practicing as consultants. It forms a cornerstone of evidence based medicine. Randomized prospective studies are amongst the highest forms of scientific evidence, however the perceived complicated nature of designing and conducting them can be discouraging for researchers. Pre-registration of a trial is required for publication to most international journals and has been required by the International Committee of Medical Journal Editors since 2005. International registration of clinical trials has increased exponentially since then.
Aims
We sought to review if Irish surgical data reflected international research trends and to analyse the registration and publication of trials here amongst surgical specialities.
Methods
Data was extrapolated from clinicaltrials.gov for all national and international collaborative trials between 2012 and 2022. This data was cross referenced with Pubmed to examine what trials had been completed and published.
Results
Surgical groups registered 96 trials over this period of which 31% were international collaborations. Of the Irish trials, 71% were randomized control trial protocols and 29% observational (retrospective and prospective). General surgery represented 50% of the registered trials. There was no increased in trial activity over the past 10 years to match international trends. 31% of the trials had published their findings at the time of the review.
Conclusions
This preliminary study demonstrates that we are not matching international colleagues in our involvement in randomized trials. There may be a role for increasing support to surgical researchers to encourage their involvement.
69. Burnout among Surgical Staff at a Tertiary Hospital One Year From the Start of COVID-19 Pandemic
Amenah Dhannoon 1 , Emmeline Nugent 2
1. Surgery, Beaumont University Hospital, Dublin, Ireland;
2. Surgery, University Hospital Galway, Ireland
Introduction
COVID-19 pandemic has had significant impact on every department in our healthcare system. Our objective was to survey healthcare professionals in the surgical department in a tertiary hospital a year after the start of the pandemic to evaluate the impact of Covid-19 pandemic on burnout level, closely identify the causative factors as well as potential key solutions to improve wellbeing.
Methods
An online survey was sent to all doctors working in various surgical departments. Burnout level was assessed using the Maslach Burnout Inventory (MBI), a 22-question survey assessing the three components of the burnout syndrome-emotional exhaustion (EE), depersonalisation (DP) and personal achievement (PA).
Results
65 doctors responded to the questionnaire of all grades from consultant (30%) to interns (27%). With the majority in the age range 24–34 years and overall male: female of 36: 28. Most common marital status was married 47%. Eighty-three percent of respondents reported increased risk of burnout during the pandemic. The most commonly reported cause was inability to meet and socialise with friends and family (92%). The mean EE was elevated (32.15), DP level was also high (16.58). However, sense of personal achievement was notably low. The three components indicated high burnout level. Both local and national changes were suggested to reduce burnout level.
Conclusion
Even during the second wave of COVID-19 pandemic, surgical staff showed high level burnout. Not surprisingly, hospitals could have alleviate this by providing basic services like maintaining the residents place, providing parking space and food facilities during out-of-hour.
70. Development of a Novel Near-Peer Surgical Simulation-based Teaching Programme for Intern Doctors in the Mid-West Region
Bridgid Ferriter 1 , Barbara Julius 1 , Julie Evers 1 , Sarita Ankatiah 1 , Uchechukwu Alanza 1 , Sinead Burke 1 , Natasha Slattery 1 , Shona Tormey 1 , Anne Merrigan 1
Surgery, University Hospital Limerick, Dooradoyle, Limerick, Ireland
Introduction
Trends in healthcare have caused a shift in training towards more competency based programmes. The COVID-19 pandemic has reduced time available for direct exposure and clinical learning, necessitating incorporation of simulation in training.
Aim
The objectives of this study were to develop, pilot and evaluate a four week simulation based surgical teaching programme.
Method
Interns pursuing a career in surgery joined a near-peer surgical training programme delivered by NCHDs. A survey established a baseline competency. Four skills workshops were delivered. Outcomes were measured using data from pre and post course surveys and a surgical skills competition.
Results
Of the 12 trainees, 71% had scrubbed in theatre before. 50% were already confident to scrub independently, increased to 75% post training. 28% were confident gowning/gloving, increased to 75% post training. 28% were confident to place a simple suture in theatre, this did not increase despite training. 42% were confident performing an instrument tie, increased to 75% post training. 14% were confident hand tying knots, this increased to 62%. 14% of participants were comfortable performing excisional biopsy in theatre, increased to 62% post training. Preparation and administration of local anaestetic could be performed confidently by 14% before training, this increased to 87%. On completion, a surgical skills competition showed that 100% were able to satisfactorily perform basic skills.
Conclusion
Near-peer delivery of surgical training has enhanced the basic surgical skills of interns. Similar programmes in other sites would ensure that interns have the skills required to safely care for surgical patients.
71. Implementation and Impact of a Bespoke Simulation Surgical Consent Workshop For Medical Undergraduates
Niamh Moynagh, Emma Kearns, Ronan Cahill
UCD Precision Surgery, Mater University Hospital, Dublin, Ireland
Introduction
Communication skills are essential for effective clinical practice. Non-technical surgical skills training is a core component of our national surgical training scheme. We implemented and audited a similar model for medical students during their core surgical rotations.
Aim
To design, effect and assess a medical student communication workshop based around consent.
Methods
Over a twelve week term, weekly tutor-led communication workshops were held. Each week 10–12 students attended a 90-min session including a simulation consent scenario. Participants were invited to complete an anonymous survey via electronic channels including Yes/No questions, Likert-based scales and free text boxes to gauge their opinion and confidence levels re patient communication/consent.
Results
100% (n = 40) of responding students stated this teaching was beneficial, relevant and should be repeated in the future. > 90% of those surveyed felt their confidence in patient communication improved secondary to the session. 80% of students stated they weren't formally taught communication skills elsewhere, with > 90% indicating they would like broader inclusion of this across their curriculum. Interactive small group sessions were highlighted as the best mode of delivery for these sessions, followed by informal clinical observation and didactic teaching. Self-rated confidence levels were positive with regards to structure of conversation (90%, n = 36), discussion of risks (77.5%, n = 31), explanation of the procedure (85%, n = 34) and ability to empathise with patients (82.5%, n = 33).
Conclusion
Consent and communication based teaching was positively received by participants with students feeling a clear, positive outcome in comfort with consent communication as a result copperfastening this learning innovation in our curriculum.
72. Medical Students’ Perspectives on the Use of 3-D Reconstructive Models in Colorectal Surgery
Emma Kearns 1 , Niamh Moynagh 1 , Christian Myles 2 , James Jones 2 , Faraz Khan 1 , Ronan Cahill 1
1. UCD Centre for Precision Surgery, Mater Misericordiae University Hospital, Dublin 7, Ireland;
2. UCD School of Medicine and Medical Sciences, UCD, Belfield, Dublin 4, Ireland
Introduction
Three-dimensional (3-D) reconstructions of patients’ individualised anatomy can accelerate personalized, precision minimally invasive surgery. Beyond their purpose in surgical planning, they could have a role in medical education.
Aims
To gain insight into medical students’ perspectives on the utility of such 3-D reconstructions.
Methods
Students were shown 3-D reconstructive virtual models and one physical 3-d printed model previously created for right-sided colorectal cancer operations as part of an interactive tutorial. A mixed-methods survey was then distributed to students following the session.
Results
Forty-eight students completed the survey. Themes drawn from open-ended questions included their utility in engagement of and as a learning resource for students in theatre, in preoperative planning and intraoperative navigation for surgeons and in patient education. 97% (n = 44) agreed that the reconstructions are an excellent resource for trainees and medical students with 86% (n = 37) preferring the virtual reconstructions to the physical model. Reasons for this included more accessibility, practicality and ease of manipulation. 93% (n = 42) agreed the images would be useful for understanding the relations of the relevant vasculature with 88% (n = 40) agreeing that they found assessing these vessels difficult via CT imaging alone. 95% (n = 43) agreed that they would be useful at the time of surgery and that they would like to have access to these reconstructions to look at other areas of anatomy.
Conclusion
Feedback on the use of 3-D reconstructive models was generally positive, with the majority of students favouring virtual models over physical ones. Students identified usefulness of these models for surgeons, patients and medical students.
SESSION 11: PLASTIC , RECONSTRUCTIVE AND HAND SURGERY
73. The Margin of Safety: A Systematic Review of the Surgical Strategy and Recurrence Rates In Lentigo Maligna
Ellen Geary 1 , Aoife Granahan 2 , Aoife Lally 2 , Roisin Dolan 1
1. Plastic and Reconstructive Surgery, St Vincent's University Hospital, Elm Park, Dublin, Ireland;
2. Dermatology, St Vincent's University Hospital, Ireland
Introduction
Lentigo Maligna (LM) is a subtype of melanoma in-situ that typically presents as a slow growing, irregularly pigmented macule. If left untreated the risk of progression to invasive disease is estimated as high as 20%. Whilst there is significant variation in the treatment approach for LM, surgical excision with a margin of 5–10 mm remains the gold standard with reported recurrence rates (RR) ranging from 6–20%.
Aim
We aim to determine the optimum histological margins required to achieve complete clearance and minimise recurrence.
Method
A literature review of the National Library of Medicine per PRISMA guidelines was conducted by a medical librarian using Pubmed, MEDLINE, Embase, Science Direct and Cochrane Library databases. All articles and clinical studies relating to the surgical management and RR of LM up to and including October 22nd 2021 were included.
Results
A total of 17 studies met inclusion criteria. 77% of studies had a retrospective observational study design with a mean sample size of 142.8. The average RR was reported at 7.5% with a mean histological margin of 5.7 mm. Of these 7 studies included, only 5 report on time to recurrence at 50.84 months on average. T5 studies report on wound closure technique, with 30% and 25% requiring skin flap and graft reconstructions respectively.
Conclusion
Following surgical excision, we report comparable recurrence rates with histological margins of 5 mm and above. We report that a wider excision may not be necessary to achieve safe histological margin.
74. Amelanotic Melanoma in Ireland
Darren Mc Cormack 1 , Jamie Martin-Smith 1 , Natasha Christodalides 2 , Michael O`Shaugnessy 1 , Lucy Burns 1
1. Plastic Surgery, Beaumont Hospital, Beaumont, Dublin, Ireland;
2. Plastic Surgery, Cork University Hospital, Cork, Ireland
Introduction
According to the National Cancer Registry of Ireland, less than 5 AM have been recorded during 2014–2016, representing 0.45% of all melanomas recorded (personal communication National Cancer Registry) 7. The prevalence of AM is not known in an Irish context.
Methods
This is a retrospective cohort study of AM patients with melanoma diagnoses made in 2019 in two large Irish hospitals (Beaumont Hospital (BH) and Cork University Hospital (CUH)).
Results
A total of 175 patients in CUH and 97 patients in BH met the eligibility criteria for further assessing their records. Following examination of the medical records and checking the histology reports, a total of 25 (14.4%) in CUH and 21 (22%) in BH were identified as amelanotic resulting in an overall prevalence of 16.9%. Incidence was calculated based on the size of the target population in the area covered by the two hospitals. Based on this population, the incidence of AM was calculated to be 5.41 per 100,000 population.
Conclusion
Our study has identified a major discrepancy between the figures supplied by the national cancer registry of Ireland, who report a prevalence of 0.5%, and our finding of 17% in two hospitals in Ireland. AM is far more prevalent than reported in an Irish context 9. This underreporting has important implications for the detection of AM. It is known that AM can present with an increased Breslow thickness which is associated with worse outcomes and decreased overall survival.
75. Frailty as a Predictor of Adverse Outcomes in Head and Neck Reconstruction: A Systematic Review
Dhruv Kapoor 1 , Eoin Cleere 2 , Ciaran Hurley 1 , Catherine de Blacam 1 , Christoph Theopold 1 , Eamon Beausang 1
1. Plastic and Reconstructive Surgery, St James's Hospital, James Street, Dublin 8, Ireland;
2. Otolaryngology Head and Neck Surgery, Galway University Hospital, Galway, Ireland
Introduction:
Frailty has been shown to adversely impact outcomes in a number of surgical disciplines. In head and neck reconstructive surgery, frailty represents a risk factor that may aid in predicting post-operative adverse outcomes in a surgical population that is typically at high risk of complications.
Aim:
To summarise the available evidence about frailty as a predictor of postoperative complications, length of hospital stay and quality of life, in patients undergoing head and neck reconstructive surgery.
Method:
A prospectively registered (PROSPERO - CRD42022302899) systematic review in keeping with PRISMA guidelines was performed. MEDLINE, EMBASE, Scopus and Cochrane databases were assessed. Bias was assessed via Newcastle Ottawa Scores. All eligible articles evaluating the effect of pre-operative frailty on peri-operative surgical, social and quality of life related outcomes were included. Qualitative synthesis was undertaken due to heterogeneity in the reporting of outcomes.
Results:
Nine studies, which reported data on 10,323 patients undergoing reconstruction of the head and neck were included in the review. A number of different tools were used to assess frailty, with the modified frailty index used most frequently. In total, 8 studies reported increased rates of complications in patients with increased levels of frailty, irrespective of the frailty tool used.
Conclusion:
An association is observed between increased rates of peri-operative complications and increased levels of frailty in patients undergoing head and neck reconstruction. Frailty tools may represent a useful method to risk stratify patients undergoing reconstructive head and neck surgery.
76. The Lessons Learned From Managing Malignant Melanoma during COVID-19 in a Plastic Surgery Unit in Ireland
Amenah Dhannoon 1 , Ciaran Martin Hurely 2 , Laura Wrafter 2 , Padraic J Regan 2
1. Surgery, Beaumont University Hospital, Ireland;
2. Plastic and Reconstructive Surgery, Galway University Hospital Ireland.
Introduction
The COVID-19 pandemic has resulted in a pragmatic shift in practice of plastic surgery units worldwide. During this period, many units reported a significant fall in urgent melanoma referrals, resulting in presentation with advanced disease.
Aim
Our objective was to evaluate our units experience with both non-invasive and invasive melanoma during the COVID-19 pandemic and compare it to that experienced by our neighbours in the UK, mainland Europe and North America.
Methods
A retrospective chart review was performed on all patients diagnosed with invasive and non-invasive cutaneous melanoma between March to December of 2019 (control) compared to 2020 (COVID-19 pandemic) in a single plastic surgery unit in Ireland.
Results
A total of 589 patients were included in the study. Of these, 314 (53%) with invasive melanoma, compared to 275 (47%) with non-invasive disease. Overall, more patients were diagnosed with both invasive and non-invasive melanoma in 2020 than 2019 (p < 0.05). However, significantly longer waiting times in 2020 (64 days) compared to 2019 (28 days) (p < 0.05) with the majority of referral being from GP in 2019 (83%) compared to 61% in 2020. Positive sentinel lymph node were higher in 2019 at 56% (n = 28) compared to 24% (n = 22) in 2020. There was no statistical significant difference in the tutor characteristics or metastasis status.
Conclusion
Our study highlights that with prompt efficient restructuring of services, effective telemedicine triaging system, specialised skin cancer nurse with regular virtual skin cancer MDT, we could reserve successful management of skin cancer even in the most devastating times.
77. The Psychology of Surgery - the Application of High-Performance Sports Psychology to Surgical Training
Gary Fenn 1 , Stephanie Bollard 1 , Christine Quinlan 1 , Shirley Potter 1 , Kate Kirby 2 , James Matthews 3
1. Plastic and Reconstructive Surgery, Mater Hospital, Mater Hospital, Eccles St, Dublin 7, Ireland;
2. Sport Ireland Institute, Sport Ireland Institute, Dublin, Ireland;
3. UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland
Introduction
Surgery is a craft-specialty, and like elite sport, successful training relies upon mastery of motor skills, as well as maintenance of concentration and management of stress. In the sporting setting, training in techniques to refine concentration, regulate emotion and sustain motivation, are commonplace, and may be applicable to surgery.
Aim
This study aims to assess the impact of mental skill training, based upon techniques used in high-performance settings, on performance anxiety levels of surgical trainees.
Methods
A prospective cohort study was performed, inviting surgical trainees to attend two small group mental skills training sessions led by an experienced Sports and Performance Psychology faculty. The programme delivered was designed around the Biopsychosocial model of Challenge and Threat. Performance anxiety was measured using the Sports Anxiety Scale-2 (SAS-2), which assesses somatic, worry and concentration disruption, before and after the workshop.
Results
The programme was attended by n = 9 trainees, with a median age of 31 years [25–39], and median training level of ST5 [1–8]. The mean pre-workshop SAS-2 score was 32. All participants reported using the techniques at least one to three times per week following the workshops. A significant decrease was seen in the SAS-2 scores, with a mean post-workshop score of 23 (p = 0.038). There was also a significant decrease observed in the mean ‘worry’ score (p = 0.017).
Conclusion
Dedicated mental skills training, using techniques utilised in high-performance settings, reduces the performance anxiety scores of surgical trainees. This is likely indicative of an improvement in self-regulation skills in stressful performance settings.
78. The Spiderman Sign - a Novel Method to Identify the Distal End of the Carpal Tunnel
Darren Mc Cormack, Ryan Sugrue
Plastic Surgery, Connolly Hospital, Blanchardstown, Dublin 15, Ireland
Aim
Identify the distal end of the carpal tunnel safely and effectively, by passive flexion of their ring and middle finger.
Method
We assessed 20 patients, prior to carpal tunnel decompression surgery and recorded the findings. A number of measurements were taken. The line at which the flexed ring and middle finger lay on the palm was marked, then following surgical exploration measurements were made with the distal end of the carpal tunnel and assessed how accurately this lined up with our pre-operative markings.
Results
Of 20 patients assessed the distal end of the carpal tunnel aligned with the pre operative markings made using the patients flexed fingers. 100% of cases the pre operative markings aligned with the distal end of the carpal tunnel found on surgical exploration.
Conclusion
There are various methods described to identify the distal end of the carpal tunnel. We feel our technique is a simple and effective method using the patients’ own anatomy to identify this important landmark, which we call the Spiderman sign.
79. TOxin for Treating Raynaud’s Conditions in Hands (The TORCh Study): A Systematic Review
Ellen Geary 1 , Patrick Gorman 1 , Kealan Blake 2 , Justin Wormald 3 , Roisin Dolan 2
1. UCD School of Medicine, St Vincent's University Hospital, Elm Park, Dublin, Ireland;
2. Plastic and Reconstructive Surgery Department, St Vincent's University Hospital, Dublin, Ireland;
3. University of Oxford, United Kingdom
Introduction
Raynaud’s disease of the hands is a complex disorder resulting in inappropriate constriction and/or insufficient dilation in microcirculation. Raynaud’s disease unresponsive to medical therapy is a significant problem for patients which can have a debilitating impact on a patient’s quality of life but a potential breakthrough in treatment could be found in botulinum toxin type-A (BXT-A).
Aim
The aims of this systematic is to qualitative synthesize the available literature to assess if BTX-A can prove an effective management strategy for primary and secondary Raynaud’s disease. Our secondary aim is to provide evidence for the design of a randomised control trial for using BXT-A in Raynaud’s disease.
Method
A medical librarian performed a literature search per PRISMA guidelines and for eligible articles using the Medline/PubMed database and Cochrane Collaboration to include studies up to, and including September 22nd 2021. Outcomes analysed were primary outcomes of each respective study; including visual analogue scale (VAS) score, healing of digital ulcers and disabilities of the arm, shoulder and hand (DASH) scores.
Results
In total, there 419 number of patients. With regards to primary outcomes assessed eight studies were concerned with improvement in VAS scores (75.7% of patients reported improvement). Nine healing of digital ulcers (74.2% of patients reported improvement). Five studies distinctively outline improvement in episodes (77.5% of patients reported improvement). Four studies reported improvement in temperature readings (78.3% of patients reported improvement).
Conclusion
This study illustrated that BTX-A can appears to be an effective management strategy for primary and secondary Raynaud’s disease.
80. A Needle in a Haystack
Lukas O Brien 1 , Mary-Ellen McMahon 2 , Ronan Cahill 3 , James Jones 4 , Barry O Sullivan 2 , Shirley Potter 1
1. Plastic Surgery, Mater Hospital, Eccles St, Dublin 7, Ireland;
2. Plastic Surgery, Beaumont Hospital, Beaumont, Dublin, Ireland;
3. Surgery, Mater Hospital, Eccles St, Dublin 7, Ireland;
4. Anatomy, University College Dublin, Belfield, Dublin 4, Ireland
Introduction
Unintentional intra-operative loss of surgical needles is a serious, yet infrequent complication during surgery. Suture calibre used for microvascular free flaps range from 8–0 to 10–0 sizes, making recovery of such needles difficult. Hospital protocols often recommend an intra-operative portable x-ray to locate the needles. There is a currently no evidence as to whether needles are visible on conventional xray.
Methods
Following ethical approval, sutures of varying needle calibres (3–0 to 10–0 Ethilon TM Ethicon) were placed on a cadaver. X-ray’s were obtained before and after needle placement. The sites imaged were the lower leg, forearm, chest, and neck, chosen to represent the areas most commonly involved in microsurgical procedures. Consultant and trainee surgeons, radiologists, and nursing staff were asked to identify the needles on the xray images.
Results
Of the 23 respondents, all participants successfully located 3/0, 4/0 5/0 and 6/0 needles on plain xrays taken at each of the 4 anatomical sites. Only 2 of the 23 participants were able to successfully localise an 8/0 needle, one on the neck xray and one on the forearm xray. None of the participants were able to successfully localise the 9/0 or 10/0 needles at any of the anatomical sites.
Conclusion
Portable xray has a definite role to play in the event of loss of needles size 3/0 to 6/0. This study has proven that suture needles smaller than 8/0 cannot be reliably detected on xray, and this modality is therefore not recommended. Hospital protocols should reflect this.
81. Applying Human Reliability Analysis to Identify and Reduce Risks in Carpal Tunnel Decompression
Áine Lucey, Sharon Kennedy, Alan Hussey, Niall Mcinerney, Jack Kelly, Kenneth Joyce
Plastic and Reconstructive Surgery, Galway University Hospital, Galway, Ireland
Introduction
Many surgical procedures are prone to human error, particularly in the learning phase of skill acquisition. Standardisation has been suggested as an approach to reducing such errors. This study used human reliability analysis methodologies to examine carpal tunnel decompression.
Methods
The subgoals, or individual steps, required to complete a carpal tunnel decompression were identified using hierarchical task analysis (HTA). The systematic human error reduction and prediction approach (SHERPA) was carried out by consensus of Subject Matter Experts in the Department of Plastic Surgery. This identified the potential human errors at each subgoal, the level of risk associated with each task and how these potential errors could be prevented.
Results
Carpal tunnel decompression was broken down into 46 subgoals, of which 21 (45%) were medium risk and 25 (55%) low risk. Of the 46 subgoals, 4 (9%) were assigned high probability, 18 (39%) assigned medium probability. High probability errors (> 1/50 cases) included selecting incorrect tourniquet size, failure to infiltrate local anaesthetic in a proximal-to-distal direction and completing WHO sign-out. Three (6%) of the subgoals were assigned high criticality which included failure to aspirate prior to anaesthetic injection, while 21 (45%) were assigned medium criticality and 22 (48%) were assigned low criticality. Remedial strategies for each potential error were then devised in order to reduce errors.
Conclusion
The use of human reliability analysis techniques provides surgeons with a platform to performing surgical procedures and identify critical steps which are prone to error. This approach will improve surgical training and enhance patient safety by reducing technical errors.
SESSION 12: TRAUMA AND ORTHOPAEDIC SURGERY
82. A Retrospective Analysis of the Incidence and Radiographic Parameters of Patients with Acetabular Protrusio Presenting For A Primary Total Hip Arthroplasty in a Tertiary Referral Centre in the Republic of Ireland.
David O Sullivan, Patrick Carroll, William Curtin, Colin Murphy
Trauma and Orthopaedic Surgery, Galway University Hospitals, Galway, Ireland
Introduction
Protrusio Acetabuli (PA) is defined as the medialisation of the femoral head relative to köhler's line and its incidence internationally is 5%. PA is multifactorial. Total Hip Arthroplasty (THA) is challenging in patients.
Aim
The aim of this study was to document the incidence of PA, the medical conditions associated with it and the technical challenges encountered in planning THA in this cohort.
Method
A retrospective analysis of patients presenting to our institution for an elective THA was performed. Radiographs were examined and the medialisation of the femoral head to köhler's line was used as the diagnosis of PA. In this cohort, a patient's medical condition or diagnosis was searched for. PA severity pre-operatively and lateralisation distance on post-operative radiographs was measured.
Results
The pre operative radiographs of 508 patients presenting for an elective THA over six years were reviewed. PA was identified in 4.3% (22/508) of patients, 73% female and 63% involving the right leg. 86% of THA were uncemented. Idiopathic PA was diagnosed in 55%, inflammatory arthropathy in 9% and cancer in 23%. Mean protrusion distance was 6.8 mm and mean lateralisation 9.59 mm.
Conclusion
The incidence of PA in our catchment area is in line with international incidence rates. These patients require considerable pre-operative planning and complex acetabular reconstruction. We propose the joint registry allows for the diagnosis of PA be included in its data collection.
83. Bibliometric Analysis on Top 50 Cited Randomised Controlled Trials in Shoulder and Elbow Surgery
Conor Kilkenny 1 , Eoghan Hurley 2 , Tom Moore 1 , Robert Hurley 2
1. Orthopaedic Surgery, Galway University Hospital, Galway, Ireland;
2. Orthopaedic Surgery, Mater University Hospital, Dublin, Ireland
Introduction
Bibliometric studies are valuable and interesting forms of research in assessing the impact of literature in a given field.
Aim
The purpose of this study was to assess the impact the top 50 cited Randomised Controlled Trials in Shoulder and Elbow Surgery are having on this subspecialty.
Methods
A Web of Science search with the keyword search of Shoulder and Elbow Surgery and Randomised Controlled Trial was performed. The top 50 cited studies were included. Data extracted were; Year most studies were published, most prominent Journals, country with most publications, number of patients involved in study, follow up time, pathology being studied and a fragility index was calculated.
Results
2011 was the most impactful year in terms of studies published with 11 papers published. The most prominent journal was The Journal of Shoulder and Elbow Surgery with 24/50 papers. Most of these studies were produced in USA with 14 papers. Follow up ranged from 0–30 months with the average follow up time being 13.7 months. Patient numbers in each study ranged from 20–660 with the average of 92. The most common pathology studied was rotator cuff tear with 22 studies. Fragility Index was calculated in 29/50 studies ranging from 0–10. 15 studies had a fragility index > 0.
Conclusion
This study analysis the most significant studies in the area of shoulder and elbow surgery. Interesting data can be concluded from this research however more high quality, less fragile and statistically significant research is needed in this sub-speciality.
84. Olecranon Fractures: Quality and Readability of Information Online
Heather Hassett, Gabrielle McDonagh, Geoff Crozier-Shaw, John Kelly
Trauma and Orthopaedic Surgery, Sligo University Hospital, Sligo, Ireland
Introduction
Patients are consuming more information online than ever before. This can lead to confusion and anxiety when reading information of poor quality, or that which is aimed at clinicians.
Aim
We aim to assess the quality and readability of online information on olecranon fractures.
Methods
Google, Bing and Yahoo were searched using terms “patient information on olecranon fractures”. DISCERN, JAMA, Health on the Net (HON), and an olecranon specific score measured quality and Flesch-Kincaid score assessed readability.
Results
70 unique websites were identified, 32 results being academic/physician focused, 38 being patient-focused. Mean Discern score was 47 for academic/physician websites, and 39.5 for patient focused (p = 0.0116). JAMA criteria were fulfilled in 43% of academic websites and 0% of the patient websites (p = 0.0001). The HON criteria were met in 9% of academic websites and 0% of patient websites (p = 0.09). For olecranon specific score, academic sites scored a mean of 1.84 compared to 1.11 mean score for patient websites (p = 0.04). On average, patient-aimed websites needed a higher reading level as compared to academic sites, mean score of 40.02 and 58.9 respectively (p = 0.0001).
Conclusion
This study found that online information on olecranon fractures was of poor quality and was often presented at an inappropriately high of a reading level, even on patient specific websites. Health care providers should direct them towards appropriate online resources when discussing management of their olecranon fractures.
85. Orthopaedic Trainee Knowledge of Metastastic Bone Disease
Ali Donnelly, Iain Feeley, Gary O’Toole, Alan Molloy
Department of Orthopaedic Surgery, St Vincent’s University, Elm Park, Dublin 4, Ireland
Introduction
Increased survivorship in patients with cancer has resulted in an increased incidence of patients presenting to orthopaedic services with metastatic bone disease. In response to this the British Orthopaedic Oncology Society and the British Orthopaedic Association produced guidelines on the best practice in metastatic bone disease.
Aim
To assess orthopaedic trainee knowledge and awareness of the guidelines for best practice in metastatic bone disease.
Method
We produced a survey of 20 questions from the guidelines but based on everyday practice in orthopaedic patients with metastatic bone disease. We also collected data based on trainee experience, prior exposure to orthopaedic oncology and whether they were pre or post FRCS examination.
Results
There was an 83% response rate to the survey. 45% of trainees were aware of the guidelines – this ranged from 20% awareness at ST3 to 100% awareness at ST8. The median score to the questionnaire was 60% (25%–90%). Those post FRCS exam scored a median of 75%, as did those with an exposure to orthopaedic oncology. The remaining scored a median of 55%. Scores did increase as training progressed. Analysis of the individual questions demonstrated a poor knowledge of the adjunct therapies and scoring systems in metastatic bone disease but a good understanding of the work-up and basic principles in surgical fixation.
Conclusion
Metastatic bone disease will be a more common presentation to future orthopaedic surgeons. Current trainees are not sufficiently aware of the current guidelines and potentially require more focused training in this area.
86. Prophylactic Use of Local Antibiotics in Open Fractures: A Systematic Review and Meta-Analysis
Dhruv Kapoor 1 , Ross Condell 2 , Niamh Kennedy 3 , Peyman Bakhshayesh 4
1. Trauma Science, Blizard Institute, Queen Mary University of London, London, United Kingdom;
2. Surgery, Galway University Hospital, Galway, Ireland;
3. Surgery, St James's Hospital, James Street, Dublin 8, Ireland;
4. Orthopaedic Trauma, Major Trauma Centre, Leeds General Infirmary, Leeds, United Kingdom
Introduction
The management of open long bone fractures is well described and has been standardised through a number of well established guidelines. However there is no consensus regarding the application of local antibiotics into the open fracture site as a means of reducing infection rates.
Aim
To summarise the literature and to assess if the prophylactic addition of local antibiotics to the standard treatment reduces infection rates at long bone open fracture sites.
Method
A systematic review and meta-analysis was undertaken as per PRISMA guidelines. PubMed, Embase, Scopus and CENTRAL were the databases assessed. The Newcastle Ottawa Scale and the Rob 2 Tool were used to assess bias. A qualitative synthesis of all included studies and meta-analysis of suitable subgroups was undertaken.
Results
In total, 12 studies (11 observational, 1 RCT) assessing 2431 open fractures were included for analysis. All compared the addition of a local antibiotic therapy to a standard treatment versus the standard treatment alone. The methods of delivery were vancomycin powder (4 papers), tobramycin polymethylmethacrylate beads (4 papers), gentamicin coated intramedullary (IM) nails (2 papers), gentamicin injections (1 paper) and antibiotic released IM core cement (1 paper). The addition of vancomycin powder did not decrease infection rates in comparison to intravenous antibiotics alone (OR 1.3, 95% CI (0.75–2.26)).
Conclusion
There are numerous methods available to deliver antibiotics locally to an open fracture site. Further high quality research is required to provide a definitive conclusion on their efficacy irrespective of delivery method.
87. Trauma Surgery Consent Documentation in Ireland
Mohamed ElZayat, Simon Callaghan, Geoffrey Crozier-Shaw, John Kelly
Orthopaedic Surgery, Sligo University Hospital, Sligo, Ireland
Aim
Ireland does not currently have a uniform and standardised method in which the consent proves is routinely documented. This study was designed to evaluate the standard consent forms used in trauma orthopaedic hospitals across Ireland while also evaluating the current guidelines regarding consent documentation in the trauma setting from Ireland and the UK.
Methods
Standard consent forms were obtained from the 16 public hospitals where trauma orthopaedic surgery is performed. These were analysed and compared based on the inclusion or exclusion of 22 unique consent related items or statements selected by the authors. Additionally the consent forms were analysed for readability, word count and format.
Results
Within the 16 public hospitals where trauma orthopaedic surgery is performed there are a variety of unique consent forms in use. There was a mean inclusion of 9 of the 22 unique items per form. This indicates many units are not utilising comprehensive consent documentation. The mean Flesch Reading Ease score was 45. The format varied throughout the consent forms and ranged in length from 1 to 4 pages.
Conclusion
This study shows the lack of uniformity being used in consent forms throughout the trauma orthopaedic units across Ireland both in terms of format and content. A national standardised consent documentation method may be useful to improve efficiency, patient experience and decreased litigation.
88. Published.
https://link.springer.com/article/10.1007/s11845-022-02939-6
89. Subscapularis Management during Open Latarjet Procedure- Does Subscapularis Split versus Tenotomy Matter? A Systematic Review & Meta-Analysis
Martin Davey, Matthew Davey, Eoghan Hurley, Hannan Mullett
Sports Surgery Clinic, Dublin, Ireland
Introduction
The aim of this study was to perform a systematic review and meta-analysis assessing clinical outcomes of open Latarjet (OL) procedure using either a Subscapularis Split (SS) or Tenotomy (ST).
Methods
A systematic review was performed as per PRISMA guidelines with studies reporting outcomes of OL procedure via a deltopectoral (DP) approach comparing both SS and ST being considered for inclusion.
Results
Overall, 5 studies including 615 shoulders (80.8% males), with average age of 27.8 ± 12.6 years (15–79) and mean follow-up of 50.1 ± 29.4 months (12–180) were included. There were 410 and 205 shoulders who underwent OL procedure via a DP approach using ST and SS techniques respectively, with both techniques resulting in significant increases in the Rowe scores postoperatively (both p < 0.0001). Additionally, there were significantly higher postoperative Constant scores in those who underwent OL using a SS technique, versus those in the ST groups (91.8 ± 7.2 vs 79.6 ± 16.1, p < 0.0001 respectively). Furthermore, there were significantly more patients in the ST group who were lift-off test positive when compared to the SS group at final follow-up (2.7% versus 10.0%, p = 0.01). However, the rate of recurrent instability was trending towards significance in favour of the SS group (0% vs 11.7%, p = 0.07).
Conclusion
For OL procedures being carried out via DP approach, the SS technique results in significantly better functional outcome measures and significantly lower rates of subscapularis insufficiency.
90. Orthopaedics Operative Notes Auditing, Improving Clinical Performance
Mohamed ElZayat, Annis Maatough, Ahmed Karkuri, John Kelly
Orthopeadic Surgery, Sligo University Hospital, Sligo, Ireland
Introduction
Precise and accurate documentation of surgical operative notes are pivotal in the postoperative care of patients. This prospective study audited the quality and completeness of documentation of all orthopaedic surgical operation performed in our unit over a 3 weeks period. Notes were assessed and compared to best practice guidelines from the Royal College of Surgeons in Ireland (2004) Good Surgical Practice guidelines and Code of Practice for Surgeons (2018).
Aim
The aim of this study was to audit performance and introduce a new operative note system, thereby improving clinical and compliance with best practice guidelines.
Method
A total of 50 operation notes were prospectively collected in a 3 week period. Documentation was measured against all 14 standards described in the Royal College of Surgeons Ireland guidelines. A list of suggested points and recommendations, including an operative proforma were formulated be presented to attempt and improve our operative documentations. Re-audit was performed and showed improvement in all standards.
Results
Our preliminary results showed that the current documentations are significantly deficient. We have recorded 100% adherence in documenting operative procedures and closure technique. But poorly in many other areas such as documenting the type of surgery (Elective or Emergency), operative time, date and medical council registration number. Re-Audit followed after 3 months of introduction of changes and new perfume and showed 95% improvement in all areas of standards described by the RCSI.
Conclusion
This study has demonstrated significant deficiencies in how operative procedures are recorded. This has facilitated the development of a new structured operative note which successfully meets all the RCSI recommended criteria, which has been introduced successfully to our unit.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
| 36471125 | PMC9734742 | NO-CC CODE | 2022-12-14 23:28:30 | no | Ir J Med Sci. 2022 Dec 6; 191(Suppl 6):187-237 | utf-8 | Ir J Med Sci | 2,022 | 10.1007/s11845-022-03228-y | oa_other |
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Landsc Ecol
Landsc Ecol
Landscape Ecology
0921-2973
1572-9761
Springer Netherlands Dordrecht
1560
10.1007/s10980-022-01560-3
Research Article
Drivers of invasion by laurel wilt of redbay and sassafras in the southeastern US
http://orcid.org/0000-0002-3206-4880
Ward Samuel F. [email protected]
http://orcid.org/0000-0003-1424-4113
Riggins John J.
grid.260120.7 0000 0001 0816 8287 Department of Biochemistry, Molecular Biology, Entomology, and Plant Pathology, Mississippi State University, Starkville, MS 39762 USA
8 12 2022
115
9 8 2022
12 11 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Context
Timely responses to mitigate economic and environmental impacts from invading species are facilitated by knowledge of the speed and drivers of invasions.
Objective
Quantify changes in invasion patterns through time and factors that governed time-to-invasion by laurel wilt, one of the most damaging, non-native disturbance agents invading forests of the United States.
Methods
We analyzed county-level occurrence data (2004–2021) for laurel wilt across the southeastern United States. A Cox proportional hazards modeling framework was used to elucidate drivers of invasion.
Results
As of 2021, laurel wilt had been detected in 275 counties and made 72 discrete jumps (averaging 164 km ± 16 SE) into counties that did not share a border with a previously invaded county. Spread decelerated from 40 km/yr to 24 km/yr after 5 years, with a marked decline in the number of counties invaded in 2021 (16) compared with 2020 (33). The Cox proportional hazards model indicated that proxies for anthropogenic movement and habitat invasibility increased invasion risk.
Conclusion
The recent decline in number of counties invaded could be due to disruptions to travel and/or surveys from the coronavirus pandemic, but exhaustion of the most suitable habitat, such as counties in the southeastern US with warm annual temperatures and high densities of host trees, could have also contributed to this trend. This work suggests that without a shift in spread driven by additional insect vectors, that rates of range expansion by laurel wilt might have peaked in 2020 and could continue decelerating.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10980-022-01560-3.
Keywords
Ambrosia beetles
Harringtonia
Invasion
Laurel wilt
Spread
Vector
Xyleborus
http://dx.doi.org/10.13039/100009168 Animal and Plant Health Inspection Service APP-16912 Ward Samuel F. http://dx.doi.org/10.13039/100005825 National Institute of Food and Agriculture Hatch projects under accession numbers 1025843 and 1018710 Hatch projects under accession numbers 1025843 and 1018710 Ward Samuel F. Riggins John J. Mississippi Agricultural and Forestry Experiment Station
==== Body
pmcIntroduction
Following establishment, the ability to predict spread is integral to managing biological invasions (Liebhold and Tobin 2008). The establishment of non-native species is expected to continue (Seebens et al. 2021), despite increased efforts to strengthen biosecurity measures (Haack et al. 2014; Poland and Rassati 2019). Increases in international shipping and resulting use of solid wood packaging material have driven increased arrival rates of bark and ambrosia beetles (Aukema et al. 2010; Meurisse et al. 2019; Lantschner et al. 2020), and multiple biosecurity measures (e.g., International standard for phytosanitary measures No. 15 (ISPM 15)) have been developed to prevent invasions by bark and wood-boring insects. Species of ambrosia beetles have continued to invade (Gugliuzzo et al. 2021), however, including in countries requiring ISPM-15 compliance such as the United states (US) (Coleman et al. 2019), United Kingdom (Inward 2020), and New Zealand (Ministry for Primary Industries 2019), among others.
The spread of invading insects is driven by short-distance dispersal via natural means (e.g., flight, crawling) and long-distance dispersal typically via human activities. Regarding domestic invasion pathways, the movement of firewood is considered the most frequent mode of long-distance dispersal for bark and woodboring insects (Meurisse et al. 2019; Solano et al. 2021). There is substantial variation in spread rates within and among invasions by woodboring insects, as spread of Agrilus planipennis (Coleoptera: Buprestidae) varied through time from 13.8 to 55.7 km/yr (Ward et al. 2020) and spread of Sirex noctilio (Hymenoptera: Siricidae) varied among regions of the southern hemisphere from 11.7 to 78.0 km/yr (Lantschner et al. 2014). Variation in rates of spread might be driven by differences in life history traits and/or habitat features (Lantschner et al. 2014; Fahrner and Aukema 2018; Nunez‐Mir et al. 2022), but the patterns and drivers of spread for invading ambrosia beetles—some of which cause severe economic and environmental damage by vectoring pathogenic fungi (Hulcr and Dunn 2011; Ranger et al. 2015; Coleman et al. 2019; Gugliuzzo et al. 2021; Olatinwo et al. 2021)—are not well understood.
Knowledge of the factors that govern spread of ambrosia beetle species could guide monitoring and trapping efforts and allow management agencies to budget and prepare for invader arrival (Sharov et al. 2002; Sadof et al. 2017). Both bark and ambrosia beetles, along with their fungal symbionts, can be vectored in firewood (Jacobi et al. 2012). However, despite having similar life histories to bark beetles, ambrosia beetles exhibit different invasion patterns, appearing more likely to undergo contiguous spread with fewer long-distance jumps (Rassati et al. 2016). Ambrosia beetles also have obligate mutualisms with fungi that they vector and feed on exclusively, and some ambrosia beetle species are parthenogenic and/or inbreeding (Andersen et al. 2012; Kirkendall et al. 2015). These life history traits might mediate their ability to invade, for example, depending on the diet breadth of mutualistic fungi or presence of parthenogenesis that might facilitate host procurement or reduce Allee thresholds, respectively (Hughes et al. 2017).
Laurel wilt is an insect-pathogen complex involving the primary vector, Xyleborus glabratus Eichhoff (Coleoptera: Curculionidae; redbay ambrosia beetle), and the damaging fungus, Harringtonia lauricola T.C. Harr., Fraedrich & Aghayeva (Ophiostomatales: Ophiostomataceae) (Kendra et al. 2013; Olatinwo et al. 2021; De Beer et al. 2022). This complex, native to Asia (Rabaglia et al. 2006; Hulcr and Lou 2013; Wuest et al. 2017), is one of the most virulent non-native disturbance agents in forests of the United States (US) (Hughes et al. 2017; Fei et al. 2019). Redbay ambrosia beetle was initially detected in the US near Port Wentworth, GA in 2002 (Rabaglia et al. 2006), with redbay mortality first attributed to laurel wilt in 2003 (Fraedrich et al. 2008; Harrington et al. 2008). Multiple species of Lauraceae are highly susceptible to laurel wilt, including avocado trees (Persea americana), a major concern for the commercial avocado industry (Mayfield et al. 2008; Kendra et al. 2013) that in 2013 was valued at US$14 million and US$415 million in Florida and California, respectively (Kendra et al. 2013). Despite the ongoing threats posed by laurel wilt to both forests and agroecosystems, little is known about the relative importance of factors, such as propagule pressure versus habitat invasibility, contributing to spread at regional scales.
The distribution of laurel wilt in the US is non-contiguous, seemingly achieved by diffusive spread and long-distance jumps (Liebhold and Tobin 2008). Investigations during the early stages of the invasion (2004–2006) indicated that spread was proceeding at approximately 55 km/yr and that invasion speed was likely to be influenced by host density and suitable climate (Koch and Smith 2008). Now that the invasion has progressed over another decade, several aspects of spread and invasion risk remain unknown. Our specific objectives were to quantify (i) any changes in rates of spread through time, (ii) the frequency and distance of long-distance jumps, and (iii) the effects of spatial contagion, forest composition, climate, and human activities on invasion risk. We hope this research will help identify factors that mediate county-level invasion risk and provide insight into the invasion dynamics of laurel wilt and, potentially, other economically and ecologically damaging insect-pathogen complexes.
Materials and methods
Invasion data
County-level data on the occurrence (presence/absence) and year of invasion (2004–2021) for laurel wilt were obtained in February 2022 from the Georgia Forestry Commission (Fig. 1). The database has been updated annually based on reports from state, federal, and university forest health experts from across the southeastern US. These reporting efforts are passive and not achieved through targeted aerial surveys aimed at detecting new infestations. Although laurel wilt is a highly virulent disease that can kill naïve North American host trees such as redbay and sassafras within weeks of initial infection (Fraedrich et al. 2008; Olatinwo et al. 2021), there is potentially a lag between establishment and detection in a county (Riggins et al. 2010) for which we were unable to account. For example, laurel wilt could have been in a county for multiple years prior to someone (e.g., a forest health specialist or landowner) noticing the disease symptoms, with detection lags potentially owing to limitations of resources for surveys and/or reporting lags by non-specialists. Moreover, even if an infestation was limited to a single stand of trees, the entire county would be recorded as invaded. Our analyses of the invasion were thus conducted on a coarse scale (county-level), potentially resulting in overestimated rates of spread. Limitations on survey and reporting efforts, as well as reporting methodology that documents invasion at the county-level, should be considered when interpreting our findings.Fig. 1 County-level invasion by laurel wilt in the southeastern US (2004–2021)
We conducted several analyses of the county-level invasion data to provide insight into patterns and drivers of laurel wilt spread. For all analyses, the first discovery point was set at 32.1480°N and 81.1629°W near Port Wentworth, GA and distances between counties were estimated using county centroids. Spatial data were projected with the Albers equal-area conic projection (NAD 1983). Spatial and statistical analyses were conducted using R (R Core Team 2021) and the following packages: geosphere (Hijmans 2019), ggpubr (Kassambara 2020), sd (Pebesma 2018), sp and spdep (Bivand et al. 2013), terra (Hijmans 2021), tidyverse (Wickham et al. 2019).
Historical spread
Spread rates were estimated by calculating the effective range radius (Shigesada et al. 1995), equivalent to the approach used by Koch and Smith (2008) to estimate annual rates of spread for this disease in the first three years following detection of tree death. This method entails summing the area of counties invaded per year (A), multiplying that value by two to reflect the semicircular distribution of the invasion (2 × A), dividing 2 × A by π, taking the square root ((2×A)/π=r), and, lastly, regressing r on year. To verify our approach was equivalent to Koch and Smith (2008) and quantify potential changes in spread rates since their analyses, three time intervals were evaluated: (i) 2004–2006 (i.e., the time interval evaluated by Koch and Smith (2008)), (ii) 2006–2021, and (iii) 2004–2021 (i.e., the entire time series). Additionally, a piece-wise regression analysis was conducted using the segmented package in R (Muggeo 2008), enabling us to quantitatively detect potential shifts in radial spread rates through time.
We then categorized each invaded county as either contiguous or non-contiguous. Contiguous counties were those with at least one invaded neighboring county at the time of their invasion, whereas non-contiguous counties had no known previously invaded neighboring counties. We use long-distance or discrete jumps here to refer to invasion of non-contiguous counties, and we assume such events were achieved with assistance from humans or—although we do not consider it a key driver—aeolian dispersal. We also caution that within county spread likely includes discrete jumps over shorter distances, but the county-level resolution of the data—the highest available for laurel wilt at regional scales—preclude accounting for such dispersal events. The number of counties invaded per year was quantified for each of the three county designations (all counties, contiguous counties, and non-contiguous counties) and length of discrete jumps (mean ± SE, median) into non-contiguous counties was estimated.
County-level drivers of spread
Cox proportional hazards (CPH) models were developed using the survival package in R (Therneau and Grambsch 2000; Therneau 2021) to identify county-level correlates of invasion risk. Annual county-level invasion data can be treated as “time-to-event” data that are amenable to survival model techniques such as CPH models (Hastings et al. 2005; Ward et al. 2020). Cox proportional hazards models can be particularly useful for modeling invasions because, in addition to time-independent predictors (e.g., mean annual temperature or human population density), they can incorporate time-varying predictors (Thomas and Reyes 2014; Therneau et al. 2022): as the area invaded grows the invasion risk to different counties changes. For example, when laurel wilt makes a long-distance jump to a given county i, the counties neighboring county i become at higher risk. Cox proportional hazards models can account for this phenomenon via incorporation of a time-varying predictor that adjusts the annual risk accordingly (Thomas and Reyes 2014; Ward et al. 2020). These models require events to be reported in intervals of time, such as a detection of laurel wilt reported between the start of year i to year i + 1 (i.e., 2004–2005, 2005–2006, …, 2021–2022). Each county was assigned a “0” until invasion occurred, at which point a”1” – indicating the occurrence of an event (invasion)—was assigned. Structuring the data for this analysis meant that each county appeared in the data set “invasion year—2004″ times, as we assumed that counties could not become uninvaded (no successful eradications of laurel wilt have been reported). For example, if a county was invaded in 2004, it was assigned a “1″ for the 2004–2005 interval and would not be associated with future intervals (e.g., 2005–2006, 2006–2007, etc.); counties that were not invaded through 2021 thus appeared 18 times each in the analysis. The response variable was “time to county-level invasion” and the unit of observation was individual county.
All candidate models were developed on invasion data from 2005 to 2018, with 2019–2021 (79 invaded counties, ~ 30% of total invaded counties) withheld for evaluating model predictions (see “Future spread” below). We excluded three county detections in 2004 from the response side of the model (i.e., counties invaded in 2004 still contributed to propagule pressure estimates, described below), given that no counties were reported as invaded prior to 2004 (meaning that using the previously invaded range to estimate propagule pressure was infeasible for those instances). We developed a predictor to account for the spatial contagion s for each county i estimated on an annual basis using an inverse-distance weighted metric:1 si=∑j=1J1dij2
in which d is the distance between county i and each previously invaded county j (Mally et al. 2021). The spatial contagion variable was estimated for each county in each year to account for annual changes in the invaded range of laurel wilt. Spatial contagion was the only time-varying predictor such that each county in each time interval had a unique estimate of spatially-derived propagule pressure based on its distance to all previously invaded counties. In addition to the term for spatial contagion, predictors representing habitat invasibility (e.g., host and non-host biomass per county (Fig. 2), bioclimatic predictors) and propagule pressure (e.g., human population density) were considered. We note that some time-independent predictors in our model, such as host biomass or human population density, are not truly static through time but we have assumed that temporal changes in these predictors did not occur systematically across the study area and/or would not be of a magnitude that would influence our conclusions. A detailed description of variables is provided in Table 1.Fig. 2 County-level biomass (kg) of a redbay (Persea borbonia) and b sassafras (Sassafras albidum) across the US
Table 1 Variables used in Cox proportional hazards models investigating drivers of county-level invasion by laurel wilt across the southeastern United States
Variable Description
Invasion Year of invasion by laurel wilt at the county level, 2004–2021. Data obtained from the Georgia Forestry Commission
Contagion Calculated for every county i in each year by estimating the inverse of the distance from the centroid of county i to the centroid of every previously invaded county. These values were summed annually for each county i
Anthropogenic movement
Humans Number of humans per county in 2019 (US Census Bureau 2022)
Campgrounds Number of campgrounds per county (Hillegass 2021)
Income Median income (US$) as of 2019 (US Department of Commerce 2021)
Habitat invasibility
Hosts Biomass (kg) of host species (Persea borbonia and Sassafras albidum) per county in 2015. All tree data were from the USDA Forest Inventory and Analysis program (Bechtold and Patterson 2005) and described in Guo et al. (2019)
Nonhosts Biomass (kg) of all non-host species per county in 2015. See Hosts for source
MinTemp Mean minimum temperature (°C) of coldest month in 1 × 1 km grid cells (Fick and Hijmans 2017). Grid cells were averaged to the county level
Precip Mean precipitation (mm) in 1 × 1 km grid cells (Fick and Hijmans 2017). Grid cells were averaged to the county level
Predictors except bioclimatic variables were ln-transformed and then all predictors were standardized ((x-mean)/sd). We confirmed there was no substantial collinearity (|r|> 0.7) (Dormann et al. 2013) between standardized predictors before proceeding. The effects of this suite of candidate variables on invasion risk were quantified through three parallel analyses: evaluating (i) counties that contained hosts (redbay and/or sassafras) according to USDA Forest Service—Forest Inventory and Analysis data (Table 1), (ii) invaded counties as of 2020 plus a 500 km buffer to reflect jump dispersal (99% of jump events were < 500 km; see “Results”), and (iii) the entire contiguous US (Appendix S1). The purpose of conducting multiple analyses was to assess the robustness of results to changes in the spatial extent considered. That is, host abundance might be expected to drive invasion when evaluating the entire contiguous US, but such an effect at that spatial extent may be due to the presence—rather than abundance—of hosts in the southeast (Fig. 2).
For each of the three parallel analyses, we fit a full model and then used multi-model inference via the MuMIn package (Barton 2022) to summarize the effects of predictors across multiple candidate models and identify three best-fitting models, one at each spatial extent. The fit of each candidate model was evaluated using Akaike’s information criterion (AIC) and then the dredge() command was used to rank models using ΔAIC compared to the best-fitting model, indicated by the lowest AIC value. Within each parallel analysis, we selected all models with ΔAIC < 2 compared to the best-fitting model and used the model.avg() and confint() functions to obtain model averaged coefficients and 95% confidence intervals. Akaike weights (wi) estimating the likelihood of each model relative to all models (Burnham and Anderson 2002; Wagenmakers and Farrell 2004) were calculated using:2 wi(AIC)=exp(-0.5×Δi(AIC))∑k=1Kexp(-0.5×Δk(AIC))
where wi can be interpreted as the probability that model i is the best model (Wagenmakers and Farrell 2004) at that spatial extent. A flow chart depicting the process of the parallel analyses is provided in Appendix S2.
Future spread
We evaluated the potential for future spread into redbay and sassafras by first estimating how much of the county-level area containing these hosts had been invaded. Separately for each of these two host tree species, we calculated the percent of (i) counties containing hosts that were invaded and (ii) total host biomass occurring in invaded vs. uninvaded counties, both taken as proxies for the amount of suitable habitat invaded. Additionally, given the importance of cold temperatures in invasion risk (see Results), we calculated the mean monthly minimum temperatures (Table 1) separately for invaded and uninvaded counties to determine the potential invasibility of remaining habitat. We caution, however, that other hosts, such as northern spicebush (Lindera benzoin), occur in more northern areas and were not considered.
Next, we used the best-fitting model developed on data from the entire contiguous US to forecast invasion risk. We used this model and spatial extent because one key motivation of this work was to estimate invasion risk outside of the natural range of redbay and sassafras, as many members of the Lauraceae occur outside the natural range of these two hosts, such as in avocado growing regions of California. Models across all spatial extents provided similar forecasts, however, especially models evaluating the two larger spatial extents for which predictions were nearly identical (Appendix S3). We also note that because CPH models do not predict outside the window of time on which they were developed (data from 2005 to 2018 were used as training data), we used the most recent hazard function in our model (i.e., the 2018–2019 interval) to generate forecasts. However, values of the spatial contagion predictor were updated to reflect the distribution of laurel wilt in the preceding time step. For example, we used all counties invaded as of 2020 to estimate/update the spatial contagion predictor when making forecasts into 2021.
We predicted three years of invasion risk (2019–2021) for every remaining uninvaded county using the predict() command from the survival package with type = survival. This approach provides an estimate, p, of the probability of survival—or remaining uninvaded—and thus “1- p” was taken as the probability of invasion. We then paired the three years of invasion estimates with invasion status data (i.e., per year each county either remained uninvaded or became invaded) and used a receiver operating characteristic curve (ROC) and area under the curve (AUC) to compare estimated invasion risk vs. observed invasion. The ROC and AUC analyses were completed using the pROC package (Turck et al. 2011).
Results
Historical spread
Analyses of county-level data from 2004 to 2021 indicated that invasion speed averaged 28 ± 1 SE km/yr (Fig. 3a) but that spread decelerated ~ 5 years after the initial detection. Our analysis using the effective range radius, an approach equivalent to Koch and Smith (2008), indicated that after progressing at 55 ± 1 km/yr from 2004 to 2006, spread was 26 ± 1 km/yr from 2006 to 2021 (Fig. 3a). When analyzing the data using piecewise regression, the spread rate decreased from 40 ± 3 to 24 ± 0.4 km/yr around 2009 ± 0.5 SE (Fig. 3b).Fig. 3 Spread rates of laurel wilt across the southeastern US (2004–2021). Spread was estimated using the effective range radius and different time intervals were considered to a quantify spread rates across the entire invasion time series as well as changes in spread following initial analyses by Koch and Smith (2008) and b identify any breakpoints in spread as determined using piecewise regression. a Model statistics [solid black; dashed black; dashed gray] along with intervals of time evaluated: F1,16 = 1032.98, p < 0.0001 (2004–2021); F1,1 = 3210.36, p < 0.0001 (2004–2006); F1,9 = 2566.44, p < 0.0001 (2006–2021). b Model statistics [solid black; dashed black] along with intervals of time evaluated: F1,4 = 195.30, p = 0.0002 (2004–2009); F1,11 = 3227.38, p < 0.0001 (2009–2021). The breakpoint in spread on panel b was estimated to have occurred in 2009 ± 0.5 yr (SE)
As of 2021, laurel wilt had been detected in 275 counties (Fig. 4a). The number of new detections from 2004 to 2021 averaged 15 ± 2 per year. The number of counties invaded per year varied markedly (3–33), with the smallest number of invaded counties per year occurring from 2004 to 2008 (i.e., < 10 counties were invaded per year in four out of those five years) and the two largest values, 30 and 33, occurring in 2019 and 2020, respectively (Fig. 4b). In 2021, 16 counties were invaded. Out of the invaded counties, 203 were into contiguous areas and 72 were into non-contiguous areas. The long-distance jumps averaged 164 ± 16 km to the nearest known previously invaded area (Fig. 4c), with the longest jump of 570 km being recorded into Jackson County, Mississippi in 2009.Fig. 4 County-level invasion by laurel wilt in the southeastern US. a Categorized by contiguous and non-contiguous invasions. b Annual number of contiguous and non-contiguous counties invaded. c Distance of long-distance jumps into non-contiguous counties
County-level drivers of spread
The CPH models we developed at three different spatial extents differed markedly in some respects, but together indicated that proximity to invaded areas (spatial contagion), warmer minimum temperatures, and number of campgrounds increased risk of invasion (Fig. 5). At the smallest spatial extent (counties containing redbay and sassafras in rural forests), the best-fitting model and model-averaged coefficients, calculated using models with ΔAIC < 2 compared to the best-fitting model, suggested that the abundance of non-host trees had the largest—yet most variable—effect on invasion risk according to standardized slope coefficients (Fig. 5a). In terms of Z-value, however, the spatial contagion (Z = 16.49, p < 0.0001) was the strongest predictor, followed by minimum temperature (Z = 7.83, p <0.0001), abundance of non-hosts (Z = 4.28, p <0.0001), and density of campgrounds (Z = 2.60, p = 0.0092), which were all positive, statistically clear associations with invasion risk (Fig. 5a). Human population size was also positively associated with invasion risk in both the best-fitting model and according to model-averaged coefficients, but this was not a statistically clear association. Additional variables contributing to model-averaged coefficients but not appearing in the best-fitting model were income (negative effect), host abundance (positive), and mean annual precipitation (positive), but none of these effects were statistically clear.Fig. 5 Slope coefficients ± 95% confidence limits for Cox proportional hazards models predicting time-to-invasion, indicative of risk of invasion, by laurel wilt at the level of US county using three different spatial extents: a counties with host trees, b invaded area + 500 km buffer, and c the contiguous US (Appendix S1). Coefficients from model-averaging and a best-fitting model (lowest AIC) are provided. Descriptions of data and predictors are provided in Table 1
In analyses at the two larger spatial extents, invaded area + 500 km buffer (Fig. 5b) and the contiguous US (Fig. 5c), the fits were nearly equivalent and, within each analysis, there were no models with ΔAIC < 2 compared to the best-fitting model. Thus, the model-averaged coefficients—all statistically clear associations—were exactly equivalent to the best-fitting models. At both extents, the spatial contagion was the most important driver of invasion risk: counties closer to previously invaded areas were at the highest risk of invasion (Fig. 5b, c). The next strongest predictor that was positively associated with invasion risk was minimum temperature, followed by precipitation, host abundance, number of campgrounds, and human population size. Income was negatively associated with invasion risk at both extents, whereas the only other predictor considered, abundance of non-host trees, did not appear to affect invasion risk when analyzing the larger spatial extents (Fig. 5b, c). We attribute the nearly equivalent results found when analyzing the largest spatial extents to the inclusion of several distantly located, uninvaded counties that have no redbay or sassafras. That is, switching extents from “the invaded area + 500 km buffer” to “the contiguous US” only contributed zeros (= uninvaded counties), and the absence of invasion events across these counties—mostly located far away from the invaded area—was likely accounted for statistically by the spatial contagion predictor.
Future spread
As of 2021, laurel wilt had invaded 68.2% of the counties that contained redbay (accounting for 60% of redbay biomass) but only 12.5% of counties that contained sassafras (accounting for 6% of sassafras biomass). However, invaded counties containing redbay and sassafras had mean monthly minimum temperatures of 4.0 and 0.57 °C, respectively, compared with 1.53 and -4.54 °C, respectively, for noninvaded counties. Thus, the remaining uninvaded counties containing biomass of redbay and sassafras are generally located in areas with lower mean monthly minimum temperatures compared with the current invaded range.
County-level invasion risk in each from year 2019–2021 was forecasted using the best-fitting model developed using data from the contiguous US. Comparing predicted probability of invasion with observed invasions on an annual basis resulted in an AUC value of 0.92 (Fig. 6a). The median invasion probabilities forecasted for counties that actually became invaded in 2019, 2020, and 2021 were 0.04, 0.03, and 0.05, respectively, compared to predicted probabilities of <0.001 in each of those three years for counties that remained uninvaded (Fig. 6b).Fig. 6 Diagnostic plots for the best-fitting Cox proportional hazards model developed on county-level data from across the contiguous US (Fig. 5c). a Receiver-operating characteristic curve with area under the curve (AUC) indicating the ability of the model to correctly predict invaded vs. uninvaded counties. b The distribution of estimated invasion probabilities split between counties that became invaded versus those that remained uninvaded
Generally, predicted invasion was low, as 2689–2846 counties (86.5–91.6%) had a predicted invasion probability < 0.01 across the 3 years (Fig. 7). Counties with predicted invasion probabilities > 0.01 were, as expected, concentrated in the southeast and near the invasion front in each of the three years in our training dataset (Fig. 7).Fig. 7 Risk of invasion by laurel wilt estimated in three years (2019–2021) using the best-fitting Cox proportional hazards model trained on data from across the contiguous US (Fig. 5c). Counties outlined in black became invaded in each corresponding year. Spatial extent has been truncated to current invaded area plus 500 km buffer and only counties with an estimated probability of invasion > 0.01 are colored
Discussion
Owing to its rapid spread and wide host range, the insect-pathogen symbiosis that results in laurel wilt has been characterized as one of the most damaging disturbance agents to invade North American forests (Hughes et al. 2017; Fei et al. 2019). We quantified landscape-level patterns of spread by laurel wilt, finding that the spatial contagion was the strongest driver of spread. Additionally, spread has been quickest into warmer regions with greater host biomass and higher human activity, although we caution that positive associations of invasion risk with human activity could in part reflect detection biases (i.e., invasions in rural areas are less likely to be noticed). Our analyses of future spread indicated that laurel wilt had invaded 68% of the counties that contain redbay and 13% of the counties that contain sassafras, but that several uninvaded counties containing sassafras are in northern, colder regions that are less likely to be invaded according to our forecasts (Fig. 7) and other climatic matching analyses (Koch and Smith 2008; Formby et al. 2018).
The invasion speed appeared to decrease approximately 6 years after the first detection of tree mortality (Fig. 3b), potentially owing to intense public awareness campaigns and/or survey efforts following initial detection. That is, initial survey efforts may have uncovered long-invaded counties that went undetected prior to increased awareness of the disease and its severity. We also provide evidence that the invasion slowed from 2020 to 2021, as the number of counties invaded dropped from 33 to 16. Whereas invasion theory suggests that spread can decrease as suitable habitat is exhausted (Shigesada et al. 1995; Shigesada and Kawasaki 1997), the recent decline in county invasion rates from 2020 to 2021 could be due to decreased travel, surveys, and/or reporting stemming from the coronavirus pandemic. However, this pattern may also indicate that laurel wilt has invaded most of the warmer counties with redbay across the southeastern US and that spread into sassafras containing regions at northern latitudes might be partially inhibited by the cold tolerance of the beetle vector (Formby et al. 2018). The pathogenic fungus has been detected on other scolytines, however, and alternative vectors that perform well in colder regions and, similar to redbay ambrosia beetle, attack healthy hosts– a somewhat unique characteristic among ambrosia beetle species—could serve to reaccelerate and/or maintain invasion speed. Additionally, there are still several uninvaded counties in the southeast that harbor sassafras (Figs. 1, 2b), which could be attributable to potentially low propagule pressure, dispersion of hosts at the sub-county level, and/or other invasibility factors not captured by our model(s).
The spatial contagion was the main driver of invasion risk, but habitat characteristics appeared more important for driving this invasion than human activities (Fig. 5). Similar analyses of other forest invaders have identified human population density, often used as a proxy for several human activities that can lead to the movement of non-native species, as one of the most important drivers of invasions (Ward et al. 2020; Cook et al. 2021; Epanchin-Niell et al. 2022). For laurel wilt, it appears that warmer temperatures, precipitation, and host tree abundance were more strongly associated with invasion risk than human population density or number of campgrounds (Fig. 5). We used a composite metric of host abundance (redbay + sassafras) and did not attempt to disentangle the effects of warmer temperatures and abundance of redbay, which is mostly distributed in warmer regions. Nonetheless, both redbay and sassafras are highly suitable hosts, and the facilitative effect of host trees could indicate the increased propensity of beetle vectors finding a host following short and/or long-distance dispersal events. This conclusion—a stronger facilitative effect of host biomass compared with human population density—corroborates previous findings from a study on several non-native insects and pathogens (Ward et al. 2022), including laurel wilt, that used a different modeling framework (i.e., a logistic regression modeling the presence/absence of county-level occurrence, rather than time-to-invasion). One potential confounding factor is that sassafras, while found across a larger area than redbay, is more patchily distributed (Peters et al. 2020) and such spatial variation could inhibit the ability of beetle vectors to locate hosts. Additionally, the low Allee threshold for redbay ambrosia beetle—the initial invasion was likely established by a single individual or a small group of clones (Hughes et al. 2017)—potentially indicates that propagule pressure is less important for invasion success compared to habitat suitability.
Analyses across all spatial extents highlighted the importance of climate in driving range dynamics (Lehmann et al. 2020). The finding that warmer minimum temperatures increased invasion risk accords well with historical forecasts of suitable habitat for redbay ambrosia beetle (Koch and Smith 2008), which is native to southeast Asia. However, we caution that redbay ambrosia beetle appears capable of surviving in colder regions of the US than the current invaded range (Formby et al. 2013, 2018) and we did not incorporate northern spicebush, another suitable host for laurel wilt. Other aspects of temperature could be driving the positive association between invasion risk and warm temperatures, however, such as additional beetle generations in warmer areas leading to increased spread capacity (Fahrner and Aukema 2018). Nonetheless, the drivers of county-level spread and subcounty-level disease incidence differ, as disease incidence at the plot level was inversely related to maximum temperature (Choudhury et al. 2021). Studies at smaller spatial scales are critical for understanding tree- and stand-level progression of the disease; we caution that our findings pertain to county-level invasion dynamics and may not hold for sub-county dynamics for either rates of spread or responses of laurel wilt to environmental conditions.
We found that 72 long-distance jumps averaging 164 km occurred since the initial detection (Fig. 4c). Given that laurel wilt is vectored by an endophytic scolytine, it is likely to move via firewood (Meurisse et al. 2019). There were some instances of counties becoming invaded in clusters, such as when several contiguous counties were invaded within the same year (Figs. 4a, 7a). This pattern potentially highlights increased surveillance in counties following the discovery of a satellite infestation, rather than a simultaneously widespread invasion of a cluster of isolated counties within a single year. Similarly, the increase in invaded counties in 2019 and 2020 (Fig. 4) could reflect intensifying inspection efforts on sassafras as the invasion expanded into northern and western counties.
Despite advances in phytosanitary regulations, non-native ambrosia beetles and the fungi they vector have continued to invade and kill trees in several regions (Coleman et al. 2019; Ministry for Primary Industries 2019; Inward 2020; Gugliuzzo et al. 2021). Few analyses of the landscape-level dynamics of ambrosia beetles exist, but knowledge on drivers of spread is critical for delimiting newly detected populations, designing potential eradication programs, slowing spread, and, ultimately, mitigating environmental and economic impacts. The long distances between avocado-growing regions of California and Mexico and the invaded range of laurel wilt results in an extremely low estimated invasion risk, and thus a long-distance dispersal event over that distance is stochastic and exceedingly difficult to predict. Lastly, our results report on spread driven by natural and human-aided dispersal of redbay ambrosia beetle, but H. lauricola can be vectored by other scolytines (Ploetz et al. 2017) and the performance of such alternative vectors could vary with climate or time and result in invasion patterns deviating from those described here.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 283 kb)
Supplementary file2 (DOCX 22 kb)
Supplementary file3 (DOCX 63 kb)
Supplementary file4 (XLSX 63 kb)
Acknowledgements
The authors thank forest health experts from across the southeastern US for surveying for and reporting laurel wilt. We also thank Lynne Womack (Georgia Forestry Commission) for sharing the county invasion data.
Author contributions
SW conceived study, conducted analyses, and wrote initial draft of the manuscript. JR contributed to interpretation, contextualization, and writing and editing subsequent drafts of the manuscript.
Funding
This research was supported by USDA APHIS PPA 7721 APP-16912. This publication is a contribution of the Mississippi Agricultural and Forestry Experiment Station and based upon work supported by the National Institute of Food and Agriculture, U.S. Department of Agriculture, Hatch projects under accession numbers 1025843 and 1018710.
Data availability
All data supporting results are freely available from sources cited in the manuscript, except for county-level invasion data for laurel wilt, which are provided in Appendix S4.
Declarations
Competing interest
The authors have no relevant financial or non-financial interests to disclose.
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References
Andersen HF Jordal BH Kambestad M Kirkendall LR Improbable but true: the invasive inbreeding ambrosia beetle Xylosandrus morigerus has generalist genotypes Ecol Evol 2012 2 247 257 10.1002/ece3.58 22408740
Aukema JE McCullough DG Von Holle B Liebhold AM Britton K Frankel SJ Historical accumulation of nonindigenous forest pests in the continental United States Bioscience 2010 60 886 897 10.1525/bio.2010.60.11.5
Barton K (2022) MuMIn: multi-model inference. R package version 1.46.0. https://CRAN.R-project.org/package=MuMIn
Bechtold W Patterson P The enhanced forest inventory and analysis program—national sampling design and estimation procedures 2005 USDA Forest Service General Technical Report
Bivand RS Pebesma EJ Gómez-Rubio V Applied spatial data analysis with R 2013 New York Springer
Burnham KP Anderson DR Model selection and multimodel inference: a practical information-theoretic approach 2002 Springer
Choudhury RA Er HL Hughes MA Smith JA Pruett GE Konkol J Ploetz RC Marois JJ Garrett KA van Bruggen AHC Host density dependence and environmental factors affecting laurel wilt disease incidence Plant Pathol 2021 70 676 688 10.1111/ppa.13314
Coleman TW Poloni AL Chen Y Thu PQ Li Q Sun J Rabaglia RJ Man G Seybold SJ Hardwood injury and mortality associated with two shot hole borers, Euwallacea spp., in the invaded region of southern California, USA, and the native region of Southeast Asia Ann for Sci 2019 10.1007/s13595-019-0847-6
Cook RT Ward SF Liebhold AM Fei S Spatial dynamics of spotted lanternfly, Lycorma delicatula, invasion of the Northeastern United States NeoBiota 2021 70 23 42 10.3897/neobiota.70.67950
De Beer ZW Procter M Wingfield MJ Marincowitz S Duong TA Generic boundaries in the Ophiostomatales reconsidered and revised Stud Mycol 2022 120 57 120 10.3114/sim.2022.101.02
Dormann CF Elith J Bacher S Buchmann C Carl v Carré G Marquéz JRG Gruber B Lafourcade B Leitão PJ Münkemüller T McClean C Osborne PE Reineking B Schröder B Skidmore AK Zurell D Lautenbach S Collinearity: a review of methods to deal with it and a simulation study evaluating their performance Ecography 2013 36 27 46 10.1111/j.1600-0587.2012.07348.x
Epanchin-Niell R Lu J Thompson A Tobin PC Gray DR Liebhold AM Socio-environmental drivers of establishment of Lymantria dispar, a nonnative forest pest, in the United States Biol Invasions 2022 24 157 173 10.1007/s10530-021-02637-x
Fahrner S Aukema BH Correlates of spread rates for introduced insects Glob Ecol Biogeogr 2018 27 734 743 10.1111/geb.12737
Fei S Morin RS Oswalt CM Liebhold AM Biomass losses resulting from insect and disease invasions in US forests Proc Natl Acad Sci 2019 10.1073/pnas.1820601116
Fick SE Hijmans RJ WorldClim 2: new 1-km spatial resolution climate surfaces for global land areas Int J Climatol 2017 37 4302 4315 10.1002/joc.5086
Formby JP Krishnan N Riggins JJ Supercooling in the redbay ambrosia beetle (Coleoptera: Curculionidae) Florida Entomologist 2013 96 1530 1540 10.1653/024.096.0435
Formby JP Rodgers III JC Koch FH Krishnan N Duerr DA Riggins JJ Cold tolerance and invasive potential of the redbay ambrosia beetle (Xyleborus glabratus) in the eastern United States Biol Invasions 2018 20 995 1007 10.1007/s10530-017-1606-y
Fraedrich SW Harrington TC Rabaglia RJ Ulyshen MD Mayfield III AE Hanula JL Eickwort JM Miller DR A fungal symbiont of the redbay ambrosia beetle causes a lethal wilt in redbay and other Lauraceae in the Southeastern United States Plant Dis 2008 92 215 224 10.1094/PDIS-92-2-0215 30769391
Gugliuzzo A Biedermann PHW Carrillo D Castrillo LA Egonyu JP Gallego D Haddi K Hulcr J Jactel H Kajimura H Kamata N Meurisse N Li Y Oliver JB Ranger CM Rassati D Stelinski LL Sutherland R Tropea Garzia G Wright MG Biondi A Recent advances toward the sustainable management of invasive Xylosandrus ambrosia beetles J Pest Sci 2021 94 615 637 10.1007/s10340-021-01382-3
Guo Q Fei S Potter KM Liebhold AM Wen J Tree diversity regulates forest pest invasion Proc Natl Acad Sci 2019 116 7382 7386 10.1073/pnas.1821039116 30910953
Haack RA Britton KO Brockerhoff EG Cavey JF Garrett LJ Kimberley M Lowenstein F Nuding A Olson LJ Turner J Vasilaky KN Effectiveness of the international phytosanitary standard ISPM No. 15 on reducing wood borer infestation rates in wood packaging material entering the United States PLoS ONE 2014 9 e96611 10.1371/journal.pone.0096611 24827724
Harrington TC Fraedrich SW Aghayeva DN Raffaelea lauricola, a new ambrosia beetle symbiont and pathogen on the Lauraceae Mycotaxon 2008 104 399 404
Hastings A Cuddington K Davies KF Dugaw CJ Elmendorf S Freestone A Harrison S Holland M Lambrinos J Malvadkar U Melbourne BA Moore K Taylor C Thomson D The spatial spread of invasions: new developments in theory and evidence Ecol Lett 2005 8 91 101 10.1111/j.1461-0248.2004.00687.x
Hijmans RJ (2019) Geosphere: spherical trigonometry. R package version 1.5–10. https://CRAN.R-project.org/package=geosphere
Hijmans RJ (2021) Terra: spatial data analysis. R package version 1.2–10. https://CRAN.R-project.org/package=terra
Hillegass TJ (2021) The most comprehensive guide to federal, state, provincial and local campgrounds http://www.uscampgrounds.info/ Accessed 30 Sep 2021
Hughes MA Riggins JJ Koch FH Cognato AI Anderson C Formby JP Dreaden TJ Ploetz RC Smith JA No rest for the laurels: symbiotic invaders cause unprecedented damage to southern USA forests Biol Invasions 2017 19 2143 2157 10.1007/s10530-017-1427-z
Hulcr J Dunn RR The sudden emergence of pathogenicity in insect-fungus symbioses threatens naive forest ecosystems Proc Royal Soc b: Biol Sci 2011 278 2866 2873 10.1098/rspb.2011.1130
Hulcr J Lou QZ The redbay ambrosia beetle (Coleoptera: Curculionidae) prefers Lauraceae in its native range: records from the Chinese national insect collection Florida Entomol 2013 96 1595 1596 10.1653/024.096.0444
Inward DJG Three new species of ambrosia beetles established in Great Britain illustrate unresolved risks from imported wood J Pest Sci 2020 93 117 126 10.1007/s10340-019-01137-1
Jacobi WR Hardin JG Goodrich BA Cleaver CM Retail firewood can transport live tree pests J Econ Entomol 2012 105 1645 1658 10.1603/EC12069 23156161
Kassambara A (2020) ggpubr: “ggplot2” based publication ready plots. R package version 0.4.0. https://CRAN.R-project.org/package=ggpubr
Kendra PE Montgomery WS Niogret J Epsky ND An uncertain future for American Lauraceae: a lethal threat from redbay ambrosia beetle and laurel wilt disease (a review) Am J Plant Sci 2013 4 727 738 10.4236/ajps.2013.43A092
Kirkendall LR Biedermann PHW Jordal BH Vega FE Hofstetter RW Evolution and diversity of bark and ambrosia beetles Bark Beetles: biology and ecology of native and invasive species 2015 London Elsevier 85 156
Koch FH Smith WD Spatio-temporal analysis of Xyleborus glabratus (Coleoptera: Circulionidae: Scolytinae) invasion in eastern U.S. forests Environ Entomol 2008 37 442 452 10.1093/ee/37.2.442 18419916
Lantschner MV Corley JC Liebhold AM Drivers of global Scolytinae invasion patterns Ecol Appl 2020 30 1 12 10.1002/eap.2103
Lantschner MV Villacide JM Garnas JR Croft P Carnegie AJ Liebhold AM Corley JC Temperature explains variable spread rates of the invasive woodwasp Sirex noctilio in the Southern Hemisphere Biol Invasions 2014 16 329 339 10.1007/s10530-013-0521-0
Lehmann P Ammunét T Barton M Battisti A Eigenbrode SD Jepsen JU Kalinkat G Neuvonen S Niemelä P Terblanche JS Økland B Björkman C Complex responses of global insect pests to climate warming Front Ecol Environ 2020 18 141 150 10.1002/fee.2160
Liebhold AM Tobin PC Population ecology of insect invasions and their management Annu Rev Entomol 2008 53 387 408 10.1146/annurev.ento.52.110405.091401 17877456
Mally R Ward SF Trombik J Buszko J Medzihorský V Liebhold AM Non-native plant drives the spatial dynamics of its herbivores: the case of black locust (Robinia pseudoacacia) in Europe NeoBiota 2021 69 155 175 10.3897/neobiota.69.71949
Mayfield III AE Peña JE Crane JH Smith JA Branch CL Ottoson ED Hughes M Ability of the redbay ambrosia beetle (Coleoptera: Curculionidae: Scolytinae) to bore into young avocado (Lauraceae) plants and transmit the laurel wilt pathogen (Raffaelea sp.) Florida Entomologist 2008 91 485 487 10.1653/0015-4040(2008)91[485:AOTRAB]2.0.CO;2
Meurisse N Rassati D Hurley BP Brockerhoff EG Haack RA Common pathways by which non-native forest insects move internationally and domestically J Pest Sci 2019 92 13 27 10.1007/s10340-018-0990-0
Ministry for Primary Industries Granulate ambrosia beetle Xylosandrus crassiusculus Biosecurity New Zealand. 2019 2019 2
Muggeo VMR (2008) Segmented: an R package to fit regression models with broken-line relationships. R News, 8/1, 20–25. https://cran.r-project.org/doc/Rnews/. Accessed 1 Dec 2019
Nunez-Mir GC Walter JA Grayson KL Johnson DM Assessing drivers of localized invasive spread to inform large-scale management of a highly damaging insect pest Ecol Appl 2022 10.1002/eap.2538
Olatinwo RO Fraedrich SW Mayfield III AE Laurel wilt: current and potential impacts and possibilities for prevention and management Forests 2021 12 1 21 10.3390/f12020181
Pebesma E Simple features for R: standardized support for spatial vector data R J 2018 10 439 446 10.32614/RJ-2018-009
Peters MP Prasad AM Matthews SN Iverson LR Climate change tree atlas, Version 4 2020 Delaware U.S Forest Service
Ploetz RC Konkol JL Narvaez T Duncan RE Saucedo RJ Campbell A Mantilla J Carrillo D Kendra PE Presence and prevalence of Raffaelea lauricola, cause of laurel wilt, in different species of ambrosia beetle in Florida, USA J Econ Entomol 2017 110 tow292 10.1093/jee/tow292
Poland TM Rassati D Improved biosecurity surveillance of non-native forest insects: a review of current methods J Pest Sci 2019 92 37 49 10.1007/s10340-018-1004-y
R Core Team R: a language and environment for statistical computing 2021 Vienna R Foundation for Statistical Computing
Rabaglia RJ Dole SA Cognato AI Review of American Xyleborina (Coleoptera: Curculionidae: Scolytinae) occurring north of Mexico, with an illustrated key Ann Entomol Soc Am 2006 99 1034 1056 10.1603/0013-8746(2006)99[1034:ROAXCC]2.0.CO;2
Ranger CM Schultz PB Frank SD Chong JH Reding ME Non-native ambrosia beetles as opportunistic exploiters of living but weakened trees PLoS ONE 2015 10 1 21 10.1371/journal.pone.0131496
Rassati D Faccoli M Haack RA Rabaglia RJ Toffolo EP Battisti A Marini L Bark and ambrosia beetles show different invasion patterns in the USA PLoS ONE 2016 11 1 17 10.1371/journal.pone.0158519
Riggins JJ Hughes M Smith JA Mayfield III AE Layton B Balbalian C Campbell R First occurrence of laurel wilt disease caused by Raffaelea lauricola on redbay trees in Mississippi Plant Dis 2010 94 634 634 10.1094/PDIS-94-5-0634C
Robin X Turck N Hainard A Tiberti N Lisacek F Sanchez J-C Müller M pROC: an open-source package for R and S+ to analyze and compare ROC curves BMC Bioinfo 2011 8 12 77
Sadof CS Hughes GP Witte AR Peterson DJ Ginzel MD Tools for staging and managing emerald ash borer in the urban forest Arboric Urban for 2017 43 15 26
Seebens H Bacher S Blackburn TM Capinha C Dawson W Dullinger S Genovesi P Hulme PE van Kleunen M Kühn I Jeschke JM Lenzner B Liebhold AM Pattison Z Pergl J Winter M Essl F Projecting the continental accumulation of alien species through to 2050 Glob Change Biol 2021 27 970 982 10.1111/gcb.15333
Sharov AA Leonard D Liebhold AM Roberts EA Dickerson W “Slow the Spread” a national program to contain the gypsy moth J Forest 2002 10.1093/jof/100.5.30
Shigesada N Kawasaki K Biological invasions: theory and practice 1997 UK Oxford University Press
Shigesada N Kawasaki K Takeda Y Modeling stratified diffusion in biological invasions Am Nat 1995 146 229 251 10.1086/285796
Solano A Rodriguez SL Greenwood L Dodds KJ Coyle DR Firewood transport as a vector of forest pest dispersal in North America: a scoping review J Econ Entomol 2021 114 14 23 10.1093/jee/toaa278 33558904
Therneau T (2021) A package for survival analysis in R. https://cran.r-project.org/web/packages/survival/vignettes/ survival.pdf. p. 1–98
Therneau TM Grambsch PM Modeling survival data: extending the Cox model 2000 Springer
Therneau T, Crowson C, Atkinson E (2022) Using time dependent covariates and time dependent coefficients in the Cox model. <https://cran.r-project.org/web/packages/survival/vignettes/timedep.pdf>. p. 1–31
Thomas L Reyes EM Tutorial: survival estimation for Cox regression models with time-varying coefficients using SAS and R J Stat Soft 2014 10.18637/jss.v061.c01
US Census Bureau (2022) County population totals: 2010–2019. https://www.census.gov/data/datasets/time-series/demo/popest/2010s-counties-total.html. Accessed 20 July 2022
US Department of Commerce (2021) Bureau of economic analysis of the United States department of commerce. https://www.bea.gov/data/income-saving/personal-income-county-metro-and-other-areas. Accessed 1 Sep 2021
Wagenmakers EJ Farrell S AIC model selection using Akaike weights Psychon Bull Rev 2004 11 192 196 10.3758/BF03206482 15117008
Ward SF Fei S Liebhold AM Temporal dynamics and drivers of landscape-level spread by emerald ash borer J Appl Ecol 2020 57 1020 1030 10.1111/1365-2664.13613
Ward SF Liebhold AM Fei S Variable effects of forest diversity on invasions by non-native insects and pathogens Biodivers Conserv 2022 31 2575 2586 10.1007/s10531-022-02443-4
Wickham H Averick M Bryan J Chang W McGowan L François R Grolemund G Hayes A Henry L Hester J Kuhn M Pedersen T Miller E Bache S Müller K Ooms J Robinson D Seidel D Spinu V Takahashi K Vaughan D Wilke C Woo K Yutani H Welcome to the Tidyverse J Open Source Soft 2019 4 1686 10.21105/joss.01686
Wuest CE Harrington TC Fraedrich SW Yun H-Y Lu S-S Genetic variation in native populations of the laurel wilt pathogen, Raffaelea lauricola, in Taiwan and Japan and the introduced population in the United States Plant Dis 2017 101 619 628 10.1094/PDIS-10-16-1517-RE 30677356
| 0 | PMC9734743 | NO-CC CODE | 2022-12-14 23:28:30 | no | Landsc Ecol. 2022 Dec 8;:1-15 | utf-8 | Landsc Ecol | 2,022 | 10.1007/s10980-022-01560-3 | oa_other |
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Indian J Otolaryngol Head Neck Surg
Indian J Otolaryngol Head Neck Surg
Indian Journal of Otolaryngology and Head & Neck Surgery
2231-3796
0973-7707
Springer India New Delhi
3209
10.1007/s12070-022-03209-8
Original Article
Impact of COVID-19 Pandemic on Older Adults Using Hearing aid/s: Indian Scenario
Nigam Manisha [email protected]
http://orcid.org/0000-0002-0320-4709
Neupane Anuj Kumar [email protected]
grid.411681.b 0000 0004 0503 0903 School of Audiology & Speech-Language Pathology, Bharati Vidyapeeth (Deemed to be University), 411043 Pune, India
8 12 2022
18
13 4 2022
23 9 2022
© Association of Otolaryngologists of India 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The present study explored the impact of COVID-19 on hearing health and problems faced by older adults using hearing aid/s. Fifty older adults in the age range of 55–95 years were selected for the study based on the inclusion and exclusion criteria. Therefore, the developed questionnaire was administered to them. Statistical analysis was performed for all the responses achieved. Closure of hearing aid companies and audiological centers was found to have a negative impact on availing audiological services. Likewise, a huge hike in the price of these services made it impossible for people to afford them. Despite the availability of tele-audiology, older adults were not able to make the best use of it due to numerous reasons. We sought to explore patients’ perceptions to break down these barriers by enhancing the quality of tele-audiology, home visits, and remote services. Therefore, the present report may facilitate in planning and implementation of policies related to audiological services, especially during times of crisis, which may help strengthen our hearing health care system.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12070-022-03209-8.
Keywords
COVID-19
Older adults
Hearing aids
Remote services
Tele-audiology
Age-related hearing loss
Audiologists
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pmcIntroduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) emerged in December 2019 and was declared a global health emergency of international concern by the World Health Organization [1]. The first case of the disease was reported in India in the first quarter of 2020, and the number continued to rise [2]. The disease featured clinical symptoms such as fever, cough, shortness of breath, sore throat, headache, muscle pain, and a change in taste and smell. The situation was of utmost concern due to its rapid transmission to a large number public, leading to high morbidity and mortality, and ultimately social and economic disruption [3–5]. Therefore, to reduce the spread of infection, urgent measures of restriction in the movement and social interactions were executed [6]. Nearly every country in the world including India implemented full or partial restrictions as part of social distancing to reduce the transmission of disease [7, 8]. Yet, these restrictions had a negative toll on the access to health care services, especially among those with a disability such as hearing impairment [5, 8, 9].
Individuals with hearing impairment need periodic evaluation, intervention, and guidance in order to cope with the effects of hearing loss. Meanwhile, hearing-related problems such as tinnitus, hearing loss, and vertigo were at an all-time high among individuals post-COVID-19 infection [10, 11]. Further, the usage of the mask as a protective mechanism highlighted even the lower degree of hearing loss among them, which was often overshadowed by their lip-reading abilities [12]. Though the strict restrictions imposed initially were relaxed in the later part of the pandemic with the slogan ‘new normal’, providing audiological services was not without obstacles. Several national and international bodies responded swiftly with the guidelines and positional statements to assist in adapting to the changing clinical scenario [13–17], yet the COVID-19 catastrophe impacted audiological services profoundly in India, requiring modifications to current practices and adaptations to the rapidly changing situations. These, in turn, resulted in a severely compromised service delivery system with a limited number of appointments [5, 18].
India reports a hearing disability of 0.3% of the total population. Around 49.8% of them are reported to have a higher degree of hearing loss [19, 20]. A higher prevalence of hearing impairment has been reported among elderly individuals as compared to the younger group. There is a trend of rise in hearing loss across age groups where till the age of 45–50 years, it is slower and rises sharply beyond it [20]. The higher prevalence of hearing loss in the elderly population has increased the need for the usage of amplification devices such as hearing aids [21, 22]. However, these older adults with hearing impairment have also been of prime victims of COVID-19 restrictions. Higher susceptibility to infections and dexterity issues often led them to be labeled as vulnerable and so, were unable to utilize hearing care services despite the fact that these services were critical to meeting their daily communication needs [5]. The strict implication of preventive measures such as wearing a mask has often led to social exclusion especially among older adults using hearing aid/s [23]. Though Alqudah et al., [24] attempted to understand the effect of the COVID-19 outbreak on hearing aids users, these effects on hearing health of older adults using hearing aid/s have never been explored previously. Also, there is a need to understand the impact of the condition in the Indian scenario which may further help to deal with the situation indigenously. Therefore, the present study aimed at understanding the impact of COVID-19 on hearing health and problems faced by older adults using hearing aid/s. The study also attempted to explore patients’ perspectives on alternative approaches to the traditional model of hearing care services.
Materials and Methods
Phase I: Development of the Questionnaire
The present study comprised the development of a questionnaire to inspect the impact of the COVID-19 pandemic and restrictions on accessing audiological services among older adults using hearing aid/s in the Hindi language. The questions were framed under two sections. Section A comprised 9 questions related to the demographic details and information on hearing health, and hearing aids worn by the participants in the study. Section B consisted of 13 questions that focused on the participants’ perception of potential factors that may have hurdled hearing care services due to the pandemic. This section also demanded input from the patients on eliminating barriers to procuring audiological services even in difficult restrictive scenarios. Hence, the developed questionnaire was validated by five audiologists fluent in the Hindi language. Each of the questions was rated in terms of its relevance, clarity, simplicity, and ambiguity on a 3-point rating scale (i.e., 3 = most appropriate; 2 = appropriate, and 1 = not appropriate). Those questions which were scored 2 and 3 were retained in the questionnaire for the study (Appendix I).
Phase II: Administration of the Questionnaire
A cross-sectional study design along with purposive sampling was utilized in the study. The developed questionnaire was administered among older adults using hearing aid/s and procuring services from the audiological centre. These participants had post-lingual hearing loss and were using digital/analog hearing aid/s for at least 2 months period. None of them reported any significant neurological, radiological, cognitive/behavioral, vestibular, or other otological problems related to hearing, speech, and language. Also, the infrequent hearing aid users (< 11 h/week) were excluded from the study [25, 26]. The questionnaire was administered as per the convenience of the patients either via face-to-face modality or telephonic conversation. A total of 15 min was required to complete the questionnaire for each participant.
Ethical statement
The study was approved by the departmental research advisory committee and the Institutional Ethics Committee (REF: BVDUMC/IEC/43). The participant information sheet was explained to each of the participants. Therefore, informed consent was obtained prior to the administration of the questionnaire. All procedures performed in the study were in accordance with the Declaration of Helsinki (1975) and subsequent amendments.
Results
In the present study, the questionnaire was administered to fifty older adults using hearing aid/s in the age range of 55–95 years. Section A shows the demographic details and information on hearing health, and hearing aid/s worn by the participants in the study (Fig. 1). The majority of the participants i.e., 36% (n = 18) belonged to the age range of 55–65 years, 22% (n = 11) of them were between 66 and 75 years of age, 32% (n = 16) were of 76–85 years, and 10% (n = 5) were above 95 years of age. Most of the participants were males, comprising 80% (n = 40) of the study population, and the rest 20% (n = 10) were females. All the individuals were diagnosed with sensorineural hearing loss but with variable degrees. Most of them had moderate to severe hearing loss, followed by mild, moderate, and severe sensorineural hearing loss. Hence, most of the participants were equipped with bilateral digital hearing aids. Regarding the style of hearing aid/s worn, most of them had Behind-The-Ear (BTE) followed by Receiver-In-Canal (RIC), Body-Level, Completely-In-Canal (CIC), and Invisible-In-Canal (IIC) hearing aids. Participants were all regular hearing aid users and had been using them for at least a year.
Fig. 1 Baseline demographic details of the participants (n = 50) along with the status of hearing health, and hearing aid/s of the participants, retrieved from section A of the questionnaire
Section B focused on the participants’ perception of potential factors that may have hurdled hearing care services due to the pandemic (Table 1). In the study, it was found that 46% (n = 23) of the participants were just as concerned about their hearing health as they were about their overall health. Most of them i.e., 84% (n = 42) reported having no variation in the severity of hearing health due to the pandemic while 16% (n = 8) reported having an increment in the severity affecting daily communication needs. Yet, 52% (n = 26) of them felt the need to increase the number of visits to audiologists during the restrictions. However, only 14% (n = 7) were able to do so while 86% (n = 43) were unable to access the audiological services. These variations in responses were further inspected with questions on possible hurdles to smooth availability of hearing care services due to the COVID-19 pandemic were asked. There were approximately 54% (n = 27) of the participants who sort of agreed that the closure of hearing aids companies and audiological centers negatively contributed the access to audiological services. Only 32% (n = 16) of the participants believed that the distance was a major obstacle for them to access audiological services, while others disagreed. Likewise, the majority of 56% (n = 28) of them did not feel the lack of transportation was the major obstacle due to the restrictions. On the other hand, 30% (n = 15) believed a lack of caretakers affected the frequency of visits to audiological centers, while another 70% (n = 35) of them need not require any assistance to make the visit. Meanwhile, most of them i.e., 66% (n = 33) agreed on the lack of concern given by the government agencies on hearing health services during the restrictions. The increased cost of hearing services including the cost of accessories and unreasonable additional charges for home delivery during restrictions were reported as the major factors by 62% (n = 31) of the participants. In the case of remote services provided, 52% (n = 26) of the participants were unable to utilize the service while 34% (n = 17) of them disagreed
Table 1 Perception of the participants on potential factors that may have hurdled hearing care services due to the COVID-19 outbreak, retrieved from section B of the questionnaire
S.N. Questions Rating scale Frequency of responses Percentage (%)
1. Priority to hearing health as compared to overall health during COVID 19 pandemic Equally Preferred 23 46
Strongly preferred 15 30
Moderately Preferred 10 20
Lowest Preferred 2 4
Not a Priority 0 0
6. Deterioration in hearing health during COVID 19 pandemic Increased 8 16
Not changed 42 84
Decreased 0 0
9. Probability of visits to audiologist in the pandemic Increased 26 52
Not changed 24 48
Decreased 0 0
12. Frequency of visits to an audiologist since the beginning of the pandemic. Never 43 86
Less often 6 12
Very often 1 2
15. Closure of audiological centres and companies manufacturing hearing equipment. Strongly disagree 5 10
Disagree 6 12
Neither agree nor disagree 12 24
Agree 13 26
Strongly agree 14 28
20. Distance as the barrier Strongly disagree 10 20
Disagree 10 20
Neither agree nor disagree 14 28
Agree 11 22
Strongly agree 5 10
25. Unavailability of caretaker to accompany during the visit to audiological centres Strongly disagree 13 26
Disagree 11 22
Neither agree nor disagree 11 22
Agree 5 10
Strongly agree 10 20
30. Lack of transportation Strongly disagree 18 36
Disagree 10 20
Neither agree nor disagree 11 22
Agree 5 10
Strongly agree 6 12
35. Lack of focus of government agencies on facilitating hearing health services Strongly disagree 6 12
Disagree 1 2
Neither agree nor disagree 9 18
Agree 19 38
Strongly agree 14 28
40. High Cost of hearing aids and accessories as well as home-based services Strongly disagree 6 12
Disagree 1 2
Neither agree or disagree 12 24
Agree 21 42
Strongly agree 10 20
45. Not able to use hearing aid technology for remote services Strongly disagree 15 30
Disagree 2 4
Neither agree nor disagree 7 14
Agree 13 26
Strongly agree 13 26
50. Experience during covid 19 Good 20 40
Got help 7 14
Didn’t get help 17 34
Hearing deteriorated 6 12
54. Suggestions to overcome the barriers to having easy access to audiological services No comments 15 30
Remote services 8 16
Home visit 9 18
Reasonable rates 6 12
Empathetic clinician 2 4
Information imparting 9 18
Relaxation with guidelines 1 2
In light of the restrictions due to the COVID-19 pandemic, inputs were taken on the experience of each of the participants. The majority of the participants i.e., 54% (n = 27) of them rated their experience as good, while 46% (n = 23) disagreed with it. Therefore, suggestions were asked from each of the participants to eliminate these barriers for smooth access to audiological services. About 16% (n = 8) suggested the need for remote services, 18% (n = 9) expressed more home visits, and 12% (n = 6) suggested reasonable charges for the provision of services. Only 4% (n = 2) of them advocated the need for empathetic clinicians whereas 18% (n = 9) reported the need to notify patients regarding their audiological findings. However, only one of the participants highlighted the need for relaxation of COVID-19 guidelines to have easy access to audiological services
The Chi-Square test was performed to understand the association between the above-mentioned variables. It was found to have a positive correlation between the age of participants and the technology of hearing aids. The degree of hearing loss was found to significantly affect the everyday life of the participants, the style of hearing aid/s opted and the duration of hearing aid/s used. There was a significant correlation between the probabilities of visits to audiologists since the beginning of the pandemic with the deterioration of hearing abilities as well.
Discussion
Hearing loss is one of the most common clinical conditions that affect older adults. This can lead to the deterioration of social functioning can be affected by hearing impairment as we age. Therefore, the primary clinical intervention for people with hearing loss is the use of hearing aids [27]. Hearing aids have been reported to enhance the quality of life in several ways such as the improvement of communication and intimacy among family members; emotional stability and perception of physical and mental well-being [28]. As with any device, handling a hearing aid can be challenging for older people due to their limitations in manual dexterity along with the lack of exposure to the proper care and maintenance of the device [29]. Furthermore, the older adults are considered the most vulnerable to COVID-19, and have resulted in the restrictions of mobility restrictions, which in turn have limited their access to hearing health care services (30). Therefore, the current study aimed at addressing the issues faced by older adults using hearing aid/s from the imposition of restrictions due to the COVID-19 pandemic in India.
The present study involved fifty older adults who were using hearing aid/s prior to the outbreak of the pandemic. Most of these individuals were in the age range of 55–66 years and the least was 86–95 years of age. Though age-related hearing loss is found to spike with age, most older adults with hearing difficulties avoid using hearing aids as they do not perceive their hearing problems to be severe enough [30]. In the present study, there were more males using hearing aid/s than females. Such a variation across gender could be due to the greater likelihood of males having a hearing impairment than women females. Previous research has demonstrated that men and women differ significantly with respect to several audiological and non-audiological factors, which are likely to influence their use of hearing aids [31]. A possibility for these differences can be explained by the fact that men are relatively exposed to greater noise levels at workplaces than females [32]. All the participants were having sensorineural hearing loss which is the most prevalent type of hearing loss among the aging population [33]. Most participants had moderately severe hearing loss followed by mild, moderate, and severe hearing loss. Although CIC and IIC are more cosmetically appealing styles of hearing aids, it was found that most of the participants were using BTE and RIC hearing aid/s. This could be due to the majority of participants with a higher degree of hearing loss. Electroacoustics measurements have revealed that the RIC hearing aids have a smoother frequency response and a wider bandwidth. Also, BTE hearing aids are more desirable due to the higher MPO along with their tubing resonance [34]. Also, the vast majority of the participants were regular bilateral digital hearing aid users. In part, this can be attributable to effective audiological counseling that emphasizes the importance of binaural amplification regardless of the degree of asymmetry of hearing loss. Also, the awareness of the benefit of digital hearing aid/s to enhance the signal-to-noise ratio could have motivated them to acquire the device [35].
The present study further attempted to explore the potential COVID-19 related factors that may have hurdled hearing care services to older adults using hearing aid/s. Most participants reported that they equally prioritized their hearing health along with overall physical and mental health well-being during COVID 19 pandemic. This could be due to the fact that all the participants in the study were hearing aid users for more than a year and were well aware of the importance of hearing in their daily communication needs [28]. The present finding revealed most of the participants experienced no significant change in their hearing health during the COVID-19 pandemic. Yet some reported deteriorating hearing health during the same time period and wished to see an audiologist. The gradual nature of age-related hearing loss would explain these findings during COVID-19 restrictions. It is therefore important to realize that many older adults still required hearing health care services during the restrictions when most of the audiological centers were closed or gradually reopening [36]. Moreover, the frequency of visits to an audiologist since the beginning of the pandemic was found to be low in the study. Therefore, as a part of the questionnaire, we tried exploring the possible reasons behind it. More than half of the study population believed that the closure of hearing aids companies and audiological centers had negatively impacted access to audiological services during the pandemic. A similar study has been reported from Jordan by Alquadah et al., [24] where patients reported the limited availability of the hearing aids and accessories. Considering the restricted scenario, these services were not feasible across India as well, thereby, affecting the patients’ satisfaction. Moreover, participants agreed that the distance, the inaccessibility to the transportation, and the lack of caretakers during the restrictions were some of the concerning factors that would have contributed to the unapproachability in availing audiological services [37]. A huge rise in the price of audiological services was perceived by most participants as the barrier to availing these services. The participants also pointed out that the government agencies could have reduced these barriers by intercepting and facilitating hearing health care services during the restrictions. Though tele-audiology was on rise during the pandemic, a mere percentage of the participants reported receiving some kind of troubleshooting services through online mode. Though many studies in the past have reported the usefulness of tele-audiology for clinical services [38], the response in the present study suggests the lack of adaptation of these technologies by audiologists and hearing providers to enhance remote practice. In addition, this might also be due to the poor internet connectivity, the use of low-end hearing aids, and a lack of exposure to online platforms among older adults using hearing aid/s [5, 24]. The present study also attempted to elicit patients’ perceptions on way to break down these barriers where suggestions such as enhancement in the quality and increment in the frequency of tele-audiology, home visits, and remote services were received. Some of the participants urged the need to have an empathetic clinician while others suggested having hearing health care friendly COVID-19 guidelines.
In the study, we observed a positive correlation between the age of the participants & technology of the hearing aid/s being used. In our study, most of the participants were in the age range of 55–65 years and so were comfortable enough with handling digital programmable hearing aids. Studies have also shown that programmable hearing aids have positive and efficient effects on hearing and the quality of life among older adults with hearing impairment [39]. In the study, the degree of hearing loss was found to significantly affect the everyday life of the participants. Hearing aids have been reported to be popular among users with higher degrees of hearing impairments and so it explains the longer duration of their usage in more severe cases [40].
Conclusion
To conclude, the present study reported the impact of the COVID-19 outbreak on older adults with hearing aid/s. In the study, the closure of hearing aid companies and audiological centers was found to have a negative impact on availing audiological services. Moreover, a huge hike in the price of these services made it impossible for people to afford them. Despite the availability of tele-audiology, older adults were not able to make the best use of it due to numerous reasons. We sought to explore patients’ perceptions to break down these barriers by enhancing the quality of tele-audiology, home visits, and remote services. Therefore, the present study may facilitate the planning and implementation of policies related to audiological services, especially during time of crisis, which may help strengthen our hearing health care system.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Supplementary Material 1
Acknowledgements
We would like to acknowledge all the participants in the study and pioneers in the field for their valuable suggestions.
Contribution
Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Software; Validation; Roles/Writing - original draft; Writing - review.
Declaration of Funding
The present study received no funds from any agencies to report.
Declarations
Conflict of Interest
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. WHO : COVID 19 Public health emergency of international concern. https://www.who.int/publications/m/item/covid-19-public-health-emergency-of-international-concern-(pheic)-global-research-and-innovation-forum
2. WHO : Report Coronavirus Disease (COVID-19) India Situation Report. https://www.who.int/india/emergencies/coronavirus-disease-(covid-19)/india-situation-report
3. Madhav N Oppenheim B Gallivan M Mulembakani P Rubin E Wolfe N Jamison DT Gelband H Horton S Pandemics: Risks, Impacts, and Mitigation Disease Control Priorities: Improving Health and Reducing Poverty 2017 3 Washington (DC) The International Bank for Reconstruction and Development / The World Bank
4. Andrews M Areekal B Rajesh K Krishnan J Suryakala R Krishnan B First confirmed case of COVID-19 infection in India: A case report Indian J Med Res 2020 151 5 490 492 10.4103/ijmr.IJMR_2131_20 32611918
5. Umashankar A, Prabhu P (2020) Effect of Covid-19 on Individuals with Hearing Impairment in India. J Clin Diagn Res 14(8). 10.7860/JCDR/2020/45054.13892
6. Lo Presti S Mattavelli G Canessa N Gianelli C Risk perception and behaviour during the COVID-19 pandemic: Predicting variables of compliance with lockdown measures PLoS ONE 2022 17 1 e0262319 10.1371/journal.pone.0262319 34986209
7. Viner R Russell S Saulle R Croker H Stansfield C Packer J School Closures During Social Lockdown and Mental Health, Health Behaviors, and Well-being Among Children and Adolescents During the First COVID-19 Wave JAMA Pediatr 2022 176 4 400 409 10.1001/jamapediatrics.2021.5840 35040870
8. Das K Paital B First week of social lockdown versus medical care against COVID-19 - with special reference to India Curr Trends Biotechnol Pharm 2020 14 2 196 216 10.5530/ctbp.2020.2.20
9. Clay JM Parker MO Alcohol use and misuse during the COVID-19 pandemic: a potential public health crisis? The Lancet Public Health 2020 5 5 e259 10.1016/S2468-2667(20)30088-8 32277874
10. Beukes E Baguley D Jacquemin L Lourenco M Allen P Onozuka J Changes in Tinnitus Experiences During the COVID-19 Pandemic Front Public Health Front 2020 8 592878 10.3389/fpubh.2020.592878
11. Savtale S, Hippargekar P, Bhise S, Kothule S (2021) Prevalence of otorhinolaryngological symptoms in Covid 19 patients. Indian J Otolaryngol Head Neck Surg 1–7. 10.1007/s12070-021-02410-5
12. Homans N, Vroegop J (2021) The impact of face masks on the communication of adults with hearing loss during COVID-19 in a clinical setting. Int J Audiol 1–6. 10.1080/14992027.2021.1952490
13. The American Academy of Audiology. COVID-19 Resources. https://www.audiology.org/practice-resources/covid-19-resources/. Accessed 2 Aug 2021
14. American Speech-Language-Hearing Association. Audiology Service Delivery Considerations in Health Care During COVID-19. https://www.asha.org/aud/audiologyservice-delivery-considerations-in-health-care-during-coronavirus-covid-19/
15. British Academy of Audiology. British Academy of Audiology Response to COVID-19: NHS England Essential Activity for Audiology. https://www.baaudiology.org/indexphpnews/news-home/british-academy-audiologyresponse-covid-19-nhs-england-essential-activity-audiology/
16. Indian Speech Language and Hearing Association. COVID-19 ISHA guidelines. https://www.ishaindia.org.in/covid_19.html. Accessed 2 Aug 2021
17. Ministry of Health and Family Welfare Government of India. Detail Question and Answers on COVID-19 for Public
18. Gunjawate DR Ravi R Yerraguntla K Rajashekhar B Verma A Impact of coronavirus disease 2019 on professional practices of audiologists and speech-language pathologists in India: A knowledge, attitude and practices survey Clin Epidemiol Glob Health 2021 9 110 115 10.1016/j.cegh.2020.07.009 32838065
19. Health in India (2020) NSS 75th Round (July 2017-June 2018) Report No. 586 (75/ 25.0). National Sample Survey Organization, Ministry of Statistics and Programme Implementation, Government of India. https://www.mospi.gov.in/sites/default/files/publication_reports/NSS%20Report%20no.%20586%20Health%20in%20India.pdf.
20. Verma RR Konkimalla A Thakar A Sikka K Singh AC Khanna T Prevalence of hearing loss in India Natl Med J India 2021 34 4 216 222 10.25259/NMJI_66_21 35112547
21. Rout N Mohapatra B Mishra S Hearing loss in elderly: An Indian Perspective J Indian Inst Speech Hear 2010 29 2 253 261
22. Anastasiadou S Al Khalili Y StatPearls Hearing Loss 2022 Treasure Island (FL) StatPearls Publishing
23. Garg S Deshmukh CP Singh MM Borle A Wilson BS Challenges of the Deaf and Hearing Impaired in the Masked World of COVID-19 Indian J Community Med 2021 46 1 11 14 10.4103/ijcm.IJCM_581_20 34035568
24. Alqudah S Zaitoun M Alqudah O Alqudah S Alqudah Z Challenges facing users of hearing aids during the COVID-19 pandemic Int J Audiol 2021 60 10 747 753 10.1080/14992027.2021.1872806 33590784
25. Bertoli S Staehelin K Zemp E Schindler C Bodmer D Probst R Survey on hearing aid use and satisfaction in Switzerland and their determinants Int J Audiol 2009 48 4 183 195 10.1080/14992020802572627 19363719
26. Chung SM Stephens SD Factors influencing binaural hearing aid use Br J Audiol 1986 20 2 129 140 10.3109/03005368609079006 3719161
27. McCormack A Fortnum H Why do people fitted with hearing aids not wear them? Int J Audiol 2013 52 5 360 368 10.3109/14992027.2013.769066 23473329
28. Kochkin S(2012) Hearing loss treatment. Better Hearing Institute. http://www.betterhearing.org/hearing_loss_treatment/index.cfm (accessed on 30th October 2012)
29. Erber N Use of hearing aids by older people: influence of non-auditory factors (vision, manual dexterity) Int J Audiol 2003 42 Sup 2 21 25 10.3109/14992020309074640
30. Öberg M Marcusson J Nägga K Wressle E Hearing difficulties, uptake, and outcomes of hearing aids in people 85 years of age Int J Audiol 2011 51 2 108 115 10.3109/14992027.2011.622301 22107444
31. Staehelin K Bertoli S Probst R Schindler C Dratva J Stutz E Gender and Hearing Aids: Patterns of Use and Determinants of Nonregular Use Ear Hear 2011 32 6 e26 e37 10.1097/AUD.0b013e3182291f94 21795978
32. Tambs K Hoffman H Borchgrevink H Holmen J Engdahl B Hearing loss induced by occupational and impulse noise: Results on threshold shifts by frequencies, age and gender from the Nord-Trøndelag Hearing Loss Study Int J Audiol 2006 45 5 309 317 10.1080/14992020600582166 16717022
33. Yueh B Shapiro N MacLean CH Shekelle PG Screening and management of adult hearing loss in primary care: scientific review JAMA 2003 289 15 1976 1985 10.1001/jama.289.15.1976 12697801
34. Kuk F Baekgaard L Hearing Aid Selection and BTEs: Choosing Among Various``Open-ear’’and``Receiver-in-canal’’Options Hear Rev 2008 15 3 22
35. Day G Browning G Gatehouse S Benefit from binaural hearing aids in individuals with a severe hearing impairment Br J Audiol 1988 22 4 273 277 10.3109/03005368809076464 3242717
36. Gaeta L Survey of Hearing Health During the COVID-19 Pandemic: Implications for Service Delivery Am J Audiol 2020 29 4 944 947 10.1044/2020_AJA-20-00037 33108213
37. Swanepoel DW Clark JL Koekemoer D Hall JW Krumm M Ferrari DV Telehealth in audiology: The need and potential to reach underserved communities Int J Audiol 2010 49 3 195 202 10.3109/14992020903470783 20151929
38. Campos PD Ferrari DV Teleaudiology: Evaluation of teleconsultation efficacy for hearing aid fitting J Soc Bras Fonoaudiol 2021 24 4 301 308 10.1590/s2179-64912012000400003
39. Lotfi Y Mehrkian S Moossavi A Faghih-Zadeh S Quality of life improvement in hearing-impaired elderly people after wearing a hearing aid Arch Iran Med 2009 12 4 365 370 19566353
40. Popelka MM Cruickshanks KJ Wiley TL Tweed TS Klein BE Klein R Low prevalence of hearing aid use among older adults with hearing loss: the Epidemiology of Hearing Loss Study J Am Geriatr Soc 1998 46 9 1075 1078 10.1111/j.1532-5415.1998.tb06643.x 9736098
| 0 | PMC9734753 | NO-CC CODE | 2022-12-14 23:28:30 | no | Indian J Otolaryngol Head Neck Surg. 2022 Dec 8;:1-8 | utf-8 | Indian J Otolaryngol Head Neck Surg | 2,022 | 10.1007/s12070-022-03209-8 | oa_other |
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Br Dent J
Br Dent J
British Dental Journal
0007-0610
1476-5373
Nature Publishing Group UK London
36473976
5272
10.1038/s41415-022-5272-9
Research
Potential discolouration of silver diamine fluoride versus silver diamine fluoride/potassium iodide in primary teeth: a randomised clinical study
Aly Mariam M. [email protected]
Yousry Yasmin M.
grid.7776.1 0000 0004 0639 9286 Lecturer of Paediatric Dentistry and Dental Public Health, Faculty of Dentistry, Cairo University, Egypt
6 12 2022
16
26 5 2022
29 7 2022
© The Author(s), under exclusive licence to the British Dental Association 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Aim This study aimed to evaluate the potential discolouration and carious lesion arresting effect of silver diamine fluoride (SDF) and silver diamine fluoride/potassium iodide (SDF/KI) in the treatment of carious primary teeth.
Materials and method A total of 30 carious primary canines were randomly assigned to treatment groups where Group I was treated with SDF while Group II was treated with SDF/KI. Caries arrest was assessed based on consistency and stability of lesion size while the discolouration of treated lesions was assessed digitally using a VITA Easyshade spectrophotometer.
Results Both treatments demonstrated 100% efficacy in arresting active caries lesions. Regarding discolouration, the total colour difference represented by delta E (ΔE) was 16.45 ± 5.69 for Group I compared to 9.54 ± 3.09 for Group II immediately post-operative, with a statistically significant difference (p = 0.003). Both groups showed similar values at 1, 3, 6 and 12 months after the treatment, with no statistically significant difference. No incidence of serious adverse effects related to either treatment and the majority of parents/guardians were satisfied with both treatments compromising their child's aesthetic appearance.
Conclusions Both SDF and SDF/KI are effective in arresting carious lesions in primary teeth but in terms of the discolouration potential, the use of KI significantly reduced the discolouration caused by SDF immediately post-operatively. Unfortunately, marked discolouration was recorded in the subsequent follow-up visits, compromising the aesthetic outcome.
Key points
Based on the results of our study, both silver diamine fluoride and silver diamine fluoride/potassium iodide were effective in arresting carious lesions in primary anterior teeth, but the application of potassium iodide didn't prevent the discolouration caused by silver diamine fluoride application.
No adverse events were reported with either materials.
Although parents/guardians perceived discolouration, they were open to compromise aesthetics in favour of using a less invasive approach.
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pmcIntroduction
Dental caries has been recognised as a major public health problem and one of the most frequent chronic diseases impacting humans worldwide, affecting 60-90% of schoolchildren.1 In children from families from a low-income background, the majority of carious lesions were left untreated due to cost and limited availability or access to dental services. For these reasons, the severity of the disease increases, which leads to pain, expense and a decreased quality of life for the affected children and their families.2
In this context, there was a great interest in simple, effective, accessible, affordable and safe treatments to halt the progress of carious lesions. Among these treatments is silver diamine fluoride (SDF), which can be used as the best strategy to control the burden of dental caries in children around the world.3
The Food and Drug Administration authorised the use of SDF as a dentine hypersensitivity agent in 2014 and acknowledged its off-label use for caries arrest and prevention in the United States, the United Kingdom and Thailand.1 Moreover, the American Dental Association and American Association of Paediatric Dentistry support its off-label usage in a comprehensive caries management programme to arrest cavitated caries lesions in primary teeth.4
Clinically, there are a multitude of benefits associated with the application of SDF in the clinical management of caries. One such benefit is the simple and relatively painless application that allow it to be widely used in special conditions, such as early childhood caries, paediatric patients with additional needs and patients with behavioural or medical issues impeding conventional therapy. Another major advantage is its cost-effectiveness, where small volumes (25 μL) of SDF can be used to treat up to five teeth. Thus, dentists can offer dental treatment to those who cannot afford or access regular dental care.5
The black discolouration of carious enamel and dentin that resulted from the application of SDF may limit its use. Because the discolouration affects the aesthetic appearance of the tooth, many parents/guardians may oppose treatment, making the dentist hesitant of proposing it as a treatment option.6
In an attempt to minimise the black discolouration, the use of a potassium iodide (KI) solution after SDF application has been suggested. Unfortunately, there is insufficient evidence to demonstrate its effectiveness in reducing tooth discolouration, so clinical studies with a long period of observation are still needed.5,7 Our study aimed to evaluate the potential discolouration and carious lesion arresting effect after application of SDF versus SDF/KI in the treatment of carious primary anterior teeth.
Materials and methods
Study design
This was a split-mouth, randomised, controlled, clinical study conducted to evaluate the potential discolouration and carious lesion arresting effect after application of SDF versus SDF/KI in the treatment of carious primary anterior teeth. The Consolidated Standards of Reporting Trials (CONSORT) guidelines were followed to ensure the reporting of this clinical study.8
Sample size
The power and sample size calculations programme (Sealed Envelope Ltd, 2012) was used to calculate the sample size.9 The continuous outcome superiority trial power calculator is available online at https://www.sealedenvelope.com/power/continuous-superiority/. Based on the results of Nguyen et al.,10 a total sample size of 30 patients was calculated, with an 80% chance of detecting an increase in the mean lightness values from 53.6 in the control group to 71.3 in the experimental group, at a 5% level of significance and a 35% dropout rate.
Ethical aspects
The current research was carried out in compliance with the Helsinki Declaration.11 Ethical approval was obtained from the Ethics Committee of Scientific Research, Faculty of Dentistry, Cairo University. After a comprehensive explanation of the treatment procedure, benefits and possible complications, informed consent was obtained by the children's parent/guardian.
This study has been registered on clinicaltrials.gov under the title 'Staining potential and caries arresting effect of silver diamine fluoride⁄potassium iodide and silver diamine fluoride' with the identifier NCT04196829.
Study setting
Children were recruited from the outpatient clinic of the paediatric dentistry and dental public health department and they were carefully assessed for eligibility to participate in the study.
Inclusion criteria
Children aged from 3-6 years old
Children with bilateral carious primary canines
Active carious lesions which have International Caries Detection and Assessment System (ICDAS)12 code 4 or 5.
Exclusion criteria
Children with spontaneous pain or any signs of pulpal infection
Children having any clinical or radiographic signs of periapical infection
Active carious lesions which have ICDAS codes other than 4 or 5
Children which have sensitivity to silver or other heavy metal ions
Children which have any gingival or perioral ulceration or stomatitis.
Randomisation and allocation concealment
Owing to the split-mouth study design, randomisation was performed to assign right side carious canines to one of the treatment modalities using a sealed envelope, while the left side carious canines were assigned to the opposite group automatically, with a 1:1 allocation ratio dividing the 30 carious primary canines into two equal groups with 15 teeth in each group as follows:Group I (n = 15): teeth treated with SDF (e-SDF, Kids e-Dental, India. One bottle [3.25 mL] containing 38% SDF)
Group II (n = 15): teeth treated with SDF/KI (Riva Star, SDI, Bayswater, Australia. Two bottles - a silver bottle [1.5 mL] containing 38% silver fluoride in an ammonia solution and a green bottle [3.0 mL] containing KI solution).
Blinding
The child participants and their legal guardians, the outcomes assessors and the statistician were blinded.
Baseline clinical examination
Participants' personal, medical and dental histories were obtained at the baseline examination. Through meticulous visual inspection of the carious lesion, the state of carious lesions was recorded and scored according to the ICDAS using a ball-ended World Health Organisation probe with gentle force.
The colour of the carious lesion was assessed digitally using a VITA Easyshade spectrophotometer after being calibrated in accordance with the manufacturer's instructions to assess the baseline shade of the carious lesion before treatment. A single operator replicated the L*, a* and b* values three times and the average values were recorded. The L* axis represented lightness ranging from black (0) to white (100), the a* axis ranging from red (+a*) to green (-a*), and the b* axis ranging from yellow (+b*) to blue (-b*).
Clinical procedure
In Group I, the gingival tissue in the anterior area was protected with petroleum jelly and the affected tooth surface was gently cleaned and dried with cotton gauze. Using a micro brush, the affected tooth surface was coated with a 38% SDF solution. Moisture control was maintained for at least one minute after SDF placement using a gentle flow of compressed air to allow for absorption, then excess SDF was removed using cotton gauze.
In Group II, the application of SDF was carried out in the same manner as in Group I, followed by the immediate application of the KI solution using a separate micro brush, saturated with KI solution, until the precipitate went from yellow to white and then clear.
The colour of the treated carious lesion was recorded immediately post-operatively using a digital VITA Easyshade spectrophotometer to calculate the delta E (ΔE) value that defines the total colour difference. Then, children were instructed to avoid rinsing, eating and drinking for one hour after treatment. All children were recalled back after 1, 3, 6, 9 and 12 months to assess treatment outcomes.
Outcomes
Discolouration of the carious lesion was assessed digitally using ΔE as follows: ΔE = ([ΔL]2 + [Δa]2 + [Δb]2)
Carious lesion arrest was judged based on:
The stability in the size of the carious lesion, evaluated using the ICDAS index, into stable or progressing
The consistency of the lesion was evaluated upon gentle probing using a ball-ended World Health Organisation probe into soft or hard
Evaluation of the presence or absence of adverse events observed or complaints from either parents/guardians or the children, including pain, transient gingival swelling and gingival bleaching
Parent/guardian satisfaction for SDF treatment was recorded using a detailed questionnaire.13
Statistical analysis
Quantitative data were represented as mean and standard deviation (mean ± SD) values and the t-test was used to assess the significant differences. Qualitative data were described as frequencies and percentages and the chi-square test was used to assess the significant differences. The p-value was considered statistically significant if ≤0.05. The IBM SPSS Statistics (22.0) software package for Microsoft Windows was used to conduct the statistical analysis.
Results
The flow of patients throughout the study, as demonstrated in Figure 1, showed that 13 patients with 26 carious lesions completed the 12-month study period, while only two subjects with four carious lesions failed to complete the entire follow-up period. Due to the COVID-19 lockdown, patients couldn't attend the clinic for follow-up at nine months.Fig. 1 Participant flow diagram through the randomised clinical trial according to CONSORT guidelines
Patients who participated in the present study were aged between 4-6 years, with a mean age of 5.33 ± 0.64 years, while the distribution of sexes was 60% boys and 40% girls. At the baseline examination by ICDAS classification, 60% scored 4 and 40% scored 5.
Regarding the discolouration of treated carious lesions, the colour parameter that changed the most in both groups was ΔL, which represented a greater darkening of the teeth. With a p-value of 0.006, there was a statistically significant difference between the two groups immediately after the treatment, while no statistically significant differences were found at 1, 3, 6 and 12 months, as shown in Table 1.Table 1 Mean and standard deviation (mean ± SD) values for ΔL representing lightness difference in both groups
Time interval Group I Group II P-value between groups
Mean ± SD Mean ± SD
Immediate post-operative - baseline -13.76 ± 5.72 -6.84 ± 3.98 0.006*
One month - baseline -28.14 ± 6.02 -24.31 ± 5.81 0.165
Three months - baseline -29.84 ± 7.35 -25.81 ± 9.29 0.312
Six months - baseline -31.23 ± 6.94 -27.63 ± 6.21 0.293
Twelve months - baseline -35.35 ± 4.56 -31.50 ± 7.52 0.236
Key:
* = significant (p ≤0.05)
Non-significant = p >0.05
Regarding the ΔE values among both groups, Group I recorded higher values immediately after treatment in comparison to Group II, with a statistically significant difference (p = 0.003). Both groups showed similar values at 1, 3, 6 and 12 months after the treatment with no statistically significant difference, as shown in Table 2.Table 2 Mean, and standard deviation (mean ± SD) values for ΔE representing the total colour difference in both groups
Time interval Group I Group II P-value between groups
Mean ± SD Mean ± SD
Immediate post-operative 16.45 ± 5.69 9.54 ± 3.09 0.003*
One month 35.84 ± 3.94 33.75 ± 8.50 0.489
Three months 37.85 ± 9.08 36.42 ± 7.87 0.717
Six months 40.29 ± 10.11 39.72 ± 6.63 0.896
Twelve months 45.24 ± 6.94 44.65 ± 5.80 0.857
Key:
* = significant (p ≤0.05)
Non-significant = p >0.05
When comparing ΔE at different time intervals, both groups showed a progressive increase in ΔE throughout the entire follow-up period, with only a statistically significant difference between the immediate post-operative and one month (p = 5.6E-08 for Group I and p = 1.1E-07 for Group II).
Assessment of the effect of both treatments in arresting carious lesions has relied on the tactile evaluation of lesion consistency and the employment of the ICDAS codes to evaluate the stability of the lesion size. In both groups, all the treated teeth were considered arrested at the 6- and 12-month follow-up periods, as shown in Figure 2.Fig. 2 Evaluation of consistency, size stability and arrest of treated carious lesions in both groups
Concerning adverse events observed or complained about from either parents/guardians or children, only one case (7.7%) in Group I complained of pain and transient gingival swelling, while gingival bleaching was observed in 23.1% and 15.4% in Group I and II, respectively, with no statistically significant difference (p = 0.30782).
Regarding parental satisfaction with treatment, most parents/guardians agreed or strongly agreed about the ease of application, the painlessness of the process and the taste of both materials, while 84.6% in Group I and 69.2% in Group II weren't comfortable with the discoloration of teeth, as shown in Figure 3.Fig. 3 The distribution of parental satisfaction for treatment in both groups
Discussion
SDF was proposed as an alternative treatment for caries prevention and arrest because it is simple, relatively painless and affordable, as well as conforming to the concept of minimally invasive dentistry. As a result, treating caries lesions with SDF appears to be particularly appropriate for younger, less compliant and socially vulnerable children.14
The discolouration that follows SDF application has significantly diminished its use in paediatric and adult patients. One of the proposed methods for preventing this adverse side effect is the application of KI immediately after SDF.15
Unfortunately, there is conflicting evidence regarding the effect of SDF/KI on tooth colour. In vitro studies on both primary and permanent teeth showed that KI was effective in preventing tooth discolouration, while a clinical study on root caries in the older population found no effect.15 Moreover, only a single clinical trial with six months of follow-up revealed a 25% reduction in the incidence of discolouration following KI application, owing to the scarcity of studies that evaluate the effect of SDF with KI and its methodological limitations.16,17 The present study aimed to evaluate the potential discolouration and carious lesion arresting effect after application of SDF versus SDF/KI in the treatment of carious primary anterior teeth.
The current study demonstrated 100% efficacy of both treatments in arresting all active caries lesions where all lesions were hard and stable in size. These findings were in accordance with previous studies and can be attributed to the high silver and fluoride ion concentrations, the synergic effect of these ions and its increased alkalinity.1,13,18,19
The silver component interacts with the sulphhydryl groups of proteins and DNA from the microorganisms, interfering in the bacterial metabolism and causing its destruction and inhibiting the formation of biofilm. Additionally, the silver salts formed on the dentin surface block the dentinal tubules, reducing tooth sensitivity and contributing to forming a very resistant dentin outer layer.1,20,21
The fluoride component of the SDF reacts with calcium phosphate and hydroxyapatite to form fluorapatite and calcium fluoride, which improves the acid resistance, mineral density and hardness of the carious dentin, which is consistent with dentin remineralisation.22
Additionally, SDF inhibits the breakdown of the exposed collagen matrix, owing to the high concentration of silver which inhibits matrix metalloproteinases and cysteine cathepsins. This is very important, as the collagen network provides the scaffold for the new remineralisation cores.22,23
The evaluation of discolouration was done using a digital VITA Easyshade spectrophotometer. VITA Easyshade measures the complex colour of tooth structure numerically, where the L*, a* and b* colour system was used to elucidate each colour three-dimensionally in space. This device has shown high reliability and reproducibility, eliminating the problems of subjectivity in colour assessment by giving quantitative values to calculate the ΔE value that defines the total colour difference between the final and baseline values.7,24,25
Immediately after the application of both materials, both groups showed a degree of discolouration represented by a mean ΔE value equal to 16.45 ± 5.69 for Group I and 9.54 ± 3.09 for Group II, which was in agreement with previous studies.7,26,27
This finding can be attributed to black precipitate formed on the surface of carious dentine because of the reaction of unreacted silver ions on the partially denatured collagen, where the excess unreacted silver ions precipitated as silver sulphide, inducing discolouration.27,28
In both groups, the degree of discolouration increased markedly at one-month follow-up, represented by the progressive increase in mean ΔE value by 35.84 ± 3.94 in Group I and 33.75 ± 8.50 in Group II, with a statistically significant difference between the immediate post-operative and one-month follow-up (p = 5.6E-08 in Group I and a p = 1.1E-07 in Group II). The difference in mean ΔE value between 1, 3, 6 and 12 months wasn't statistically significant in both groups.
This finding can be linked to the fact that metallic silver was formed by the reaction of SDF and hydroxyapatite and its production was accelerated when exposed to light and high temperatures that eventually increase the brown-black appearance of the carious lesion over time.24,27,28,29
When discolouration was compared in both groups immediately post-operatively, Group I showed more discolouration, represented by a higher mean ΔL value (-13.76 ± 5.72), compared to Group II (-6.84 ± 3.98), with a statistically significant difference (p = 0.006) and a higher mean ΔE value (16.45 ± 5.69) compared to Group II (9.54 ± 3.09), with a statistically significant difference (p = 0.003), which was in agreement with previous studies.26,27,28,29
The ability of KI in reducing the discolouration caused by SDF can be justified through reaction with the free silver ions, producing a creamy white precipitate of silver iodide.27,28
On the contrary, both groups showed a similar degree of discolouration represented by mean ΔE values equal to 35.84 ± 3.94, 37.85 ± 9.08, 40.29 ± 10.11 and 45.24 ± 6.94 at 1, 3, 6 and 12 months, respectively, for Group I, and mean ΔE values equal to 33.75 ± 8.50, 36.42 ± 7.87, 39.72 ± 6.63 and 44.65 ± 5.80 at 1, 3, 6 and 12 months, respectively, for Group II. There was no statistically significant difference between groups at 1, 3, 6 and 12 months, with a p-value of 0.489, 0.717, 0.896 and 0.857, respectively.
These findings were in accordance with several studies2,16,17,26,30 that reported the ability of KI to improve initial aesthetic appearance after SDF application. However, after time, KI does not seem to result in any significant difference in discolouration. This can be attributed to the fact that silver iodide, which is formed upon the application of KI following SDF, is a photosensitive material that can dissociate into silver and iodine when exposed to light.15,29
No incidence of serious adverse effects related to both treatments occurred during the whole study period. Oral pain, transient gum swelling and gum bleaching were seldom reported in the present study, which were in accordance with previous studies reporting no major side effects among children.20,31,32 This finding can be attributed to the diffusion of SDF onto surrounding tissues, resulting in temporary irritation of gingiva that subsided within days.17
The majority of parents/guardians in the present survey were satisfied with both treatments in terms of ease of application, painlessness of the process and material taste compromising their child's aesthetic appearance. These findings were in accordance with several studies13,18,33 and can be attributed to the fact that parents/guardians may perceive the discolouration from SDF in anterior teeth as being unaesthetic, but most parents/guardians are open to compromise aesthetics in favour of using a less invasive approach, especially when the child's co-operation becomes a barrier for traditional treatment to avoid the possibility of their children having to undergo sedation or general anaesthesia.3,28
Since parents/guardians may not have other affordable options for treating and alleviating pain in their children, the simplicity and cost-effectiveness of SDF make it a very favourable treatment for children of lower socioeconomic status.6
Conclusions
Based on the results of our study, both SDF and SDF/KI were effective in arresting carious lesions in primary anterior teeth but the application of KI didn't prevent the discolouration caused by SDF application. No adverse events were reported with both materials. Although parents/guardians perceived the discolouration, they were open to compromising aesthetics in favour of using a less invasive approach.
Acknowledgements
The authors acknowledge the children and their parents/guardians for their co-operation in accomplishing this work.
Author contributions
Mariam M. Mohsen and Yasmin M. Yousry contributed to the study's conception and design, material preparation, data collection and analysis. The first draft of the manuscript was written by Mariam Mohsen and Yasmin Yousry contributed. Both authors read and approved the final manuscript.
Funding information
No funding was received for conducting this study.
Ethics declaration
This study was approved by the Ethics Committee of Scientific Research, Faculty of Dentistry, Cairo University with approval number 19-12-23. The research was carried out in accordance with the Declaration of Helsinki. Written informed consent to participate was obtained from the children's parents/guardians.
The authors have no relevant financial or non-financial interests to disclose.
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References
1. Abdellatif H M, Ali A M, Baghdady S I, ElKateb M A. Caries arrest effectiveness of silver diamine fluoride compared to alternative restorative technique: randomized clinical trial. Eur Arch Paediatr Dent 2021; 22: 575-585.
2. Garg S, Sadr S, Chan D. Potassium Iodide Reversal of Silver Diamine Fluoride Staining: A Case Report. Oper Dent 2019; 44: 221-226.
3. Crystal Y O, Janal M N, Hamilton D S, Niederman R. Parental perceptions and acceptance of silver diamine fluoride staining. J Am Dent Assoc 2017; 148: 510-518.
4. Gao S S, Amarquaye G, Arrow P et al. Global Oral Health Policies and Guidelines: Using Silver Diamine Fluoride for Caries Control. Front Oral Heal 2021; DOI: 10.3389/froh.2021.685557.
5. Roberts A, Bradley J, Merkley S, Pachal T, Gopal J V, Sharma D. Does potassium iodide application following silver diamine fluoride reduce staining of tooth? A systematic review. Aust Dent J 2020; 65: 109-117.
6. Sabbagh H, Othman M, Khogeer L, Al-Harbi H, Al Harthi A, Abdulgader Yaseen Abdulgader A. Parental acceptance of silver Diamine fluoride application on primary dentition: a systematic review and meta-analysis. BMC Oral Health 2020; 20: 227.
7. Fröhlich T T, Gindri L D O, Pedrotti D, Cavalheiro C P, Soares F Z M, de Oliverira Rocha R. Evaluation of the Use of Potassium Iodide Application on Stained Demineralized Dentin Under Resin Composite Following Silver Diamine Fluoride Application. Paediatr Dent 2021; 43: 57-61.
8. Sarkis-Onofre R, Poletto-Neto V, Cenci M S, Moher D, Pereira-Cenci T. CONSORT endorsement improves the quality of reports of randomized clinical trials in dentistry. J Clin Epidemiol 2020; 122: 20-26.
9. Sealed Envelope Ltd. Power calculator for continuous outcome superiority trial. 2012. Available at https://www.sealedenvelope.com/power/continuous-superiority/ (accessed November 2022).
10. Nguyen V, Neill C, Felsenfeld J, Primus C. Potassium Iodide. The Solution to Silver Diamine Fluoride Discoloration? Adv Dent Oral Heal 2017; 5: 1-6.
11. World Medical Association Inc. Declaration of Helsinki. Ethical principles for medical research involving human subjects. J Indian Med Assoc 2009; 107: 403-405.
12. Pitts N B, Ekstrand K, ICDAS Foundation. International Caries Detection and Assessment System (ICDAS) and its International Caries Classification and Management System (ICCMS) - methods for staging of the caries process and enabling dentists to manage caries. Community Dent Oral Epidemiol 2013; DOI: 10.1111/cdoe.12025.
13. Clemens J, Gold J, Chaffin J. Effect and acceptance of silver diamine fluoride treatment on dental caries in primary teeth. J Public Health Dent 2018; 78: 63-68.
14. Oliveira B H, Rajendra A, Veitz-Keenan A, Niederman R. The Effect of Silver Diamine Fluoride in Preventing Caries in the Primary Dentition: A Systematic Review and Meta-Analysis. Caries Res 2019; 53: 24-32.
15. Haiat A, Ngo H C, Samaranayake L P, Fakhruddin K S. The effect of the combined use of silver diamine fluoride and potassium iodide in disrupting the plaque biofilm microbiome and alleviating tooth discoloration: A systematic review. PLoS One 2021; DOI: 10.1371/journal.pone.0252734.
16. Li R, Lo E C M, Liu B Y, Wong M C M, Chu C H. Randomized clinical trial on arresting dental root caries through silver diammine fluoride applications in community-dwelling elders. J Dent 2016; 51: 15-20.
17. Turton B, Horn R, Durward C. Caries arrest and lesion appearance using two different silver fluoride therapies with and without potassium iodide: 6-month results. Heliyon 2020; DOI: 10.1016/j.heliyon.2020.e04287.
18. Vollú A, Rodrigues G, Rougemount Teixeira R et al. Efficacy of 30% silver diamine fluoride compared to atraumatic restorative treatment on dentine caries arrestment in primary molars of preschool children: A 12-months parallel randomized controlled clinical trial. J Dent 2019; 88: 103165.
19. Gao S S, Zhao I S, Hiraishi N et al. Clinical Trials of Silver Diamine Fluoride in Arresting Caries among Children: A Systematic Review. JDR Clin Trans Res 2016; 1: 201-210.
20. Rosenblatt A, Stamford T C M, Niederman R. Silver diamine fluoride: A caries 'silver-fluoride bullet'. J Dent Res 2009; 88: 116-125.
21. Fung M H T, Duangthip D, Wong M C M, Lo E C M, Chu C H. Arresting Dentine Caries with Different Concentration and Periodicity of Silver Diamine Fluoride. JDR Clin Trans Res 2016; 1: 143-152.
22. Mei M L, Lo E C M, Chu C H. Arresting Dentine Caries with Silver Diamine Fluoride: What's Behind It? J Dent Res 2018; 97: 751-758.
23. Thanatvarakorn O, Islam S, Nakashima S, Sadr A, Nikaido T, Tagami J. Effects of zinc fluoride on inhibiting dentin demineralization and collagen degradation in vitro: A comparison of various topical fluoride agents. Dent Mater J 2016; 35: 769-775.
24. Sayed M, Matsui N, Hiraishi N, Nikaido T, Burrow M F, Tagami J. Effect of Glutathione Bio-Molecule on Tooth Discoloration Associated with Silver Diammine Fluoride. Int J Mol Sci 2018; 19: 1322.
25. AlGhazali N, Burnside G, Smith R W, Preston A J, Jarad F D. Performance assessment of Vita Easy Shade spectrophotometer on colour measurement of aesthetic dental materials. Eur J Prosthodont Restor Dent 2011; 19: 168-174.
26. Zhao I S, Mei M L, Burrow M F, Lo E C-M, Chu C-H. Effect of Silver Diamine Fluoride and Potassium Iodide Treatment on Secondary Caries Prevention and Tooth Discolouration in Cervical Glass Ionomer Cement Restoration. Int J Mol Sci 2017; 18: 340.
27. Gupte M, Saraf T, Jawdekar A M, Khare D S, Tiku A. A comparative analysis of staining propensity of SDF, SDF with potassium iodide and SDF with glutathione biomolecule on demineralized enamel: An in vitro study. Int J Appl Dent Sci 2021; 7: 297-301.
28. Vennela E, Sharada J, Hasanuddin S, Suhasini K, Haemachandrika I, Singh I. Comparison of staining potential of silver diamine fluoride versus silver diamine fluoride and potassium iodide under tooth-coloured restorations: An in vitro study. J Indian Soc Pedod Prev Dent 2021; 39: 47-52.
29. Zhao I S, Chu S, Yu O Y, Mei M L, Chu C H, Lo E C M. Effect of silver diamine fluoride and potassium iodide on shear bond strength of glass ionomer cements to caries-affected dentine. Int Dent J 2019; 69: 341-347.
30. Miller M B, López L A, Quock R L. Silver diamine fluoride, potassium iodide, and esthetic perception: An in vitro pilot study. Am J Dent 2016; 29: 248-250.
31. Duangthip D, Jiang M, Chu C H, Lo E C M. Non-surgical treatment of dentin caries in preschool children - systematic review. BMC Oral Health 2015; 15: 44.
32. Duangthip D, Fung M H T, Wong M C M, Chu C H, Lo E C M. Adverse Effects of Silver Diamine Fluoride Treatment among Preschool Children. J Dent Res 2018; 97: 395-401.
33. Chaurasiya A, Gojanur S. Evaluation of the clinical efficacy of 38% silver diamine fluoride in arresting dental caries in primary teeth and its parental acceptance. J Indian Soc Pedod Prev Dent 2021; 39: 85-89.
| 36473976 | PMC9734755 | NO-CC CODE | 2022-12-14 23:28:30 | no | Br Dent J. 2022 Dec 6;:1-6 | utf-8 | Br Dent J | 2,022 | 10.1038/s41415-022-5272-9 | oa_other |
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Curr Psychiatry Rep
Curr Psychiatry Rep
Current Psychiatry Reports
1523-3812
1535-1645
Springer US New York
36480149
1400
10.1007/s11920-022-01400-w
Psychiatry in the Digital Age (J Shore, Section Editor)
Telemental Health for the Homeless Population: Lessons Learned when Leveraging Care
DeLaCruz-Jiron Evelyn J. [email protected]
1
Hahn Lauren M. 1
Donahue Amy L. 1
Shore Jay H. 12
1 Access Management Services LLC, 11100 East Bethany Drive, Aurora, CO 80014 USA
2 grid.430503.1 0000 0001 0703 675X Department of Psychiatry and Family Medicine, School of Medicine and Centers for American Indian and Alaska Native Health Colorado School of Public Health, Anschutz Medical Campus, Aurora, USA
8 12 2022
16
15 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose of Review
The purpose of this paper is to review key lessons when using telehealth within the context of mental health and homelessness. We examine technological and bandwidth issues the homeless population might face when getting telehealth services, discuss clinical process adaption needed for working remotely, and highlight the lessons learned when leveraging mental health services to homeless patients across telehealth platforms.
Recent Findings
Homelessness is associated with chronic, mental health disparities and access to mental health services is often less accessible among communities with unstable housing. Telehealth provides “OnDemand” treatment options while removing specific barriers found with in-person health care such as transportation, overwhelmed mental health facilities, i.e., appointment availability, and office hour limitations while reducing costs for both providers and patients.
Summary
We provide two case examples to demonstrate successful delivery of telemental health services to homeless patients and review lessons learned when leveraging care.
Keywords
Homelessness
Telemental health
Technology
Mental health
Telehealth
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pmcIntroduction: Homelessness and Mental Health Disparities
The US Department of Housing and Urban Development reported roughly just under 10,000 people experience homelessness in Colorado and slightly over a half a million people in the USA are living in state of homelessness on any given day [1]. While the majority of Americans are homeless for a limited/short period of time, 22% are chronically homeless, federally defined as being homeless for at least a year or more than 4 times in the past 3 years for a period of a year or more [2]. A growing body of research supports there are multiple detrimental health outcomes associated with loss of housing, including chronic illness, substance use disorders, and unmet mental health needs. Chronic health conditions such as heart disease, diabetes, and HIV/AIDs are found to be 3–6 times higher in homeless populations compared to the general population, with 20% of the homeless people reporting to have a serious mental illness [2]. Although many people experiencing homelessness present with co-occurring disorders, treatment to improve their mental/physical health is lacking; thus, the pattern of homelessness and chronic health conditions appears to perpetuate one another.
The current research indicates the primary barriers faced by someone experiencing homelessness when trying to get adequate treatment were (1) being stigmatized/differential treatment, i.e., patients reported being treated poorly by providers and members of the community when homeless, (2) higher order tasks needed for daily care, i.e., homeless patients had to carefully plan for basic needs such as hygiene, eating, and charging their phones which took away from time allocated for seeking/receiving mental health services, and (3) overall instability, which is attributed to the ability to sustain contact with important others including providers, family, or other sources of support [3]. It should also be noted that within the context of homelessness, self-efficacy, and the perception of asserting and maintaining control over their daily lives, their belongings, health, and safety were also potential barriers.
Researchers support that emergency department (ED) for homeless populations is utilized more than any other service type by people without housing and up to 3 times more than that of the non-homeless population [4••]. There are many common factors attributing to high ED utilization for people without housing, including lack of health insurance, lack of transportation, and poor access to primary care [5]. Although repeated ED visits are common for homeless patients, overall health outcomes have not been noted to significantly improve for the homeless population. In general, a homeless person’s mortality rate is 3–6 times higher than that of the general population [4••]. Likewise, many people experiencing homelessness are less likely to get the care they need when faced with a medical or mental health problem. People who are experiencing homelessness commonly receive multiple services from various providers; hence, frequent ER visits to different hospitals without data sharing can lead to the risk of misdiagnosing and/or giving patients duplicate treatment/tests or the wrong medications/treatment.
Telehealth as a Proposed Solution
Technology-based treatments for mental health including tele-therapy, text messages, and mobile apps have been promising in delivering treatment to various populations. The COVID-19 pandemic certainly increased the popularity of telehealth solutions, transforming the way people receive health care; however, many providers from all specialties were developing telehealth tools prior to the pandemic [6–8].
During the initial COVID peak, a 2020 study reported that telehealth visits went from less than 1% to as much as 80% in places where COVID cases were high [9••]. Although telehealth utilization has dropped since the initial peak of COVID, telehealth usage continues to remain high. Karimi reported out of 670,155 participants, 23.1% reported they used telehealth, either audio or video within the last month, with the highest rates among Medicaid users at 29.3% [9••].
It may come as surprising, but ongoing research supports that many homeless people have access to technology; thus, the concept of using technology to break-down access barriers is not a new concept [10, 11]. Recent research supports that generally over half of the homeless population have a cell phone; however, in some studies, up to 90–100% of homeless sample groups had access to a cell phone or mobile device [12••]. Despite cell phone ownership, overall digital access is still an issue. A mixed-methods study of internet and social media use among homeless youth found 56% used the internet at least once a day and 86% once a week. Smartphones were associated with greater odds of internet access and were the most frequently used method to access the internet, while homelessness sample internet access frequency decreased by 68%. [12••, 13].
Age also appears to be a factor in mobile phone ownership and telehealth use [12••, 14–16]. Heaslip et al. found that young homeless people with mental health concerns were up to 5× more likely to find help online [12••]. Youth aging 16–25 are more likely to use telehealth or fully automated phone interventions, while older homeless people have lower cell phone ownership, hence are less likely to use telehealth services. Older age may also be associated with lower telehealth use due to increased barriers such as expectations of in-person social contact, psychological aging, and digital literacy. Digital literacy as well as comfort with and past experiences using technology varies widely in the homeless as it does in other populations, with age being one of several important mediating factors around digital literacy and comfort [12••, 16].
Other practical problems with cell phone technology mentioned throughout the literature include issues with battery life, limited options when charging devices, breakages, and theft. Lack of trust was also mentioned in various studies as a common barrier when linking people who are experiencing homelessness to telehealth services via their phone or mobile device [12••, 17]. Though there is increasing mobile phone ownership among the homeless, many struggle with affordability of data plans and rely on public spaces for internet access, with COVID aggravating this with associated lockdowns limiting access to public spaces [18]. In addition, challenges can exist around adequacy of bandwidth when using any technology for health care. Bandwidth requirements differ across digital health care applications. The bandwidth needed to access a patient portal or psychoeducational material on the internet is significantly lower than the bandwidth needed for two-way live interactive videoconferencing [17, 19•]. Rural homeless populations may have additional access barriers, although a recent study in this population found high rates of cell phone ownership (87%) and internet access (83%). There was a willingness to use technology for health care but reluctance to engage in direct telehealth [20•]. The reasons for the resistance varied; however, resistance to treatment and general non-compliance with medication management and therapy occurs in both virtual and face-to face platforms for several reasons.
In terms of success outcomes, telehealth modalities to improve access, specifically video visits, have been found to have high levels of satisfaction for both patients and providers [6, 19•, 21]. Recent research reveals technological interventions show high rates of clinical benefit, including reduction of symptoms of psychopathology, specifically for PTSD, depression, and anxiety [6, 15, 16]. As a means to overcome barriers with digital technology, research supports that incorporating telehealth into an urban permanent supportive housing setting also proves to be helpful in allowing clients to access tele-therapy from the comfort of their own home, or from a designated room located at the housing facility [22].
The Veteran’s Affairs (VA) has been known to lead clinical video telehealth and has had some success in delivering mental health care virtually. Between 2017 and 2019, the VA health care system issued 12,148 video-enabled tablets to homeless veterans to receive telehealth. Tablets came with WiFi and data plans and VA representatives guided participants through the technology set-up. Nearly half of the veterans experiencing homelessness had a telehealth visit within 6 months of receiving the tablet, most frequently for mental health [23].
Moving toward a blockchain technology in health care also appears to be a low-cost solution for people experiencing homelessness as a means to track and store their health care information when seeing multiple providers. Blockchain technology, also known as distributed ledger technology (DLT), creates a network among users, making data portable so the coordination of care can be assessable to any provider. Khurshid and Gadnis proposed the concept of blockchain technology (DLT) to allow people who are experiencing homelessness to become a part of data sharing system, connecting providers, and allowing patients to maintain their health care information in one place [24].
Using mobile technology for appointment reminders was recommended throughout the literature for the homeless population, suggesting to improve adherence and a sense of connectiveness [12••]. In effect, the research supports that technology facilitates self-management and people experiencing homelessness are more likely to accomplish daily tasks including coordinating/scheduling appointments if they have access to mobile technology, specifically the internet [3, 7, 25, 26•].
Special Considerations/Requirements
High rates of technology access among certain cohorts of homeless populations including mobile phone, computer, and access to internet make virtual options for mental health services appealing. However, additional issues for both patients and providers when creating and accessing telehealth services need to be considered. Standard telehealth considerations include providers’ clinical protocols around safety, consent, and HIPAA compliance, hence adequate training for both patients and providers on using televideo or other technologies [21, 27]. Providers and organizations need to understand and develop strategies to address legal requirements at both the state and federal level, backup plans for technological malfunctions and internet outages, and finally level of comfort, when delivering remote treatment [11, 26•, 28].
Another critical area under-addressed in the literature is the adaption of treatment along with the technology, delivering it to match the specific homeless populations’ environment and resources. Adherence to mental health treatment in the aforementioned study on rural homelessness ranged from 43 to 60% [20•, 21, 29]. Previous studies have demonstrated the challenges of mental health treatment among the homeless [30]. Treatment adherence is further complicated by mobility, access, and housing for this population which is overlayed on the previously discussed technology access issues. The adherence and access impact both the length and types of treatments that maybe most effective in working with this population [17, 18, 24]. A better understanding is required around the feasibility of different types of technology-based treatments. The homeless may benefit from more time limited and focal treatments as well as those that can be delivered asynchronously. Promising explorations should look at existing interventions known to have impact (e.g., case management, psychosocial rehab, and outreach) and opportunities to enhance and amplify these by appropriate paring with technology-based treatments [31].
Case Reports
Below we present cases drawn from two recently established telemental health services. These offer medication and therapy treatments for homeless populations established in 2020 and 2021 respectively. By the summer of 2022, a total of 37 clients where provided with treatment across 71 sessions (33% session no show rate), with 75% of the visits used for therapy and 25% for psychiatric assessment and medication.
Case Example 1
“Jean” is a telemental health therapist who is a provider for a virtual integrated care team that delivers telemental health services to primary care offices either direct to consumer (patients located at their home) or from a designated room located at the primary care practice. The team consists of two psychiatrists, four licensed behavioral health therapists, and four administrative staff who facilitate scheduling, technology set-up, and billing. In June 2020, “Jean” began seeing patients via videoconferencing, from an urban shelter for women and transgender individuals experiencing homelessness. With support and funding from the integrated care team, the shelter was able to create a designated telehealth room, equipped with a telephone, computer/laptop, and comfortable seating where guests can get both therapy and psychiatry services. The staff at the shelter were trained on setting-up videoconferencing via Zoom and facilitated in getting patient consents and Medicaid information to the virtual integrated care team, prior to scheduling visits. From June 2020 to June 2022, 24 guests at the shelter were seen, two for psychiatry and 22 for therapy with a total of 49 visits, 31 no shows, 2 reschedules, and 10 cancelations. Patients who had multiple visits reported satisfaction with modality and indicated they appreciated the convenience of timely meetings, i.e., being seen within days or the same week of requesting an appointment, eliminating travel, and having the same provider each time they were seen. One client, “Bob,” who was diagnosed with agoraphobia, reported that as a result of his condition, he had not left his permanent residency at the shelter to receive mental health treatment and therefore would not have received the treatment he needed without the telehealth program located at the shelter. “Bob” received a total of 26 therapy sessions with “Jean” and reported improved psychopathology over the course of treatment.
“Jean” indicated that due to the unforeseen circumstances people without housing generally face, no show rates continued to be high when treating shelter guests. Other issues with leveraging care to this particular shelter included staff attrition, technology problems, guests transiting to other places, or guests not having adequate insurance. Another challenge this telehealth provider faced was around triage and “goodness of fit.” Jean reported she was referred many complex individuals with acute mental health needs that sometimes felt outside the scope of what telehealth could provide, however faced limited triage options. “Jean” indicated her biggest take-aways when working with guests at this shelter were that (1) the essential need to build trust and rapport was ongoing with this population; (2) harm reduction and guidance around basic human needs often become the standard of care; and (3) not having access to primary care for labs etc. can interfere with getting adequate treatment, specifically for med management. Overall, “Jean” and the shelter staff found the partnership between the shelter and the integrated care team was effective in meeting clients where they are at while using collaboration across organizations, and allowed them to develop a telehealth model that services homeless individuals in a timely, cost-effective way.
Case Example 2
“Sandy,” a tele-behavioral health therapist, and “Jacob,” a psychiatrist on the same telehealth team, began seeing clients at a shelter for families experiencing homelessness in March 2021. The shelter staff put together a private telehealth room in their facility which included a computer to access Zoom, a camera, and a telephone in case of internet connectivity issues. Shelter staff facilitated gathering insurance information and getting consent forms signed. The shelter staff helped clients gain access to the telehealth room and connect with the providers through Zoom at the time of their appointments. From March 2021 to July 2022, 14 clients were seen for 22 visits, 4 no shows, 2 rescheduled, and 6 canceled. Six clients were seen by “Sandy” for therapy services and 8 were seen by “Jacob” for psychiatry services.
“Jennifer,” a resident at the shelter, was seen by both providers during the time she resided at the shelter. Prior to receiving mental health treatment, “Jennifer” had received multiple citations for behaviors such as breaking rules and speaking to staff inappropriately. During her course of treatment with “Sandy,” “Jennifer” addressed anger outbursts which led to citations, excessive crying, and sleep disturbance while also starting medication regimen with “Jacob” to address symptoms. “Jennifer” learned skills to manage symptoms and behavior in the shelter environment. “Jennifer” gained stability with emotions and thoughts which led to increased attendance to appointments for housing and other social services as well as enabled “Jennifer” to maintain employment throughout this time.
Clients and shelter staff reported the benefits of this service were the timeliness and convenience of appointments. On most occasions, clients were able to be seen by both psychiatry and therapy within 1 week of referral. Clients reported improvement in symptoms which helped with organization and management of schedules. Finally, clients reported receiving emotional support during stressful transitions was beneficial.
Collaboration between the telehealth providers and on-site case managers was imperative to the success of this program. One barrier that arose in this setting was having adequate childcare for individuals during sessions as all clients were on the family unit. Another barrier was trouble filling prescriptions due to various insurance limitations. Finally, an inability to follow up with guests after leaving the shelter for alternate housing was an issue at times, specifically with medication management.
Overall, “Sandy” believes this model was effective in treating individuals experiencing homelessness and assisted clients in gaining stability in a time of transition.
Clinical Considerations when Working with Homeless Populations
Synthesizing the existing literature and the clinical case experience, we proffer some initial considerations for organizations and providers in supporting mental health care in homeless populations through videoconferencing and other technologies.Review the technology access considerations: [11, 26•, 27, 28].What technology platform will the patient(s) be using? Personal, loaned, or given device. Cell, phone, tablet, or computer.
What will be the data and bandwidth available? Will there be continuous or intermittent service.
Where will the technology be access or used? Will they be connecting through a shelter/housing, public space, or private mobile device.
What is the best assessment of the length of time that patient could be expected to engage in both individual sessions and ongoing treatment?
What is the digital literacy and comfort of the patient with the specific technology treatment/device being deployed?
Given the technology access, literacy, and comfort considerations, what is the most appropriate technology and intervention to be used and what additional adaptations to the technology and its associated workflow and processes should be undertaken?
What are the opportunities to further embed the technology/intervention into a larger system of care for the patient (e.g., care coordination, outreach, and care management)? Can existing technologies be leveraged to enhance and provide more holistic treatment?
Conclusion
Homelessness continues to be a complex public health concern requiring innovative intervention models that “meet clients where they’re at” and overcome ongoing barriers to treatment. Telehealth for mental health treatment has grown substantially in the last 3 years with increasing presence of diverse platforms offering both synchronous and asynchronous options for therapy and psychiatry [9••]. Appointment reminders via text appear to have promising results for keeping telehealth appointments and although the literature is limited, researchers support that programs delivering telemental health to homeless patients have found more success when (1) providing the technological device tablet/phone/computer for the patient, (2) incorporating telehealth into supportive housing facilities, and (3) having a multi-agency approach to develop a structured coordination of care [12••, 21, 22, 26•]. Further work is needed to best understand how existing treatments and technologies can best be adapted to serve of the needs of this community that address their mental health needs.
Acknowledgements
The editors would like to thank Dr. Robert Caudill for taking the time to review this manuscript.
Declarations
Conflict of Interest
Evelyn DeLaCruz-Jiron, Lauren Hahn, and Amy Donahue each declare no potential conflicts of interest. Jay Shore is Chief Medical Officer of AccessCare which provides telemental health services in Colorado and Alaska.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Psychiatry in the Digital Age
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
1. U.S. Department of Housing and Urban Development. Colorado Homelessness Statistics. 2022. https://www.usich.gov/homelessness-statistics/co/. Last accessed on 9 Sept 2022.
2. Tsai J O’Toole T Kearney L Homelessness as a public mental health and social problem Psychol Serv 2017 14 2 113 117 10.1037/ser0000164 28481596
3. Thurman W Semwal M Moczygemba L Hilbelink M Smartphone technology to empower people experiencing homelessness: secondary analysis J Med Internet Res 2021 23 9 e27787 10.2196/27787 34586073
4. •• Salhi B, White M, Pitts S, Wright D. Homelessness and emergency medicine: A review of the literature. Acad Emerg Med. 2017. 10.1111/acem.13358. Reviewed 28 studies on homeless people using ED services.
5. Moore DT Rosenheck RA Comprehensive services delivery and emergency department use among chronically homeless adults Psychol Serv 2017 14 184 192 10.1037/ser0000111 28481603
6. Adams C Player M Berini C Perkins S Fay J Walker L A telehealth initiative to overcome health care barriers for people experiencing homelessness Telemed e-Health 2021 27 8 851 858 10.1089/tmj.2021.0127
7. Dorsey ER Topol EJ State of telemedicine N Engl J Med 2020 2 154 161
8. Khan SK Manum M Griffiths M Ullah I The mental health impact of the COVID-19 pandemic across different cohorts Int J Ment Heal Addict 2022 20 380 386 10.1007/s11469-020-00367-0
9. •• Karimi M, Lee E, Couture S, Gonzales A, Grigorescu V, Smith S, De Lew N, Sommers B. National survey trends in telehealth use in 2021: disparities in utilization and audio vs. video services. ASPE Office of Health Policy; 2022. Issues Brief 1–12. Discussed recent data in telehealth usage.
10. Conn D Gajaria A Madan R Telepsychiatry: effectiveness and feasibility Smart Homecare Technol TeleHealth 2015 3 59 67 10.2147/SHTT.S45702
11. Yellowlees P Shore J Roberts L Practice guidelines for videoconferencing-based telemental health-October 2009 Telemed eHealth 2009 16 1074 1089 10.1089/tmj.2010.0148
12. •• Heaslip V, Richer S, Simkhada B, Dogan H, Green S. Use of technology to promote health and wellbeing of people who are homeless: a systematic review. Int J Environ Res Public Health. 2021. https://www.mdpi.com/1660-4601/18/13/6845. Last accessed on 10 Sept 2022. A review on recent data for homeless groups using telehealth.
13. VonHoltz L, Frasso R, Golinkoff J, Lozano A, Hanlon A, Dowshen N. Internet and social media access among youth experiencing homelessness: mixed-methods study. J Med Internet Res. 2018;20(5):e184. https://www.jmir.org/2018/5/e184. 10.2196/jmir.9306. Last accessed on 20 Sept 2022.
14. Adkins EC Zalta AK Boley RA Glover A Karnick NS Schueller SM Exploring the potential of technology-based mental health for homeless youth: a qualitative study Psychol Serv 2017 14 238 245 10.1037/ser0000120 28481610
15. Adolescent Psychiatry AACAP Committee on Telepsychiatry Clinical update: telepsychiatry with children and adolescents J Am Acad Child Adolesc Psychiatry 2017 56 875 893 10.1016/j.jaac.2017.07.008 28942810
16. Glover A Schueller S Winiarski D Smith D Karnik N Zalta A Automated mobile phone–based mental health resource for homeless youth: pilot study assessing feasibility and acceptability JMIR Ment Health 2022 6 10 e15144 10.2196/15144
17. Rural behavioral health: telehealth challenges and opportunities. 2016. https://store.samhsa.gov/sites/default/files/d7/priv/sma16-4989.pdf. Last accessed on 20 Sept 2022.
18. Midler L, Wit J, Cijsouw I, Francois L. Digital exclusion of the homeless in America: COVID-19’s impact. Diggit Magazine; 2021. https://www.diggitmagazine.com/articles/digital-exclusion-homeless-america-covid-19s-impact. Last accessed on 20 Sept 2022.
19. • Hubley S, Lynch SB, Schneck C, Thomas M, Shore J. Review of key telepsychiatry outcomes. World J Psychiatry. 2016;6:269–82. Reviews satisfaction results for both patients and providers when engaging in telehealth services. Provides patient and provider satisfaction results when using telehealth.
20. • Easterday A, Driscoll D, Ramaswamy S. Rural homelessness: its effect on healthcare access, healthcare outcomes, mobility, and perspectives of novel technologies. J Soc Distress Homeless. 2019;28(1):56–64. Describes outcomes for telehealth in rural population.
21. Gardner JS Plaven BE Yellowlees P Shore JH Telepsychiatry workforce: a solution to psychiatry’s workforce issues Curr Psychiatry Rep 2020 22 1 9 10.1007/s11920-020-1128-7 31912372
22. Henwood B Madden D Lahey J Thomson H Islam N Testing the feasibility of telemental health services in permanent supportive housing J Soc Distress Homelessness 2021 30 1 1 5 10.1080/10530789.2019.1688541
23. Garvin L, Hu J, Slightam C, Mclnnes K, Zulman D. Use of video telehealth tablets to increase access for veterans experiencing homelessness | SIREN. Sirenetwork.ucsf.edu; 2022. https://sirenetwork.ucsf.edu/tools-resources/resources/use-video-telehealth-tablets-increase-access-veterans-experiencing. Cited 12 Sept 2022.
24. Khurshid A Gadnis A Using blockchain to create transaction identity for persons experiencing homelessness in America: Policy Proposal JMIR Res Protoc 2019 8 3 e10654 10.2196/10654 30839279
25. Melek SP Norris DT Paulus J Matthews K Waever A Potential economic impact of integrated medical-behavioral healthcare 2021 Milliman Research
26. • Shore JH, Yellowlees P, Caudill R, Johnston B, Turvey C, Mishkind M, et al. Best practices in videoconferencing-based telemental health 2018. Telemed e-Health. 2018;24:827–32. Describes best practices for telemental health delivery based on evidenced-based treatment, available resources, and patient needs.
27. Hilty DM Rabinowitz T Mccarron RM Katzelnick DJ Chang T Bauer AM An update on telepsychiatry and how it can leverage collaborative, stepped, and integrated services to primary care Psychosomatics 2018 59 227 250 10.1016/j.psym.2017.12.005 29544663
28. Schwamm LH Telehealth: seven strategies to successfully implement disruptive technology and transform health care Health Aff 2014 33 200 206 10.1377/hlthaff.2013.1021
29. Fortney JC Pyne JM Kimbrell TA Hudson TJ Robinson DE Schnieder R Telemedicine-based collaboration care for post-traumatic stress disorder JAMA Psychiarty 2015 72 58 67 10.1001/jamapsychiatry.2014.1575
30. Rezansoff SN Moniruzzaman A Fazel S Procyshyn R Somers JM Adherence to antipsychotic medication among homeless adults in Vancouver, Canada: a 15-year retrospective cohort study Soc Psychiatry Psychiatr Epidemiol 2016 51 12 1623 1632 10.1007/s00127-016-1259-7 27338740
31. Parpouchi M Moniruzzaman A Rezansoff SN Russolillo A Somers JM The effect of Housing First on adherence to methadone maintenance treatment Int J Drug Policy 2018 56 73 80 10.1016/j.drugpo.2018.03.012 29609153
| 36480149 | PMC9734763 | NO-CC CODE | 2022-12-14 23:28:30 | no | Curr Psychiatry Rep. 2022 Dec 8;:1-6 | utf-8 | Curr Psychiatry Rep | 2,022 | 10.1007/s11920-022-01400-w | oa_other |
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Curr Psychiatry Rep
Curr Psychiatry Rep
Current Psychiatry Reports
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Springer US New York
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10.1007/s11920-022-01400-w
Psychiatry in the Digital Age (J Shore, Section Editor)
Telemental Health for the Homeless Population: Lessons Learned when Leveraging Care
DeLaCruz-Jiron Evelyn J. [email protected]
1
Hahn Lauren M. 1
Donahue Amy L. 1
Shore Jay H. 12
1 Access Management Services LLC, 11100 East Bethany Drive, Aurora, CO 80014 USA
2 grid.430503.1 0000 0001 0703 675X Department of Psychiatry and Family Medicine, School of Medicine and Centers for American Indian and Alaska Native Health Colorado School of Public Health, Anschutz Medical Campus, Aurora, USA
8 12 2022
16
15 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose of Review
The purpose of this paper is to review key lessons when using telehealth within the context of mental health and homelessness. We examine technological and bandwidth issues the homeless population might face when getting telehealth services, discuss clinical process adaption needed for working remotely, and highlight the lessons learned when leveraging mental health services to homeless patients across telehealth platforms.
Recent Findings
Homelessness is associated with chronic, mental health disparities and access to mental health services is often less accessible among communities with unstable housing. Telehealth provides “OnDemand” treatment options while removing specific barriers found with in-person health care such as transportation, overwhelmed mental health facilities, i.e., appointment availability, and office hour limitations while reducing costs for both providers and patients.
Summary
We provide two case examples to demonstrate successful delivery of telemental health services to homeless patients and review lessons learned when leveraging care.
Keywords
Homelessness
Telemental health
Technology
Mental health
Telehealth
==== Body
pmcIntroduction: Homelessness and Mental Health Disparities
The US Department of Housing and Urban Development reported roughly just under 10,000 people experience homelessness in Colorado and slightly over a half a million people in the USA are living in state of homelessness on any given day [1]. While the majority of Americans are homeless for a limited/short period of time, 22% are chronically homeless, federally defined as being homeless for at least a year or more than 4 times in the past 3 years for a period of a year or more [2]. A growing body of research supports there are multiple detrimental health outcomes associated with loss of housing, including chronic illness, substance use disorders, and unmet mental health needs. Chronic health conditions such as heart disease, diabetes, and HIV/AIDs are found to be 3–6 times higher in homeless populations compared to the general population, with 20% of the homeless people reporting to have a serious mental illness [2]. Although many people experiencing homelessness present with co-occurring disorders, treatment to improve their mental/physical health is lacking; thus, the pattern of homelessness and chronic health conditions appears to perpetuate one another.
The current research indicates the primary barriers faced by someone experiencing homelessness when trying to get adequate treatment were (1) being stigmatized/differential treatment, i.e., patients reported being treated poorly by providers and members of the community when homeless, (2) higher order tasks needed for daily care, i.e., homeless patients had to carefully plan for basic needs such as hygiene, eating, and charging their phones which took away from time allocated for seeking/receiving mental health services, and (3) overall instability, which is attributed to the ability to sustain contact with important others including providers, family, or other sources of support [3]. It should also be noted that within the context of homelessness, self-efficacy, and the perception of asserting and maintaining control over their daily lives, their belongings, health, and safety were also potential barriers.
Researchers support that emergency department (ED) for homeless populations is utilized more than any other service type by people without housing and up to 3 times more than that of the non-homeless population [4••]. There are many common factors attributing to high ED utilization for people without housing, including lack of health insurance, lack of transportation, and poor access to primary care [5]. Although repeated ED visits are common for homeless patients, overall health outcomes have not been noted to significantly improve for the homeless population. In general, a homeless person’s mortality rate is 3–6 times higher than that of the general population [4••]. Likewise, many people experiencing homelessness are less likely to get the care they need when faced with a medical or mental health problem. People who are experiencing homelessness commonly receive multiple services from various providers; hence, frequent ER visits to different hospitals without data sharing can lead to the risk of misdiagnosing and/or giving patients duplicate treatment/tests or the wrong medications/treatment.
Telehealth as a Proposed Solution
Technology-based treatments for mental health including tele-therapy, text messages, and mobile apps have been promising in delivering treatment to various populations. The COVID-19 pandemic certainly increased the popularity of telehealth solutions, transforming the way people receive health care; however, many providers from all specialties were developing telehealth tools prior to the pandemic [6–8].
During the initial COVID peak, a 2020 study reported that telehealth visits went from less than 1% to as much as 80% in places where COVID cases were high [9••]. Although telehealth utilization has dropped since the initial peak of COVID, telehealth usage continues to remain high. Karimi reported out of 670,155 participants, 23.1% reported they used telehealth, either audio or video within the last month, with the highest rates among Medicaid users at 29.3% [9••].
It may come as surprising, but ongoing research supports that many homeless people have access to technology; thus, the concept of using technology to break-down access barriers is not a new concept [10, 11]. Recent research supports that generally over half of the homeless population have a cell phone; however, in some studies, up to 90–100% of homeless sample groups had access to a cell phone or mobile device [12••]. Despite cell phone ownership, overall digital access is still an issue. A mixed-methods study of internet and social media use among homeless youth found 56% used the internet at least once a day and 86% once a week. Smartphones were associated with greater odds of internet access and were the most frequently used method to access the internet, while homelessness sample internet access frequency decreased by 68%. [12••, 13].
Age also appears to be a factor in mobile phone ownership and telehealth use [12••, 14–16]. Heaslip et al. found that young homeless people with mental health concerns were up to 5× more likely to find help online [12••]. Youth aging 16–25 are more likely to use telehealth or fully automated phone interventions, while older homeless people have lower cell phone ownership, hence are less likely to use telehealth services. Older age may also be associated with lower telehealth use due to increased barriers such as expectations of in-person social contact, psychological aging, and digital literacy. Digital literacy as well as comfort with and past experiences using technology varies widely in the homeless as it does in other populations, with age being one of several important mediating factors around digital literacy and comfort [12••, 16].
Other practical problems with cell phone technology mentioned throughout the literature include issues with battery life, limited options when charging devices, breakages, and theft. Lack of trust was also mentioned in various studies as a common barrier when linking people who are experiencing homelessness to telehealth services via their phone or mobile device [12••, 17]. Though there is increasing mobile phone ownership among the homeless, many struggle with affordability of data plans and rely on public spaces for internet access, with COVID aggravating this with associated lockdowns limiting access to public spaces [18]. In addition, challenges can exist around adequacy of bandwidth when using any technology for health care. Bandwidth requirements differ across digital health care applications. The bandwidth needed to access a patient portal or psychoeducational material on the internet is significantly lower than the bandwidth needed for two-way live interactive videoconferencing [17, 19•]. Rural homeless populations may have additional access barriers, although a recent study in this population found high rates of cell phone ownership (87%) and internet access (83%). There was a willingness to use technology for health care but reluctance to engage in direct telehealth [20•]. The reasons for the resistance varied; however, resistance to treatment and general non-compliance with medication management and therapy occurs in both virtual and face-to face platforms for several reasons.
In terms of success outcomes, telehealth modalities to improve access, specifically video visits, have been found to have high levels of satisfaction for both patients and providers [6, 19•, 21]. Recent research reveals technological interventions show high rates of clinical benefit, including reduction of symptoms of psychopathology, specifically for PTSD, depression, and anxiety [6, 15, 16]. As a means to overcome barriers with digital technology, research supports that incorporating telehealth into an urban permanent supportive housing setting also proves to be helpful in allowing clients to access tele-therapy from the comfort of their own home, or from a designated room located at the housing facility [22].
The Veteran’s Affairs (VA) has been known to lead clinical video telehealth and has had some success in delivering mental health care virtually. Between 2017 and 2019, the VA health care system issued 12,148 video-enabled tablets to homeless veterans to receive telehealth. Tablets came with WiFi and data plans and VA representatives guided participants through the technology set-up. Nearly half of the veterans experiencing homelessness had a telehealth visit within 6 months of receiving the tablet, most frequently for mental health [23].
Moving toward a blockchain technology in health care also appears to be a low-cost solution for people experiencing homelessness as a means to track and store their health care information when seeing multiple providers. Blockchain technology, also known as distributed ledger technology (DLT), creates a network among users, making data portable so the coordination of care can be assessable to any provider. Khurshid and Gadnis proposed the concept of blockchain technology (DLT) to allow people who are experiencing homelessness to become a part of data sharing system, connecting providers, and allowing patients to maintain their health care information in one place [24].
Using mobile technology for appointment reminders was recommended throughout the literature for the homeless population, suggesting to improve adherence and a sense of connectiveness [12••]. In effect, the research supports that technology facilitates self-management and people experiencing homelessness are more likely to accomplish daily tasks including coordinating/scheduling appointments if they have access to mobile technology, specifically the internet [3, 7, 25, 26•].
Special Considerations/Requirements
High rates of technology access among certain cohorts of homeless populations including mobile phone, computer, and access to internet make virtual options for mental health services appealing. However, additional issues for both patients and providers when creating and accessing telehealth services need to be considered. Standard telehealth considerations include providers’ clinical protocols around safety, consent, and HIPAA compliance, hence adequate training for both patients and providers on using televideo or other technologies [21, 27]. Providers and organizations need to understand and develop strategies to address legal requirements at both the state and federal level, backup plans for technological malfunctions and internet outages, and finally level of comfort, when delivering remote treatment [11, 26•, 28].
Another critical area under-addressed in the literature is the adaption of treatment along with the technology, delivering it to match the specific homeless populations’ environment and resources. Adherence to mental health treatment in the aforementioned study on rural homelessness ranged from 43 to 60% [20•, 21, 29]. Previous studies have demonstrated the challenges of mental health treatment among the homeless [30]. Treatment adherence is further complicated by mobility, access, and housing for this population which is overlayed on the previously discussed technology access issues. The adherence and access impact both the length and types of treatments that maybe most effective in working with this population [17, 18, 24]. A better understanding is required around the feasibility of different types of technology-based treatments. The homeless may benefit from more time limited and focal treatments as well as those that can be delivered asynchronously. Promising explorations should look at existing interventions known to have impact (e.g., case management, psychosocial rehab, and outreach) and opportunities to enhance and amplify these by appropriate paring with technology-based treatments [31].
Case Reports
Below we present cases drawn from two recently established telemental health services. These offer medication and therapy treatments for homeless populations established in 2020 and 2021 respectively. By the summer of 2022, a total of 37 clients where provided with treatment across 71 sessions (33% session no show rate), with 75% of the visits used for therapy and 25% for psychiatric assessment and medication.
Case Example 1
“Jean” is a telemental health therapist who is a provider for a virtual integrated care team that delivers telemental health services to primary care offices either direct to consumer (patients located at their home) or from a designated room located at the primary care practice. The team consists of two psychiatrists, four licensed behavioral health therapists, and four administrative staff who facilitate scheduling, technology set-up, and billing. In June 2020, “Jean” began seeing patients via videoconferencing, from an urban shelter for women and transgender individuals experiencing homelessness. With support and funding from the integrated care team, the shelter was able to create a designated telehealth room, equipped with a telephone, computer/laptop, and comfortable seating where guests can get both therapy and psychiatry services. The staff at the shelter were trained on setting-up videoconferencing via Zoom and facilitated in getting patient consents and Medicaid information to the virtual integrated care team, prior to scheduling visits. From June 2020 to June 2022, 24 guests at the shelter were seen, two for psychiatry and 22 for therapy with a total of 49 visits, 31 no shows, 2 reschedules, and 10 cancelations. Patients who had multiple visits reported satisfaction with modality and indicated they appreciated the convenience of timely meetings, i.e., being seen within days or the same week of requesting an appointment, eliminating travel, and having the same provider each time they were seen. One client, “Bob,” who was diagnosed with agoraphobia, reported that as a result of his condition, he had not left his permanent residency at the shelter to receive mental health treatment and therefore would not have received the treatment he needed without the telehealth program located at the shelter. “Bob” received a total of 26 therapy sessions with “Jean” and reported improved psychopathology over the course of treatment.
“Jean” indicated that due to the unforeseen circumstances people without housing generally face, no show rates continued to be high when treating shelter guests. Other issues with leveraging care to this particular shelter included staff attrition, technology problems, guests transiting to other places, or guests not having adequate insurance. Another challenge this telehealth provider faced was around triage and “goodness of fit.” Jean reported she was referred many complex individuals with acute mental health needs that sometimes felt outside the scope of what telehealth could provide, however faced limited triage options. “Jean” indicated her biggest take-aways when working with guests at this shelter were that (1) the essential need to build trust and rapport was ongoing with this population; (2) harm reduction and guidance around basic human needs often become the standard of care; and (3) not having access to primary care for labs etc. can interfere with getting adequate treatment, specifically for med management. Overall, “Jean” and the shelter staff found the partnership between the shelter and the integrated care team was effective in meeting clients where they are at while using collaboration across organizations, and allowed them to develop a telehealth model that services homeless individuals in a timely, cost-effective way.
Case Example 2
“Sandy,” a tele-behavioral health therapist, and “Jacob,” a psychiatrist on the same telehealth team, began seeing clients at a shelter for families experiencing homelessness in March 2021. The shelter staff put together a private telehealth room in their facility which included a computer to access Zoom, a camera, and a telephone in case of internet connectivity issues. Shelter staff facilitated gathering insurance information and getting consent forms signed. The shelter staff helped clients gain access to the telehealth room and connect with the providers through Zoom at the time of their appointments. From March 2021 to July 2022, 14 clients were seen for 22 visits, 4 no shows, 2 rescheduled, and 6 canceled. Six clients were seen by “Sandy” for therapy services and 8 were seen by “Jacob” for psychiatry services.
“Jennifer,” a resident at the shelter, was seen by both providers during the time she resided at the shelter. Prior to receiving mental health treatment, “Jennifer” had received multiple citations for behaviors such as breaking rules and speaking to staff inappropriately. During her course of treatment with “Sandy,” “Jennifer” addressed anger outbursts which led to citations, excessive crying, and sleep disturbance while also starting medication regimen with “Jacob” to address symptoms. “Jennifer” learned skills to manage symptoms and behavior in the shelter environment. “Jennifer” gained stability with emotions and thoughts which led to increased attendance to appointments for housing and other social services as well as enabled “Jennifer” to maintain employment throughout this time.
Clients and shelter staff reported the benefits of this service were the timeliness and convenience of appointments. On most occasions, clients were able to be seen by both psychiatry and therapy within 1 week of referral. Clients reported improvement in symptoms which helped with organization and management of schedules. Finally, clients reported receiving emotional support during stressful transitions was beneficial.
Collaboration between the telehealth providers and on-site case managers was imperative to the success of this program. One barrier that arose in this setting was having adequate childcare for individuals during sessions as all clients were on the family unit. Another barrier was trouble filling prescriptions due to various insurance limitations. Finally, an inability to follow up with guests after leaving the shelter for alternate housing was an issue at times, specifically with medication management.
Overall, “Sandy” believes this model was effective in treating individuals experiencing homelessness and assisted clients in gaining stability in a time of transition.
Clinical Considerations when Working with Homeless Populations
Synthesizing the existing literature and the clinical case experience, we proffer some initial considerations for organizations and providers in supporting mental health care in homeless populations through videoconferencing and other technologies.Review the technology access considerations: [11, 26•, 27, 28].What technology platform will the patient(s) be using? Personal, loaned, or given device. Cell, phone, tablet, or computer.
What will be the data and bandwidth available? Will there be continuous or intermittent service.
Where will the technology be access or used? Will they be connecting through a shelter/housing, public space, or private mobile device.
What is the best assessment of the length of time that patient could be expected to engage in both individual sessions and ongoing treatment?
What is the digital literacy and comfort of the patient with the specific technology treatment/device being deployed?
Given the technology access, literacy, and comfort considerations, what is the most appropriate technology and intervention to be used and what additional adaptations to the technology and its associated workflow and processes should be undertaken?
What are the opportunities to further embed the technology/intervention into a larger system of care for the patient (e.g., care coordination, outreach, and care management)? Can existing technologies be leveraged to enhance and provide more holistic treatment?
Conclusion
Homelessness continues to be a complex public health concern requiring innovative intervention models that “meet clients where they’re at” and overcome ongoing barriers to treatment. Telehealth for mental health treatment has grown substantially in the last 3 years with increasing presence of diverse platforms offering both synchronous and asynchronous options for therapy and psychiatry [9••]. Appointment reminders via text appear to have promising results for keeping telehealth appointments and although the literature is limited, researchers support that programs delivering telemental health to homeless patients have found more success when (1) providing the technological device tablet/phone/computer for the patient, (2) incorporating telehealth into supportive housing facilities, and (3) having a multi-agency approach to develop a structured coordination of care [12••, 21, 22, 26•]. Further work is needed to best understand how existing treatments and technologies can best be adapted to serve of the needs of this community that address their mental health needs.
Acknowledgements
The editors would like to thank Dr. Robert Caudill for taking the time to review this manuscript.
Declarations
Conflict of Interest
Evelyn DeLaCruz-Jiron, Lauren Hahn, and Amy Donahue each declare no potential conflicts of interest. Jay Shore is Chief Medical Officer of AccessCare which provides telemental health services in Colorado and Alaska.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Psychiatry in the Digital Age
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
1. U.S. Department of Housing and Urban Development. Colorado Homelessness Statistics. 2022. https://www.usich.gov/homelessness-statistics/co/. Last accessed on 9 Sept 2022.
2. Tsai J O’Toole T Kearney L Homelessness as a public mental health and social problem Psychol Serv 2017 14 2 113 117 10.1037/ser0000164 28481596
3. Thurman W Semwal M Moczygemba L Hilbelink M Smartphone technology to empower people experiencing homelessness: secondary analysis J Med Internet Res 2021 23 9 e27787 10.2196/27787 34586073
4. •• Salhi B, White M, Pitts S, Wright D. Homelessness and emergency medicine: A review of the literature. Acad Emerg Med. 2017. 10.1111/acem.13358. Reviewed 28 studies on homeless people using ED services.
5. Moore DT Rosenheck RA Comprehensive services delivery and emergency department use among chronically homeless adults Psychol Serv 2017 14 184 192 10.1037/ser0000111 28481603
6. Adams C Player M Berini C Perkins S Fay J Walker L A telehealth initiative to overcome health care barriers for people experiencing homelessness Telemed e-Health 2021 27 8 851 858 10.1089/tmj.2021.0127
7. Dorsey ER Topol EJ State of telemedicine N Engl J Med 2020 2 154 161
8. Khan SK Manum M Griffiths M Ullah I The mental health impact of the COVID-19 pandemic across different cohorts Int J Ment Heal Addict 2022 20 380 386 10.1007/s11469-020-00367-0
9. •• Karimi M, Lee E, Couture S, Gonzales A, Grigorescu V, Smith S, De Lew N, Sommers B. National survey trends in telehealth use in 2021: disparities in utilization and audio vs. video services. ASPE Office of Health Policy; 2022. Issues Brief 1–12. Discussed recent data in telehealth usage.
10. Conn D Gajaria A Madan R Telepsychiatry: effectiveness and feasibility Smart Homecare Technol TeleHealth 2015 3 59 67 10.2147/SHTT.S45702
11. Yellowlees P Shore J Roberts L Practice guidelines for videoconferencing-based telemental health-October 2009 Telemed eHealth 2009 16 1074 1089 10.1089/tmj.2010.0148
12. •• Heaslip V, Richer S, Simkhada B, Dogan H, Green S. Use of technology to promote health and wellbeing of people who are homeless: a systematic review. Int J Environ Res Public Health. 2021. https://www.mdpi.com/1660-4601/18/13/6845. Last accessed on 10 Sept 2022. A review on recent data for homeless groups using telehealth.
13. VonHoltz L, Frasso R, Golinkoff J, Lozano A, Hanlon A, Dowshen N. Internet and social media access among youth experiencing homelessness: mixed-methods study. J Med Internet Res. 2018;20(5):e184. https://www.jmir.org/2018/5/e184. 10.2196/jmir.9306. Last accessed on 20 Sept 2022.
14. Adkins EC Zalta AK Boley RA Glover A Karnick NS Schueller SM Exploring the potential of technology-based mental health for homeless youth: a qualitative study Psychol Serv 2017 14 238 245 10.1037/ser0000120 28481610
15. Adolescent Psychiatry AACAP Committee on Telepsychiatry Clinical update: telepsychiatry with children and adolescents J Am Acad Child Adolesc Psychiatry 2017 56 875 893 10.1016/j.jaac.2017.07.008 28942810
16. Glover A Schueller S Winiarski D Smith D Karnik N Zalta A Automated mobile phone–based mental health resource for homeless youth: pilot study assessing feasibility and acceptability JMIR Ment Health 2022 6 10 e15144 10.2196/15144
17. Rural behavioral health: telehealth challenges and opportunities. 2016. https://store.samhsa.gov/sites/default/files/d7/priv/sma16-4989.pdf. Last accessed on 20 Sept 2022.
18. Midler L, Wit J, Cijsouw I, Francois L. Digital exclusion of the homeless in America: COVID-19’s impact. Diggit Magazine; 2021. https://www.diggitmagazine.com/articles/digital-exclusion-homeless-america-covid-19s-impact. Last accessed on 20 Sept 2022.
19. • Hubley S, Lynch SB, Schneck C, Thomas M, Shore J. Review of key telepsychiatry outcomes. World J Psychiatry. 2016;6:269–82. Reviews satisfaction results for both patients and providers when engaging in telehealth services. Provides patient and provider satisfaction results when using telehealth.
20. • Easterday A, Driscoll D, Ramaswamy S. Rural homelessness: its effect on healthcare access, healthcare outcomes, mobility, and perspectives of novel technologies. J Soc Distress Homeless. 2019;28(1):56–64. Describes outcomes for telehealth in rural population.
21. Gardner JS Plaven BE Yellowlees P Shore JH Telepsychiatry workforce: a solution to psychiatry’s workforce issues Curr Psychiatry Rep 2020 22 1 9 10.1007/s11920-020-1128-7 31912372
22. Henwood B Madden D Lahey J Thomson H Islam N Testing the feasibility of telemental health services in permanent supportive housing J Soc Distress Homelessness 2021 30 1 1 5 10.1080/10530789.2019.1688541
23. Garvin L, Hu J, Slightam C, Mclnnes K, Zulman D. Use of video telehealth tablets to increase access for veterans experiencing homelessness | SIREN. Sirenetwork.ucsf.edu; 2022. https://sirenetwork.ucsf.edu/tools-resources/resources/use-video-telehealth-tablets-increase-access-veterans-experiencing. Cited 12 Sept 2022.
24. Khurshid A Gadnis A Using blockchain to create transaction identity for persons experiencing homelessness in America: Policy Proposal JMIR Res Protoc 2019 8 3 e10654 10.2196/10654 30839279
25. Melek SP Norris DT Paulus J Matthews K Waever A Potential economic impact of integrated medical-behavioral healthcare 2021 Milliman Research
26. • Shore JH, Yellowlees P, Caudill R, Johnston B, Turvey C, Mishkind M, et al. Best practices in videoconferencing-based telemental health 2018. Telemed e-Health. 2018;24:827–32. Describes best practices for telemental health delivery based on evidenced-based treatment, available resources, and patient needs.
27. Hilty DM Rabinowitz T Mccarron RM Katzelnick DJ Chang T Bauer AM An update on telepsychiatry and how it can leverage collaborative, stepped, and integrated services to primary care Psychosomatics 2018 59 227 250 10.1016/j.psym.2017.12.005 29544663
28. Schwamm LH Telehealth: seven strategies to successfully implement disruptive technology and transform health care Health Aff 2014 33 200 206 10.1377/hlthaff.2013.1021
29. Fortney JC Pyne JM Kimbrell TA Hudson TJ Robinson DE Schnieder R Telemedicine-based collaboration care for post-traumatic stress disorder JAMA Psychiarty 2015 72 58 67 10.1001/jamapsychiatry.2014.1575
30. Rezansoff SN Moniruzzaman A Fazel S Procyshyn R Somers JM Adherence to antipsychotic medication among homeless adults in Vancouver, Canada: a 15-year retrospective cohort study Soc Psychiatry Psychiatr Epidemiol 2016 51 12 1623 1632 10.1007/s00127-016-1259-7 27338740
31. Parpouchi M Moniruzzaman A Rezansoff SN Russolillo A Somers JM The effect of Housing First on adherence to methadone maintenance treatment Int J Drug Policy 2018 56 73 80 10.1016/j.drugpo.2018.03.012 29609153
| 0 | PMC9734766 | NO-CC CODE | 2022-12-14 23:28:30 | no | NeuroTransmitter. 2022 Dec 9; 33(12):20-21 | latin-1 | null | null | null | oa_other |
==== Front
Bone Marrow Transplant
Bone Marrow Transplant
Bone Marrow Transplantation
0268-3369
1476-5365
Nature Publishing Group UK London
36481838
1894
10.1038/s41409-022-01894-1
Correspondence
Tixagevimab/cilgavimab for Omicron SARS-CoV-2 infection in patients with haematologic diseases
Otiniano Armelle 1
van de Wyngaert Zoe 1
http://orcid.org/0000-0003-4471-418X
Brissot Eolia 1
http://orcid.org/0000-0002-5024-1713
Dulery Rémy 1
Gozlan Joel 2
Daguenel Anne 3
Abi Aad Yasmine 4
Ricard Laure 1
http://orcid.org/0000-0001-7316-5832
Stocker Nicolas 1
Banet Anne 1
Bonnin Agnes 1
Alsuliman Tamim 1
Marjanovic Zora 1
Schnuriger Aurélie 2
Coppo Paul 1
Legrand Ollivier 1
Lacombe Karine 4
http://orcid.org/0000-0002-7264-808X
Mohty Mohamad 1
http://orcid.org/0000-0002-3474-0002
Malard Florent [email protected]
1
1 grid.462844.8 0000 0001 2308 1657 Service d’Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, INSERM UMRs 938, Paris, France
2 grid.412370.3 0000 0004 1937 1100 Service de virologie, APHP, Hôpital Saint Antoine, Paris, France
3 grid.412370.3 0000 0004 1937 1100 Pharmacie, Hôpital Saint-Antoine, AP-HP, Paris, France
4 grid.462844.8 0000 0001 2308 1657 Sorbonne Université, IPLESP UMR-S1136, Service de maladies infectieuses et tropicales, Hôpital Saint Antoine, AP-HP, Paris, France
8 12 2022
13
29 9 2022
24 11 2022
1 12 2022
© The Author(s), under exclusive licence to Springer Nature Limited 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Subject terms
Haematological cancer
Infectious diseases
==== Body
pmcTo the Editor:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is life-threatening for patients with haematologic malignancies [1]. The Omicron variant that emerged at the end of 2021 harbors multiple novel spike mutations, leading to immune escape from vaccination-induced antibodies [2]. The Omicron variant is associated with decreased hospital admission and mortality in immunocompetent patients [3]. In patients with hematologic malignancies, a mortality rate of 16.5% among hospitalized patients has been reported [4], which is lower than that observed during the COVID-19 waves of 2020 and 2021 [1]. However, it remains considerably higher compared to the mortality of immunocompetent patients [3]. Therefore, effective treatment remains indispensable to improve clinical outcomes in this population at high risk of severe evolution of Covid19.
While several monoclonal antibodies have been developed, some completely lost neutralizing activity against Omicron’s original lineage (B.1.1.529) whereas others exhibit a highly reduced (tixagevimab-cilgavimab combination, ~12-fold decrease) or a partially reduced (sotrovimab) [2] activity. Low availability of sotrovimab coupled to its decreased neutralizing activity against Omicron BA.2, BA.3, BA.4, BA.5 and descendent lineages lead to the authorization of tixagevimab-cilgavimab 300–300 mg in France through a compassionate use program. It is indicated for the treatment of adults and adolescents with suspected or proven Omicron infection, who are at increased risk of progressing to severe COVID-19 and are unvaccinated or have a weak or absent response to vaccination (anti-S IgG < 260 BAU/ml). A large, randomized, double blind study recently reported that while tixagevimab-cilgavimab did not improve patient recovery, it was associated with a significantly lower mortality compared to placebo (hazard ratio, 0.70; 95% CI, 0.50–0.97, p = 0.032) [5]. However, only 57 of the 1417 included patients were immunocompromised (of whom 26 had a malignancy), and there is no available data regarding tixagevimab-cilgavimab’s efficacy in the specific subset of patients with haematologic malignancies. Furthermore, the majority of patients in this study were infected with the Delta strain, which is not circulating anymore.
Given the scarcity of data, we performed a single center retrospective study aiming at analysing clinical outcomes in patients with haematologic malignancies, treated with tixagevimab-cilgavimab for an infection with the Omicron SARS-CoV-2 variant.
From January to July 2022, we included 13 patients hospitalized in the haematology department at Saint Antoine Hospital in France with an Omicron SARS-CoV-2 infection confirmed by a type-specific multiplex RT-PCR assay (Novaplex SARS-Cov-2 variant 1 and IV, Seegen) and with SARS-CoV-2 IgG anti-S < 260 BAU/ml (Alinity Abbott CLIA Assay), who were treated with intravenous tixagevimab-cilgavimab (300–300 mg) (Table 1). The Omicron sub-variant was BA.1 in five patients and BA.2 in eight patients. Median patient age was 67 years (range, 43–88). Nine patients had a lymphoid malignancy and four had a myeloid malignancy. All but one patient had a history of chemotherapy, including eight with ongoing chemotherapy. Eight patients had received B-cell targeting treatment within the last 12 months and three patients had a history of allogeneic hematopoietic cell transplantation (allo-HCT). Nine patients were vaccinated for COVID-19 (7 and 2 patients received 3 and 2 vaccine doses, respectively), four were unvaccinated and one received prophylactic casirivimab-imdevimab in addition to 3 doses of COVID-19 vaccine. Nevertheless, all patients had low anti-S IgG level at the time of diagnosis of SARS-CoV-2 infection [median, 24.8 BAU/mL (range, 0–103)]. Interestingly, two of the four unvaccinated patients were positive for anti-N IgG (Alinity Abbott CLIA Assay), indicating a history of COVID-19. In the 7 patients with serological assessment performed at a median of 52 days (range, 21–72) after tixagevimab-cilgavimab, median anti-S IgG increased to 2056.9 BAU/mL (range, 1045–3701.5), while anti-N IgG remain negative (except for the two patients with an history of COVID-19), indicating that anti-S IgG increase is related to the tixagevimab-cilgavimab administration and not to the immune response to SARS-CoV-2 infection.Table 1 Clinical characteristics and outcomes of patients with hematological malignancies and SARS-CoV-2 infection treated with tixagevimab-cilgavimab.
Patient 1 2 3 4 5 6 7 8 9 10 11 12 13
Age (years) 62 78 67 62 72 58 71 88 49 71 63 72 43
BMI (kg/m2) 21 30 28 19 17 29 22 23 27 17 30 26 26
Sex F M M M F F M M F F M M M
Malignancy CLL CLL L-HES NHL MDS NHL NHL MM MDS AITL AML NHL AML
Current status Untreated Progressing disease Stable disease CR CR PR CR CR CR CR Progressing disease PR CR
History of chemotherapy – Ongoing Ongoing Ongoing Previous Ongoing Previous Previous Previous Ongoing Ongoing Ongoing Ongoing
Cell therapy – – – – Allo-HCT – – – Allo-HCT – Allo-HCT – –
History of anti-CD 19 therapy within the last 12 months – Anti-CD20 monoclonal antibody and Ibrutinib – Anti-CD20 monoclonal antibody Anti-CD20 monoclonal antibodya Anti-CD20 monoclonal antibody Anti-CD20 monoclonal antibody – Anti-CD20 monoclonal antibodya – Anti-CD20 monoclonal antibodya and Venetoclax Anti-CD20 monoclonal antibody –
SARS CoV-2 variant Omicron BA.1 Omicron BA.1 Omicron BA.2 Omicron BA.2 Omicron BA.1 Omicron BA.1 Omicron BA.1 Omicron BA.2 Omicron BA.2 Omicron BA.2 Omicron BA.2 Omicron BA.2 Omicron BA.2
Anti-S IgG prior to hospitalization(BAU/ml) 3.92 0 224 51.35 44.19 2 0 0 18.36 37.18 58.21 103 24.84
Anti-N IgG prior to hospitalization(index) 0,01 0,04 0,04 0,02 0,04 0,05 0,01 0,00 0,06 8,08 0.04 0.01 4.89
Anti-S IgG 6 weeks post T/Cb (BAU/ml) – – – 2543.5 1045 1045.2 – – 3701.5 1750.1 2056.9 – 3603.8
Anti-N IgG 6 weeks post T/Cb (index) – – – 0.01 0.03 0.35 – – 0.03 2.19 0.05 6.0
Vaccine status, days between last dose and infection 3 doses, 46 days 3 doses, 148 daysc 3 doses, 170 days 3 doses, 152 days 2 doses, 309 days 2 doses, 208 days 3 doses, 50 days 3 doses, 181 days Unvaccinated Unvaccinated Unvaccinated 3 doses, 212 days Unvaccinated
SARS-CoV-2 symptoms COVID-19 pneumonia COVID-19 pneumonia Asymptomatic Asymptomatic COVID-19 pneumonia COVID-19 pneumonia COVID-19 pneumonia COVID-19 pneumonia COVID-19 pneumonia Rhinitis COVID-19 pneumonia Rhinitis Asymptomatic
Additional COVID-19 treatment Dexamethasone, oxygen Dexamethasone, oxygen No No Dexamethasone, oxygen Oxygen Dexamethasone, oxygen Dexamethasone, oxygen Remdesivird tocilizumab, convalescent plasma Prednisolone, oxygen, tocilizumab No Oxygen No No
COVID-19 outcome post T/C Recovery Worsening, deaths at D4 of T/C. No ICU Recovery Recovery Initial recovery, worsening at D41 of T/C death at D42, no ICU Recovery Recovery Stability, convalescent plasma at D12 of T/C, clinical recovery, PCR negativity at 4 months Initial recovery, worsening and ICU admission at D18 of T/C, death at D23 Recovery Initial recovery worsening at D21 of T/C, death at D31, no ICU Recovery Recovery
BMI body mass index, F female, M male, CCL chronic lymphocytic leukemia, L-HES Lymphocytic variant hypereosinophilic syndromes, MM multiple myeloma, AITL angioimmunoblastic T-cell lymphoma, AML acute myeloid leukemia, MDS myelodysplastic syndrome, CR complete response, PR partial response, alloHCT allogeneic hematopoietic cell transplantation, T/C tixagevimab-cilgavimab, D day.
aFor EBV viraemia.
bMedian time period between tixagevimab-cilgavimab treatment and the serology is 44 days.
cThis patient also received casirivimab-imdevimab 1 month prior to the SARS-CoV-2 infection.
dRemdesivir was administered 3 weeks before tixagevimab-cilgavimab when the patient had mild COVID19. (rhinitis).
In five patients, SARS-CoV-2 infection was diagnosed with a routine PCR test performed at patient admission before chemotherapy administration, three of them were asymptomatic and two had mild symptoms (rhinitis). These five patients received tixagevimab-cilgavimab according to the compassionate use program at a median of 3 days (range 2–4) after SARS-CoV-2 infection diagnosis and all recovered without additional COVID-19 treatment. The remaining eight patients were symptomatic, and all required supplemental oxygen. Of note in some of this patients, COVID19 pneumonia was preceded by a long asymptomatic or mild COVID19, since median time between COVID-19 diagnosis and initiation of oxygen was 17 days (range, 2–45). Tixagevimab-cilgavimab was administered in the 8 patients at time of hospitalisation and oxygen initiation. Six patients had an inflammatory syndrome and received steroids alone (n = 4 dexamethasone) or tocilizumab and steroids (n = 1 dexamethasone and n = 1 prednisolone). Treatment with tixagevimab-cilgavimab ± steroids was effective in three patients who completely recovered from SARS-CoV-2 infection with no additional treatment. Three patients persistent COVID-19 symptoms with positive nasopharyngeal PCR remained positive for SARS-CoV-2 and after initial improvement (oxygen withdrawal), suddenly worsened with acute respiratory distress at day 41, 18, and 21 post tixagevimab-cilgavimab administration, leading to death. Only one of these patients was admitted to the intensive care unit, the remaining two patients were ineligible because of their comorbidities. One patient, who did not initially improve, received convalescent plasma and clinically recovered thereafter, but had prolonged viral shedding (4 months). One patient had a rapidly worsening COVID-19 pneumonia and died 4 days post tixagevimab-cilgavimab administration (not eligible for intensive care treatment).
Despite a small and heterogeneous patient population, this study is the first to report detailed outcomes after curative treatment with tixagevimab-cilgavimab for Omicron SARS-CoV-2 infection, in patients with hematologic malignancies. We found that asymptomatic patients that receive tixagevimab-cilgavimab at a dose of 300–300 mg did not developed severe COVID-19, despite being at high risk, and could immediately resume their chemotherapy without adversely affecting their hematologic disease. This finding suggests that while prophylactic tixagevimab-cilgavimab 300–300 mg is effective in preventing Omicron SARS-CoV-2 infection [6, 7], it may remains effective in preventing the progression to severe COVID-19 in patients with a haematologic malignancy and asymptomatic or pauci-symptomatic Omicron SARS-CoV-2 infection. Of note we could not exclude that in those patients COVID19 could have recover spontaneously in the absence of tixagevimab-cilgavimab administration.
In the eight patients with Omicron COVID-19 pneumonia requiring oxygen, three completely recovered after administration of tixagevimab-cilgavimab alone (n = 1) or combined with dexamethasone (n = 2). Of note, these 3 patients had omicron BA1 despite tixagevimab-cilgavimab being less active against omicron BA1 compared to BA2 [2]. In addition, one patient recovered after additional administration of convalescent plasma [8, 9]. While the remaining four patients died, we must highlight that tixagevimab-cilgavimab alone (n = 1) or combined with anti-inflammatory treatment (n = 2) lead to a clinical recovery with oxygen weaning in three of them. Nevertheless, those patients had a prolonged viral shedding with persistently positive nasopharyngeal PCRs and presented an acute respiratory distress syndrome secondary to the SARS-CoV-2 pneumonia 3–6 weeks later. This highlights the importance of close monitoring of such patients and the necessity of developing new strategies to prevent worsening in patients with prolonged viral shedding. Repeated administration of tixagevimab-cilgavimab may be worthy of investigation since there is a dose-effect in neutralizing the Omicron variant [6]. Furthermore, convalescent plasma remains effective for Omicron neutralisation [10] and its early administration in patients who remain SARS-CoV-2 positive should be considered.
Overall, in the current Omicron and vaccine era, while COVID-19 clinical outcomes have significantly improved, it remains life-threatening in patients with haematologic malignancies. In patients who are infected with the Omicron SARS-CoV-2 variant, unvaccinated or who did not respond to vaccination and did not receive prophylactic tixagevimab-cilgavimab, preemptive tixagevimab-cilgavimab at a dose of 300–300 mg seems effective. In patients with SARS-CoV-2 pneumonia who require oxygen, additional therapeutic strategies must be developed.
Author contributions
AO recruited patients, collected, assembled and analyzed data, and wrote the first draft of the manuscript. ZV, EB, RD, AD, YA, LR, NS, AB, AB, TA, ZM, PC, OL, KL, MM recruited patients, collected data and helped write the manuscript. J.G. and A.S. performed virological test and helped write the manuscript. MM and FM designed the study, assembled and analyzed data, supervised research, analyzed data, helped with writing the manuscript and revised the manuscript.
Data availability
All data supporting this letter are provided in the manuscript (Table 1).
Competing interests
MM reports grants and lecture honoraria from Janssen, Sanofi, Maat Pharma and JAZZ pharmaceuticals, lecture honoraria from Celgene, Amgen, BMS, Takeda, and Pfizer, grants from Roche, all outside the submitted work. FM reports lecture honoraria from Therakos/Mallinckrodt, Janssen, Novartis, Gilead, Sanofi, JAZZ pharmaceuticals and Astellas, all outside the submitted work. The other authors declare no competing financial interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References
1. Vijenthira A Gong IY Fox TA Booth S Cook G Fattizzo B Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients Blood 2020 136 2881 92 10.1182/blood.2020008824 33113551
2. Dejnirattisai W Huo J Zhou D Zahradník J Supasa P Liu C SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses Cell 2022 185 467 484.e415 10.1016/j.cell.2021.12.046 35081335
3. Nyberg T Ferguson NM Nash SG Webster HH Flaxman S Andrews N Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study Lancet 2022 399 1303 12 10.1016/s0140-6736(22)00462-7 35305296
4. Blennow O Salmanton-García J Nowak P Itri F Van Doesum J López-García A Outcome of infection with omicron SARS-CoV-2 variant in patients with hematological malignancies: An EPICOVIDEHA survey report Am J Hematol 2022 97 E312 e317 10.1002/ajh.26626 35702878
5. Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial. Lancet Respir Med. 2022. 10.1016/s2213-2600(22)00215-6.
6. Stuver R Shah GL Korde NS Roeker LE Mato AR Batlevi CL Activity of AZD7442 (tixagevimab-cilgavimab) against Omicron SARS-CoV-2 in patients with hematologic malignancies Cancer Cell 2022 40 590 1 10.1016/j.ccell.2022.05.007 35598602
7. Kertes J, David SSB, Engel-Zohar N, Rosen K, Hemo B, Kantor A, et al. Association between AZD7442 (tixagevimab-cilgavimab) administration and SARS-CoV-2 infection, hospitalization and mortality. Clin Infect Dis. 2022. 10.1093/cid/ciac625.
8. Lanza F Agostini V Monaco F Passamonti F Seghatchian J Therapeutic use of convalescent plasma in COVID-19 infected patients with concomitant hematological disorders Clin Hematol Int 2021 3 77 82 10.2991/chi.k.210403.001 34820612
9. Hueso T Godron AS Lanoy E Pacanowski J Levi LI Gras E Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis Leukemia 2022 36 1025 34 10.1038/s41375-022-01511-6 35105946
10. Li M Beck EJ Laeyendecker O Eby Y Tobian AAR Caturegli P Convalescent plasma with a high level of virus-specific antibody effectively neutralizes SARS-CoV-2 variants of concern Blood Adv 2022 6 3678 83 10.1182/bloodadvances.2022007410 35443020
| 36481838 | PMC9734768 | NO-CC CODE | 2022-12-14 23:28:30 | no | Bone Marrow Transplant. 2022 Dec 8;:1-3 | utf-8 | Bone Marrow Transplant | 2,022 | 10.1038/s41409-022-01894-1 | oa_other |
==== Front
Knee Surg Sports Traumatol Arthrosc
Knee Surg Sports Traumatol Arthrosc
Knee Surgery, Sports Traumatology, Arthroscopy
0942-2056
1433-7347
Springer Berlin Heidelberg Berlin/Heidelberg
36478285
7253
10.1007/s00167-022-07253-3
Knee
A BMI above 30 results in satisfying outcomes in patients undergoing fixed-bearing lateral unicompartmental knee arthroplasty
Giordano Lorenzo [email protected]
1
http://orcid.org/0000-0002-5327-3702
Maffulli Nicola [email protected]
123
Morenghi Emanuela [email protected]
45
Quaglia Alessandro [email protected]
6
Prospero Emanuele [email protected]
6
Rosa Francesco [email protected]
6
Volpi Piero [email protected]
6
1 grid.11780.3f 0000 0004 1937 0335 Department of Musculoskeletal Disorder, Faculty of Medicine and Surgery, University of Salerno, Salerno, Italy
2 grid.4868.2 0000 0001 2171 1133 Centre for Sports and Exercise Medicine, Queen Mary University of London, London, UK
3 grid.9757.c 0000 0004 0415 6205 UKSchool of Pharmacy and Bioengineering, Keele University School of Medicine, Staffordshire, UK
4 grid.417728.f 0000 0004 1756 8807 Biostatistics Unit, Humanitas Research Hospital, IRCCS, Rozzano, 20089 Milan, Italy
5 grid.452490.e Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, PieveEmanuele, 20090 Milan, Italy
6 grid.417728.f 0000 0004 1756 8807 Knee Surgery and Sport Traumatology Unit, Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
7 12 2022
17
28 7 2022
21 11 2022
© The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose
The purpose of this study is to analyse the effect of BMI on clinical outcomes of cemented fixed-bearing lateral unicompartmental knee arthroplasty (UKA) on a 2- to 12-year follow-up.
Methods
Between January 2010 and January 2020, a total of 103 lateral UKAs were implanted. The Oxford Knee Score (OKS) and the Western Ontario and McMaster University Osteoarthritis Index for pain, stiffness, function, and total score were administered to estimate patients’ overall health status pre- and post-operatively. Results were considered good or excellent for WOMAC values > 85 points and OKS > 40 points. Survivorship, described with Kaplan–Meier method, was defined as the lack of revision at the latest follow-up. Complications or further operations were recorded. p values of < 0.05 were considered significant.
Results
One hundred one lateral UKAs were assessed at a mean follow-up of 77.8 months. No patients underwent revision, but 2 patients (2, 0%) developed aseptic loosening of the implant 2 and 5 years after surgery but for clinical reasons neither undergo revision (5-year survivor 97.2%). Overall satisfaction was generally high, with excellent scores in all WOMAC subscales and OKS for all BMI groups. Considering the pain subscale (WOMAC pain), patients with normal weight and overweight achieve excellent results more frequently [10 (25.64%) vs 10 (23.81%) p = 0.026] than obese patients (n = 0); on the other hand, considering the quality of life (WOMAC QoL), obese patients most frequently reach excellent values, even statistically significant [n = 15 (75.00%) p = 0.040].
Conclusion
Although obesity has historically been described as a contraindication to UKA, improved outcomes with modern UKA implant designs have challenged this perception. Therefore, the classic contraindication of UKAs in patients with BMI > 30 kg/m2 may not be justified. According to the present study, lateral UKA patients with BMI > 30 kg/m2 had satisfactory patient-reported outcome measures compared to non-obese patients on a long term with survival rates comparable to medial UKA. Obese patients should not be excluded from the benefit of lateral UKA surgery.
Keywords
Body mass index
Obesity
Mid-long-term outcomes
Lateral unicondylar knee arthroplasty
==== Body
pmcIntroduction
The number of knee replacements performed annually is rapidly increasing, with many overweight and obese patients now needing joint replacements [1, 17]. Unicompartmental knee arthroplasty (UKA) offers some important advantages for the management one compartment knee’s osteoarthritis, both in terms of good clinical outcomes, and in terms of low incidence of adverse events and complications [28, 29, 36, 37]. According to the (1989) Kozinn and Scott criteria, body weight over 82 kg is a contraindication to UKA [16], but, more recently, many of the “traditional” contraindications have been questioned, including a high BMI [3, 26, 33]. Compared to other types of knee arthroplasty there is a lack of studies available about lateral UKA, especially when a 15-year survivorship is considered [19]. This because lateral UKA is less frequent (lower incidence of isolated lateral osteoarthritis [25] but also because of reluctance in surgical indication), shorter follow-up and limited data about implant survivorship and complications [24, 35, 44]. Studies of the effect of BMI on UKA outcomes have given conflicting results [7, 21, 24], and currently little is known about the effect of obesity on the clinical outcome of lateral UKA[19]. In the present study, our primary endpoint is the rate of survival and peri-postoperative complications, while a secondary endpoint was to compare the effect of BMI on the subscales of reported patients outcome measures. The study hypothesis is that patients who underwent a lateral UKA with a high BMI have a higher rate of peri-postoperative complications, a higher revision rate, and worse clinical outcomes compared to those with a BMI within the normal range.
Materials and methods
Consecutive patients who underwent lateral UKA with the cemented metal backed Unicompartmental High Flex Knee System prosthesis (ZUK, Lima Corporate®) were included in the retrospective analysis, with a minimum 2-year follow-up. Between January 2010 and January 2020, a total of 103 lateral UKAs were implanted; of these, 2 patients were lost to follow-up. Finally, 101 knees were assessed in 96 patients (Fig. 1). All operations were performed or directly supervised by a senior surgeon (PV) with extensive experience in UKA, in the same institute. The clinical sheet and the surgery records were checked for any intraoperative (fracture of the lateral tibial condyle, intercondylar eminence fracture, rupture of the lateral collateral ligament, TKA conversion) or postoperative (aseptic loosening of the femoral component, polyethylene bearing dislocation, suprapatellar bursitis, periprosthetic fracture, delayed healing of the surgical wound) complications or further operations. All patients were contacted by telephone for a post-operative structured interview that included assessment of the status of the implant and need for revision surgery, weight changes that led the patient to move from one BMI group to another, and to collect data on patient outcome measures. These included the Oxford Knee Score (OKS) and the Western Ontario and McMaster University Osteoarthritis Index for pain, stiffness, function, and total score. [22] Results were considered good or excellent for WOMAC values higher than 85 points and OKS higher than 40 points. [2] All the scores were administered by an orthopaedic surgeon who was not involved in the surgical procedure. Patients who could not be contacted by telephone were sent a written questionnaire to complete. Informed consent was obtained by each patient enrolled in the study. Finally, each patient's BMI was calculated at the time of surgery and at the last follow-up. Survivorship was defined as the lack of revision at the latest follow-up. Patients who received bilateral intervention were considered as receiving two independent procedures.Fig. 1 Patients enrollment flowchart
All patients included presented severe osteoarthritis of the lateral compartment with full thickness articular cartilage loss or avascular necrosis of the lateral femoral condyle. In all patients, the anterior cruciate ligament and the medial and lateral collateral ligaments were functionally intact, the valgus deformity was manually correctable and there was no evidence of osteoarthritis in the medial compartment. Osteoarthritis of the patellofemoral joint was not considered a contraindication unless there was deep eburnation. Exclusion criteria were fixed valgus deformity, previous osteotomy, or a flexion deformity > 15° (Fig. 1). All procedures were performed using a midline incision and a lateral parapatellar approach; the tibial and femoral cuts were made using the appropriate guides. The vertical cut was placed tightly against the tibial spine, as this allows the tibial component to cover the largest possible area of the tibial plateau. Thereafter, anatomical positioning of the femoral component was performed to avoid a variation in the height of the joint line, and selection of the thickness of the insert was performed with the knee in full extension. After removal of the trial components, the tibial surface was prepared for the pegs, and the tibial component was cemented in place before the femoral component was implanted. Physiotherapy started early after surgery, mainly focused, in this initial phase, on the recovery of the full range of motion with full weight bearing supported by two crutches. The independent ethics committee of the IRCCS Istituto Clinico Humanitas has authorised the present retrospective study no. 40/22.
Statistical analysis
For the descriptive nature of the study, no power analysis was performed a priori, and all patients’ data fulfilling inclusion and exclusion criteria were included in the analysis. Data were reported as number and percentage, or mean and standard deviation, or median and range, as appropriate. We have limited the number of decimals to one throughout the manuscript.
Patients were categorised into three BMI groups at the time of surgery: (1) Normal weight (≥ 18.5 to < 25 kg/m2), (2) Overweight (BMI ≥ 25 to < 30 kg/m2), (3) Obese (BMI ≥ 30 kg/m2) [39]. The dichotomous dependent variable was post-operative outcome score (excellent vs good), while independent variables were BMI (≤ 25 vs 25 < BMI < 30 vs ≥ 30 kg/m2) and the pre-operative clinical score. The adherence of continuous variables to Gaussian distribution was assessed with Shapiro–Wilk test. Differences among groups were explored with chi square test, with Fisher correction if necessary, or ANOVA or Kruskal–Wallis test, as appropriated. To assess implant survival and cumulative failure rate for both reoperation and revision (failure) endpoints the Kaplan–Meier method was utilised. Given that more than half of the patients have a follow-up of less than 5 years, results were expressed as 5-year survival. Statistical analyses were all performed in Stata version 14 (STATA Corp, TX). p values of < 0.05 were considered significant.
Results
The baseline characteristics and the composition of BMI groups are summarised in Table 1. No patient experienced peri-or postoperative complications. Considering the whole cohort of patients, UKA survival analysed with Kaplan–Meier method was 97.2% (n = 99) at 5 years. No patients underwent prosthetic revision, but 2 patients (2, 0%), 1 in the normal weight group and 1 in the overweight group, underwent UKA failure: both developed aseptic loosening of the implant 2 and 5 years after surgery (5-year survival 100% in obese group, versus 96.6% in non-obese group.) (Fig. 2). Given their age and comorbidities, neither wished to undergo revision. Moreover, another patient had a periprosthetic fracture and underwent internal fixation with plate and screw.Table 1 Demographics
All Normal weight (BMI < 25 kg/m2) Overweight (25 < BMI < 30 kg/m2) Obesity (BMI > 30 kg/m2) p
Total number of knees 101 39 42 20
BMI (mean ± SD) 26.3 ± 3.7 22.7 ± 1.6 27.1 ± 1.4 31.6 ± 2.0
Age (mean ± SD) 71.0 ± 8.9 71.8 ± 9.5 71.7 ± 8.3 68.1 ± 8.5 NS
Sex (M) 14 (13.8%) 2 (5.1%) 9 (21.4%) 3 (15.0%) NS
Follow up (months)
Mean ± DS and median (range)
77.8 ± 36.1
70 (24–145)
83.8 ± 39.1
88 (24–144)
74.8 ± 36.5
58.5 (25–145)
72.5 ± 28.7
64 (24–123)
NS
Fig. 2 Kaplan–Meier survival curve for patients with BMI less and higher 30
The WOMAC and OKS were administered to 96 patients (5 with a bilateral UKA). The mean and median postoperative OKS and WOMAC subscales improved in all BMI groups (Table 2) compared to each group’s respective preoperative scores. Specifically, patients with high BMI achieved good results in all WOMAC subscales, while normal weight or overweight patients tended to achieve excellent results more frequently [30.77% (n = 12) vs 26.19% (n = 11) of overweight and 10.00% (n = 2) of obese] (Table 2). Considering the pain subscale (WOMAC pain), patients with normal weight and overweight achieve excellent results more frequently [10 (25.64%) vs 10 (23.81%) p = 0.026] than obese patients (n = 0); on the other hand, considering the quality of life (WOMAC QoL), obese patients frequently reach excellent scores, even statistically significant [n = 15 (75.00%) p = 0.040].Table 2 Scores of the three BMI groups
All Normal weight (BMI < 25 kg/m2) Overweight (25 < BMI < 30 kg/m2) Obesity (BMI > 30 kg/m2) P
n 101 39 42 20
Pre-OKS 19.8 ± 3.4 20.6 ± 3.5 20.0 ± 3.3 17.8 ± 2.3 0.013
Post-OKS 41.7 ± 3.8 41.4 ± 4.4 42.0 ± 3.8 41.8 ± 2.5 NS
Delta from pre 21.9 ± 4.7 20.7 ± 4.9 22.0 ± 4.6 24.1 ± 4.0 0.057
Pre-WOMAC-Stiffness 35.0 ± 6.3 37.7 ± 5.8 35.3 ± 5.9 29.0 ± 3.3 < 0.001
Post-WOMAC-Stiffness 79.5 ± 7.8 80.0 ± 9.6 79.6 ± 7.1 78.4 ± 5.4 NS
> 89 7 (6.9%) 4 (10.2%) 2 (4.8%) 1 (5.0%) NS
Delta from pre 44.5 ± 9.9 42.3 ± 11.2 44.3 ± 9.4 49.4 ± 6.3 0.009
Pre-WOMAC Pain 36.2 ± 5.8 36.8 ± 5.6 38.1 ± 4.7 31.2 ± 5.5 < 0.001
Post-WOMAC Pain 80.0 ± 8.6 79.8 ± 10.5 80.9 ± 8.4 78.2 ± 3.7 NS
> 88 20 (19.8%) 10 (25.6%) 10 (23.8%) 0 0.026
Delta from pre 43.710.3 43.1 ± 13.1 42.8 ± 8.5 46.9 ± 7.0 NS
Pre-WOMAC QoL 35.4 ± 5.9 35.7 ± 5.7 37.7 ± 5.5 30.2 ± 3.8 < 0.001
Post-WOMAC QoL 81.3 ± 8.7 79.4 ± 10.6 82.0 ± 8.0 83.6 ± 4.5 NS
> 82 62 (61.4%) 18 (46.1%) 29 (69.0%) 15 (75.0%) 0.040
Delta from pre 45.9 ± 10.1 43.8 ± 11.8 44.3 ± 8.8 53.3 ± 4.7 < 0.001
Pre-WOMAC 35.7 ± 4.9 36.4 ± 4.6 37.4 ± 4.3 30.7 ± 3.6 < 0.001
Post-WOMAC 81.0 ± 7.2 80.6 ± 8.4 81.2 ± 7.4 81.3 ± 3.2 NS
> 85 25 (24.7%) 12 (30.8%) 11 (26.2%) 2 (10.0%) NS
Delta from pre 45.3 ± 8.5 44.2 ± 10.1 43.9 ± 7.5 50.7 ± 8.5 < 0.001
The obesity groups had the lowest preoperative PROM scores comparing with the other BMI groups, resulting in statistically significant increase in all scores and subscales (Table 2).
Discussion
The most important finding in this study is that obese patients with a BMI > 30 kg/m2 have good clinical outcomes after lateral UKA. Overall satisfaction in our patient cohort was generally high, with excellent scores across all WOMAC and OKS subscales at 2- to 12-year follow-up after surgery. Furthermore, the 5-year survival rate of lateral UKAs of the patient cohort was higher in obese patients than in normal weight patients. Recent registry studies showed an increase in the use of medial UKA, while the use of lateral UKA has remained constant over time [19] with a ratio of 1–10 between lateral and medial unicompartmental prostheses. This difference may be caused by the more challenging nature of lateral compared to medial UKA, the lower incidence of isolated lateral OA, the different anatomy and kinematics of the lateral compartment [14, 23, 25, 27], and the differences in volume of surgical procedures [9, 25, 30]. To complicate lateral UKA, some cofactors [11], including body weight, have been shown as modifiable risk factor for knee osteoarthritis and disease progression but also for dislocation, aseptic loosening, superficial, deep infection and revision surgery [10, 12, 20, 32]. As most populations worldwide are suffering from the pandemic of obesity, various studies evaluated the influence of high BMI on the outcome of medial UKA. In a series of 79 patients, early implant failure in 22% of patients at a mean follow-up of 40.2 months (range 24–49 months) was reported. The failures resulted from tibial loosening, tibial plateau fracture, persistent medial pain, progressive arthritis and sepsis. UKAs in patients with a BMI greater than 32 kg/m2 were associated with a reduced survivorship [4]. Similarly, a higher (12.5%) failure rate was evident in the more obese group of UKA patients [5]. In recent meta-analysis, obesity was a well-defined risk factor for conversion to TKA after UKA, especially at 10 years of follow-up. To prevent this issue, some surgeons propose TKA instead of UKA in obese patients with unicompartmental osteoarthrosis, although obesity increases risk of revision even after TKA[15, 32]. Conventionally, patients with higher BMI were thought to have poorer outcome with risk of early implant failure but this is not necessarily true for lateral UKA. In the present study, the PROM scores reported by obese patients ranged from good to excellent, comparable to those of normal and overweight people, but with lower initial scores. Survival reached a rate of 100% at 12 years for patients with a BMI > 30 kg/m2. At 3 and 5 years after surgery, the only two patients who experienced failure were of normal weight and overweight. Late failures were most commonly caused by osteoarthritis progression but, in the present series, with a maximum follow-up of 12 years, no significant clinical progression of osteoarthritis in the medial compartment had occurred. The length of follow-up in most studies may not be sufficient to observe medial osteoarthritis progression and increased revision rate in obese patients [6]. A similar study showed that obesity had no adverse outcome in UKA patients, with 10-year survival rates of 93% [7]. In 178 patients, the outcome of UKA was not influenced by patient age, BMI and early degeneration of the patello-femoral joint [38]. Tabor et al. reported higher survivorship in obese patients compared with those who were not obese in a 20-year follow-up study of 82 patients [31]. In a meta-analysis, the risk ratios for all-cause revision surgical procedures were 1.19 (p = 0.02) in severely obese (BMI > 35 kg/m2), 1.93 (p < 0.001) in morbidly obese (BMI > 40 kg/m2), and 4.75 (p < 0.001) in super-obese (BMI > 50) patients compared to patients with a normal BMI [8]. In this study, patients had an average BMI of 31.1 kg/m2 with only one patient reaching 38 kg/m2. Most patients had BMI between 30 and 33, i.e. class 1 obesity. Probably, with class 2 or 3 obesity, the risks associated with obesity, poorer outcome, early implant failure, wound or prosthetic infection, increase dramatically. There are several hypotheses that could justify the stability of these implants and the high survival and satisfaction rates of the lateral UKAs in patients with BMI higher than 30 kg/m2: obese patients are likely to perform less physical activity than non-obese patients, therefore imparting less use to their implant; reduced physical activity may compensate for the increased load of the obese patients in terms of prosthesis survival. Instead, people with a normal weight, demanding a more active lifestyle and frequently, as in our cohort, continue to practice amateur sports, tennis, skiing, hiking: this may amplify every sensation of pain [6, 35]. Furthermore, a recent biokinematic study shows that in lateral UKA the rotational kinematics of the native knee was restored but not after medial UKA [34]. Finally, the obese patients tended to be younger at surgery time with high satisfaction rates [18]; in our work, the highest BMI group present slightly lower mean age and lowest preoperative scores but also a greater improvement in scores compared to other groups as shown in Table 2. Patient selection and education is mandatory to obtain long-lasting results with lateral UKAs especially in obese patients.
Limitations
Our work has several limitations, the most important being the relatively small number of obese patients included in the study. In addition, all patients, given the restrictions related to the sars-cov-2 pandemic, were evaluated through PROMs and a telephone interview, making our work susceptible to a possible patient’s assessment bias. Another limitation is the lack of intermediate follow-up. On the other hand, this is one of the few studies that focus on lateral UKAs by comparing the outcome of obese patients with those of normal weight on 2- to 12-year follow-up and provides evidence that high BMI does not lead to inferior patient-reported or survival outcomes and supports the recommendation that a BMI threshold should not be considered a contraindication with respect to these outcomes.
Conclusion
Although obesity has historically been described as a contraindication to UKA, improved outcomes with modern UKA implant designs have challenged this perception. Therefore, the classic contraindication of UKAs in patients with BMI > 30 kg/m2 may not be justified. According to the present study, lateral UKA patients with BMI > 30 kg/m2 had no inferior patient-reported outcome measures compared to non-obese patients on a long term with survival rates comparable to medial UKA. Obese patients should not be excluded from the benefit of lateral UKA surgery.
Author contributions
LG made substantial contributions to study conception, acquired the data, design, and wrote the paper. EM performed the statistical analysis. AQ, EP, and FR interpreted the results and revised the manuscript critically. NM and PV conceived the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
Funding
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
Data availability statement
The data that support the findings of this study are available on request from the author LG. The data are not publicly available because them containing information that could compromise research participant privacy.
Declarations
Conflict of interest
All authors declare to have no competing interests relating to the present paper.
Ethical approval
The present study was performed in accordance with the Ethical Standards of the 1964 Helsinki Declaration and its later amendments, and IRB approval was obtained as attached documents.
Informed consent
All subjects were advised of the study objectives and the confidentiality of their data, but that their medical records may be reviewed for study purposes by authorised individuals other than their treating physician. It is emphasised that participation is voluntary and that the subject can refuse further participation in the protocol whenever he wishes. Documented informed consent was obtained for all subjects included in the study in accordance with national and local regulatory requirements.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Amin AK Clayton R a. E, Patton JT, Gaston M, Cook RE, Brenkel IJ, Total knee replacement in morbidly obese patients. Results of a prospective, matched study J Bone Joint Surg Br 2006 88 1321 1326 10.1302/0301-620X.88B10.17697 17012421
2. Bellamy N Buchanan WW Goldsmith CH Campbell J Stitt LW Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee J Rheumatol 1988 15 1833 1840 3068365
3. Berend KR Lombardi AV Adams JB Obesity, young age, patellofemoral disease, and anterior knee pain: identifying the unicondylar arthroplasty patient in the United States Orthopedics 2007 30 19 23 17549861
4. Berend KR Lombardi AV Mallory TH Adams JB Groseth KL Early failure of minimally invasive unicompartmental knee arthroplasty is associated with obesity Clin Orthop Relat Res 2005 440 60 66 10.1097/01.blo.0000187062.65691.e3 16239785
5. Bonutti PM Goddard MS Zywiel MG Khanuja HS Johnson AJ Mont MA Outcomes of unicompartmental knee arthroplasty stratified by body mass index J Arthroplasty 2011 26 1149 1153 10.1016/j.arth.2010.11.001 21256695
6. Campi S Papalia GF Esposito C Albo E Cannata F Zampogna B Papalia R Denaro V Unicompartmental knee replacement in obese patients: a systematic review and meta-analysis J Clin Med 2021 10 3594 10.3390/jcm10163594 34441889
7. Cavaignac E Lafontan V Reina N Pailhé R Wargny M Warmy M Laffosse JM Chiron P Obesity has no adverse effect on the outcome of unicompartmental knee replacement at a minimum follow-up of seven years Bone Joint J 2013 95-B 1064 1068 10.1302/0301-620X.95B8.31370 23908421
8. Chaudhry H Ponnusamy K Somerville L McCalden RW Marsh J Vasarhelyi EM Revision rates and functional outcomes among severely, morbidly, and super-obese patients following primary total knee arthroplasty: a systematic review and meta-analysis JBJS Rev 2019 7 e9 10.2106/JBJS.RVW.18.00184
9. Demange MK Von Keudell A Probst C Yoshioka H Gomoll AH Patient-specific implants for lateral unicompartmental knee arthroplasty Int Orthop 2015 39 1519 1526 10.1007/s00264-015-2678-x 25645437
10. Dowsey MM Liew D Stoney JD Choong PF The impact of pre-operative obesity on weight change and outcome in total knee replacement: a prospective study of 529 consecutive patients J Bone Joint Surg Br 2010 92 513 520 10.1302/0301-620X.92B4.23174 20357327
11. Emerson RH Higgins LL Unicompartmental knee arthroplasty with the oxford prosthesis in patients with medial compartment arthritis J Bone Joint Surg Am 2008 90 118 122 10.2106/JBJS.F.00739
12. Gelber AC Hochberg MC Mead LA Wang N-Y Wigley FM Klag MJ Body mass index in young men and the risk of subsequent knee and hip osteoarthritis 1 Am J Med Elsevier 1999 107 542 548 10.1016/S0002-9343(99)00292-2
13. Heyse TJ Tibesku CO Lateral unicompartmental knee arthroplasty: a review Arch Orthop Trauma Surg 2010 130 1539 1548 10.1007/s00402-010-1137-9 20559645
14. Iwaki H Pinskerova V Freeman MA Tibiofemoral movement 1: the shapes and relative movements of the femur and tibia in the unloaded cadaver knee J Bone Joint Surg Br 2000 82 1189 1195 10.1302/0301-620X.82B8.0821189 11132285
15. Kerkhoffs GMMJ Servien E Dunn W Dahm D Bramer JAM Haverkamp D The influence of obesity on the complication rate and outcome of total knee arthroplasty: a meta-analysis and systematic literature review J Bone Joint Surg Am 2012 94 1839 1844 10.2106/JBJS.K.00820 23079875
16. Kozinn SC Scott R Unicondylar knee arthroplasty J Bone Joint Surg Am 1989 71 145 150 10.2106/00004623-198971010-00023 2643607
17. Kurtz S Ong K Lau E Mowat F Halpern M Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030 J Bone Joint Surg Am 2007 89 780 785 10.2106/00004623-200704000-00012 17403800
18. Kyriakidis T, Asopa V, Baums M, Verdonk R, Totlis T (2022) Unicompartmental knee arthroplasty in patients under the age of 60 years provides excellent clinical outcomes and 10-year implant survival: a systematic review: a study performed by the early osteoarthritis group of Esska-European knee associates section. Knee Surg Sports Traumatol Arthrosc Official Journal of the ESSKA. 2022 Jun
19. van der List JP McDonald LS Pearle AD Systematic review of medial versus lateral survivorship in unicompartmental knee arthroplasty Knee 2015 22 454 460 10.1016/j.knee.2015.09.011 26507286
20. Messier SP Gutekunst DJ Davis C DeVita P Weight loss reduces knee-joint loads in overweight and obese older adults with knee osteoarthritis Arthritis Rheum 2005 52 2026 2032 10.1002/art.21139 15986358
21. Molloy J Kennedy J Jenkins C Mellon S Dodd C Murray D Obesity should not be considered a contraindication to medial Oxford UKA: long-term patient-reported outcomes and implant survival in 1000 knees Knee Surg Sports Traumatol Arthrosc 2019 27 2259 2265 10.1007/s00167-018-5218-6 30361754
22. Murray DW Fitzpatrick R Rogers K Pandit H Beard DJ Carr AJ Dawson J The use of the Oxford hip and knee scores J Bone Joint Surg Br 2007 89 1010 1014 10.1302/0301-620X.89B8.19424 17785736
23. Nakagawa S Kadoya Y Todo S Kobayashi A Sakamoto H Freeman MA Yamano Y Tibiofemoral movement 3: full flexion in the living knee studied by MRI J Bone Joint Surg Br 2000 82 1199 1200 10.1302/0301-620X.82B8.0821199 11132287
24. Nettrour JF Ellis RT Hansen BJ Keeney JA High failure rates for Unicompartmental knee arthroplasty in morbidly obese patients: a two-year minimum follow-up study J Arthroplasty 2020 35 989 996 10.1016/j.arth.2019.11.003 31796233
25. Ollivier M Abdel MP Parratte S Argenson J-N Lateral unicondylar knee arthroplasty (UKA): contemporary indications, surgical technique, and results Int Orthop 2014 38 449 455 10.1007/s00264-013-2222-9 24337799
26. Pandit H Jenkins C Gill HS Smith G Price AJ Dodd C a. F, Murray DW, Unnecessary contraindications for mobile-bearing unicompartmental knee replacement J Bone Joint Surg Br 2011 93 622 628 10.1302/0301-620X.93B5.26214 21511927
27. Pennington DW Swienckowski JJ Lutes WB Drake GN Lateral Unicompartmental Knee arthroplasty: survivorship and technical considerations at an average follow-up of 12.4 Years J Arthroplasty 2006 21 13 17 10.1016/j.arth.2004.11.021 16446180
28. Polat AE Polat B Gürpınar T Çarkçı E Güler O The effect of morbid obesity (BMI ≥ 35 kg/m2) on functional outcome and complication rate following unicompartmental knee arthroplasty: a case-control study J Orthop Surg Res 2019 14 266 10.1186/s13018-019-1316-5 31439046
29. Scott CEH Howie CR MacDonald D Biant LC Predicting dissatisfaction following total knee replacement: a prospective study of 1217 patients J Bone Joint Surg Br 2010 92 1253 1258 10.1302/0301-620X.92B9.24394 20798443
30. Scott RD Lateral unicompartmental replacement: a road less traveled Orthopedics 2005 28 983 984 10.3928/0147-7447-20050901-34 16190078
31. Tabor OB Tabor OB Bernard M Wan JY Unicompartmental knee arthroplasty: long-term success in middle-age and obese patients J Surg Orthop Adv 2005 14 59 63 16115429
32. Vasso M Corona K Gomberg B Marullo M European Knee Associates Small Implants focus group Obesity increases the risk of conversion to total knee arthroplasty after unicompartmental knee arthroplasty: a meta-analysis Knee Surg Sports Traumatol Arthrosc 2021 30 12 3945 3957 10.1007/s00167-021-06780-9 34718836
33. Volpi P Marinoni L Bait C Galli M Denti M Lateral unicompartmental knee arthroplasty: indications, technique and short-medium term results Knee Surg Sports Traumatol Arthr 2007 15 1028 1034 10.1007/s00167-007-0342-8
34. Wada K Hamada D Takasago T Nitta A Goto T Tonogai I Tsuruo Y Sairyo K Native rotational knee kinematics is restored after lateral UKA but not after medial UKA Knee Surg Sports Traumatol Arthrosc 2018 26 3438 3443 10.1007/s00167-018-4919-1 29582097
35. Waldstein W Kolbitsch P Koller U Boettner F Windhager R Sport and physical activity following unicompartmental knee arthroplasty: a systematic review Knee Surg Sports Traumatol Arthrosc 2017 25 717 728 10.1007/s00167-016-4167-1 27209192
36. Walker T Gotterbarm T Bruckner T Merle C Streit MR Total versus unicompartmental knee replacement for isolated lateral osteoarthritis: a matched-pairs study Int Orthop 2014 38 2259 2264 10.1007/s00264-014-2473-0 25112651
37. Weston-Simons JS Pandit H Kendrick BJL Jenkins C Barker K Dodd CAF Murray DW The mid-term outcomes of the Oxford Domed Lateral unicompartmental knee replacement Bone Joint J 2014 96-B 1 59 64 10.1302/0301-620X.96B1.31630 24395312
38. Xing Z Katz J Jiranek W Unicompartmental knee arthroplasty: factors influencing the outcome J Knee Surg 2012 25 369 373 10.1055/s-0031-1299666 23150345
39. (2000) Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 894:i–xii, 1–253
| 36478285 | PMC9734769 | NO-CC CODE | 2022-12-14 23:28:30 | no | Knee Surg Sports Traumatol Arthrosc. 2022 Dec 7;:1-7 | utf-8 | Knee Surg Sports Traumatol Arthrosc | 2,022 | 10.1007/s00167-022-07253-3 | oa_other |
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Research Article
Updates on cowpea viruses in Southwest Nigeria: distribution, prevalence and coinfection
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Ogunsola Kayode Ezekiel [email protected]
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Elegbeku Olusegun Akinleye 1
1 grid.442659.8 0000 0004 1778 7487 Department of Biological Sciences, (Biotechnology Programme), Bells University of Technology, PMB 1015, Ota, Ogun State Nigeria
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Cowpea is an important source of dietary proteins in the semi-arid regions of sub-Saharan Africa. Its productivity is constrained by several viral diseases and there are limited updates on the incidence and distribution of these diseases in Nigeria. This study assessed the distribution and prevalence of cowpea viruses in Southwest Nigeria. Field surveys were conducted in 2017 and 2018, in which a total of 600 leaf samples were randomly collected from 60 cowpea fields in four (Oyo, Ogun, Ondo and Osun) states at 15 fields per state and 10 samples per field. Disease incidence and severity were recorded while virus infections were confirmed by enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction. Viral disease symptoms of systemic mosaic, mottling, puckering, vein-banding, leaf deformation and stunted growth were observed. Highest virus incidence and severity (100% and 4.8 ± 0.4) were observed at Adeosun Avenue, Ondo state, whereas Boredun, Osun state had the least (80% and 3.8 ± 0.7), with some symptomless fields found among the states. Seven viruses, viz.: cowpea aphid-borne mosaic virus (CABMV), cowpea mild mottle virus (CPMMV), bean common mosaic virus-blackeye cowpea mosaic strain (BCMV-BlCM), cucumber mosaic virus (CMV), southern bean mosaic virus (SBMV), cowpea mottle virus (CMoV) and cowpea yellow mosaic virus (CYMV) were detected from 173 (28.8%) samples collected from 32 (53.3%) fields across the states. CPMMV was prevalent, detected from 30.0% of surveyed fields, whereas CYMV was the least prevalent (3.3%). Multiple infections of two to four viruses were observed among 12.5% of samples from 51.7% of fields. Highest incidence of single and multiple virus infections were observed in Ondo state. This updates on virus distributions in Southwest Nigeria will be useful for multiple virus resistance-breeding programs and other viral disease management strategies for improved cowpea productivity.
Supplementary Information
The online version contains supplementary material available at 10.1007/s42360-022-00576-8.
Keywords
Cowpea fields
Disease management
Mosaic virus
Multiple infections
RT-PCR
Survey
==== Body
pmcIntroduction
Cowpea (Vigna unguiculata (L.) Walp) is a key grain legume and an important source of dietary proteins in the semi-arid regions of sub-Saharan Africa (SSA). The high protein content, nitrogen fixation abilities and drought tolerance make it very important in SSA, in the context of food and nutritional security (Gomes et al. 2019). It is widely cultivated in West Africa for its protein-enriched seeds for human consumption and the stems used as fodder for livestock (Boukar et al. 2013). About 75% of the cowpea production is concentrated in Niger, Burkina Faso and Nigeria, with the last being the main producer, accounting for about 40.9% of the 8.9 million tons annual global production (FAOSTAT 2020).
The bulk of the production of cowpea is attributed to the semi-arid zones of northern Nigeria despite the increasing economic importance of the commodity in the southern states. However, the current security challenges in the Northern part of Nigeria has been identified as a major factor behind the reduction in cowpea supply to the southern part of the country (Aluko et al. 2016). The attendant threat on food security has thus become an impetus to the need to increase production in other suitable agro-ecologies. Southwest Nigeria is endowed with some spread of savannah agro-ecologies suitable for cowpea production and also blessed with vast genetic pool of local varieties of cowpea cultivated by farmers under different production systems (Saka et al. 2018). Several farmers grow cowpea in Southwest Nigeria either under sole cropping or inter-cropped, usually with cassava (Saka et al. 2018), while most of the national systems as well as International Research Institute in Nigeria, which cultivate large hectares of land for cowpea research and multiplication, are located in the Southwest region. Research efforts have also consistently produced cowpea varieties that are of different maturity periods and adaptability to diverse agro-ecologies of Nigeria (Brader 2002).
Cowpea yield is however constrained by both biotic and abiotic factors. Although, environmental factors such as ozone pollution reduces cowpea productivity (Hayes et al. 2000), biotic factors cause higher and more economical yield losses. The average cowpea yield in Nigeria (about 777 kg ha−1) is low compared to that of many other countries such as Egypt (3674 kg ha−1) and Iraq (5591 kg ha−1) (FAOSTAT 2020), mainly due to infestations by insect pests, parasitic weed striga, and infections by bacterial, fungal and viral diseases (Boukar et al. 2013). Viral diseases are known to reduce cowpea grain yields by 20–80% (Legg et al. 2019). Farmers in Nigeria usually plant cowpea cultivars which are susceptible to viruses. Most of their commercial varieties only consider sweetness, preferred seed colour, seed size and cooking value, and not virus resistance.
The seven cowpea viruses frequently reported in Nigeria are: cowpea aphid-borne mosaic virus (CABMV, genus Potyvirus), bean common mosaic virus-blackeye cowpea mosaic strain (BCMV-BlCM, genus Potyvirus), cowpea yellow mosaic virus [(CYMV, also known as cowpea mosaic virus (CPMV), genus Comovirus)], cowpea mild mottle virus (CPMMV, genus Carlavirus), cucumber mosaic virus (CMV, genus Cucumovirus), southern bean mosaic virus (SBMV, genus Sobemovirus) and cowpea mottle virus (CMoV, genus Gammacarmovirus) (Thottappilly and Rossel 1996; Boukar et al. 2013). These viruses have a wide host range, are transmitted by insect vectors especially by aphids, whiteflies or beetles and are also seed-transmitted in cowpea (Odedara and Kumar 2016). Virus infected cowpea produces different mosaic symptoms, mottling and reduction in yield or plant death in highly susceptible plants (Shoyinka et al. 1997). Some foliar symptoms such as vein-banding from BCMV-BlCM infection and veinal or mid-rib chlorosis for CMV seem to be characteristic of the viruses on cowpea. However, most of these viruses produce common systemic symptoms of mosaic, mottling, puckering, leaf deformation and stunted growth. Hence, symptoms induced on plants by different virus infection can only indicate the presence of virus but cannot be used to identify specific viruses, in which case, diagnostic tools are required for effective identification (Ogunsola et al. 2021).
Coinfection of more than one virus is frequent on the field and multiple infections of two to five viruses on a plant have been reported in Nigeria (Shoyinka et al. 1997), Uganda (Urawu et al. 2015) and Ghana (Adams et al. 2020). Multiple infection is enhanced by infestation by several virus transmitting insect vectors and the occurrence of same insect vectors transmitting many viruses of the same genus or different genera (e.g. Aphis crassivora transmits CABMV, BCMV-BlCM and CMV) (DaPalma et al. 2010). Multiple infections usually result in virus-virus interactions among the co-infecting viruses, which might produce a synergy that can break down the host’s resistance to a single viral disease, leading to a severe pathological response in form of a devastating reduction in cowpea productivity (Ogunsola et al. 2021).
Systematic pest and disease surveillance is a critical component of biovigilance and is key in identifying current problems and anticipating potential threats to crops (Carisse et al. 2017). A survey of cowpea viruses conducted in 1991–1993 throughout all agro-ecological zones in Nigeria earlier indicated the incidence of six viruses, viz; CABMV, CYMV, CMoV, BCMV-BlCM, SBMV and CMV in single and multiple infections, with prevalence of SBMV (in 1991) and CABMV (in 1992 and 1993) (Shoyinka et al. 1997). Another field survey in northern Nigeria confirmed the incidence of five of these viruses, with exception only to CYMV (Eni et al. 2013). However, up-to-date information on the incidence, prevalence and distribution of the cowpea viruses is sparse in Nigeria, while this is essential for effective management of viral diseases. Variations in virus population are expected from previous statistics of cowpea viruses in Nigeria due to the fast-evolving nature of viruses and the anthropogenic climate change (Legg et al. 2019). Genetic recombination between isolates originating from different host plants and geo-climatic locations as well as mutations have been reported as the significant mechanisms playing roles in generating diverse populations of plant viruses (Basavaraj et al. 2019).
To remedy the poor yield and low productivity of cowpea caused by viral diseases, information upon the occurrence and distribution of viruses seems to be of utmost important. This will provide the breeding objectives for virus-resistant high yielding cowpea varieties to overcome the low productivity and enhance food and nutritional security in the developing nations, where cowpea is an important source of dietary protein (Ajeigbe et al. 2012). Thus, field surveys of cowpea virus infections, under single or multiple conditions, were conducted in Oyo, Ogun, Ondo and Osun states of Southwestern Nigeria, to obtain a more recent information on the incidence, prevalence and distribution of cowpea infecting viruses in the region. The results of these surveys will be useful in designing appropriate, effective and sustainable management strategies against cowpea viral diseases.
Materials and methods
Field survey of cowpea viruses
A total of 600 cowpea plants (with or without symptoms) were randomly sampled by walking in a “W” shaped path, across 60 cowpea fields (10 leaf samples per field) in four states (Oyo, Ogun, Ondo and Osun states) of the Southwest region of Nigeria as described in Aliyu et al. (2012). Five local government areas (LGA) where cowpea are predominantly cultivated were selected in each state, choosing three fields per LGA. The surveys were conducted during September 2017 and October 2018, coinciding with the vegetative growth or early flowering stage of the plants. Coordinates and altitude of the field locations were measured by a Geographical Positioning System (GPS) device (eTrex Garmin, Taiwan). After collection, the samples were placed in plastic sample bags, kept in an ice box on the field and later stored at 4 °C before the laboratory diagnostic test for viruses. Virus detection was carried out at the Virology and Molecular Diagnostics Laboratory (MDV), International Institute of Tropical Agriculture (IITA) Ibadan, Nigeria.
Evaluation of viral disease incidence, prevalence and severity
Disease incidence was expressed in percentage, by dividing the number of infected samples (samples on which at least one viral species were detected) over the total samples collected × 100 (Odedara et al. 2008). Virus prevalence (virus with the widest occurrence) was assessed by the ratio of the number of fields from which virus was detected over the total number of surveyed fields, expressed as a percentage. Disease severity was determined visually by the symptoms of virus infection on the sampled plants using a symptom severity rating scale of 1–5, where 1 = no visible symptoms, 2 = mild mosaic or mottling on few leaves, 3 = mosaic or mottling on many leaves, 4 = severe mosaic on all the leaves, puckering and mild stunting and 5 = severe mosaic, puckering, leaf distortion, severe stunting with necrosis or death of leaves or plants (Fig. 1) (Shoyinka et al. 1997; Ogunsola et al. 2021).Fig. 1 Disease symptom severity rating scale 1–5 of some cowpea viruses: a BCMV-BlCM, b CABMV, c SBMV, d CMoV and e CMV symptoms. Healthy control (1) and symptomatic leaves of virus infected Ife Brown (2–5)
Virus detection by ACP-ELISA
Samples were tested for seven cowpea viruses (CABMV, CPMMV, BCMV-BlCM, CMoV, CMV, SBMV and CYMV) already reported in Nigeria, using homologous anti-rabbit antibodies to individual virus available at the VMD Unit of IITA, Nigeria, with Antigen Coated Plate-Enzyme-linked Immunosorbent Assay (ACP-ELISA) as described in Kumar et al. (2001). About 100 mg of tissue from the leaf apex was used for virus testing in a 96- well NUNC MaxiSorb (Nunc, Denmark) ELISA plate. Alkaline phosphatase (ALP)-labelled anti-rabbit antibodies were used to detect the immobilized antigen–antibody complex, and p-nitrophenylphosphate (Sigma, Gillingham, UK) was used as substrate. After 1 h of incubation, readings were taken at absorbance of 405 nm (A405 nm) in a Multiscan Plus ELISA plate reader (Labsystems, Helsinki, Finland). Sample with ELISA reading (A405 nm) value that is at least twice (2 ×) that of the healthy control was considered as positive to virus.
Virus detection using RT-PCR
Samples that tested negative for virus in ELISA were verified by reverse transcription-polymerase chain reaction (RT-PCR) for reconfirmation. RT-PCR test was performed on four of the seven viruses (BCMV-BlCM, CABMV, CMV and CPMMV) due to some constraints. Total RNA was extracted from 100 mg leaf tissue according to a modified Cetyltrimethyl Ammonium Bromide (CTAB) method (Abarshi et al. 2010) and used for detection of the viruses. Quality of the extracted RNA was analysed by agarose gel electrophoresis earlier described by Kumar (2009). The total RNA concentration and purity were estimated by agarose gel electrophoresis and Nano Drop (2000) spectrophotometer (Thermo Scientific Tegrant Corporation; Wilmington, Delaware, USA), according to the manufacturer’s instructions.
RT-PCR was performed following the procedure described by Kumar (2009) using specific primer pairs (Table 1) corresponding to the respective viruses. PCR amplification was carried out in 12.5 µl reaction mixture comprising 10 × PCR reaction buffer (supplied with Taq enzyme), 0.75 µl of 25 mM MgCl2, 0.25 µl mixture of 10 mM deoxynucleotide triphosphates (dNTPs), 0.25 µl of respective primers, 12 units of Molony-murine leukaemia virus (M-MLV) reverse transcriptase (RT) (Promega Corporation, USA), 0.3 units of Taq DNA polymerase (Promega Corporation, Madison, Wisconsin, USA), 2.0 µl of 10 ng/µl total RNA and sterile distilled water. Amplification was performed with Applied Biosystems (GeneAmp® PCR System 9700) Cycler machine. Amplification of BCMV-BlCM RNA was carried out as follows: one cycle for 30 min at 42 °C and 35 cycles of denaturation at 94 °C for 1 min, primer annealing at 52 °C for 1 min, extension at 72 °C for 1 min and finally, 7 min of extension at 72 °C. CABMV cycling conditions were one cycle for 30 min at 42 °C and 35 cycles of denaturation at 94 °C for 30 s, annealing at 54 °C for 30 s, extension at 72 °C for 30 s and final extension at 72 °C for 5 min. The thermal cycler conditions for CMV and CPMMV were similar to that of CABMV except that annealing temperature was 55 °C for both CMV and CPMMV. Amplified RT-PCR products were separated in 1% (w/v) agarose gels electrophoresis in 0.5 × TBE and visualized under UV transilluminator (BioRad) after staining in ethidium bromide (0.5 µg/ml).Table 1 Primers used in RT-PCR
Virus Primer Sequence (5ʹ → 3ʹ) Fragment size (bp) References
BCMV-BlCM BCMV F ATGTGGTACAATGCTGTGAAG 470 Kumar (2009)
BCMV R TTTCAGTATTCTCGCTGGTTG
CABMV CABMV F GTACTCCAGTCTGATGGAAAGG 525 Kumar (2009)
CABMV R GTCCGAGAAGTGGTGCATAA
CMV CMV F GCCGTAAGCTGGATGGACAA 538 Wylie et al. (1993)
CMV R CCGCTTGTGCGTTTAATGGCT
CPMMV CPMMV F CACTTGGAATTTTATGTTGAC 250 Yadav et al. (2013)
CPMMV R TCATTTCGATTGGACCTATC
BCMV-BlCM bean common mosaic virus-blackeye cowpea mosaic strain, CABMV cowpea aphid borne mosaic virus, CMV cucumber mosaic virus, CPMMV cowpea mild mottle virus
Data analysis
Disease incidence data were transformed using Arcsine Transformation and the incidence and severity data were subjected to analysis of variance (ANOVA) using the PROC GLM statement of Statistical Analysis System, version 9.2 (SAS 2008). The means were separated using Duncan multiple range test (DMRT).
Results
Virus incidence and symptom severity
Symptoms of cowpea virus diseases observed at different locations across the four states were mosaic, puckering, mottling, vein-banding, leaf deformation and stunted growth. Although, foliar symptoms, such as vein banding from BCMV-BlCM infection, puckering and leaf deformation by SBMV, mottling for CMoV and veinal chlorosis with mild puckering by CMV, seem characteristic of some of the viruses on cowpea, a systemic foliar symptoms of mosaic, chlorosis and stunting were common among the viruses. Symptoms severity ranged from moderate to severe whereas, some cowpea plants were symptomless. Aphids and whiteflies were the main insect vectors found on most of the infected fields, while leaf beetles and other cowpea infecting insects were observed in some locations. Symptomatology and diagnosis demonstrated that virus incidence and severity differed significantly (p < 0.0001) among field locations (Table 2). Higher incidence corresponded to higher virus disease severity in most of the fields. Among the areas with virus presence, highest incidence and severity of viruses were observed at Adeosun Avenue, Ondo state (100% and 4.8 ± 0.4), followed by Ogun (90% and 4.8 ± 0.4), Oyo (90% and 3.3 ± 0.5) while the least disease incidence and severity were recorded in Osun state (80% and 3.8 ± 0.7). However, some fields in each of the states had no viral symptom (0% and 1.0) while Ogun state had the highest number of symptomless fields (10).Table 2 Incidence and severity of single and multiple viral infections of cowpea in Southwest Nigeria
State LGAa Field locationb Location coordinates Elevation (m) Detected virusc Incidence (%) Severity
Oyo Ido Omi Adio 7° 22′ 57.32″ N 3° 45′ 0.14″ E 158 CP, CM 30efg* 3.3 ± 0.6hij
Idi-amu Ido 7° 31′ 10.20″ N 3° 41′ 56.33″ E 184 – 0g 1.0 ± 0n
Bako 7° 24′ 5.90″ N 3° 46′ 20.97″ E 175 CP 80abc 2.8 ± 0.5kl
Ibadan N.E Monantan 7° 25′ 9.08″ N 3° 57′ 51.8″ E 237 – 0g 1.0 ± 0n
Iwo Road 7° 24′ 11.48″ N 3° 56′ 34.19″ E 232 – 0g 1.0 ± 0n
Academy 7° 24′ 45.50″ N 3° 57′ 14.83″ E 256 – 0g 1.0 ± 0n
Akinyele Alabata 7° 35′ 22.2″ N 3° 52′ 11.50″ E 280 – 0g 1.0 ± 0n
Elekuru 7° 35′ 42.0″ N 3° 51′ 48.24″ E 272 CP 30efg 3.0 ± 0jk
Moniya 7° 29′ 53.84″ N 3° 54′ 24.62″ E 245 – 0g 1.0 ± 0n
Oyo East Fashola Odo ogun 7° 52′ 59.98″ N 3° 31′ 0.0″ E 248 SB, CY 30efg 3.0 ± 1.0jk
Shonku, Oyo rd 7° 54′ 0.0″ N 3° 45′ 0.0″ E 213 – 0g 1.0 ± 0n
Fashola 7° 53′ 27.35″ N 3° 46′ 59.88″ E 291 – 0g 1.0 ± 0n
Ibadan S.W IAR&T Apata 7° 22′ 41.30″ N 3° 50′ 38.33″ E 158 CP, CA, BC 50cdef 4.0 ± 0.7ef
NCRI Apata 7° 23′ 12.44″ N 3° 50′ 30.3″ E 167 CA, CP 90ab 3.3 ± 0.5hij
Odo Ona 7° 23′ 1.18″ N 3° 50′ 48.84″ E 172 SB, CY 30efg 3.7 ± 0.6fgh
Ogun Odeda Alabata 7° 14′ 4.34″ N 3° 26′ 36.24″ E 175 CP, CM 40def 2.5 ± 0.6l
Odeda 7° 13′ 58.55″ N 3° 32′ 51.61″ E 127 – 0g 1.0 ± 0n
Osiele Idera 7° 11′ 49.2″ N 3° 27′ 10.8″ E 161 – 0g 1.0 ± 0n
Ifo Onihale 6° 45′ 54.83″ N 3° 12′ 53.17″ E 49 – 0g 1.0 ± 0n
Kajola 6° 46′ 49.51″ N 3° 13′ 56.35″ E 66 CP, SB, CM, CMo 90ab 4.8 ± 0.4abc
Oko Paki 6° 46′ 36.41″ N 3° 13′ 58.51″ E 70 CP, CA, BC 20fg 2.0 ± 0m
Ipokia Idiroko 6° 38′ 21.91″ N 2° 44′ 42.32″ E 84 – 0g 1.0 ± 0n
Ilase 6° 41′ 24.61″ N 2° 47′ 15.22″ E 48 – 0g 1.0 ± 0n
Ihunbo 6° 41′ 16.30″ N 2° 44′ 39.48″ E 70 – 0g 1.0 ± 0n
Ado Odo Ota Otta 6° 41′ 32.82″ N 3° 9′ 53.71″ E 21 – 0g 1.0 ± 0n
Iju 6° 39′ 17.42″ N 3° 8′ 9.78″ E 38 – 0g 1.0 ± 0n
Atan 6° 38′ 18.96″ N 3° 8′ 17.77″ E 27 – 0g 1.0 ± 0n
Yewa South Alagbo 6° 41′ 13.24″ N 3° 0′ 38.48″ E 51 CP, CM 0g 1.0 ± 0n
Owode 6° 41′ 59.24″ N 2° 57′ 43.38″ E 52 CP, CA, BC 60bcde 4.2 ± 0.8de
Ajilete 6° 41′ 59.64″ N 2° 55′ 52.67″ E 42 – 0g 1.0 ± 0n
Ondo Akure North Adeosun Avenue 7° 15′ 50.58"N 5° 14′ 23.75"E 360 CP, CA, BC, CMo 100a 4.8 ± 0.4ab
Omowale 7° 15′ 33.21″ N 5° 14′ 36.18″ E 351 CM 60bcde 4.2 ± 0.4de
Oba Ile Estate 7° 15′ 16.70″ N 5° 14′ 23.88″ E 328 CM 80abc 4.8 ± 0.5abc
Ose Elegbeka 6° 58′ 49.52″ N 5° 40′ 23.91″ E 144 CP, CA, CMo 40def 2.8 ± 0.5kl
Ifon 6° 55′ 56.68″ N 5° 45′ 57.01″ E 153 BC, CMo 80abc 4.4 ± 0.5cde
Elegbeka Express 7° 0′ 2.58″ N 5° 41′ 56.33″ E 197 CP, CA, BC, CMo 70abcd 5.0 ± 0a
Akoko N.E Okorun Titun 7° 30′ 59.10″ N 5° 42′ 44.67″ E 448 unidentified 80abc 4.7 ± 0.5abc
Apen 7° 31′ 20.33″ N 5° 41′ 15.71″ E 446 – 0g 1.0 ± 0n
Asere Awara 7° 30′ 59.09″ N 5° 42′ 45.15″ E 452 CP, CA, BC 70abcd 3.7 ± 0.5gfh
Akoko S.W Oba Akoko 7° 22′ 9.78″ N 5° 43′ 25.53″ E 310 CP, CA 70abcd 4.6 ± 0.8bc
Oba Expressway 7° 21′ 2.13″ N 5° 41′ 55.45″ E 267 CP, CA 60bcde 3.2 ± 0.8ij
Ose Oba Akoko 7° 19′ 4.77″ N 5° 40′ 26.19″ E 241 – 0g 1.0 ± 0n
Akure South Owena 7° 14′ 10.00″ N 5° 8′ 35.85″ E 328 – 0g 1.0 ± 0n
Emiloro Oda 7° 10′ 9.37″ N 5° 13′ 41.35″ E 327 – 0g 1.0 ± 0n
Alagbaka 7° 13’37.10”N 5° 12’55.28”E 352 - 0 g 1.0 ± 0n
Osun Boripe Oni oba 7° 48’25.21”N 4° 37’26.98”E 348 CM 0 g 1.0 ± 0n
Idi Okiti 7° 48’26.99”N 4° 36’39.66”E 367 CA, BC 50cdef 4.4 ± 0.6bcd
Idi Okiti 2 7° 48’28.31”N 4° 36’28.78”E 378 CP, CA, BC 40def 4.5 ± 0.6bcd
Osogbo Boredun 7° 34’55.21”N 4° 36’29.48”E 351 CA 80abc 3.8 ± 0.7 fg
Uni. Osun 7 ° 45’26.56”N 4° 36’17.92”E 330 - 0 g 1.0 ± 0n
Oke Bale 7° 45’47.11”N 4° 34’29.38”E 356 CA, BC 20 fg 3.5 ± 0.7ghi
Olorunda Kelebe 7° 48’5.01”N 4° 35’49.28”E 355 CP, CA 20 fg 2.5 ± 0.7 L
Agric. Min. 7° 47’53.37”N 4° 36’37.02”E 351 unidentified 50cdef 4.6 ± 0.6abc
Kelebe 2 7° 48’6.12”N 4° 36’23.00”E 364 CA, CY 30efg 3.0 ± 1.0jk
Ifelodun Dominion Ikirun 7° 55’35.05”N 4° 38’52.04”E 358 - 0 g 1.0 ± 0n
Oshogbo rd 7° 51’14.99”N 4° 37’15.85”E 385 CM 0 g 1.0 ± 0n
Beehive 7° 51’18.19”N 4° 37’14.63”E 383 - 0 g 1.0 ± 0n
Irewole Orisumbare Ikire 7° 23’0.99”N 4° 11’28.50”E 194 - 0 g 1.0 ± 0n
Irewole 7° 22’26.92”N 4° 10’31.04”E 206 - 0 g 1.0 ± 0n
Irewole II 7° 22’44.42”N 4° 10’34.37”E 224 - 0 g 1.0 ± 0n
*Means (values represent means from 2017 and 2018 data) followed by the same letter are not significantly different by DMRT (p < 0.0001)
aLGA, Local government area, N.E., North east, S.W., Southwest
bUni. Osun, Osun state University; Agric. Min., Ministry of Agriculture
cCP, CPMMV; CA, CABMV; BC, BCMV-BlCM; CY, CYMV; SB, SBMV; CMo, CMoV; “unidentified”, detection of non-identified virus
“-”, no detection of virus
Detection and distribution of cowpea viral infections in Southwest Nigeria
The two diagnostic assays confirmed and identified the viruses on infected plant samples. Viruses were detected from 173 (28.8%) of the total samples collected from 32 (53.3%) of the surveyed fields. Incidence of seven viruses; viz.: CPMMV, CABMV, BCMV-BlCM, CMV, SBMV, CYMV and CMoV were confirmed from cowpea samples collected across the four states of Southwest Nigeria. The seven viruses were detected by ACP-ELISA in many samples, while six of the samples that were negative to viruses by ACP-ELISA tested positive by RT-PCR, one each for BCMV-BlCM and CMV, and four for CPMMV (Fig. 2a, c, d). Oyo and Ogun states were the ones with more virus species diversity, having six species each, with the presence of CPMMV, CABMV, BCMV-BlCM, CMV, SBMV, and CYMV in the first, and CPMMV, CABMV, BCMV-BlCM, CMV, SBMV and CMoV in the second state. Meanwhile, five virus species were detected at both Ondo (CPMMV, CABMV, BCMV-BlCM, CMV and CMoV) and Osun state (CPMMV, CABMV, BCMV-BlCM, CMV and CYMV). In addition, CPMMV, CABMV, BCMV-BlCM, CMV were identified in the four states surveyed whereas SBMV (Oyo and Ogun states), CYMV (Oyo and Osun states) and CMoV (Ogun and Ondo states) were detected only in two states.Fig. 2 Detection of A BCMV-BlCM, B CABMV, C CMV and D CPMMV in cowpea by RT-PCR; M = DNA size marker (100 bp ladder; Promega); lanes 1–10 = extracts of 10 cowpea samples with negative results to virus by ACP-ELISA (a = BCMV-BlCM, b = CABMV, c = CMV and d = CPMMV); B = no template control, H = uninfected cowpea sample; D = virus positive control
Single virus infections were detected in some cowpea fields while multiple infections (detection of two of more viruses on a sample) were observed in most of the fields (Table 2). Multiple virus infections generally showed a more severe symptoms in most of the plants and produced a combination of symptoms showed by each of the coinfecting viruses under single infection. The highest number of virus infected plants was recorded in Ondo state in 71 (47.3%) samples collected from 10 (66.7%) fields. This was followed by Osun state with 38 (25.3%) infected samples from 9 (60.0%) fields. Thirty-four (22.7%) infected samples were recorded from 7 (46.7%) fields in Oyo state, while the least was from Ogun state with 30 (20.0%) infected samples obtained from 5 (33.3%) fields.
Latent infections, in which symptomless plants tested positive via ACP-ELISA, were observed. CPMMV and CMV were detected from some symptomless cowpea samples from Alagbo in Ogun state, and CMV from Oni oba and Oshogbo road in Osun state by ACP-ELISA (Table 2). Although, BCMV-BlCM, CMV and CPMMV were detected by ACP-ELISA in many samples, this was not the case for BCMV-BlCM in a sample from Oko paki, CMV in a sample at Alabata both in Ogun state, and CPMMV in four samples from IAR&T Apata in Oyo state, which were detected only by RT-PCR (Fig. 2a, c, d and Table 2). Moreover, all symptomatic leaf samples were positive for viruses with the exception of samples from Okorun Titun, Ondo state and Ministry of Agriculture, Osun state, which were negative to the seven viruses assayed in this study both by ELISA and RT-PCR hence, the suspected viruses were not identified (Table 2).
Prevalence of cowpea viruses in Southwest Nigeria
Of the seven cowpea viruses identified from the study areas, CPMMV was prevalent, detected from 18 (30%) fields (Table 3). Although, CABMV showed wider occurrence on the number of infected samples (16.3%) than CPMMV (12.3%), CPMMV was more widely distributed, detected on more cowpea fields than CABMV. CYMV was the least prevalent (3.3%) on the field.Table 3 Prevalence of cowpea viruses in Southwest Nigeria
Detected Oyo State Ogun State Ondo State Osun State Prevalence
virus Sa S (%) Fb F (%) S S (%) F F (%) S S (%) F F (%) S S (%) F F (%) TSc TS (%) TFd TF (%)
CPMMVe 28 18.7 5 33.3 23 15.3 5 33.3 10 6.7 6 40.0 13 8.67 2 13.3 74 12.3 18 30
CABMV 16 10.7 2 13.3 8 5.3 3 20.0 50 33.3 6 40.0 24 16 6 40.0 98 16.3 17 28.3
BCMV-BlCM 4 2.7 1 6.7 6 4.0 3 20.0 32 21.3 4 26.7 19 12.7 3 20.0 61 10.2 11 18.3
CMV 16 10.7 2 13.3 10 6.7 2 13.3 16 10.7 2 13.3 20 13.3 2 13.3 62 10.3 8 13.3
SBMV 6 4.0 2 13.3 6 4.0 2 13.3 – – – – – – – – 12 2.0 4 6.7
CYMV 6 4.0 1 6.7 – – – – – – – – 3 2 1 6.7 9 1.5 2 3.3
CMoV – – – – 5 3.3 3 20.0 14 9.3 4 26.7 – – – – 19 3.2 7 11.7
aS, number of samples from which virus was detected out of 150 samples collected per state
bF, number of fields where virus was detected out of the 15 cowpea fields surveyed per state, (F add to more than 15 and F (%) add to more than 100% in some cases due to multiple virus infections)
cTS, total number of infected samples from 600 samples collected across the states
dTF, total number of fields where virus was detected out of the 60 surveyed fields across the states
e“–”, no detection of virus
Incidence and distribution of multiple viral infections of cowpea
Multiple infections of two to four viruses on a plant were observed on 12.5% of the total samples taken from 51.7% of the surveyed cowpea fields in Southwest Nigeria (Table 4). The highest number of samples (27) and fields (12) with multiple viral infections were found in Ondo state, followed by Osun (21 and 6) and Ogun (15 and 8), with the least from Oyo state (12 and 5). Among the multiple infections scenarios, dual infection was prevalent, both on the number of samples (45.3%) and fields where detected (51.6%). This was followed by triple infection (42.7% and 38.7%) while coinfection with four viruses (12% and 9.7%) was the least prevalent, observed only in Ogun and Ondo states. Triple infection of CPMMV + CABMV + BCMV-BlCM was observed in all the states, while coinfections involving CPMMV with either CMV or CABMV were the most frequent among dual infections.Table 4 Detection of intra-host multiple viral infections of cowpea from Southwest Nigeria
State Multiple virus infectionsa Coinfection per sample Coinfection per field
No. of samples S (%)b No. of fields F (%)c
Oyo CP + CA + BC 2 1.3 1 6.7
CP + CA 2 1.3 1 6.7
CP + CM 2 1.3 1 6.7
SB + CY 6 4.0 2 13.3
Ogun CP + CM + SB + CMo 8 5.3 1 6.7
CP + CA + BC 2 1.3 2 13.3
CA + BC + CMo 1 0.7 1 6.7
CP + CM 1 0.7 1 6.7
CA + BC 2 1.3 2 13.3
SB + CMo 1 0.7 1 6.7
Ondo CP + CA + BC + CMo 1 0.7 2 13.3
CP + CA + CMo 5 3.3 1 6.7
CP + CA + BC 10 6.7 5 33.3
CP + CA 5 3.3 2 13.3
CP + CMo 1 0.7 1 6.7
BC + CMo 5 3.3 1 6.7
Osun CP + CA + BC 12 8.0 2 13.3
CP + CA 6 4.0 1 6.7
CA + BC 2 1.3 2 13.3
CA + CY 1 0.7 1 6.7
Totald 75 12.5 31 51.7
aCP, CPMMV; CA, CABMV; BC, BCMV-BlCM; CY, CYMV; SB, SBMV; CMo, CMoV
bS (%), percentage of coinfected samples out of the 150 samples collected per state
cF (%), percentage of number of fields where coinfections were observed out of the 15 surveyed fields per state
dTotal number and percentages of coinfected samples out of 600 samples from 60 fields across the states
Discussion
Virus diseases are part of the major constraints to agricultural production especially in West Africa, where control methods are either not available, not affordable or not readily accessible by farmers (Legg et al. 2019). Effective surveillance of plant diseases usually identifies potential pest problems before they create major crop losses, while permitting sufficient time for mitigation strategies to be developed, tested, and implemented (McCallum et al. 2021). Field surveys of cowpea viruses conducted in Southwest Nigeria showed incidence of seven cowpea viruses, viz: CPMMV, CABMV, BCMV-BlCM, CMV, SBMV, CYMV and CMoV. Virus symptoms of mosaic, puckering, mottling, vein-banding, leaf deformation and stunted growth, confirmed by ELISA or RT-PCR, revealed the geographical distribution of these viruses in the region.
Higher virus incidence and severity observed in Ondo than in other states and the virus distribution pattern indicate variation in the incidence and distribution of cowpea viruses in Southwest Nigeria. Such variation among field locations can be attributed to differences in the vector spread, seed-borne virus inoculum and alternative hosts or volunteer plants from the previous crops (Biemond et al. 2013; Odedara and Kumar 2016). Edema et al. (1997) and Shoyinka et al. (1997) attributed the variability to changes in weather conditions within seasons and farming systems in different environments. This implies that effective virus disease management approach needs to consider the variation in type and distribution of viruses as well as the dynamics of occurrence of viruses, especially in the proactive plans to prevent epidemic spread of cowpea viral diseases.
The survey results provided updated information on the incidence and distribution of cowpea viruses in Southwest Nigeria. Previous surveys reported incidence of six viruses (CABMV, BCMV-BlCM, CMV, SBMV, CMoV and CYMV) in all agro-ecological zones of Nigeria, with no report of virus in Ondo and Osun State (Shoyinka et al. 1997). However, we observed in addition to these six viruses, a high incidence and widest distribution of CPMMV on cowpea in Southwest region of Nigeria.
Although, CPMMV has been reported to be prevalent on cowpea in Uganda (Urawu et al. 2015), previous surveys of cowpea fields in the Savanna zones of Nigeria reported low incidence and distribution of the virus (Odedara and Kumar 2016), while this virus was not detected in other cowpea field surveys in Nigeria (Aliyu et al. 2012; Eni et al. 2013). A recent report has however categorised CPMMV among the important and most frequent seed transmitted cowpea viruses (Kumar et al. 2021). The observed prevalence of CPMMV in cowpea is contrary to the previous report of prevalence of CABMV in Nigeria (Shoyinka et al. 1997). CABMV was referred to as a cosmopolitan cowpea virus causing high yield losses of up to 40% in cowpea (Bashir et al. 2002). However, this survey result indicates a recent upsurge of the occurrence of CPMMV on cowpea in Southwest Nigeria.
The observed high incidence and prevalence of CPMMV, under single and multiple infections, might be attributable to the high population of its insect vectors (Bemisia tabaci) on farmers’ fields in Southern Nigeria (Vetten and Allen 1983), supplemented by the seed transmission rate (3%) of the virus in cowpea (Nain et al. 1994). This virus is already known as a limiting factor to the production of soybean (Glycine max (L.) Merr.) in many countries such as Argentina, Egypt, Israel, Kenya, Brazil, Thailand, Malaysia and Nigeria (Zubaidah and Kuswantoro 2016). Thus, there is a need to investigate into the level of yield loss attributable to CPMMV infection in cowpea.
To the best of our knowledge, this is the first report of the occurrence of cowpea viruses in Ondo and Osun states of Southwest Nigeria. The novel reports on the incidence of five viruses in each of the two states, with Ondo state having highest incidence and severity in the survey areas, will be helpful in the viral disease management in Southwest region of Nigeria for improved cowpea productivity. Virus management options readily available to farmers include: keeping fields free of weeds and volunteer plants (alternative hosts for viruses and their vectors); ensuring old crops are completely destroyed after harvest to remove sources of infection; removing (rogueing) plants showing virus disease symptoms, the use of insect traps or insecticides to control vector populations and planting virus resistant varieties (Karim 2016; Schreinemachers et al. 2015). Moreover, the use of host plant resistance has been considered the most effective, economical and environmentally friendly control measure for cowpea viruses (Urawu et al. 2013). This updates on cowpea virus incidence and distribution will provide useful information to virologists and cowpea breeders on screening for sources of multiple resistance to viruses among cowpea genotypes, putting the virus disease distribution and prevalence in Southwest Nigeria into consideration. This is important in developing improved, multiple-virus resistant cowpea varieties. For instance, CYMV was not prevalent in Southwest Nigeria, detected only in one field each in Oyo and Osun states. This implies that much breeding efforts will be channelled on CPMMV, which is currently prevalent in the zone, as well as to other viruses in the introgression of genes for resistances to viruses and other plant diseases into the susceptible cowpea land races and commercial varieties in Nigeria. However, the use of host resistance can be supplemented with other preventive measures against the spread of viruses to the locations where they were not yet detected. Schreinemachers et al. (2015) suggested that host plant resistance should be used in combination with other crop management such as good field sanitation and vector control, for legume viruses, as this make the control method more effective and prolongs the period that the host-plant resistance remains effective since virus species have the potential to evolve quickly and may thus overcome the resistance.
Several cultivars of cowpea have also been reported in Nigeria and other African countries. Boukar et al. (2019) reported the released of many cowpea varieties by National and International Research Institutes in Africa. In Nigeria, released varieties include Ife brown, IAR 339-1, IAR 341, IT97K-499-35, IT99K-573-1-1, etc. In Senegal, there were Ndambour, Mougne, Bambey 21 and 23, while in Tanzania and Burkina Faso, there were TKx133-16D-2, IT00K-1263 and IT99K-573-2-1, and KN-1 (Vita 7), TVx3236 and IT98K-205-8, respectively. Many cowpea varieties and landraces of various phenotypic (e.g. seed coat colour and texture, and seed sizes) and agronomic characters are usually cultivated in Southwest Nigeria, depending on farmer’s and consumers’ preferences. Among these varieties, sources of resistance to some viruses have been reported. For instance, cowpea varieties: IT82D-889, IT90K-277-2, and TVu201 were found to be resistant to several isolates of BCMV-BlCM and CABMV (VanBoxtel et al. 2000) while IT85F-2841, MU-93 and SECOW-2W were resistant to CABMV (Urawu et al. 2013). Unfortunately, most of the available commercial varieties and landraces in Nigeria are susceptible to viruses which contributed to the high viral infections observed from most of the surveyed cowpea fields..
Under multiple viral infections, higher symptom severity was observed in most of the plants than in single infections. The occurrence of multiple infections on 51.7% of the surveyed fields is an indication that multiple infection is becoming commonplace on cowpea fields in Southwest Nigeria. Such infection type have been earlier reported to have caused a more devastating disease conditions, resulting in high loss of yield and productivity in Nigeria (Shoyinka et al. 1997; Nsa and Kareem 2015) as well as other countries (Urawu et al. 2015; Adams et al. 2020). Multiple infections have also influenced the titer of the coinfecting viruses. This influence on disease severity and virus accumulation by coinfection however, depend on the type of virus, host resistance status, type of virus-virus-host interaction (either synergistic or antagonistic), and climatic factors (Ogunsola et al. 2021).
The incidence, geographical distribution and prevalence of the viruses seem to influence the type of multiple infection. For instance, the least prevalent CYMV was observed only in double infections with either SBMV or CABMV whereas CPMMV or CABMV were involved in most of the coinfections. In addition, although, Oyo and Ogun states have the highest diversity of virus species (of six viruses each), Ondo state, with the highest virus incidence and severity also showed highest occurrence of multiple virus infections. This suggests that virus incidence, distribution and prevalence may influence virus coinfection, evolution and coevolution dynamics. The high incidence of multiple infections in Ondo state might also be attributable to cultivation of highly susceptible cowpea landraces by the farmers. Since double infections involving CPMMV is predominant among coinfections, and triple infections of CPMMV + CABMV + BCMV-BlCM was observed in all the surveyed states, development of multiple viral disease resistant cowpea varieties, based-on the present knowledge of the coinfecting viruses, will be helpful in the effective management of the viral diseases in the affected areas.
The observed latent infection of CPMMV and CMV has been previously reported in cowpea (Legg et al. 2019; Ogunsola et al. 2021). This is capable of causing unnoticeable spread of the two viruses on farmers’ fields, which might have also enhanced the observed wide distribution of CPMMV in cowpea. This necessitates random sampling of symptomless plants in addition to symptomatic ones for an effective field survey of cowpea viruses. The situation whereby CPMMV and CMV were detected only by RT-PCR and not ACP-ELISA in few samples from Oyo and Ogun state might be due to very low virus concentration in those samples or probably the presence of serologically variable strains of the viruses (Aliyu et al. 2012), since the two viruses were detected serologically from other plant samples. On the other hand, the highly symptomatic plant samples from Ondo state and Osun state, which were not diagnosed by ACP-ELISA or RT-PCR suggests infections by viruses outside the seven frequently reported on cowpea in Nigeria, and which were not assayed in this study. These might be single or multiple infections of the seldom reported cowpea viruses in Nigeria such as cowpea golden mosaic virus (CGMV, genus Begomovirus), a non seed-transmitted virus (Boukar et al. 2013), cowpea chlorotic mottle virus (CCMV, genus Bromovirus) (Thottappilly et al. 1993), sunn-hemp mosaic virus (SHMV, genus Tobamovirus), which is not yet known to be insect-transmissible (Legg et al. 2019) or bean pod mosaic virus (BPMV, genus Comovirus) (Odedara and Kumar 2016). Alternatively, it might be infections of new variants of cowpea viruses not yet identified, and capable of emerging from the occurrence of multiple virus infections. Coinfections can lead to virus-virus interactions as a result of cross-protection, mutual exclusion or recombination among the viruses and some of these interactions usually result in the development of a new variant of virus (Renteria-Canett et al. 2011; Syller 2012). Since new virus variants can be more devastating than the existing ones, likelihood of their occurrence in cowpea should be investigated.
The widespread of multiple infections, coupled with the effects of global Covid-19 pandemic in which lock-down and restrictions in movement hinder farmers’ activities on farms and markets (Andama et al. 2020) and the recent occasional attacks on farmers by cattle herdsmen which deprive farmers of easy access to farms and cause losses of farm produce (Okoro 2018), might drastically reduce cowpea production in Southwest Nigeria. This is capable of posing a negative impact on the food and nutritional security of Nigeria, where cowpea is the most important and cheapest source of dietary protein to both rural and urban communities (Ajeigbe et al. 2012). Recently in Nigeria, attention is being focused on the dual purpose cowpea varieties to be used both as grain for consumption and as fodder (Boukar et al. 2020). However, the high incidence and wide distribution of multiple viral infections on farmers’ fields with the consequent more severe foliar damages than in single infections, can impair such dual functions.
The observed variation in the incidence and prevalence of single and multiple cowpea viruses in Southwest Nigeria, over the years, might have been enhanced by climate change, which impact has been reported in Nigeria (Adepitan and Falayi 2019), changes occurring within farming systems and crop intensification (Legg et al. 2019), usage of virus susceptible landraces and poor insect vector management. Disease control measures need to consider compatibility with sustainable and climate-resilient crop production systems, soil resources regeneration, protection of water and air, and development of crop germplasm with increased tolerance or resistance to pathogens and pests, which can also produce more food of high nutritional quality (Roberts et al. 2021). Effective cowpea viral disease management strategies are thus required, especially the integrated management that combines the use of multiple-disease resistant varieties with regulating of insect vectors population and use of clean seed germplasm. These updates on virus incidence and distributions in Southwest Nigeria will be useful in such virus disease management measures to achieve higher cowpea productivity.
Conclusion
The survey results provided a more recent information on virus incidence, prevalence and distribution in the Southwest Nigeria. The study revealed incidence of seven seed transmitted viruses (CPMMV, CABMV, BCMV- BlCM, CMV, SBMV, CYMV and CMoV) and a prevalence of CPMMV in cowpea in the surveyed region, under single and multiple infection scenarios. This necessitates disease management methods that integrate introgression of multiple virus disease resistance into the consumers’ preferred cowpea varieties and adoption of efficient seed certification systems for improved and sustainable cowpea productivity. The novel observation of a high incidence of single and multiple viruses in Ondo state of Nigeria calls for attention to the affected areas. An occasional survey of cowpea fields is required in Nigeria to identify new and emerging viruses which might be more devastating in cowpea. The variation in the incidence and prevalence of cowpea viruses in Nigeria over the years also necessitates a re-evaluation of the losses in yield and productivity that are attributable to viral diseases under single and multiple infections.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (XLSX 28 KB)
Supplementary file2 (PPTX 777 KB)
Acknowledgements
We thank Dr. P. Lava Kumar, the Head of Virology and Molecular Diagnostics Unit/ Germplasm Health Unit of IITA, Ibadan, Nigeria, for professional advice and extending IITA laboratory diagnostic facilities for this study. The survey equipment provided by the Head of Post Entry Plant Quarantine, Surveillance and Diagnostic Station, Nigeria Agricultural Quarantine Service, Moor Plantation Ibadan, Nigeria, is also appreciated.
Author contributions
KEO contributed to conceptualization, methodology, analysis, resources, survey supervision and writing of the original draft of the manuscript. AY: contributed to resources, editing, survey data collection and laboratory diagnosis. OAE contributed to survey data collection and laboratory diagnosis. All authors have read and approved the final article.
Data Availability Statement
Supplementary data on virus disease incidence and severity; and RT-PCR confirmatory test are available.
Declarations
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Abarshi MM Mohammed IU Wasswa P Hillocks RJ Holt J Legg JP Seal SE Maruthi MN Optimization of diagnostic RT-PCR protocols and sampling procedures for the reliable and cost-effective detection of cassava brown streak virus J Virol Methods 2010 163 353 359 10.1016/j.jviromet.2009.10.023 19879299
Adams FK Kumar L Kwoseh C Akromah R Occurrence of cowpea viruses in the forest and savannah agro-ecological zones of Ghana Afr Crop Sci J 2020 28 3 441 448 10.4314/acsj.v28i3.8
Adepitan JO Falayi EO Variability changes of some climatology parameters of Nigeria using wavelet analysis Sci Afr 2019 2 e00017 10.1016/j.sciaf.2018.e000172468-2276/©2018
Ajeigbe HA, Saidou AK, Singh BB, Hide O, Satoshi T (2012) Potentials for cowpea (Vigna unguiculata) for dry season grain and fodder production in the Sudan and Sahel zones of West Africa. In: Boukar O, Coulibaly O, Fatokun C, Lopez K, Tamò M (eds) Innovative research along the cowpea value chain, proceedings of the 5th World Cowpea conference on improving livelihoods in the cowpea value chain through advancement in science, IITA, Nigeria, held in Senegal, pp 189–201
Aliyu TH Balogun OS Kumar L Survey of the symptoms and viruses associated with cowpea (Vigna Unguiculata L.) in the Agro-ecological zones of Kwara state, Nigeria Ethiop J Environ Stud Manag 2012 5 4 613 619 10.4314/ejesm.v5i4.S22
Aluko OJ Osikabor B Adejumo AA Sumade S Perceived effect of Boko-Haram insurgency on means of accessing cowpea from north-east Nigeria to Bodija market, Ibadan, Oyo State, Nigeria Open Access Libr J 2016 3 e2723 10.4236/oalib.1102723
Andama K Edeha H Obohb V Pauwc K Thurlowc J Impacts of COVID-19 on food systems and poverty in Nigeria Adv Food Sustain 2020 5 2452 2635 10.1016/bs.af2s.2020.09.002
Basavaraj YB Kumar A Jain RK Kumar P Parameswari B Prakash J Molecular diversity of Papaya ringspot virus in India: genetic recombination and mutations between the isolates from different hosts and geo-climatic locations are role players in virus evolution Indian Phytopathol 2019 72 497 511 10.1007/s42360-019-00157-2
Bashir M Ahmad Z Ghafoor A Cowpea aphid borne mosaic potyvirus: a review Int J Pest Manag 2002 48 155 168 10.1080/09670870110118722
Biemond PC Oguntade O Kumar PL Stomph TJ Termorshuizen A Struik P ‘Does the informal seed system threaten cowpea seed health’? Crop Prot 2013 43 166 174 10.1016/j.cropro.2012.09.007
Boukar O Bhattacharjee R Fatokun C Kumar PL Gueye B Singh M Upadhyaya HD Bisht IS Cowpea Genetic and genomic resources of grain legume improvement 2013 London Elsevier 137 156
Boukar O Belko N Chamarthi S Togola A Batieno J Owusu E Haruna M Diallo S Umar ML Olufajo O Fatokun C Cowpea (Vigna unguiculata): genetics, genomics and breeding Plant Breed 2019 138 415 424 10.1111/pbr.12589
Boukar O Abberton M Oyatomi O Togola A Tripathi L Fatokun C Introgression breeding in cowpea (Vigna unguiculata (L.) Walp.) Front Plant Sci 2020 11 567425 10.3389/fpls.2020.567425 33072144
Brader L (2002) Forward. In: Fatokun, CA, Tarawali SA, Singh BB, Kormawa PM, Tamò M (eds) Challenges and opportunities for enhancing sustainable cowpea production. Proceedings of the World cowpea conference III held at the International Institute of Tropical Agriculture (IITA), Ibadan, Nigeria, 4–8 September 2000. P vi, IITA, Ibadan, Nigeria
Carisse O Fall ML Vincent C Using a biovigilance approach for pest and disease management in Quebec vineyards J Indian Dent Assoc 2017 39 393 404
DaPalma T Doonan BP Trager NM Kasman LM A systematic approach virus-virus interactions Virus Res 2010 149 1 9 10.1016/j.virusres.2010.01.002 20093154
Edema R Adipala E Florini DA Influence of season and cropping system on the occurrence of cowpea diseases in Uganda Plant Dis 1997 81 465 468 10.1094/PDIS.1997.81.5.465 30861923
Eni AO Ogunsanya P Oviasuyi T Hughes Jd’A, Alarming increase in the incidence of cucumber mosaic virus in cowpea (Vigna Unguiculata (L.) Walp.) in Northern Nigeria Arch Phytopathol Plant Prot 2013 46 16 1958 1965 10.1080/03235408.2013.782218
FAOSTAT (2020) Food and Agriculture Organization of the United Nations. FAO Statistics Division, Rome, Italy. http://www.fao.org/faostat/en/#data/QC. Accessed 13 July 2022
Gomes AMF Nhantumbo N Ferreira-Pinto M Massinga R Ramalho JC Ribeiro- Barros A Breeding elite cowpea (Vigna unguiculata (L.) Walp.) varieties for improved food security and income in Africa: opportunities and challenges Legume Crops 2019 10.5772/Intechopen.84985
Hayes F Harmens H Sharps K Radbourne A Ozone dose–response relationships for tropical crops reveal potential threat to legume and wheat production, but not to millet Sci Afr 2000 9 e00482 10.1016/j.sciaf.2020.e00482
Karim FA (2016) Survey of cowpea viral disease symptoms and detection of associated viruses in selected cowpea growing areas in Ghana. Thesis, Kwame Nkrumah University of Science and Technology, Kumai, Ghana. http:hdi.handle.net/123456789/9269
Kumar PL Jones AT Sreenivasulu P Fenton B Reddy DVR Characterization of a virus from pigeon pea with affinities to species in the genus Aureus virus, family Tombusviridae Plant Dis 2001 85 208 215 10.1094/PDIS.2001.85.2.208 30831944
Kumar PL Cuervo M Kreuze JF Muller G Kulkarni G Kumari SG Massart S Mezzalama M Alakonya A Muchugi A Graziosi I Ndjiondjop M Sharma R Negawo AT Phytosanitary interventions for safe global germplasm exchange and the prevention of transboundary pest spread: the role of CGIAR Germplasm Health Units Plants 2021 10 2 328 10.3390/plants10020328 33572058
Kumar PL (2009) Methods for the diagnosis of plant virus diseases. Laboratory manual. International Institute of Tropical Agriculture 5–90 Ibadan, Nigeria, IITA
Legg JP, Kumar PL, Mahuku G, Wosula E, Stavolone L, Terry E, Bosque-Perez N (2019) Viruses affecting African crops and their vectors. In: Neuenschwander P, Tamo M (eds) Critical issues in plant health: 50 years of research in African agriculture. 19–23. Cambridge, UK: BurleighDodds Science Publishing, ISBN: 978 1786762320. www.bdspublishing.com. 10.19103/AS.2018.0043.05
McCallum BD Geddes CM Chatterton S Peng G Carisse O Turkington TK Olfert O Leeson J Sharpe S Stephens E We stand on guard for thee: a brief history of pest surveillance on the Canadian Prairies Crop Prot 2021 149 105748 10.1016/j.cropro.2021.105748
Nain PS Rishi N Bishnoi SS Profile of viral diseases of cowpea (Vigna unguiculata) in northern India Indian J Virol 1994 10 2 128 136
Nsa IY Kareem KT Additive interactions of unrelated viruses in mixed infections of cowpea (Vigna unguiculata L. Walp) Front Plant Sci 2015 6 812 825 10.3389/fpls.2015.00812 26483824
Odedara OO Hughes Jd’A, Odebode AC, Odu BO, Multiple virus infections of lablab (Lablab purpureus L. Sweet) in Nigeria J Gen Plant Pathol 2008 74 322 325 10.1007/s10327-008-0098-0
Odedara O Kumar P Incidence and diversity of viruses in cowpea and weeds in the unmanaged farming systems of savanna zones in Nigeria Arch Phytopathol Plant Prot 2016 50 1 12 10.1080/03235408.2016.1241203
Ogunsola KE Ilori C Fatokun CA Boukar O Ogunsanya P Kumar PL Disease incidence and severity in cowpea lines evaluated for resistance to single and multiple infections of endemic viruses in Nigeria J Crop Improv 2021 35 3 427 452 10.1080/15427528.2020.1824952
Okoro JP (2018) Herdsmen/farmers conflict and its effects on socio-economic development in Nigeria. J Peace, Secur Dev 4(1):143–158. https://www.researchgate.net/publication/335778034
Renteria-Canett I Xoconostle-Cazares B Ruiz-Medrano R Rivera-Bustamante RF Geminivirus mixed infection on pepper plants: synergistic interaction between Pepper huasteco yellow vein virus and Pepper golden mosaic virus Virol J 2011 8 104 10.1186/1743-422X-8-104 21385390
Roberts DP Short NM Sill J Lakshman DK Hu X Buser M Precision agriculture and geospatial techniques for sustainable disease control Indian Phytopathol 2021 74 287 305 10.1007/s42360-021-00334-2
Saka JO Agbeleye OA Ayoola OT Lawal BO Adetumbi JA Oloyede-Kamiyo QO Assessment of varietal diversity and production systems of cowpea (Vigna unguiculata (L.) Walp.) in Southwest Nigeria J Agric Rural Dev Trop Subtrop 2018 119 2 43 52 10.17170/kobra-2018121864
SAS (Statistical Analysis System) (2008) SAS user’s guide version 9.2. SAS Institute Incorporated, Cary
Schreinemachers P Balasubramaniam S Boopathi NM Ha CV Kenyon L Praneetvatakul S Sirijinda A Le NT Srinivasan R Wu M Farmers’ perceptions and management of plant viruses in vegetables and legumes in tropical and subtropical Asia Crop Prot 2015 75 115 123 10.1016/j.cropro.2015.05.012
Shoyinka SA Thottappilly G Adebayo GG Anno-Nyako FO Survey on cowpea virus incidence and distribution in Nigeria Int J Pest Manag 1997 43 127 132 10.1080/096708797228816
Syller J Facilitative and antagonistic interactions between plant viruses in mixed infection Mol Plant Pathol 2012 13 204 216 10.1111/j.1364-3703.2011.00734.x 21726401
Thottappilly G Rossel HW Viral disease of cowpea in Africa IITA Res Guide 1996 53 28
Thottappilly G Sehgal OP Rossel HW Characteristics of a cowpea chlorotic mottle virus isolate from Nigeria Plant Dis 1993 77 60 63 10.1094/PD-77-0060
Urawu M Melis R Laing M Derera J Genetic inheritance of resistance to cowpea aphid-borne mosaic virus in cowpea Euphytica 2013 189 191 201 10.1007/s10681-012-0756-3
Urawu M Obuo J Omadi R Distribution and detection of cowpea viruses infecting cowpea in Uganda Am J Plant Sci 2015 6 5 574 581 10.4236/ajps.2015.65062
VanBoxtel J Singh BB Thottappilly G Maule AJ Resistance of (Vigna Unguiculata (L.) Walp.) Breeding Lines to blackeye cowpea mosaic and cowpea aphid borne mosaic potyvirus isolates under experimental conditions J Plant Dis Prot 2000 107 2 197 204
Vetten HJ Allen DJ Effects of environment and host on vector biology and incidence of two whitefly-spread diseases of legumes in Nigeria Ann Appl Biol 1983 102 2 219 227 10.1111/j.1744-7348.1983.tb02687.x
Wylie S Wilson CR Jones RAC Jones MGK A polymerase chain reaction Assay for Cucumber mosaic virus in lupin seeds Austr J Agric Res 1993 44 41 51 10.1071/AR9930041
Yadav MK Biswas KK Lal SK Baranwal VK Jain RK A distinct strain of Cowpea mild mottle virus infecting soybean in India J Phytopathol 2013 161 10 739 744 10.1111/jph.12119
Zubaidah S Kuswantoro H Foliar symptoms recovery: developing scoring technique for assessment of soybean resistance to CPMMV (cowpea mild mottle virus) J Biol Res 2016 21 2 85 89 10.23869/bphjbr.21.2.20167
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With N,N′-methylenebisacrylamide (MBA) and polyvinyl alcohol (PVA) as raw materials, a polymer (PVA-MBA) containing N-halamine precursor functional groups was obtained via grafting reaction between the active hydroxyl groups on PVA and α, β-unsaturated functional groups of MBA under the catalysis of sodium carbonate in an aqueous solution. An acyclic N-halamine precursor-grafted PVA (MBA-PVA) film was formed by simply spreading PVA-MBA aqueous solution in a glass dish and drying it. An antimicrobial acyclic N-halamine-grafted PVA (PVA-MBA-Cl) film was achieved by spraying the diluted sodium hypochlorite solution onto the surface of PVA-MBA film. The performance test of PVA-MBA-Cl film under the optimal preparation conditions showed that the tensile performance and the hydrophobicity were improved, compared to the PVA film. The storage stability test indicated that the oxidative chlorine content Cl+ (atoms/cm2) of the as-prepared PVA-MBA-Cl film only reduced by 14.3% after storage for 9 weeks, showing that the antibacterial N-halamine functional groups in PVA-MBA-Cl film has excellent storage stability under room temperature. Antibacterial test showed that the PVA-MBA-Cl film had very strong antibacterial efficacies and could completely kill 1.28 × 106 CFU/mL S. aureus and 1.89 × 106 CFU/mL E. coli within 1 min. Therefore, PVA-MBA-Cl film will have more potential applications in food package.
Keywords
Acyclic N-halamine
Antibacterial
Polyvinyl alcohol film
Food package
Shanghai Pujiang Talent Project11PJ1407600 Liang Jie
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pmcIntroduction
Microbial contamination and infection caused by pathogens are increasing global public health awareness. This issue is highlighted by the outbreak of Coronavirus disease (COVID-19) pandemic, which has caused more than 400 million confirmed cases and 6 million deaths worldwide. It is still increasing, causing immeasurable pain and economic losses [1]. The common way to prevent the proliferation of microorganisms and the spread of pathogens is disinfection and sterilization. It is well-known that the antibacterial agent is a core material, which can be divided into three categories: inorganic [2], organic [3–6], and natural antimicrobial agents [7, 8]. For the inorganic antibacterial agents, most of them are metal/metal oxide nanoparticles [9, 10], such as silver, copper, and zinc oxide. Their advantages are strong heat resistance, good antibacterial durability, and no drug resistance. However, complicated manufacturing processes, relatively expensive costs, and color issues restricted their applications. Commonly used organic antibacterial agents include aldehydes (ketones), phenols, quaternary ammonium salts [11], halides, thiophenes, biguanides, and diphenyl ethers. The advantages of organic antibacterial agents are wide range of sources, low production cost, fast sterilization rate, convenient processing, good stability, and their disadvantage is the poor heat resistance. The natural antibacterial agents such as chitosan, bacteriocin, lysozyme, plant essential oils are mainly obtained from animal or plant extracts or synthesized by microorganisms. The advantages of them are high safety, non-toxicity, good biocompatibility, and abundant resources. Their disadvantages are poor heat resistance, short pot life, and restricted production condition and equipment. As a kind of organic antibacterial agents, N-halamine antibacterial agents have higher stability, much stronger antibacterial efficacies, less harm to the environment, and easier use for antibacterial treatment on the surface of materials. It is generally believed that the sterilization mechanism of N-halamine antibacterial agents is that N-halamine molecules first contact the bacteria, and then the oxidized chlorines oxidize the receptors in the cell, thereby destroying the bacterial metabolism and killing them. At the same time, the bactericidal ability of N-halamines can be regenerated after rinsing with dilute bleaching water solution to convert the N–H bonds in the molecules into N–Cl ones [6, 12, 13].The immobilization of the antibacterial agent refers to the process of introducing the antibacterial groups to the surface of the material by physical action [14–18], such as van der Waals force or electrostatic attraction and covalent bond coupling. At present, the immobilization methods of N-halamine antibacterial agents mainly include physical modification methods represented by surface coating and blending, and chemical modification methods [18, 19] represented by surface electrophilic, nucleophilic reactions, and surface graft polymerization reactions [20–24]. When the material is modified by physical coating, the interaction force between the antibacterial agent molecules and the material is weak, the antibacterial agent molecules are easy to detach during use. When the material is modified by physical blending, most of the antibacterial agent molecules are deeply buried inside the material and are difficult to exert antibacterial effect, resulting in a relatively low utilization rate of antibacterial agents. In this paper, the chemical grafting method [25–28] was used to obtain modified film [29–31] materials with the superior stability of antimicrobial N-halamine groups and high-efficacy antimicrobial capacity.
Environmental pollution caused by plastic waste is an increasingly serious global problem. Many industries are turning the way of packaging food to a more sustainable choice and developing biodegradable antibacterial food packaging materials. In the meantime, Omicron variant (COVID-19) pandemic broke out in Shanghai. There are still many positive cases during long-term home closure. Experts say there is a risk of Omicron carrying in group buying packages and items. As a result, the development of antibacterial films for packaging applications is a meaningful research field. PVA is a water-soluble polymer material, which has the features of degradability, biocompatibility, non-toxicity, safety, and environmental friendliness. It has broad application prospects in respect of packaging materials. Li et al. [32] prepared a cyclic N-halamine-grafted PVA film and evaluated its antimicrobial efficacy against Escherichia coli O157:H7 and Staphylococcus aureus within contact times of 5 and 10 min. However, the storage of antimicrobial N-halamine groups in the PVA film was not unsatisfactory. In this paper, we developed a three-step process to prepare an acyclic N-halamine-grafted antibacterial PVA (PVA-MBA-Cl) film. The preparation route of antimicrobial PVA-MBA-Cl film and its schematic diagram of the preparation and sterilization are shown in Fig. 1. The two terminals of MBA molecules are the carbon–carbon double bonds, which obviously could react with the hydroxy groups of PVA in water under the base catalysis to form a MBA-grafted PVA (PVA-MBA) aqueous solution. After PVA-MBA film was formed, the antimicrobial function was achieved via converting the amide groups of MBA to N-halamine groups with an addition of NaClO aqueous solution. The as-prepared PVA-MBA-Cl film exhibits super antibacterial efficacies and excellent stability of antimicrobial N-halamine groups.Fig. 1 Synthetic route for antimicrobial PVA-MBA-Cl film (a) and its schematic diagram of the preparation and sterilization (b)
Experimental section
Materials and instruments
Methylene-bis-acrylamide (MBA) and polyvinyl alcohol (PVA, the average molar mass is 7.5 × 104 g/mole) were purchased from Macleans Shanghai Reagent Co., Ltd. Sodium hypochlorite, sulfuric acid, sodium carbonate, and potassium iodide were bought from Sinopharm Chemical Reagent Co., Ltd. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
Hitachi S4800 scanning electron microscope was used to obtain field emission scanning electron microscope (FE-SEM) images. X-ray photoelectron spectroscopy (XPS) spectra were obtained by using PerkinElmer PHI 5000 ESCT System. Dmax-2000 x-ray diffraction was used to obtain x-ray diffraction (XRD) spectra. Thermo Scientific NicoletiN10 infrared spectrometer was adopted to obtain Fourier-transform infrared spectroscopy (FT-IR) spectra. JC2000D2 contact angle measuring instrument bought from Shanghai Zhongchen Digital Technology Co., Ltd. was used to characterize by the contact angle.
Preparation of PVA-MBA film
PVA (4.40 g) was dissolved in 80 mL of distilled water and stirred. The temperature was gradually risen to 90 °C and was kept at 90 °C for about 30 min to ensure that PVA was dissolved completely. MBA (0.088 g) and K2CO3 (0.300 g) were dissolved in 20 mL of distilled water and stirred. After the MBA and K2CO3 solution was added into PVA solution. The reaction mixture solution was stirred for 6 h at 90 °C to form a PVA-MBA aqueous solution. PVA-MBA aqueous solution was spread on a glass dish and air-dried to form a PVA-MBA film.
Preparation of PVA-MBA-Cl film
20 mL of 5.0% sodium hypochlorite solution was added into 100 mL distilled water at room temperature. The pH of the solution was adjusted to about 7 via slowly adding sulfuric acid solution. Then, the diluted sodium hypochlorite solution was sprayed onto the surface of PVA-MBA film. After 2 h, the film was washed with distilled water to ensure no free sodium hypochlorite on the surface of the film.
Determination of oxidative chlorine content of PVA-MBA-Cl film
Iodometric method was used to determine the oxidative chlorine content of PVA-MBA-Cl film. The specific process was as follows: about 1 cm × 1 cm of PVA-MBA-Cl film was added into 45 mL of 0.1 N H2SO4 solution, and then about 0.15 g potassium iodide was added to the above solution. The above solution was titrated with 0.0100 N sodium thiosulfate standard solution until the color of the titrated solution became light yellow. After 0.30 mL of 1% starch aqueous solution was added, the solution was continued to be titrated with sodium thiosulfate standard solution to reach the end of titration when the titrated solution became colorless. The oxidative chlorine content of PVA-MBA-Cl film can be calculated by the following formula:Cl+atoms/cm2=N×V×6.02×10232×S
where Cl+ (atoms/cm2) is the oxidation state chlorine content on the surface of the film, N is the molar concentration of the sodium thiosulfate standard solution, V is the volume (L) of the sodium thiosulfate standard solution consumed, S is the surface area of PVA-MBA-Cl film (cm2).
Tensile strength [33, 34] and elongation at break of PVA-MBA-Cl film
Take PVA, PVA-MBA, PVA-MBA-Cl films and cut them into the intact 10 cm × 1 cm films. Make 3 samples of each film and fix the film on the texture analyzer. The film was made up to a distance of 3 cm, the stretching speed was 2 cm/min, and the test results were averaged. The thickness of the PVA-MBA-Cl film was measured with a micrometer, and 10 points were taken at different places of the film, and the average value was taken as the thickness of the film. Regarding the tensile strength δ, the formula is as follows:δ=Fbd
where δ is the tensile strength (MPa) of the film, F is the maximum force (N) during the entire stretching process, b is the width (mm) of the film, and d is the thickness (mm) of the film.
Contact angle test
The hydrophilicity change of the film was determined by measuring the contact angle of the film. The specific steps are as follows:
The ultrapure water droplets were tested on the surface of the film for 5 s. The test temperature was room temperature and the volume was fixed by the device needle. Each sample was measured in turn and the test was averaged three times.
Solubility test
The PVA film, PVA-MBA film, and PVA-MBA-Cl film were cut into a size of 1 cm × 1 cm and dried for 12 h in a vacuum oven at 45 ℃.The PVA film, PVA-MBA film, and PVA-MBA-Cl film were respectively placed in a desiccator and cooled to room temperature and weighed as an initial mass of m0.The PVA film, PVA-MBA film, and PVA-MBA-Cl film were completely immersed in a beaker containing 45 mL of deionized water for 24 h before being taken out. The water on the surface of the film was wiped dry and dried for 12 h in a vacuum oven at 45 °C. Weigh the film, the mass after dissolution (m1), the dissolution rate is calculated as follows:D=m0-m1m0×100%
where D is the solubility (%), m0 (g) is the initial mass, m1 (g) is the mass after dissolution.
Water absorption test
The PVA film, PVA-MBA film, and PVA-MBA-Cl film were cut into a size of 1 cm × 1 cm and then dried in a vacuum oven at 45 ℃ for 12 h. The film was taken out and placed in a desiccator to cool to room temperature. The mass of the film was weighed and recorded as the initial mass m0. The film was placed flat into a small amount of deionized water in a watch glass and sealed with plastic wrap for 24 h. Take out the sample and weigh it as the final film mass m1. The water absorption formula is as follows:C=m1-m0m0×100%
where C is the water absorption (%), m0 (g) is the initial mass, and m1 (g) is the mass after water absorption.
Storage stability test of N-halamine functional groups in PVA-MBA-Cl film
The stability of the N-halamine functional groups in PVA-MBA-Cl film was determined by measuring the change of the oxidized chlorine content in PVA-MBA-Cl film during the storage. The film was stored at room temperature in a dark condition, and one portion was taken every seven days for measurement of the Cl+ content. Specific steps are as follows: the as-prepared PVA-MBA-Cl film was cut into a size of 1 cm × 1 cm. The Cl+ content of the film was determined for three times after each week to explore the change tendency of the Cl+ content of PVA-MBA-Cl film during storage.
Antibacterial performance test of PVA-MBA-Cl film [35]
In this paper, Gram-positive bacterium S. aureus and Gram-negative bacterium E. coli were selected to measure the antibacterial efficacy of the PVA-MBA-Cl film. The process is as follows: Firstly, 25 μL of the buffered bacterial solution (pH was about 7) was added onto the surface of the film with a size of 2 cm × 2 cm and then the other film with the same size was covered on it. Above these two films, a sterile weight was pressed onto them. After contact time of 1 min, 5 min, 10 min, and 30 min, the square films were transferred into 10.0 mL of 0.02 N sterile sodium thiosulfate solution in a sterile centrifuge tube to remove oxidative chlorines, and vortexed for 2 min. Secondly, after vortexed, the above solution was serially diluted with sterile phosphate buffer solution (pH was about 7). Finally, 100 μL of the diluted solution was taken in a solid medium, and the number of colonies on the plate medium was counted after incubation at 37 °C for 24 h.
Results and discussion
Preparation of PVA-MBA-Cl film
Synthesis of antibacterial films for packaging applications is significant fields of research [36]. In this paper, we developed a simple and green process to prepare a very high-efficacy antimicrobial film, an acyclic N-halamine-modified PVA (PVA-MBA-Cl) film. Firstly, an aqueous solution of N-halamine precursor-grafted PVA (PVA-MBA solution) was prepared via the oxa-Michael addition reaction between the active hydroxyl groups on PVA and α,β-unsaturated functional groups of MBA under the catalysis of sodium carbonate in an aqueous solution. Secondly, PVA-MBA film was formed by spreading a certain amount of PVA-MBA solution on a glass dish and drying it. Finally, after spraying the diluted sodium hypochlorite solution on the surface of PVA-MBA film, PVA-MBA-Cl film was formed. Higher oxidative chlorine content on the surface of the film means more N-halamine functional groups on the film surface and stronger antimicrobial efficacy. It is our desire to obtain a PVA-MBA-Cl film with higher oxidative chlorine content to ensure stronger and lasting antibacterial efficacy without affecting other important properties of the film such as the transparency and tensile strength. For this purpose, we studied the effects of mass ratio of MBA and PVA (mMBA/mPVA), mass of catalyst, reaction time, reaction temperature, and chlorination time on the oxidative chlorine content on the surface of the as-prepared PVA-MBA-Cl film.
Figure 2 showed the effects of mMBA/mPVA, mass of catalyst, reaction temperature reaction time, and chlorination time on the oxidative chlorine content on the surface of the as-prepared PVA-MBA-Cl film. As seen in Fig. 2a, it was found that the oxidative chlorine content increased from 1.46 × 1019 to 6.86 × 1019 atoms/cm2 with an increase of mMBA/mPVA from 1:200 to 12:200 in the aqueous solution. The increase in the oxidative chlorine content is attributed to more MBA grafted onto PVA with the increase of mMBA/mPVA. However, while mMBA/mPVA was 6:200, some white substance could be seen in the film, which affected the transparency of the film. Therefore, 4:200 should be an appropriate mMBA/mPVA for the preparation of PVA-MBA-Cl film. As shown in Fig. 2b, as the mass of catalyst increased from 0 to 0.30 g, the oxidative chlorine content increased from 1.56 × 1019 to 3.83 × 1019 atoms/cm2. This is because the addition of K2CO3 can speed up the oxa-Michael addition reaction, which makes more MBA grafted on the PVA. However, when the mass of K2CO3 was more than 0.30 g, the increase in catalyst mass resulted in the decrease in the oxidative chlorine content. This is mainly because that much more K2CO3 in the aqueous solution may accelerate the amide hydrolysis of MBA. Therefore, 0.30 g should be an appropriate mass of catalyst for the preparation of PVA-MBA-Cl film. As shown in Fig. 2c, the oxidative chlorine content increased from 0.34 × 1019 to 3.81 × 1019 atoms/cm2 with the increase in reaction temperature from 60 °C to 90 °C. When the reaction was at 100 °C, the oxidative chlorine content decreased, compared to that at 90 °C. Therefore, 90 °C should be an appropriate reaction temperature for the preparation of PVA-MBA-Cl film. As shown in Fig. 2d, the oxidative chlorine content increased from 1.10 × 1019 to 3.81 × 1019 atoms/cm2 with the increase in reaction time from 1 to 6 h. After 6 h, continuous increasing the reaction time from 6 to 8 h, the oxidative chlorine content remained almost unchanged. Therefore, 6 h should be an appropriate reaction time for the preparation of PVA-MBA-Cl film. As shown in Fig. 2e, the oxidative chlorine content increased from 1.10 × 1019 to 3.81 × 1019 atoms/cm2 with the increase in chlorination time from 0.5 h to 2 h. After 2 h, continuously increasing the chlorination time from 2 to 5 h, the oxidative chlorine content didn’t change a lot. Therefore, 2 h should be an appropriate chlorination time for the preparation of PVA-MBA-Cl film. Fig. 2 Effects of mMBA/mPVA (a), mass of catalyst, reaction temperature (c), reaction time (d), and chlorination time (e) on the oxidative chlorine content (atoms/cm2) of the as-prepared PVA-MBA-Cl film [mMBA/mPVA = 4:200 (b–e); mass of catalyst = 0.30 g (a, c– e); reaction temperature: 90 ℃ (a, b, d, e); reaction time: 6 h (a–c, e); chlorination time: 2 h (a–d)]
Characterization of PVA-MBA-Cl film
FE-SEM
The morphology of film surfaces was inspected by FE-SEM. Figure 3 showed FE-SEM images of the surface of PVA(a), PVA-MBA(b) and PVA-MBA-Cl(c), the section of PVA(d), PVA-MBA(e) and PVA-MBA-Cl(f) films. It is obvious that the surface of the films are all flat. In general, the grafting and chlorination did not rupture and damage the surface of the film. However, the sectional structures of PVA-MBA film and PVA-MBA-Cl film are more complicated than that of PVA film. The possible reason is that the grafting reaction caused the molecular cross-linking in the modified film.Fig. 3 FE-SEM images of the surface of PVA (a), PVA-MBA (b) and PVA-MBA-Cl (c), the section of PVA (d), PVA-MBA (e) and PVA-MBA-Cl (f) films
FT-IR and XPS spectra
The FT-IR spectra of PVA and PVA-MBA-Cl films are shown in Fig. 4a. It could be seen that the strong –OH stretching vibration absorption peaks appear close to 3330 cm−1 for two spectral lines, declaring that the functional group –OH does exist in two films. The peak area of PVA-MBA-Cl film is significantly smaller, compared with that of PVA film, indicating that the part of the –OH on the PVA molecular chain reacts with the MBA, thereby reducing the amount of –OH on the PVA-MBA-Cl molecular chain [37]. The peak at 2924 cm−1 is ascribed to the C-H stretching vibration in the polyvinyl alcohol unit for both two samples. Compared with PVA, PVA-MBA-Cl film exhibits a new peak at 2849 cm−1, which corresponds to the symmetrical stretching vibration of the C–H on CH2–CH2–. Because the double bond on the MBA molecule is opened to become a continuous CH2–CH2– functional group while PVA react with MBA. PVA-MBA-Cl film has a new peak at 826 cm−1, which corresponds to the stretching vibration of the N–Cl bond. This is caused by the conversion of N–H bonds on the amide groups of MBA into N-Cl ones after chlorination [38], indicating that MBA molecules have been successfully grafted onto PVA and the amide groups of MBA have been chlorinated. The XPS spectra of PVA-MBA and PVA-MBA-Cl films are shown in Fig. 4b. As seen in Fig. 4b, compared to PVA film, PVA-MBA-Cl film has a new Cl 2p peak at 200 eV [39, 40], indicating that the chlorination reaction has been successfully carried out.Fig. 4 FT-IR (a) and XPS (b) spectra of PVA and PVA-MBA-Cl films
Performance evaluation
Water absorption, solubility, tensile strength, and elongation at break
Figure 5a showed the water absorption and the solubility of PVA, PVA-MBA, and PVA-MBA-Cl films. It is obvious that PVA-MBA film has lower water absorption and solubility than PVA film, which is due to the nucleophilic reaction between the –OH in PVA and MBA under the action of a base to reduce the hydrophilic groups in the molecules. Compared to PVA-MBA film, PVA-MBA-Cl film exhibits higher water absorption and solubility due to the destruction of the intermolecular action [36]. The tensile strengths and elongations at break of PVA, PVA-MBA, and PVA-MBA-Cl films are shown in Fig. 5b. Compared to PVA film, PVA-MBA film exhibits much higher tensile strength and elongation at break. The improvement in tensile strength and elongation at break is ascribed to the cross-linking reaction between PVA and MBA. Very interestingly, PVA-MBA-Cl film has lower tensile strength, but much higher elongation than PVA film. The decrease in tensile strength is due to the depolymerization of the PVA molecules. The increase in elongation is ascribed to crystallinity decrease in PVA molecular chain due to the oxidative NaClO [41].Fig. 5 Water absorption, solubility, tensile strength, and elongation at break of PVA, PVA-MBA and PVA-MBA-Cl films
Contact angle
Figure 6 showed the contact angles of PVA and PVA-MBA-Cl films and the data of the contact angles are summarized in Table 1. Compared to PVA film, PVA-MBA-Cl film exhibits much larger contact angle. The improvement in contact angle is ascribed to the cross-linking reaction between PVA and MBA. MBA consumes the part of polar –OH groups on the PVA molecular chain. Therefore, the hydrophilicity of the film is weakened, resulting in a larger contact angle. It is very interesting that the grafted MBA improves the hydrophobicity of the modified PVA film and solves the problem that the PVA film is too hydrophilic and easily soluble.Fig. 6 Contact angles (a) of PVA and PVA-MBA-Cl (b) films
Table 1 Contact angles of PVA and PVA-MBA-Cl films
Sample PVA film PVA-MBA-Cl film
Contact angle/° 37 49
Storage stability of N-halamine functional groups in PVA-MBA-Cl film
Figure 7 showed the storage stability of the antibacterial N-halamine functional groups in PVA-MBA-Cl film. It was found that the oxidative chlorine content of PVA-MBA-Cl film decreased by 14.3% after stored for 9 weeks. It means that the antibacterial N-halamine functional groups in PVA-MBA-Cl film have excellent storage stability under room temperature. Therefore, the as-prepared PVA-MBA-Cl film has long-lasting antibacterial effect.Fig. 7 The storage stability of the antibacterial N-halamine functional groups in the PVA-MBA-Cl film
Antibacterial performance
S. aureus and E. coli were adopted for the antibacterial efficacy test of PVA, PVA-MBA, and PVA-MBA-Cl films. The results are summarized in Table 2. It was found that PVA-MBA-Cl film exhibited very strong antibacterial efficiencies against both S. aureus and E. coli. PVA-MBA-Cl film with an oxidative chlorine content of 3.82 × 1019 atoms/cm2 could completely inactivate 1.28 × 106 CFU/mL S.aureus and 1.89 × 106 CFU/mL E. coli within a contact time of 5 min. By comparison, the unchlorinated PVA and PVA-MBA films had low reduction of bacteria. They respectively provided 9.71% and 16.45% reductions of S. aureus and 12.69% and 20.21% reductions of E. coli within a contact time of 30 min. In comparison with some N-halamine coatings reported from Worley's group, the as-prepared PVA-MBA-Cl film shows stronger antimicrobial efficacies [42, 43].Table 2 Antibacterial efficiencies of PVA, PVA-MBA, and PVA-MBA-Cl films against bacteria S. aureus and E. coli
Sample Contact time (min) Antibacterial rate (%)
PVA S. aureusa reduction (%) E. colib reduction (%)
PVA-MBA 30 9.71 12.69
30 16.45 20.21
1 99.99 99.99
PVA-MBA-Cl 5 100 100
10 100 100
30 100 100
aInoculum population: 1.28 × 106 CFU/mL
bInoculum population: 1.89 × 106 CFU/mL
Conclusion
In summary, an environmentally friendly method was developed to prepare a high-efficacy antibacterial acyclic N-halamine-grafted PVA (PVA-MBA-Cl) film. The whole process only used water as the solvent. Definitely, the as-prepared PVA-MBA-Cl film exhibited very strong antibacterial efficacies and excellent storage stability of antimicrobial N-halamine moieties. Very interestingly, the as-prepared PVA-MBA-Cl film also showed lower water absorption and solubility, higher tensile strength and elongation at break than PVA film. With all above-mentioned advantages, it is very clear that the antimicrobial PVA-MBA-Cl film will have potential applications in food packaging. Moreover, the successful development of a practical process to prepare an antibacterial N-halamine precursor solution provides more possibilities for the development of useful antibacterial coating materials for various applications such as bactericidal paintings and long-lasting disinfection of hard surface in future.
Acknowledgements
The authors acknowledge the financial support from Shanghai Pujiang Talent Project (11PJ1407600) for this work. They also acknowledge experimental support from the Program of Shanghai Normal University (DZL124) PCSIRT (RT1269).
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References
1. Parihar A Sonia ZF Akter F Phytochemicals-based targeting RdRp and main protease of SARS-CoV-2 using docking and steered molecular dynamic simulation: a promising therapeutic approach for tackling COVID-19 Comput Biol Med 2022 154 105468 10.1016/j.compbiomed.2022.105468
2. Ji J Zhang W Bacterial behaviors on polymer surfaces with organic and inorganic antimicrobial compounds J Biomed Mater Res Part A 2009 88 2 448 453 10.1002/jbm.a.31759
3. Shen M Liao X Xianyu Y Polydimethylsiloxane membranes incorporating metal–organic frameworks for the sustained release of antibacterial agents[J] ACS Appl Mater Interfaces 2022 14 10 12662 12673 10.1021/acsami.1c24921 35239326
4. Taghipour T Karimipour G Ghaedi M Mild synthesis of a Zn (II) metal organic polymer and its hybrid with activated carbon: application as antibacterial agent and in water treatment by using sonochemistry: optimization, kinetic and isotherm study[J] Ultrason Sonochem 2018 41 389 396 10.1016/j.ultsonch.2017.09.056 29137766
5. Sun Y Sun G Synthesis, characterization, and antibacterial activities of novel N-halamine polymer beads prepared by suspension copolymerization Macromolecules 2002 35 23 8909 8912 10.1021/ma020691e
6. Dong A Sun Y Lan S Barbituric acid-based magnetic N-halamine nanoparticles as recyclable antibacterial agents ACS Appl Mater Interfaces 2013 5 16 8125 8133 10.1021/am402191j 23915243
7. Gould GW Industry perspectives on the use of natural antimicrobials and inhibitors for food applications J Food Prot 1996 59 13 82 10.4315/0362-028X-59.13.82
8. Tiwari Brijesh K Valdramidis Vasilis P O’Donnell Colm P Kasiviswanathan M Paula B Cullen PJ Application of natural antimicrobials for food preservation J Agric Food Chem 2009 57 14 5987 10.1021/jf900668n 19548681
9. Hernández-Sierra JF Ruiz F Pena DCC The antimicrobial sensitivity of Streptococcus mutans to nanoparticles of silver, zinc oxide, and gold Nanomed Nanotechnol Biol Med 2008 4 3 237 240 10.1016/j.nano.2008.04.005
10. Nan G Yingjie C Jiang J Ag@Fe2O3-GO nanocomposites prepared by a phase transfer method with long-term antibacterial property ACS Appl Mater Interfaces 2013 5 21 11307 10.1021/am403538j 24138679
11. Chen Y Chen Q Wang Z Bactericidal silicone with one quaternary ammonium salt and two N-halamine sites in the repeating unit for improved biocidability on magnetic submicrospheres J Mater Sci 2022 57 1 15
12. Natan M Gutman O Lavi R Killing mechanism of stable N-halamine cross-linked polymethacrylamide nanoparticles that selectively target bacteria ACS Nano 2015 9 2 1175 1188 10.1021/nn507168x 25602279
13. Xu J Wang Z Yu L A novel reverse osmosis membrane with regenerable anti-biofouling and chlorine resistant properties J Membr Sci 2013 435 80 91 10.1016/j.memsci.2013.02.010
14. Cloutier M Mantovani D Rosei F Antibacterial coatings: challenges, perspectives, and opportunities Trends Biotechnol 2015 33 11 637 652 10.1016/j.tibtech.2015.09.002 26463723
15. Zhou B Li Y Deng H Antibacterial multilayer films fabricated by layer-by-layer immobilizing lysozyme and gold nanoparticles on nanofibers Colloids Surf B 2014 116 432 438 10.1016/j.colsurfb.2014.01.016
16. Imazato S Ehara A Torii M Antibacterial activity of dentine primer containing MDPB after curing J Dent 1998 26 3 267 271 10.1016/S0300-5712(97)00013-4 9594480
17. Wang Q Fan X Hu Y Antibacterial functionalization of wool fabric via immobilizing lysozymes Bioprocess Biosyst Eng 2009 32 5 633 639 10.1007/s00449-008-0286-5 19082843
18. Huh MW Kang IK Lee DH Surface characterization and antibacterial activity of chitosan-grafted poly (ethylene terephthalate) prepared by plasma glow discharge J Appl Polym Sci 2001 81 11 2769 2778 10.1002/app.1723
19. Chen X Liu Z Cao W Preparation, characterization, and antibacterial activities of quaternarized N-halamine-grafted cellulose fibers J Appl Polym Sci 2015 10.1002/app.42702
20. Ma K Liu Y Xie Z Synthesis of novel N-halamine epoxide based on cyanuric acid and its application for antimicrobial finishing Ind Eng Chem Res 2013 52 22 7413 7418 10.1021/ie400122h
21. Bastarrachea LJ Goddard JM Antimicrobial coatings with dual cationic and N-halamine character: characterization and biocidal efficacy J Agric Food Chem 2015 63 16 4243 4251 10.1021/acs.jafc.5b00445 25871333
22. Liu S Sun G Durable and regenerable biocidal polymers: acyclic N-halamine cotton cellulose Ind Eng Chem Res 2006 45 19 6477 6482 10.1021/ie060253m
23. Luo J Porteous N Lin J Acyclic N-halamine-immobilized polyurethane: preparation and antimicrobial and biofilm-controlling functions J Bioact Compat Polym 2015 30 2 157 166 10.1177/0883911515569007 26089593
24. Dong A Zhang Q Wang T Immobilization of cyclic N-halamine on polystyrene-functionalized silica nanoparticles: synthesis, characterization, and biocidal activity J Phys Chem C 2010 114 41 17298 17303 10.1021/jp104083h
25. Thome J Holländer A Jaeger W Ultrathin antibacterial polyammonium coatings on polymer surfaces Surf Coat Technol 2003 174 584 587 10.1016/S0257-8972(03)00703-5
26. Wang R Xue H Leng J Preparation and antibacterial properties of hemp cellulose-based material based on Schiff base between lysine grafted N-halamine and dialdehyde hemp[J] Ind Crops Prod 2022 176 114388 10.1016/j.indcrop.2021.114388
27. Wang F Si Y Yu J Tailoring nanonets-engineered superflexible nanofibrous aerogels with hierarchical cage-like architecture enables renewable antimicrobial air filtration Adv Func Mater 2021 31 49 2107223 10.1002/adfm.202107223
28. Jiang L Jia Z Xu X Preparation of antimicrobial poly (ethylene-co-vinyl alcohol) membrane by grafting with N-halamine React Funct Polym 2022 172 105187 10.1016/j.reactfunctpolym.2022.105187
29. Islamipour Z Zare EN Salimi F Biodegradable antibacterial and antioxidant nanocomposite films based on dextrin for bioactive food packaging J Nanostruct Chem 2022 12 991 10.1007/s40097-022-00491-4
30. Aksakal B Denktaş C Bozdoğan A Influence of ultraviolet radiation on structural and uniaxial tensile characteristics of tannic acid/poly (vinyl alcohol) composite films J Appl Polym Sci 2022 139 52350 10.1002/app.52350
31. Fathi M Rostami H Youseftabar Miri N Development of an intelligent packaging by incorporating curcumin into pistachio green hull pectin/poly vinyl alcohol (PVA) films J Food Meas Charact 2022 16 1 10 10.1007/s11694-022-01318-0
32. Li R Sheng J Cheng X Biocidal poly (vinyl alcohol) films incorporated with N-halamine siloxane Compos Commun 2018 10 89 92 10.1016/j.coco.2018.07.005
33. Zhou J Zhang L Shu H Chen F Regenerated cellulose films from NaOH/urea aqueous solution by coagulating with sulfuric acid J Macromol Sci Part B 2002 41 1 15 10.1081/MB-120002342
34. Davoodi M Kavoosi G Shakeri R Preparation and characterization of potato starch-thymol dispersion and film as potential antioxidant and antibacterial materials Int J Biol Macromol 2017 104 Pt A 173 179 10.1016/j.ijbiomac.2017.05.145 28579465
35. Tian H Zhai Y Xu C Durable antibacterial cotton fabrics containing stable acyclic N-halamine groups Ind Eng Chem Res 2017 56 28 7902 7909 10.1021/acs.iecr.7b00863
36. Ali HE Elbarbary AM Abdel-Ghaffar AM Preparation and characterization of polyvinyl alcohol/polylactic acid/titanium dioxide nanocomposite films enhanced by γ-irradiation and its antibacterial activity J Appl Polym Sci 2022 24 52344 10.1002/app.52344
37. Mittal H Kaith BS Jindal R Mishra SB Mishra AK A comparative study on the effect of different reaction conditions on graft co-polymerization, swelling, and thermal properties of Gum ghatti-based hydrogels Therm Anal Calorim 2015 119 1 131 144 10.1007/s10973-014-4140-5
38. Li J Liu Y Jiang Z Ma K Ren X Huang T-S Antimicrobial cellulose modified with nanotitania and cyclic N-halamine Ind Eng Chem Res 2014 53 33 13058 13064 10.1021/ie502479h
39. Nawaz MA Gaiani C Fukai S Bhandari B X-ray photoelectron spectroscopic analysis of rice kernels and flours: measurement of surface chemical composition Food Chem 2016 212 349 357 10.1016/j.foodchem.2016.05.188 27374542
40. Demir B Broughton RM Huang TS Bozack MJ Worley SD Polymeric antimicrobial N-halamine-surface modification of stainless steel Ind Eng Chem Res 2017 56 41 11773 11781 10.1021/acs.iecr.7b02412
41. Tang X Xu H Shi Y Porous antimicrobial starch particles containing N-halamine functional groups Carbohyd Polym 2020 229 115546 10.1016/j.carbpol.2019.115546
42. Idris C Kocer Hasan B Worley SD Broughton RM Huang TS N-halamine biocidal coatings via a layer-by-layer assembly technique Langmuir 2011 27 7 4091 10.1021/la104923x 21348478
43. Kocer Hasan B Akin A Worley SD Orlando A Broughton RM Yonnie W Mechanism of photolytic decomposition of N-halamine antimicrobial siloxane coatings ACS Appl Mater Interfaces 2010 2 8 2456 10.1021/am100511x 20669910
| 0 | PMC9734778 | NO-CC CODE | 2022-12-14 23:28:30 | no | Polym Bull (Berl). 2022 Dec 6;:1-15 | utf-8 | Polym Bull (Berl) | 2,022 | 10.1007/s00289-022-04614-3 | oa_other |
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Appl Intell (Dordr)
Appl Intell (Dordr)
Applied Intelligence (Dordrecht, Netherlands)
0924-669X
1573-7497
Springer US New York
4294
10.1007/s10489-022-04294-6
Article
Effective machine learning, Meta-heuristic algorithms and multi-criteria decision making to minimizing human resource turnover
https://orcid.org/0000-0002-6294-9487
Pourkhodabakhsh Nima [email protected]
1Nima Pourkhodabakhsh
is PhD candidate in Organizational Behavior and human resources management. He is a management consultant at ILIA Corporation and has served more than 100 clients as a senior engagement manager and team leader. His research is focused on teaming and psychological safety in organizations.
https://orcid.org/0000-0002-7651-5735
Mamoudan Mobina Mousapour [email protected]
2Mobina Mousapour Mamoudan
is a researcher and master’s student at the University of Tehran in the field of Industrial and Systems Engineering, majoring in socio-economic macroeconomic systems. Her research is focused on the use of artificial intelligence and data science in management systems and system performance improvement.
http://orcid.org/0000-0002-1180-9572
Bozorgi-Amiri Ali [email protected]
2Ali Bozorgi-Amiri
is an Associate Professor of Industrial Engineering at the School of Industrial Engineering and Head of Business Process Rng. And Resource Manag. Research Center (BPERM) at the University of Tehran. He received his Ph.D.in Industrial Engineering from Iran University of Science and Technology, Iran. He has impactful researches in the fields of Data-Driven Decision Making, Business Process Redesign, Operations Management, Supply Chain Resilience and Humanitarian logistics. He has published several papers in related filed in refereed journals and conferences.
1 grid.472338.9 0000 0004 0494 3030 School of Advanced Sciences and Technology, College of Management, Islamic Azad University of Medical Sciences, Tehran, Iran
2 grid.46072.37 0000 0004 0612 7950 School of Industrial Engineering, College of Engineering, University of Tehran, Tehran, Iran
5 12 2022
123
24 10 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Employee turnover is one of the most important issues in human resource management, which is a combination of soft and hard skills. This makes it difficult for managers to make decisions. In order to make better decisions, this article has been devoted to identifying factors affecting employee turnover using feature selection approaches such as Recursive Feature Elimination algorithm and Mutual Information and Meta-heuristic algorithms such as Gray Wolf Optimizer and Genetic Algorithm. The use of Multi-Criteria Decision-Making techniques is one of the other approaches used to identify the factors affecting the employee turnover in this article. Our expert has used the Best-Worst Method to evaluate each of these variables. In order to check the performance of each of the above methods and to identify the most significant factors on employee turnover, the results are used in some machine learning algorithms to check their accuracy in predicting the employee turnover. These three methods have been implemented on the human resources dataset of a company and the results show that the factors identified by the Mutual Information algorithm can show better results in predicting the employee turnover. Also, the results confirm that managers need a support tool to make decisions because the possibility of making mistakes in their decisions is high. This approach can be used as a decision support tool by managers and help managers and organizations to have a correct insight into the departure of their employees and adopt policies to retain and optimize their employees.
Keywords
Human resource management
Employee turnover
Meta-heuristic algorithms
Multi-criteria decision making
Machine learning
Data mining
==== Body
pmcIntroduction
Human resources in any organization constitute the most complex social system for management that can develop itself. They are also a combination of decision-making and planning. That is why the decision to allocate humans, hiring, turnover, labor analysis, talent analysis, rewards, and human resource optimization is recognized as one of the challenging issues for managers in organizations to achieve the desired performance. Human resource management is a complex process that includes subjective and unpredictable factors and measurements [33]. Managing this complex process not only can increase employee efficiency but also can control the organization’s costs, which would increase the productivity of the organization as well.
On the other hand, human resources are considered as a source for creating values and strategic policies of the organization, and the long-term success and competitive advantage of organizations will depend on their human resources. In fact, the human resources of any organization are very significant and valuable talents that are very difficult to replace, especially for organizations that need knowledge workers. This concept shows that maintaining and developing qualify employees in organizations is very important, and organizations are obliged to maintain their human resources because hiring, training and then socializing people are costly and time-consuming. The experience and skills that employees gain in any organization are fundamental and hidden investments for the organization. In other words, it can be said that scarce, valuable and inimitable resources such as human resources are considered a kind of capital loss.
The employee turnover is often the result poor hiring decisions, and poor management and directly affects the organization’s strategic plans. In other words, poor management and managerial performance gaps in decision making can increase the employee turnover rate [9]. According to Zhu et al. [38], many companies had to adjust, improve and upgrade their management systems to reduce their turnover rate and private companies and governments spend billions of dollars annually to manage this problem. It can be said that maintaining and optimizing expensive and scarce resources such as human recourses is one of the most important concerns of managers, which requires more advantage and more innovative tools to improve decisions. This is the reason why identifying the factors affecting employee turnover is a very valuable measure that can lead to corrective measures to prevent employee turnover and helps managers to making better decision.
Therefore, in order to solve this research gap and improve the performance of manager’s decisions, there is a need for more advanced approaches to find out which features has more significant effect on employee turnover, how can employee turnover be prevented and how well can managers identify the factors influencing the employee turnover? In order to solve this research gap and increase the performance of organizations, this study uses the IBM Dataset, which were obtained from the Keggel, in three different approaches to identify the most effective factors on employee turnover using each of the methods. Also, by predicting the employee turnover and use the results of each approach in machine learning algorithms, the performance of these approach has been compared. These three approaches are Feature Selection algorithms in machine learning, Meta-heuristic algorithms and Multi-Criteria Decision-Making techniques.
With increasing progress of science and technology and the use of artificial intelligence in data analysis, it is possible to play a significant role in solving the problems of managers and increasing profitability for organizations. It can be said that the best companies compete by analyzing the people, abilities, and talents of their employees and trying to maximize the performance, participation, and retention of top talent [16]. One of the practical techniques to find useful information from a large amount of data is the data mining approach that has a wide range of real-world applications can be done by machine learning [15]. One of the most significant parts before designing machine learning models is Feature Selection, which is very important for producing an optimal model.
Feature Selection means to selecting the most influential variables in a Dataset on the target variable. This process will be very effective before creating predictive models using machine learning algorithms because all the machine learning algorithms use input data to generate output results. This input data contains a series of features whose structure usually appears in the form of columns and affects the target variable. Other approaches that can be used to find the optimal features are Meta-heuristics algorithms. Many of the optimizing features that are selected for machine learning models in the real world are large in size and complexity, and it will be very time-consuming to reach a definitive optimal solution for them. Meta-heuristic algorithms make the search space smaller. Although in this method, there is no guarantee to find a definitive solution, but these algorithms can approach the optimal solution with an acceptable percentage.
Human resource management is always influenced by the decisions of managers, whose poor decisions can bring a lot of costs to the organization and increase the employee turnover. For this purpose, in this study, in addition to using feature selection approaches in machine learning and Meta-heuristic algorithms, we also used the opinions of managers (decision-makers) regarding the identification of effective factors in the employee turnover by using Best-Worst Method (BWM), which is one of the Multi-Criteria Decision-Making (MCDM) techniques. In general, Multi-Criteria Decision-Making techniques are very popular tools among managers, which can choose the best options. Decision-makers can use these mathematical tools to evaluate and rank potential options in complex situations [4]. Determining decision criteria, selecting the worst and best criteria, prioritizing all criteria, comparing the criteria with the best and worst criteria, and calculating the optimal weight of each criterion by solving the mathematical planning model are the steps of this approach.
This study presents a new combined approach to identify the factors affecting employee turnover using feature selection algorithms in machine learning, Meta-heuristic algorithms and Multi-Criteria Decision-Making techniques. By doing this work, we want to compare the results of these approaches with each other and find the most identification factors for employee turnover. Also, the results of these methods have been used is some machine learning algorithms such as Logistic regression, Decision Tree, Random Forest, Super Vector Machine, Gradient Boosting, and Adaptive Boosting to predict the employee turnover.
With all of these interpretations, human resources analysis must be done in a way that facilitates complex modeling and experiments to understand cause and effect. The results of these analyzes should be such that managers can use them to make decisions. Accordingly, identifying the most influential factors on employee turnover can help predict the future employee turnover rate of the organization and lead to the development of more accurate models. Using feature selection, Meta-heuristic algorithms and Multi-Criteria Decision-Making techniques, which are very practical tools for managers, this article seeks to identify the factors influencing the employee turnover. Also, in order to check the performance of the proposed models, some machine learning algorithms have been used to predict the turnover rate of human resources in order to compare the accuracy of the features selected from the above methods using these algorithms. Identifying the factors affecting employee turnover can be used as a decision support tool to help managers to make the best decision for the strategic planning of employees and take the necessary corrective measures to reduce the turnover rate of their employees, which leads to increased productivity of organizations.
In general, this article is arranged as follows; In Section 2, we will review the literature on this topic. Our literature review consists of two sections: literature on the Data Mining Approach in Human Resource Problems, and literature on Multi-Criteria Decision-Making Techniques and Human Resource Problems. In Section 3, the problem Description and Data Description were presented. In Section 4, the methodology is presented. Section 5 is dedicated to Performance Evaluation. Section 6 presents the results and Section 7 compares the discussion. Finally, Section 8 is devoted to the conclusion.
Literature review
In this part, we will review the literature related to the use of data mining approach and the Multi-Criteria Decision-Making techniques in human resource management issues.
Data mining approach in human resource problems
Over the years, human resource management has undergone significant changes, and issues such as the use of data mining [10], artificial intelligence [19] become very popular. Certainly, the desire to improve human resource management in recent years will continue to be more widespread in the future and the use of data analysis in human resource management will be very popular. Esmaieeli Sikaroudi, RouzbehGhousi, and Sikaroudi [6] identified the factors affecting employee turnover to predict the unstable employee in order to use the results to reduce the obvious and hidden costs of the organization. Also, by analyzing the organization’s historical data, they found that the recruitment strategy should be improved. In the same years, Other researchers used linear and multivariate regression to analyze data such as organizational financial performance, employee turnover rate, employee age, organizational performance, and employee participation rate [22]. By doing this job, they sought to examine the impact of employee turnover rates on organizational performance.
Zhu et al. [38] used time-series data to predict the employee turnover rate to increasing the ability of predicting employee turnover without considering the impact of economic indicators. Y. Zhao, Hryniewicki, Cheng, Fu, and Zhu [35] predicted and evaluated employee turnover by using human resource data sets on some machine learning algorithms such as Decision Tree, Random Forest, Gradient Boosting. In 2019, other researchers examined data such as employee age, organizational role, and job nature to find ways to influence employee decision-making and performance in marketing, finance, human resources, research, and create development [26]. Other researchers used standardized tests to examine the relocation data of schoolteachers in New York to determine the effect of teacher relocation on student performance and by doing this they shows that the organizational performance was negatively related to subsequent employee turnover [27].
W. Zhao, Pu, and Jiang [34] introduced team member errors as one of the problems in human resource allocation, and to solve this problem, they analyzed some of the characteristics of resources from the perspective of demographics and business process analysis. In the same year, Lyons and Bandura [13] used statistical discussions to examine the factors affecting employee turnover. Their results show that there are multiple motivations or triggers that encourage an employee to leave an organization, which is much more complex than issues related to job satisfaction, rewards, or an unfavorable boss. Nagpal and Mishra [18] analyzed factors such as recruitment, training, and performance management to improve decision-maker’s ability to make informed decisions about human resources. X. Wang and Zhi [28] proposed an analytical framework based on machine learning due to the variety of factors affecting the employee turnover, the lack of comprehensive data, and the existence of machine learning models to predict the employee turnover. Recently, researchers investigated the effect of the strength of COVID-19 on the turnover intention of hotel employees by combining perceived operational performance and job insecurity [30].
Multi-criteria decision-making techniques and human resource problems
Human resource management and related issues include soft and hard constraints that make these issues a little more complicated. Therefore, multi-criteria decision-making techniques, which are practical tools for managers, have many applications in this field. One of the problems in human resource management is personal selection. In 2016, some researchers from China wanted to utilize human resources to increase the sustainable development of society and the economy. To evaluate and classify overseas talents in China under the intuitionistic relations environment they used the BWM method [29].
By using the BWM and the TOPSIS, Gupta [7] tried to identify important actions and practices of Green Human Resource Management (GHRM) and evaluate its performance using a three-phase methodology. Due to the effect of soft (human-resource-related) dimensions on Green Supply Chain Management (GSCM), Kumar, Mangla, Luthra, and Ishizaka [11] used the BWM and Decision-Making Trial and Evaluation Laboratory (DEMATEL) to minimize the negative environmental effect of the value chain. Chou, Yen, Dang, and Sun [3] used FAHP and fuzzy technique for ordering priority based on similarity to ideal solution (FTOPSIS) to evaluate the performance of human resources in science and technology (HRST) in Southeast Asian countries. Results They show that Singapore, South Korea and Taiwan have similarities in desirable levels of HRST performance and have better HRST performance than other Southeast Asian countries. Soba, Ersoy, Tarakcioğlu Altınay, Erkan, and Şik [25] used some multi-criteria decision-making techniques such as gray relationship analysis (GRA) method and PROMETHEE grading and ranking method for personnel selection. Esangbedo, Bai, Mirjalili, and Wang [5] evaluated the human resource information systems provided by different vendors using two new hybrid Multi-Criteria Decision-Making techniques that require ordinal data as inputs.
Many studies have used inferential statistics to find relationships between variables in human resource management. Also, Multi-Criteria Decision-Making techniques have been used in various fields. However, no article in human resource management has used Meta-heuristic and feature selection algorithms that are very useful and accurate to discover patterns and relationships between variables. Also, the use of Multi-Criteria Decision-Making techniques to find the importance of variables is not seen in the literature. Since the world of human resources is full of quality issues, using these methods to solve problems can also be very practical. On the other hand, deep searching for the relationships between variables, Meta-heuristic, and machine learning approaches can lead us to the correct use and modeling. In order to evaluate the results of the models, in the next step, we will use machine learning algorithms to predict the departure of employee turnover to ensure how practical the above results can be. Although many researchers have used data mining techniques and Multi-Criteria Decision-Making techniques in various human resource topics, combining and comparing these approaches shows a research gap that this study tries to cover.
Problem description and data description
From the organization’s point, employee turnover is in two forms: voluntary turnover and involuntary turnover. Involuntary turnover occurs when the employee wants to stay in the organization, but the organization wants the employee leaves in various forms such as retirement. In voluntary turnover, the organization wants to keep the employee, especially its talented and knowledgeable workers, but the employee wants to leave the organization [1]. Both employee turnovers cost the organization dearly, but voluntary exits are always a concern for managers. One of the best things that can be done for an organization is to retain its valuable employees. Regardless of the economic situation, companies are always at risk of losing their best employees and joining them to the organization’s competitors. The narrowing of the labor market and economic growth has created competition among companies to attract labor. This means that organizations are in fierce competition to attract talent. This competition creates conditions that make it difficult for any party to retain a talented employee, resulting in increased employee turnover rates.
When talented leave their jobs, the company will be losing knowledge and skills that it has acquired with difficulty and often at great expense. With the departure of these people, the high knowledge and expertise of these talented and efficient employees who guaranteed your success will leave your company with their turnover. It should be noted that reducing the employee turnover does not mean continuous work with all employees, but it means keeping qualified employees as long as their performance is in line with the organization’s goals. Although some voluntary employee turnover in the organization is inevitable, it can be minimized by identifying the factors affecting the employee turnover and applying correct management approaches in the next step. For this purpose, in this study, using various approaches such as Mutual Information, Recursive Feature Elimination, Best-Worst Method, Genetic Algorithm, Gray Wolf Optimizer, we identify the factors affecting the employee turnover. In the next step, we used the suggested variables from each of the above algorithms in some machine learning algorithms to examine the validity of the above models by using the current accuracy of machine learning algorithms in predicting the employee turnover.
There are many factors that can have a direct impact on the employee turnover. For this reason, we used the IBM data set obtained from the Keggel to determine the impact of important parameters such as years since the last promotion, work-life balance, percentage of salary increase, years of service, overtime, and number of trainings to employee turnover. The IBM Dataset includes 1470 employees and 38 features. From the total number of employees, 237 employees have left their jobs. After cleaning the data, all features with unique values that were the same across all employee inputs were removed. A total of 1470 employees with 31 characteristics remain. The features intended for analysis can be classified into 3 types continuous, discrete ordinal variables, and Nominal categorical variables like gender. The target variable in this data set is binary and divided into two classes of people, who left the organization, and people who did not leave the organization, as shown in Fig. 1. Figure 1 shows a general graph of the number of people who have left the organization. Fig. 1 Employee turnover number
Age, employee turnover, Business Travel, Daily Rate, Department, Distance From Home, Education, Education Field, Employee Number, Environment Satisfaction, Gender, Hourly Rate, Job Involvement, Job Level, Job Role, Job Satisfaction, Marital Status, Monthly Income, Monthly Rate, Number of Companies Worked, Over18, Overtime, Percent Salary Hike, Performance Rating, Relationship Satisfaction, Standard Hours, Stock Option Level, Total Working Years, Training Times Last Year, Work Life Balance, Years At Company, Years In Current Role, Years Since Last Promotion, Years With Current Manager are the features that we used. Some features such as over 18 and Standard Hours were not considered in data analyzation because they had no variance.
Methodology
In this article, in order to identify the factors affecting the employee turnover, Meta-heuristic, Feature Selection algorithms and Multi-Criteria Decision-Making techniques, which are very practical tools for managers, have been used. These algorithms include Mutual Information, Recursive Feature Elimination, Best-Worst Method, Genetic Algorithm, Gray Wolf Optimizer. Each of these approaches identify some features as the main factors affecting the employee turnover. In order to check the performance, and validation of the above methods, their results are used in some machine learning algorithms such as Logistic regression, Decision Tree, Random Forest, Gradient Boosting, Super Vector Machine and Adaptive Boosting.
One of the widely used techniques in observational learning is the classification technique. The classification technique is a kind of classic data mining approach for data analysis, which is based on machine learning. The classification process is based on a training set, the system learns to divide the data into the right groups with the least error. The training set contains data whose category is known; Each pattern or category has a label and data with the same target label are placed in a group. The goal of this method is to learn a function that maps input patterns (feature vectors) to their corresponding labels. Finally, in order to make the results of Mutual Information, Recursive Feature Elimination, Best-Worst Method, Genetic Algorithm, Gray Wolf Optimizer more practical, by using the results of the classification algorithms, we will predict the employee turnover, so that the results can be examined. The higher the accuracy of the prediction models, the more the variables proposed by the algorithms have had a greater impact on the employee turnover. Machine learning algorithms are compared using F1-score. Figure 2 shows the steps and application of these methods. Fig. 2 Steps of this article
Mutual information
Mutual Information is a concept of information theory that measures the uncertainty of a random variable. Considering the two-dimensional random variables X and Y, the Mutual Information between X and Y can calculate as Eq. 1. In this Equation p(x, y) shows the probability of variables X and Y. If X and Y are independent to each other, the joint probability of variables X and Y, that shown as I(X, Y) will equals to 0. Nonlinear correlation can be extracted from Mutual Information because the calculation of Mutual Information is based on the estimation of probability density. Mutual Information is more usable for nonlinear systems [37]. 1 IXY=∑xyPXYlogPXYPXPY
Recursive feature elimination
Feature Selection is one of the most important concepts in machine learning. Feature selection methods play a significant role in the optimal performance of learning models. One of these feature selection methods is the Recursive Feature Elimination (RFE) method. The characteristics that a machine learning engineer or data scientist uses to teach a machine learning model will have a tremendous impact on the performance, accuracy, and optimal performance of the implemented system. Also, unrelated or somewhat related features can harm system performance.
The Recursive Feature Elimination method is a greedy method for selecting features. In this method, the features are selected retrospectively by considering smaller and smaller sets of features (in each step). In this method, features are ranked based on the order in which they are removed from the feature space. RFE requires a certain number of features to maintain, however it is often not clear in advance how many features are optimal. However, as with other methods, we found nine of the most influential variables on employee turnover.
Best-worst method
Best-Worst Method (BWM) is a Multi-Criteria Decision-Making techniques based on the pairwise comparison in various fields such as green innovation [8], evaluation and selection of technology [20], evaluation and selection of technology [24], evaluation of research performance has been used [23]. BMW can reduce inconsistencies in results and reduce the number of pairwise comparisons required [12].
The concept and objectives of this method are described in the following sections.
Suppose we have n criteria and we want to make a pairwise comparison matrix, in fact, gaining the weight of each criterion starts from this part. As it is shown below, each element of this matrix shows the relative preference of the criteria over each other; moreover, the pairwise comparison matrix will be filled by the decision-maker (DM) by using the number between 1 to 9 scales. For instance, aij is the relative preference of criterion i to the criterion j. If aij = 1, it shows that criterion i and criterion j have the same importance and ifaij > 1, it shows that i is regarded as much more important one. If aij = 9, it is an indication of extreme importance of I to j [21]. 2 A=a11a12a21a22⋯a1na2n⋮⋱⋮an1an2⋯ann
Considering the cross-matrix property, (n − 1)/2 pairwise comparison is performed to complete the above-mentioned matrix. The consistency of the matrix is high. The literature on the matrix of consistent pairwise comparisons is shown as follows: 3 aik×akj=aij,∀i,j
The topic we talked about above was the basics of the pairwise comparison matrix. Still, we didn’t answer a question, and that one is related to the assurance and reliability of this matrix. To use experts’ ideas, we need to be sure that those ideas are not biased and eventually can express the strength of criterion i to criterion j appropriately. The Best-worst method is introduced by [21] to obtain the weights of each criterion by comparing the other’s criterion with the best one and also comparing them with the worst, so by applying this method DM can express his preferences more easily. At last, the comparing process will be simplified.
In this section, we describe the BWM steps for extracting the weight of criteria [21]. Step 1. In this step the decision criteria are determined. Criteria {c1, c2, c3, …cn} have been considered for decision making.
Step 2. We have to find the best criterion and the worst criterion. The DM will specify the most important or desirable as well as the lowest criteria.
Step 3. To highlight the preference of the best one over other criteria, a number between 1 and 9 is assigned to each criterion. This will, at last, make the best-to- others vector.
4 AB=aB1aB2…aB2
Step 4. To highlight the preference of the worst one over other criteria, a number between 1 and 9 is assigned to each criterion. This will, at last, make others- to-worst vector.
5 Aw=aw1aw2…awnT
Step 5. In the last step, we get the desired weights (w1, w2, w3, …wn). The optimal weight for each criteria is the one for which wBWJ=aij and also wjWW=ajW.
To meet the requirements mentioned for obtaining criteria’s weights, the maximum absolute differences ∣wBWJ-aij∣, ∣wjWW-ajW∣ for all j needs to be minimized. Hence the model is shown in Eq. 5: 6 minmaxjWBWj−aBjWjWw−ajws.t.∑jWj=1Wj≥0,farallj
The linear form is also obtained as: 7 minξs.t.WBWj−aBj≤ξforalljWjWw−ajW≤ξforalljWj≥0,farallj
Genetic algorithm
One of the Metaheuristic algorithms that is used to find the optimal formula for predicting or matching the pattern is the Genetic Algorithm. This algorithm uses biological techniques such as inheritance, biological mutation, and Darwin’s principles of choice. In many cases, Genetic Algorithms are referred to as function optimizers. This algorithm is used to optimize objective functions of various problems. The implementation of a genetic algorithm usually begins with the production of a population of chromosomes that are usually randomly generated. Next, the generated data structures, or chromosomes, are evaluated. Chromosomes that can better represent the Optimal Solution to a problem have a better chance of Reproduction than weaker answers. It can be said that the opportunity for reproduction is assigned to these chromosomes. The goodness of an answer is usually measured against the population of the current candidate’s answers.
Changes in chromosomes occur during the reproductive process. Parent’s chromosomes are exchanged randomly through a special process called crossover. Thus, children inherit and display some of the traits or characteristics of the father and some of the traits or characteristics of the mother. There is a process called mutation that causes changes in the properties or characteristics of living things. This process rarely occurs between modes. On the other hand, sometimes there may be an error in the process of copying chromosomes, which is called mitosis. Mutations can lead to newer and more graceful species of living things.
To solve the problem of feature selection using a genetic algorithm, a space is selected by coding each person and its degree of competence is calculated according to the degree of class resolution in that space. In each experiment, the genetic algorithm is run several times with different initial populations. Finally, after several runs, the best person will select. The genetic algorithm has features compared to other methods.
This algorithm does not work directly with the variables themselves, but with the coded decision variables, and does not start with a single point, but with a set of points. Also, this algorithm does not use computational rules but uses random transfer. The genetic algorithm uses only the output information of the competency function and does not use derivatives or other ancillary information.
Gray wolf optimizer
The Gray Wolf Algorithm Optimizer (GWO) is a Meta-heuristic algorithm first introduced in 2014 [14, 17]. This algorithm is inspired by the hieratical hierarchical structure and social behavior of gray wolves. GWO is population-based, has a simple process, and can be easily generalized to large-scale problems. Gray wolves prefer to live in a group, and each group has an average of 5–12 members. There are 4 degrees in each herd of wolves. The leader wolf is called Alpha (the fittest solution). The wolf beta (the second-best solution) is a wolf that follows the alpha wolf and is prone to be chosen instead of the alpha wolf in the decision-making process. Wolf Delta (the third-best solution) follows the wolf alpha and beta. After selecting these three wolves, the other wolves fall into the category of omega wolves (the rest of the candidate solutions). In the GWO algorithm, these wolves mentioned as α, β, δ and ω.
In explaining the GOW, we can say that this algorithm consists of 3 main steps. The first step involves tracking and approaching. The second step is pursing and encircling, and the third one is attacking.
According to the Yu, Xu, Wu, and Wang [31] when the prey is surrounded by wolves and stops moving, the attack is led by alpha wolf. Modeling of this process is done using the reduction of thea→. Since A→ is a random vector in the interval [−2a, 2a], as decreases, the coefficient A→ also decreases. If ∣ A ∣ < 1, the wolf alpha will approach the prey (and the rest of the wolves), and if ∣ A ∣ > 1 the wolf will stay away from the prey (and the rest of the wolves). The gray wolf algorithm requires all wolves to update their position according to the position of alpha, beta, and delta wolves. During the hunt, gray wolves surround the prey. The mathematical model of the siege behavior is shown in Eqs. 8 and 9. In these equations, t represents the current iteration, A→ and C→represent the coefficient vectors, Xp→represents the prey position vector, and X→ represents the gray wolf position vector. 8 D→=C→.X→Pt−X→t
9 X→t+1=X→pt−A→.D→
A→ and C→ are calculated as A→=2a→.r→1−a→ and C→=2.r→2. In these relations, the variable a decreases linearly from 2 to 0 during the iterations, andr→1, r→2 are random vectors in the range [0, 1]. Attracting operations are usually led by alpha. Beta and delta wolves may occasionally participate in hunting. In the mathematical model of gray wolf hunting behavior, we hypothesized that alpha, beta, and delta have better knowledge of prey potential positions. The first three solutions are best stored and the other agent is required to update their positions according to the position of the best search agents according to the following Eqs. 10, 11 and 12. 10 D→α=C→1.X→α−X→,D→β=C→2.X→β−X→,D→δ=C→3.X→δ−X→
11 X→1=X→α−A→1.D→α,X→2=X→β−A→2.D→β,X→3=X→δ−A→3.D→δ
12 X→t+1=X→1+X→2+X→33
C→ is considered as an obstacle in nature that slows down wolves approaching prey. C→ gives weight to the prey and makes it more inaccessible to wolves. Unlikea→, this vector does not decrease linearly from 2 to 0.
Performance evaluation
In this part, some machine learning algorithms such as Logistic Regression, Decision Tree, Random Forest, Gradient Boosting, Super Vector Machine, and Adaptive Boosting, were used to check the accuracy of the results obtained from Mutual Information, Recursive Feature Elimination, Best-Worst Method, Genetic Algorithm and Gray Wolf Optimizer. Evaluation of prediction models has been done using F1-score.
Logistic regression
One of the algorithms used for classification problems is logistic Regression. Logistic regression is a type of regression that is used to provide solutions for problems with binary objective variables. Logistic Regression uses to classify these problems. Equation 13 is shown the logistic Regression formulation. In this equation, y is the estimated value for the dependent variable, which is represented by Eq. 14. Equation 14 represents a simple linear regression equation. In this equation, b represents the width of the origin, and b1 represents the slope of the line. 13 p=11−e−y
14 y=b0+b1x
Decision tree
The Decision Tree is one of the most widely used tools and techniques in data mining skills and can be used for both classification and regression problems. This approach is widely used by project managers and business analysts because, it is a utilizable tool for decision making, and it can show well the complexity between variables. It can also examine large volumes of data in a short amount of time by eliminating unnecessary comparisons. In general, each tree contains roots, nodes, leaves, and branches. The highest node in the tree is called the root node and represents the set of all samples. Nodes represent a set of samples and specify divisions. In other words, the tree is divided according to the middle nodes. The branches of the tree represent possible outcomes. Finally, the leaves represent the nodes of the class or target states.
Also, items such as the number of nodes, the number of leaves, the number of characteristics to be considered, and the depth of the roots determine the size of each decision tree, which is usually due to the smaller volume making the decision tree more understandable. They control it by pruning.
Decision Tree algorithms start with selecting a test to perform the best separation for the categories, and it will be repeated for all other nodes. The Decision Tree can be built using several algorithms. Here we used entropy as the division criterion. If we classify the members of a set into k categories and pkshows the probability that the members belong to the k category, the expected information that is needed for the members to belong to the correct category is called entropy. Equation 15 shows the relationship of entropies. If the sample is completely homogeneous, the entropy is zero, and if the sample is the same, the entropy is one. In other words, the most entropy degree occurs when the probability of belonging to all categories is equal. It is necessary to calculate two types of entropy in the process of constructing each decision tree, which is entropy using the frequency table of one property and entropy using the frequency table of two properties, respectively. Equation 16 also shows the relationship of the Gini Index. The Gini Index is a statistical measure of distribution that measures the degree or likelihood of misclassification of a particular variable by random selection. 15 Entropyp1p2…pk=−∑p1log2p1
16 IG=1−∑J=1CPJ2
Random Forest
One of the multipurpose machine learning algorithms is the Random Forest. This algorithm can perform both classification and regression methods. The Random Forest algorithm is made up of several Decision Trees. It can be said that a set of Decision Trees together produce a forest. Each Decision Tree is unique to the Random Forest, which reduces the overall variance of the Random Forest classifier. The Random Forest algorithm can make better decisions than a Decision Tree. In other words, Random Forest decisions are more stable and reliable than a tree. Especially when each of the trees is not correlated with each other. The Random Forest collects the decisions of individual trees through a voting scheme such as a majority vote that is, for each observation, each tree decides on a group of votes, and selects the group with the highest number of votes. Random Forest has some adjustment parameters that can be optimized. These include the number of trees, the number of predictor variables randomly selected in each node, the ratio of observations for example in each Decision Tree, and the minimum number of observations in the final node of the Decision Tree. Random Forrest algorithm, like the decision tree, consists of two important concepts: Entropy and information gain which are shown in Eq. 15, and 16.
Gradient boosting
Gradient Boosting is one of the ensembles learning techniques for both regression and classification. Each iteration of the training set that is randomly selected is checked from the base model of the gradient boosting algorithm. The speed and accuracy of the gradient for execution can be improved by randomly sub-sampling the training data. It is also can help to prevent over-fitting. The smaller fraction of training data can increase the regression’s speed because the model has to fit smaller data at each iteration.
In Gradient Boosting regression, we required some tuning ntrees and shrinkage rate. ntrees shows the number of trees that have to be grown, the value of ntrees should not be set to too small. The shrinkage parameter is often known as the learning rate applied to each tree in the expansion. In gradient boosting it is invariant to the scaling of inputs and it can learn higher-order interactions between features. Different from other tree ensemble methods, gradient tree boosting is trained in an additive manner. The other tree that is grown at each time step t to minimize the residual of the current model [2]. Formally, the objective function can be described as Eq. 17. In this Equation, L shows the loss function that measures the difference between the label of the i − th instance yi and the prediction at the last step plus the current tree output. Ω(ft) is the regularization term that penalizes the complexity of the new tree. 17 Lt=∑i=1nLyiyi^t−1+ftxi+Ωft
Super vector machine
Support Vector Machine (SVM) is one of the supervised Machine Learning algorithms that is used for both regression and classification problems. When we use this algorithm with random forest algorithms or other machine learning tools, this algorithm can provide a very compelling model for data classification. A backup machine algorithm is a great option when high predictive power is required. In the training phase, the SVM algorithm tries to select the decision boundary in such a way that the “minimum” distance, boundary, Decision-Making, or separator is maximized with each of the categories. In other words, the margin model is more reliable. According to Zhang, Zheng, Pang, and Zhou [32] the SVM would build a Hyperplane H when y is the list of targeted applications or classes that Eq. 18 shows this formulation. In this Equation, x is the input from net flow data, a shows the vector of the weights for each flow feature, b shows the bias term and ∅(0) is fixed feature-space transformation. 18 H:aT∅x+b=0
In this algorithm, the problem is to find the Hyperplanes H that separate different classes, and the SVM assumes that the classes are linearly separable.
Adaptive boosting
Adaptive Boosting (AdaBoost) is one of the most successful amplification algorithms for binary classification. AdaBoost is generally used with small Decision Trees. Each input training Dataset is presented and labeled as in Eq. 19. In this Equation n is training data set size, xi ∈ T and yi ∈ {−1, 1}. In this algorithm, each training sample of data could be a point in a multidimensional feature space. 19 x1y1,x2y2,…,xnyn
AdaBoost can implement a probability distribution over all the training samples of data. This distribution could be modified by iterations with a new weak classifier to the data. Dt(xi) shows the probability distribution and the successive iterations is shown by T. In this algorithm ht is the weak classifier chosen for the iteration t. ht(xi) denoted the class label assigned by xi. After comparing ht(xi) with yi for i = 1, 2, …, n we will have an error that we noted it ϵi. This error shows the classification error rate for the classifier ht. Each classifier candidate is trained over iterations using a subsample of all the training data provided by the Dt(x) probability distribution. The higher the probability of Dt(x) for a given training sample x, the greater the chance of selecting it for the instruction of candidate h(t) classifier. The htmust be selected in a way to minimize the amount of misclassification rate ϵ. The trust level αt, of the weak classifier in which we trust, is the point of the AdaBoost algorithm. The bigger the value of error, ϵt for a classifier, the lower the trust must be. Eq. 20 shows the relation between αt and ϵt. 20 αt=12ln1−ϵtϵt
The trust level of the candidate classifier h(t) will get a value in the scale of −∞ and∞, if the epsilon rate gets closer to 1 starting from 0. If the ϵ gets closer to 1, the weak classifier almost completely fails on the overall training Dataset. If the ϵ gets closer to 0, the weak classifier will be powerful as also stated. Finally, the classifier H will be obtained. After n iterations, H classifier in the AdaBoost will be evaluated as shown in Eq. 21. 21 Hx=sign∑t=1kαt.htx
In this Equation x shows the new data element. This data element denotes as information strength in the training data. For example, if we have a binary classification and H(x) would be positive, then the prediction class would be 1, otherwise, it would be −1.
Evaluation of machine learning models
The F1-score is a machine learning metric that can be used in classification models. Although there are many metrics for classification models, the F1-score is a common metric that captures class imbalance well and has a very simple function. Another criterion used in classification problems is accuracy, but it works well for data that is perfectly balanced and has no class bias or imbalance. The evaluation of machine learning models in this study is done using the F1-score, because in addition to the fact that our data is imbalanced (From the total number of employees, 237 employees have left their jobs), that is, the ratio of our 1 and 0 variables is not equal to one another, we are looking to identify the number of people who left the organization and we want identified them correctly. Since the accuracy criterion cannot distinguish between False Negative and False Positive errors, we have used F1-score to check the performance of machine learning models. Since in some problems, Recall and Precision are both very important factors, criterion F1-score is used. They are also the basis of F1-score, which means that the F1-score is actually a balanced combination of Precision and Recall, and can be used in cases where the cost of false positives and false negatives is different [36].
In this study, we seek to correctly identify the people who leave the organization. The higher the ratio of False Negatives (cases that we expected to be predicted but were not correctly predicted) to True Positives (correct predictions), the lower the Recall value. On the other hand, the higher the number of False Positives (cases that the Athens model has incorrectly predicted) compared to True Positives (correct predictions), the lower the Precision will be. In fact, the higher the number of false diagnoses of the program, the lower its recall, and the higher the number of things that should be obtained but not predicted, the lower the precision. The F1-score is equal to the geometric mean of these two criteria. It can be said that, the F1-score is a suitable criterion for evaluating the accuracy of our models because, considering the large volume of our data, this test, in addition to considering the Precision and Recall criteria together, only needs to train the model once. Using the k-fold method can be very useful, but it is usually used for data whose volume is small because by increasing k, this method leads to the training of more models and turns the training process into a costly and time-consuming process.
The classification process has two phases, Train and Test. In the Train phase, the data in the dataset are selected as training data, and in the Test section, the remaining data are used for testing and validating the selection. In the test phase, the patterns whose labels are not known are given to the system and the designed system predicts their output or labels with the help of the learned function. The data in this article are divided into two parts with the ratio of 25–75 to the train set and test set. Also, the performance of the MCDM techniques, Meta-heuristic, and Feature Selection models were evaluated by F1-score in prediction models. These tests are calculated based on recall and precision. True positive (Tp) counts the number of positive instances that are classified correctly. The number of negative instances that are classified correctly counts in true negative (Tn). False positive (Fp), means the number of negative instances that are classified as positive and also false negative (Fn), shows the number of positive instances that are classified as negative. Finding the exact point for the classifier on which the number of true positives is maximum, and the number of true negatives is minimum makes our objective. Recall shows how much the system is capable of classifying. Precision, Recall, and F1 score can be calculated as Eq. 22, 23 and 24. 22 Precision=TpTp+Fp
23 Recall=TpTp+Fn
24 F1score=2×precision×recallprecision+recall
Results
Mutual information
According to Mutual Information, the most influential variable on employee turnover is the years with the current manager. Nine of the most influential variables that we also used for the prediction model are years with the current manager, gender, distance from home, hourly rate, total working years, years at the company, work life balance, environmental satisfaction, and job level. Figure 3 shows the feature importance in Mutual Information. In this Figure, the more important a feature is, the higher its graph. As shown in the Fig. 3, some features, such as business travel and departments, do not affect the employee turnover. Fig. 3 Feature Importance in Mutual Information
Recursive feature elimination
Mutual Information gives us the importance and the Score of features. In Mutual Information, the higher the numerical value of a feature, the more important that feature is. Unlike the Mutual Information method in the Recursive Feature Elimination method, we have a ranking of features. Features with ranking one are the most effective features on employee turnover. According to this method, age, business travel, daily rate, distance from home, education, gender, work life balance, distance from home, job environment, and monthly rate are the most influential variable on employee turnover. The feature importance of Recursive Feature Elimination is shown in Fig. 4. Fig. 4 Feature importance of Recursive Feature Elimination
Best-worst method
Among 31 features, our expert has selected 9 of the most significant features that affect employee turnover. Among these 9 significant criteria, our expert identified the most influential criteria (best criteria) and the least influential criteria (worst criteria) on the employee turnover. In the next step, by using the number 1 to 9, he weighs the other variables against the worst and the best criteria. Table 1 shows the weight of the variables relative to the best criteria, and Table 2 shows the weight of the variables relative to the worst criteria. The criteria that are used for the BWM method are job level, job satisfaction, monthly income, relationship satisfaction, total work years, work life balance, years at the company, years since the last promotion, and years with the current manager. The best criteria are job satisfaction and the worst criteria are years with the current manager. These results show that with the weight of 0.30658026, job satisfaction has the most effect on employee turnover. Table 1 The expert weight of best criteria
The score of best criteria to other Job level Job satisfaction Monthly income Relationship satisfaction Total work years Work life balance Years at the company Years since last promotion Years with current manager
Job satisfaction 9 1 5 6 4 5 4 6 4
Table 2 The expert weight of the worst criteria
The score of other criteria to the worst Job level Job satisfaction Monthly income Relationship satisfaction Total work years Work life balance Years at the company Years since last promotion Years with current manager
Years with current manager 5 4 5 9 7 7 4 9 1
Table 3 shows the standard effectiveness coefficient in the employee turnover and the weights obtained by the BWM for each criteria. Table 3 The weights obtained from the BWM
Job level Job satisfaction Monthly income Relationship satisfaction Total work years Work life balance Years at the company Years since last promotion Years with current manager
Weights 0.05483549 0.30658026 0.09870389 0.08225324 0.12337986 0.09870389 0.12337986 0.08225324 0.02991027
Meta-heuristic algorithms
Genetic Algorithm and Gray Wolf Optimizer are two Meta-heuristic Algorithms that are used to find the factors identification on employee turnover. The results of the Genetic Algorithm show that age, department, education field, job level, job role, job satisfaction, monthly income, overtime, and years in the current role are the most significant factors. Gray Wolf Optimizer shows that distance from home, job role, monthly income, number of companies worked, overtime, years at the company, years in the current role, years since last promotion, and years with the current manager are the most significant factors. The GWO shows that the Employees whose homes are 4–6 miles far away from the company make up 10% of all employee turnover at the company. In the field of job roles, managers and human resources also have the most employee turnover rate in the organization. Managers also make up 4% and Human Resources 23% of the organization’s employee turnover rate. Also, people who work with their managers for 1 or 6 years and employees who have overtime are more likely to leave their jobs.
Some of these features are the same in both algorithms. One of these features is monthly income. The monthly income of $2000–3000, has a high employee turnover rate and this represents 40% of the employee turnover in the company. 1000–2000 monthly income, which has a high employee turnover in its income, is 54.5%. As monthly income increases, the employee turnover rate decreases. However, at a monthly income of $900–11,000, there is an increase in turnover compared to the monthly income itself. Table 4 shows statistical information on employee monthly income. Table 4 Statistical information of employee Monthly Income
Monthly Income Total Employee Number Turnover Number % of Employee Turnover in the Company % of Employee Turnover in the Monthly Income
1000–2000 33 18 7.594937% 54.545455%
2000–3000 362 95 40.084388% 26.243094%
3000–4000 148 24 10.126582% 16.216216%
4000–5000 206 26 10.970464% 12.621359%
5000–7500 310 30 12.658228% 9.677419%
7500–9000 78 10 4.219409% 12.820513%
9000–11000 118 22 9.282700% 18.644068%
11000–15000 82 7 2.953586% 8.536585%
15000–20000 133 5 2.109705% 3.759398%
Overtime is another common feature of these two algorithms. 30.5% of employees who have overtime work in the company left their job, which includes 53.5% of all employee turnover in the companies. Although only 10% of people who do not have over time have left their jobs, they account for 46% of the total employee turnover rate in an organization. By comparing both groups, overtime employees are much more likely to leave the company. Table 5 shows statistical information on employee overtime. Table 5 Statistical information of Employee Overtime
Over time Total Employee Number Turnover Number % of Employee Turnover in the Company % of Employee Turnover in the Over Time
No 1054 110 46.413502% 10.436433%
Yes 416 127 53.586498% 30.528846%
Discussion
As mentioned before, we used Mutual Information, Recursive Feature Elimination, Best-Worst Method, Genetic Algorithm, Gray Wolf Optimizer to identify the factors affecting employee turnover. In this section, we are looking for a comparison between the results of the above algorithms. In summary, Table 6 shows the factors affecting the departure of employee turnover by these algorithms. Table 6 Result Trade-off Table
Mutual Information Recursive Feature Elimination Best-Worst Method Genetic Algorithm Gray Wolf Optimizer
years with the current manager age job level age distance from home
gender business travel job satisfaction department job role
distance from home daily rate monthly income education field monthly income
hourly rate distance from home relationship satisfaction job level number of companies worked
total working years education total work years job role overtime
years at the company work life balance work life balance job satisfaction years at the company
work life balance gender years at the company monthly income years in the current role
environmental satisfaction job environment years since the last promotion overtime years since last promotion
job level monthly rate years with the current manager and years in the current role years with the current manager
We used different classification algorithms to check the accuracy of the features selected by MCDM, Genetic Algorithm, Gray Wolf Optimizer, Mutual Information, and Recursive Feature Elimination results. Logistic Regression, Decision Tree, Random Forest, Super Vector Machine, Gradient Boosting, and Adaptive Boosting are the algorithm that we used for prediction. By predicting this data, we obtained the accuracy of each method on employee turnover and have a tradeoff between the results of each method. The results of these predictions are shown in Table 7. Table 7 Results of Prediction Models
All Features Mutual Information Recursive Feature Elimination BWM Genetic Algorithm GWO Total Improvement
Logistic regression 0.816687 0.837067 0.832493 0.788572 0.833074 0.825792 0.0250
Decision Tree 0.784938 0.841585 0.750696 0.773001 0.79717 0.79250 0.0722
Random Forest 0.821058 0.841129 0.803081 0.782144 0.827831 0.823401 0.0244
Super Vector Machine 0.810444 0.839416 0.823767 0.770328 0.834032 0.830987 0.0357
Gradient Boosting 0.847921 0.841412 0.807959 0.784461 0.839441 0.826848 0.000
Adaptive Boosting 0.851632 0.825090 0.825792 0.789016 0.824271 0.802664 0.000
As shown in Table 7, we once predicted the employee turnover using the entire Dataset, once we predicted the employee turnover with results of BWM, Genetic Algorithm, Gray Wolf Optimizer, Mutual Information, and Recursive Feature Elimination. The Total Improvement of the prediction model by the best algorithm is shown in the last column. For example, in the Decision Tree model, the use of 9 features that the Mutual Information algorithm considers to be the most influential variables on employee turnover has been able to give better performance to our model than using all the features. In other words, its Total Improvement has grown by 0.0494%. Among BWM methods, Genetic Algorithm, Mutual Information, and Recursive Feature Elimination results, the method that has shown better and more efficient results in most algorithms is the Mutual Information algorithm. Figure 5 shows a comparison diagram of the results of the prediction models. Fig. 5 Comparison of classifiers with different feature selection
As shown in Fig. 5, the most accurate among the proposed models is Algorithm Mutual Information algorithm. The criteria selected by this algorithm are years with the current manager, gender, distance from home, hourly rate, total working years, years at the company, work life balance, environmental satisfaction, and job level. When the results of this algorithm are used in machine learning models, the F1-score of most algorithms such as algorithm Logistic regression, Decision Tree, Random Forest and Super Vector Machine has increased compared to using all algorithms. Figure 6 shows these results well. Fig. 6 Comparation results of Mutual Information Vs. all features
Using the suggested variables of Mutual Information can show better results in all machine learning algorithms than other algorithms in predicting the employee turnover. In all algorithms, including Gradient Boosting and Adaptive Boosting, which had shown weaker results compared to using all features, they have been able to show better results. In Adaptive boosting algorithm, the results of Mutual Information and Recursive Feature Elimination are almost equal. The comparison of Mutual Information with BWM shows much better results in all machine learning models. Figure 7 shows a tradeoff between the results of two algorithms. Fig. 7 Tradeoff between Mutual Information, Recursive Feature Elimination and BWM
Using the results of Mutual Information compared to the results of Genetic algorithm and GWO in machine learning models, has been able to show much better results. Figure 8 shows a trade-off between the results of Mutual Information, Genetic algorithm and GWO. Fig. 8 Tradeoff between Mutual Information, Genetic algorithm and GWO
Some of these features are common to some algorithms. There are 4 categories bad, best, better and good for work-life balance in this company. Throughout the company, work-life balance is satisfactory generally. But we have the highest employee turnover number and percentage throughout the company. 127 of the 893 people who are in a better category of work life balance have left the organization. This means that 14% of the employees who have a better work life balance left the organization and 53.58% of people who have left the organization are in the better category of work life balance. It should be noted that a total of 31.25% of people with bad work-life balance left the organization, which is a significant percentage. Table 8 shows statistical information on work-life balance in the company. The tradeoff of employee turnover according to work-life balances and the impact of work-life balances on employee turnover is shown in Fig. 9. Table 8 Statistical information of Work Life Balances
Work life balance Total employee Number Turnover number % Of Employee Turnover in Company % Of Employee Turnover in the Work Life Balance
Bad 80 25 10.548523% 31.25%
Best 153 27 11.392405% 17.647059%
Better 893 127 53.586498% 14.221725%
Good 344 58 24.472574% 16.860465%
Fig. 9 Statistical diagrams of Work Life Balances
This company has five job levels. At job level 5, 5 employees of 69 employees have left their jobs, which includes 2.1% of all employee turnover in the company, and 7.2% of employees with job category 5 have left their jobs. By increasing job levels, there is a decrease in employee turnover number throughout the company. As the results show in Fig. 5 and Table 6, the highest turnover rate is observed in job level 1. 143 employees in job level 1, who compose 60.3% of all employee turnover, left the company. Table 9 shows statistical information on employee job levels. The tradeoff of employee turnover according to job level and the impact of job level on employee turnover is shown in Fig. 10. Table 9 Statistical information of employee Job Level
Job Level Total Employee Number Turnover Number % Of Employee Turnover in the Company % Of Employee Turnover in the Job Level
Level 1 543 143 60.337553% 26.335175%
Level 2 534 52 21.940928% 9.737828%
Level 3 218 32 13.502110% 14.678899%
Level 4 106 5 2.109705% 4.76981%
Level 5 69 5 2.109705% 7.246377%
Fig. 10 Statistical diagram of Job Level
With 31.6% of all employee turnover at the company, employees who don’t fulfill their first year and in their first year in their current role are more likely to leave the company. The genetic algorithm also confirms this result. with36.7% of all employee turnover at the company, the employees who have 2–5 years of experience have the maximum employee turnover rate. Moreover, after many years in the current position, the employee is ready to leave the company. Table 9 shows statistical information of years at the company. Table 10 shows the statistical information for years at the company. The tradeoff of employee turnover according to years at the company and the impact of years at the company on employee turnover is shown in Fig. 11. Table 10 Statistical information of Years at Company
Years at Company Total Employee Number Turnover Number % Of Employee Turnover in the Company % of Employee Turnover in the Years at Company
1 215 75 31.645570% 34.883721%
2–5 561 87 36.708861% 15.508021%
6–10 448 55 23.206751% 12.276786%
+10 246 20 8.438819% 8.130081%
Fig. 11 Statistical diagrams of Years at Company
With 35.8% of all employee turnover at the company, most of the employees leave the company before completing their first year with their current manager. After that, the employee who worked two years with the current manager leaves the company. That includes 21% of all employee turnover in the company. With 13% of all employee turnover at the company, the employees who work seven years with the current manager leaves the company. Table 11 shows the statistical information for years with the current manager. The tradeoff of employee turnover according to years with the current manager and the impact of years with the current manager on employee turnover is shown in Fig. 12. Table 11 Statistical information of employee Years with Current Manager
Years With Current Manager Total Employee Number Turnover Number % Of Employee Turnover in the Company % of Employee Turnover in the Years With Current Manager
0 263 85 35.864979% 32.319392%
1 76 11 4.641350% 14.473684%
2 344 50 21.097046% 14.534884%
3 142 19 8.016878% 13.380282%
4 98 11 4.641350% 11.224490%
5 31 4 1.687764% 12.903226%
6 29 4 1.687764% 13.793103%
7 216 31 13.080169% 14.351852%
8 107 10 4.219409% 9.345794%
9 64 6 2.531646% 9.375000%
+10 100 6 2.531646% 6.00000%
Fig. 12 Statistical diagram of Years with Current Manager
Managerial insight
As indicated in the results, there are four main factors affecting employee turnover within the companies: Work-life balance, Job level, years with the company, and years with the current manager.
By putting all these results together, it can be highlighted that the early stages of employee engagement with the company are vital in several manners. The employees are more likely to leave the company in their early years of working, which can make their satisfaction levels and commitment levels of them in the early years a crucial factor for retaining them. Due to these facts, the authors suggest companies invest in increasing the satisfaction and commitment levels, by designing and benefitting from productive onboarding programs as well as their employer branding. An effective onboarding program specifically in an era in which the workplace is changing its nature, is a tailored authentic experience for employees that would affect their purpose and elevate their energy and performance. After all, employees are seeking for fulfilling their purpose, trust and social bonding in their careers.
Also, it is worth mentioning that due to the results, after 5 years of working employees are less likely to leave the company, which can be referred to as the importance of the early years of employees’ experiences with the company- how the employer has created their unique experience in the workplace bundled and multiplied by the employer brand within the market.
Also, considering the job level and years with the current manager as another vital affecting factor on employee turnover, it can be referred the importance of succession planning and career progress within the job. The more the employees feel their career progress in the company the less they are likely to leave. This factor also can be referred to as the fact that finding a meaning in employees’ everyday jobs, as well as, living their purpose through their job is an effecting underlying factor for creating commitment and decreasing the turnover. However, since the factor of employee generation seems to be affecting in purpose and meaning of the job, the authors suggest that it can be determined through separate research for complementary purposes.
On the other hand, to make the employees’ progress fruitful and meaningful it seems necessary for companies to invest in their leadership development by conducting different leadership development programs to minimize the risk of employees’ dissatisfaction with their current managers through better leadership, also, managers need to hold a crystal clear plan for their employees’ career path and growth journey which may result in a better-satisfied employee in their early stages through progressing in their job level. The mentioned leadership development programs can be conducted by several training and consulting firms in a variety of concepts. From result driven leadership programs to conscious leadership and self-realization, that may vary in use based on the nature of the work, company culture and the most important the employees themselves. However, it’s vital to mention that a well-defined and structured talent journey plan, based on the competency model, would affect in engaging multi layers of employees in different development programs as well as, clearly communicating the growth roadmap for them.
Finally, the work-life balance as indicated in the results has a considerable effect on the turnover. Although at a glance it may come to one’s mind that the better the work-life balance the more the employees are likely to leave, it’s absolutely important to mention that due to the results, 31.25% of employees with bad work-life balance are intended to leave the company. This brings the fact that the companies are going to need to invest in creating and maintaining a culture of work-life balance security and to improve it via broad communication through the organization and creating rituals for it.
In conclusion, by investing in creating better employer brands, better effective onboarding programs, clarifying better career paths and succession planning for early years joiners of the company, and maintaining all by enriching everyday experience via better leadership and better work-life balance rituals, it seems to be able to minimize the risk of turnover in employees early years with the company, which would result in better company culture and employer brand and long run, minimize the investments spent by companies on retaining right talents.
Contributions, limitations, and future works
There are many factors that directly and indirectly affect the employee turnover and can impose a lot of costs on organizations. On the other hand, in some cases, the departure of human resources can be the result of the manager’s wrong decisions. For this purpose, identifying the factors affecting the employee turnover has been one of the most important challenges for managers, so that by providing appropriate management approaches, they can reduce the rate of departure of human resources in their organizations. In order to identify the factors affecting the employee turnover, this article has used three approaches of Meta-heuristic algorithms, Multi-Criteria Decision-Making techniques, Feature Selection algorithms in machine learning.
Multi-Criteria Decision-Making is an advanced field of operations research dedicated to the development and implementation of decision support tools and methods. These methods are very practical tools for managers that can be used to solve complex decision-making problems such as the existence of several criteria, goals or objectives with a contradictory nature. In this study, Best-Worst Method has been used to identify the most influential factor on employee turnover. There are many problems in various sciences that are of the optimization type, that is, among a set of possible solutions, the best solution is sought that maximizes or minimizes the objective function, which are very large in terms of size and complexity. In these cases, it takes a lot of time to reach the definitive optimal solution, and the use of Meta-heuristic algorithms can approach the optimal solution with an acceptable percentage. Genetic Algorithm and Gray Wolf Optimizer have been used in this article in order to optimize and identify the factors influencing the employee turnover.
Other methods used are method Mutual Information and Recursive Feature Elimination, which are part of feature selection methods. This method helps people to have a better view of the variables by stating which features are more important and how the features are related to each other. All three approaches above are very practical methods that can be used to identify and optimize the factors affecting the employee turnover. However, past researches were limited to the use of statistical charts. In order to evaluate the performance of these methods, the results have been used in some machine learning algorithms. Machine learning models have been compared with each other using F1-score, and the most influential factors on the employee turnover have been identified. Some of these variables have been the same in different models, which have been discussed in detail.
However, when using approach Best-Worst Method, our expert selected 9 of all the features and then evaluated and ranked them. It is suggested that future researchers first cluster the criteria into a number of clusters. This way, you add one level to the hierarchy of the problem, and solve the problem. Finally, a general weight for all variables will obtain after doing some pairwise comparison among the sub-sets. The Meta-heuristic methods used in this article are limited to methods Genetic Algorithm and Gray Wolf Optimizer and do not show the priority of the selected features. Researchers are requested to show the results of other Meta-heuristic algorithms and their prioritization. Researchers can focus on improving the results and optimizing the Hyper-parameters of the models. It is suggested to use these methods on the data of other organizations and compare the results with this study.
The data used in this study is not a time series, which suggests that these methods should be implemented on time series data and some deep learning algorithms. It is suggested to consider fuzzy logic in models or in data. Identifying the factors affecting the employee turnover can lead to the improvement of macro policies of organizations to plan human resources so that the organization does not face a shortage of human resources when it is needed. The results of this study can be used as a decision support tool to improve organizational strategies and improve manager’s performance. These results can be used in various mathematical models to optimize human resources.
Conclusion
Employee turnover is always one of the main concerns of managers because it is a kind of loss of capital and is often the result of poor hiring decisions, and management, and directly affect the organization’s strategic plans. For this purpose, identifying the factors influencing the employee turnover is a very practical issue for organizations that have been limited to using statistical charts. In order to identify the most influential factors on employee turnover, three approaches are used in this article, which are Feature Selection, Multi-Criteria Decision-Making techniques and Meta-heuristic algorithms. Each of these methods are very practical techniques that can be available to managers as a tool, and their use in organizations has been neglected.
Method Best-Worst method is one of the most practical approaches in Multi-Criteria Decision-Making techniques used in this article. Our expert weighed the factors influencing employee turnover using the Best-Worst method. The results of this method show that job level, job satisfaction, monthly income, relationship satisfaction, total work years, work-life balance, years at the company, years since the last promotion, and years with the current manager are the most influential factors, respectively. The Genetic algorithm is one of the Meta-heuristic algorithms, used for optimization. The results show that age, department, education field, job level, job role, job satisfaction, monthly income, overtime, and years in the current role are the most significant factors. Gray Wolf Optimizer shows that distance from home, job role, monthly income, number of companies worked, overtime, years at the company, years in the current role, years since last promotion, and years with the current manager are the most significant factors.
The other method is to use the Feature Selection approach, which is of the main steps to using the learning machine. Using two approaches, Mutual Information and Recursive Feature Elimination, we examined the factors affecting employee turnover. The results show that in the Mutual Information method, the most influential factors are years with the current manager, gender, distance from home, hourly rate, total work years, years at the company, work-life balance, environmental satisfaction, and job level. In the Recursive Feature Elimination method, the most influential factors are age, business travel, daily rate, education, gender, work-life balance, distance from home, job environment, and monthly rate.
In the next step, the results of Mutual Information, Recursive Feature Elimination, Best-Worst Method, Genetic Algorithm, Gray Wolf Optimizer algorithms are used in machine learning algorithms so that the results can be applied in predicting the departure of the required human resources. Used and then compared. The results obtained in logistic regression, decision tree, random forest, super vector machine, gradient boosting and adaptive boosting are the algorithms used for prediction. Prediction models using all features have also been implemented and their results have been compared with each other. The results of the prediction show that the Mutual Information algorithm has been able to show better results than using all the features. The results of a case study based on IBM’s Dataset show that among these three methods that we used to identify the factors that affect employee turnover, total working years, years with the current manager and work-life balance are common. Managers should pay more attention to these two factors to better control the rate of employee turnover.
This approach can help managers and organizations to have a vision of the future based on data and make the best decision to plan for their employees. It may not be possible for all companies to collect and record this Dataset and find these results, so this research can help the manager and promote a data-driven decision approach in their organization, especially in human resource management, and reduce the costs of making poor decisions. By doing this, managers can retain their knowledge workers and prevent unconventional employee turnover in their company. In other words, the use of data mining approach, Multi-Criteria Decision Making techniques and the above results can be used as a decision support tool. These approaches can influence future decisions by using the historical data of the organization and reduce the costs caused by mistakes. Data is increasingly viewed as a corporate asset that can be used to make informed business decisions, improve marketing activities, optimize business operations, and reduce costs, with the goal of increasing revenue, profit, and organizational productivity.
Most of the previous articles that used data to identify factors were limited to using charts and graphs. We tried to use other approaches such as using Multi-Criteria Decision-Making techniques, feature selection algorithms and Meta-heuristic algorithms. However, there are also limitations in this research. The Meta-heuristic algorithms used in this article do not show the priority of the selected features, and future researchers are asked to improve it. In addition, in this article, only two algorithms are used, which researchers are asked to expand. Therefore, we ask researchers to increase the accuracy of this model and add more factors.
In this article, the prediction algorithms are not optimized. It is suggested that the results after the optimization of the algorithms should also be examined. Also, by using Best-Worst Method, our expert selected 9 of all the features and then evaluated and ranked these features. It is suggested that first cluster all the features into a number of clusters. In addition, for future research, we propose to use deep learning models such as the Convolutional Neural Network algorithm and Artificial neural network to predict the employee turnover rate using these features. They can also optimize these results using Meta-heuristic algorithms. Researchers are also advised to use mathematical modeling to minimize the employee turnover rate. Researchers can predict the employee turnover rate and use it to optimize, locate and allocate human resources. They can also findi the features using fuzzy logic.
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References
1. Aksu A (2008) Chapter 10 - Employee turnover: calculation of turnover rates and costs. In: Tesone DV (ed.) Handbook of Hospitality Human Resources Management. Butterworth-Heinemann, Oxford, pp 195–222
2. Arora Y, Sikka S (2023) Reviewing fake news classification algorithms. In: Goyal D, Kumar A, Piuri V, Paprzycki M (eds) Proceedings of the Third International Conference on Information Management and Machine Intelligence. Algorithms for Intelligent Systems. Springer, Singapore. 10.1007/978-981-19-2065-3_46
3. Chou Y-C Yen H-Y Dang V Sun CC Assessing the human resource in science and Technology for Asian Countries: application of fuzzy AHP and fuzzy TOPSIS Symmetry 2019 11 251 10.3390/sym11020251
4. Dotoli M Epicoco N Falagario M Multi-criteria decision making techniques for the management of public procurement tenders: A case study Appl Soft Comput 2020 88 106064 10.1016/j.asoc.2020.106064
5. Esangbedo MO Bai S Mirjalili S Wang Z Evaluation of human resource information systems using grey ordinal pairwise comparison MCDM methods Expert Syst Appl 2021 182 115151 10.1016/j.eswa.2021.115151
6. Esmaieeli Sikaroudi A, Ghousi R, Sikaroudi A (2015) A data mining approach to employee turnover prediction (case study: Arak automotive parts manufacturing). J Indust Syst Eng 8:108–121
7. Gupta H Assessing organizations performance on the basis of GHRM practices using BWM and fuzzy TOPSIS J Environ Manag 2018 226 201 216 10.1016/j.jenvman.2018.08.005
8. Gupta H Barua MK A framework to overcome barriers to green innovation in SMEs using BWM and fuzzy TOPSIS Sci Total Environ 2018 633 122 139 10.1016/j.scitotenv.2018.03.173 29573679
9. Han, JW (2020) A review of antecedents of employee turnover in the hospitality industry on individual, team and organizational levels. International hospitality review, ahead-of-print(ahead-of-print). 10.1108/IHR-09-2020-0050
10. Kim J Dibrell C Kraft E Marshall D Data analytics and performance: the moderating role of intuition-based HR management in major league baseball J Bus Res 2021 122 204 216 10.1016/j.jbusres.2020.08.057
11. Kumar A Mangla SK Luthra S Ishizaka A Evaluating the human resource related soft dimensions in green supply chain management implementation Prod Plan Control 2019 30 9 699 715 10.1080/09537287.2018.1555342
12. Liu P Zhu B Wang P A weighting model based on best–worst method and its application for environmental performance evaluation Appl Soft Comput 2021 103 107168 10.1016/j.asoc.2021.107168
13. Lyons P Bandura R Employee turnover: features and perspectives Dev Learn Organ Int J 2020 34 1 1 4 10.1108/DLO-02-2019-0048
14. Mammadova M Jabrayilova Z Application of fuzzy optimization method in decision-making for personnel selection Intell Control Autom 2014 5 190 204 10.4236/ica.2014.54021
15. Mamoudan, M, Forouzanfar, D, Mohammadnazari, Z, Aghsami, A, Jolai, F (2021) Factor identification for insurance pricing mechanism using data mining and multi criteria decision making. J Ambient Intell Humaniz Comput 10.1007/s12652-021-03585-z
16. Margherita A Human resources analytics: A systematization of research topics and directions for future research Hum Resour Manag Rev 2022 32 2 100795 10.1016/j.hrmr.2020.100795
17. Mirjalili S Mirjalili SM Lewis A Grey wolf optimizer Adv Eng Softw 2014 69 46 61 10.1016/j.advengsoft.2013.12.007
18. Nagpal, T, Mishra, M (2021) Analyzing human resource practices for decision making in banking sector using HR analytics. Materials Today: Proceedings. 10.1016/j.matpr.2020.12.460
19. Qi L Yao K Artificial intelligence enterprise human resource management system based on FPGA high performance computer hardware Microprocess Microsyst 2021 82 103876 10.1016/j.micpro.2021.103876
20. Ren J Technology selection for ballast water treatment by multi-stakeholders: a multi-attribute decision analysis approach based on the combined weights and extension theory Chemosphere 2018 191 747 760 10.1016/j.chemosphere.2017.10.053 29080536
21. Rezaei J Best-worst multi-criteria decision-making method Omega 2015 53 49 57 10.1016/j.omega.2014.11.009
22. Rijamampianina R Employee turnover rate and organizational performance in South Africa Probl Perspect Manag 2015 13 240 253
23. Salimi N Rezaei J Evaluating firms’ R&D performance using best worst method Evaluation Program Plan 2018 66 147 155 10.1016/j.evalprogplan.2017.10.002
24. Shoji Y Kim H Kubo T Tsuge T Aikoh T Kuriyama K Understanding preferences for pricing policies in Japan’s national parks using the best–worst scaling method J Nat Conserv 2021 60 125954 10.1016/j.jnc.2021.125954
25. Soba M Ersoy Y Tarakcioğlu Altınay A Erkan B Şik E Application of multiple criteria decision-making methods in assignment place selection Math Probl Eng 2020 2020 6748342 6748313 10.1155/2020/6748342
26. Varma C, Chandrahauns C (2019) A case of HR analytics – to understand effect on employee turnover (June 1, 2019). J Emerg Technol Innov Res 6(6). Available at SSRN: https://ssrn.com/abstract=3619634
27. Wang W Sun R Does organizational performance affect employee turnover? A re-examination of the turnover–performance relationship Public Adm 2020 98 210 225 10.1111/padm.12648
28. Wang X Zhi J A machine learning-based analytical framework for employee turnover prediction J Manag Anal 2021 8 3 351 370 10.1080/23270012.2021.1961318
29. Yang Q Zhang Z You X Chen T Evaluation and classification of overseas talents in China based on the BWM for intuitionistic relations Symmetry 2016 8 137 10.3390/sym8110137
30. Yin J Bi Y Ni Y The impact of COVID-19 on turnover intention among hotel employees: A moderated mediation model J Hosp Tour Manag 2022 51 539 549 10.1016/j.jhtm.2022.05.010
31. Yu X Xu W Wu X Wang X Reinforced exploitation and exploration grey wolf optimizer for numerical and real-world optimization problems Appl Intell 2022 52 8 8412 8427 10.1007/s10489-021-02795-4
32. Zhang L Zheng X Pang Q Zhou W Fast Gaussian kernel support vector machine recursive feature elimination algorithm Appl Intell 2021 51 12 9001 9014 10.1007/s10489-021-02298-2
33. Zhao D Li J Tan Y Yang K Ge B Dou Y Optimization adjustment of human resources based on dynamic heterogeneous network Physica A: Stat Mech Appl 2018 503 45 57 10.1016/j.physa.2018.02.168
34. Zhao W Pu S Jiang D A human resource allocation method for business processes using team faultlines Appl Intell 2020 50 9 2887 2900 10.1007/s10489-020-01686-4
35. Zhao Y, Hryniewicki MK, Cheng F, Fu B, Zhu X (2019) Employee turnover prediction with machine learning: a reliable approach. In: Arai K, Kapoor S, Bhatia R (eds) Intelligent Systems and Applications. IntelliSys 2018. Adv Intell Sys Comput 869. Springer, Cham. 10.1007/978-3-030-01057-7_56
36. Zheng W Zhong J Zhang Q Zhao G MTT: an efficient model for encrypted network traffic classification using multi-task transformer Appl Intell 2022 52 9 10741 10756 10.1007/s10489-021-03032-8
37. Zhou H Wang X Zhu R Feature selection based on mutual information with correlation coefficient Appl Intell 2022 52 5 5457 5474 10.1007/s10489-021-02524-x
38. Zhu X Seaver W Sawhney R Ji S Holt B Sanil GB Upreti G Employee turnover forecasting for human resource management based on time series analysis J Appl Stat 2017 44 8 1421 1440 10.1080/02664763.2016.1214242
| 0 | PMC9734781 | NO-CC CODE | 2022-12-14 23:28:30 | no | Appl Intell (Dordr). 2022 Dec 5;:1-23 | utf-8 | Appl Intell (Dordr) | 2,022 | 10.1007/s10489-022-04294-6 | oa_other |
==== Front
Curr Psychol
Curr Psychol
Current Psychology (New Brunswick, N.j.)
1046-1310
1936-4733
Springer US New York
4086
10.1007/s12144-022-04086-8
Article
How trait gratitude relates to teachers’ burnout and work engagement: job demands and resources as mediators
Nicuță Elena Gabriela [email protected]
Diaconu-Gherasim Loredana R.
Constantin Ticu
grid.8168.7 0000000419371784 Department of Psychology, Faculty of Psychology and Education Sciences, Alexandru Ioan Cuza University, Iași, Romania
5 12 2022
110
27 11 2022
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The benefits of gratitude in the workplace, in general, and for teachers, in particular, are still understudied. In the present study, we investigated whether teachers’ trait gratitude is linked to their work engagement and burnout. Moreover, we explored whether perceived job demands and job resources mediate the relation between employees’ gratitude and these two outcomes. A sample of 312 Romanian teachers participated in the study. Participants filled out questionnaires assessing trait gratitude, perceived job characteristics, as well as burnout and work engagement. Results indicated that teachers’ trait gratitude was positively associated with their work engagement and negatively with burnout. The relation between trait gratitude and work engagement was mediated by perceived job resources, whereas the link between trait gratitude and burnout was mediated by both job demands and job resources. Our findings suggest that educational institutions could cultivate teachers’ gratitude in order to create a healthier and more motivated workforce.
Keywords
Trait gratitude
Burnout
Work engagement
Job demands-resources model
Teachers
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pmcIntroduction
Burnout and work engagement are two distinct indicators of employees’ well-being in the workplace (Maricuțoiu et al., 2017). Burnout was defined as physical, cognitive, and affective exhaustion experienced by employees dealing with a lot of job demands for extended periods of time, as well as a detached attitude (or disengagement) in relation to work (Demerouti et al., 2003). Work engagement, on the other hand, characterizes employees who demonstrate vigor, dedication, and absorption (Schaufeli, 2013). These employees work hard and are persistent when confronted with adversity, find purpose in their work, and are fully concentrated on their tasks.
Teachers’ burnout and work engagement are linked to a variety of important outcomes. Specifically, meta-analytic evidence indicates that teachers’ burnout has a negative influence on students’ academic achievement and motivation (Madigan & Kim, 2021a). Burnout is a predictor of teachers’ depressive symptoms and anxiety (e.g., Burić et al., 2019; Méndez et al., 2020; Shin et al., 2013), self-reported physical symptoms (e.g., Baka, 2015; Vargas Rubilar & Oros, 2021), intention to quit (Madigan & Kim, 2021b), as well as sickness absence from work (e.g., Salvagioni et al., 2022), just to name a few. These negative effects are all the more concerning, seeing the high prevalence rates of burnout in this professional category (García-Carmona et al., 2019). In contrast, teachers’ work engagement is associated with positive outcomes, such as reduced withdrawal intentions (e.g., Mérida-López et al., 2020) an increased sense of teaching efficacy (e.g., Minghui et al., 2018), in addition to higher levels of self-reported job performance and job satisfaction (Høigaard et al., 2012; Li et al., 2017; Song et al., 2018). Therefore, seeking to cultivate teachers’ work engagement and to decrease their burnout symptoms is essential. Being able to achieve this goal requires a comprehensive investigation of the individual and contextual factors that might predict these two outcomes.
According to the job demands-resources (JD-R) theory, employees’ personal resources are important predictors of work engagement and burnout (Bakker & Demerouti, 2017). In this study we examined whether trait gratitude, conceptualized as a personal resource, can protect teachers from depersonalization and emotional exhaustion, as well as promote their work engagement. Research on this topic is still limited, especially in Eastern European countries, such as Romania. Moreover, the underlying mechanisms of these relations were not previously investigated. To advance the literature, the present study explored how trait gratitude is related to burnout and work engagement in a sample of Romanian teachers and whether job characteristics might play a mediating role in these relations.
The relation of trait gratitude with burnout and work engagement
Personal resources refer to “aspects of the self that are generally linked to resiliency” (Hobfoll et al., 2003, p. 632) and have a prominent place in the JD-R theory. These personal traits (e.g., self-efficacy, self-esteem) are positively linked to work engagement and negatively to burnout (e.g., Ott et al., 2019; Wang et al., 2016). Trait gratitude, defined as people’s inclination to observe and value the positive aspects around them (Wood et al., 2010), could also be a valuable personal resource for employees, as it seems to improve their ability to successfully adapt to and impact their work environment. Recently, scholars began exploring the benefits of thankfulness in the workplace and the results showed that trait gratitude was associated with positive outcomes, such as increased job performance and job satisfaction or improved well-being (e.g., Cho, 2019; Cortini et al., 2019; Garg et al., 2022). Further, trait gratitude was shown to be negatively related to burnout in various samples, including teachers (Guan & Jepsen, 2020; Lanham et al., 2012; Lee et al., 2018). Specifically, these studies showed that grateful employees are less likely to experience emotional exhaustion and depersonalization, while also feeling competent and accomplished at work. Of note, in Lee et al.’s study (2018), trait gratitude was a significant predictor of firefighters’ burnout, even after controlling for Big Five personality traits, depression, and anxiety. Moreover, there is some empirical evidence indicating that work-specific gratitude is related to work engagement (e.g., Cain et al., 2019). Thus, employees who experience gratitude more frequently at their jobs also report increased levels of vigor, dedication, and absorption (i.e., work engagement). Nonetheless, no previous studies investigated trait gratitude in relation with work engagement. To advance the literature, we explored how trait gratitude is related to burnout and work engagement in a sample of Romanian teachers. Relying on previous studies, we hypothesized that trait gratitude would be negatively related to employees’ burnout and positively to work engagement.
Job characteristics as antecedents of burnout and work engagement
The JD-R theory (Bakker & Demerouti, 2017; Demerouti et al., 2001) argues that job characteristics (i.e., job demands and job resources) are important determinants of employees’ work-related outcomes. Job demands refer to various aspects of the work environment that put a strain on the employees, whereas job resources are characteristics of the job that help employees reach their work-related targets, by facilitating their own betterment and reducing the adverse impact of high job demands (Demerouti et al., 2001). According to the JD-R model, dealing with job demands (e.g., workload, emotional strain) depletes employees’ energy resources, thus leading to burnout and health issues. In contrast, job resources (e.g., autonomy, feedback, social support) promote employees’ work engagement. When employees view their work environment as resourceful, they are more motivated to repay their organizations by investing additional energy and dedication into their tasks (Schaufeli, 2013). However, when job resources are insufficient, employees cannot fulfill their innate psychological needs, a situation which causes burnout (Van den Broeck et al., 2008; Fernet et al., 2013). Previous studies conducted on various samples provide support for these relations (see Lesener et al., 2019; Mazzetti et al., 2021, for meta-analyses).
Research conducted specifically on teachers showed that social job resources protect teachers from burnout and promote their work engagement (Han et al., 2020; Minghui et al., 2018; Van Droogenbroeck et al., 2014). Opportunities for learning and development, receiving feedback or coaching were also found to be predictive of teachers’ work engagement (Bakker & Bal, 2010; Guglielmi et al., 2016; Shibiti, 2020). On the other hand, job demands, such as student misbehavior, time pressure/ workload, and high emotional demands, were related to teachers’ burnout (e.g., Bottiani et al., 2019; Skaalvik & Skaalvik, 2011; Van Droogenbroeck et al., 2014; Yin et al., 2016). Relying on the JD-R model and the empirical evidence presented above, we hypothesized that social and developmental job resources would be positively related to teachers’ work engagement and negatively related to burnout, whereas job demands would be positively related to burnout.
How trait gratitude relates to burnout and work engagement: The mediating role of job demands and resources
According to the JD-R model (Bakker & Demerouti, 2017), personal resources help employees generate (or at least perceive) more job resources and cope with job demands more effectively. Empirical evidence indicates that personal resources (e.g., self-efficacy, organizational based self-esteem) might predict more job resources (e.g., autonomy, feedback, opportunities for professional development) (e.g., Vera et al., 2012; Xanthopoulou et al., 2009). Personal resources also influence the way employees evaluate their job demands. That is, employees scoring high on optimism, hope, self-efficacy, or resilience report that job demands (e.g., workload, emotional and physical demands, task complexity, etc.) are not as burdensome (Boudrias et al., 2011; Grover et al., 2018).
In this study, we argue that trait gratitude could impact the way teachers perceive job characteristics. The social-cognitive model of trait and state levels of gratitude (Wood et al., 2008) suggests that people who are high in trait gratitude show a bias towards appraising situations in a more positive manner. Specifically, individuals who are more grateful consider that the benefits they receive are more valuable, imply higher costs for the benefactor, and are provided because of the other person’s sincere desire to help. Moreover, when faced with difficulties, grateful people are able to use reinterpretation in order to see the bright side of the situation, as studies found that trait gratitude is associated with positive reframing (Lambert et al., 2009, 2012; Lau & Cheng, 2017; Wood et al., 2007). Relying on these previous contributions, we expected that grateful teachers would evaluate workplace stressors as being less frequent and/or less demanding, in addition to being more inclined to notice and appreciate job resources. Specifically, we hypothesized that gratitude would be positively related to job resources and negatively related to job demands.
Some empirical studies revealed that the relation between personal resources and employee outcomes could be accounted for by job characteristics. In the study conducted by Grover et al. (2018), perceived job resources mediated the relation between psychological capital (i.e., efficacy, optimism, hope, and resilience) and employees’ work engagement. Higher scores on psychological capital were related to higher perceptions of job resources, which in turn were associated with increased work engagement. In another study, Boudrias et al. (2011) found that the relation between personal resources and psychological health at work was explained by perceived job demands. Results showed that employees characterized by increased optimism and resilience reported fewer job demands that exceeded their capacities, which explained why they experienced better psychological health (i.e., reduced distress and increased well-being in the workplace). To advance the literature, we explored whether job demands and resources would mediate the association between trait gratitude, burnout, and work engagement. We hypothesized that job resources would mediate the relation between trait gratitude and work engagement, whereas job demands and job resources would mediate the relation between trait gratitude and burnout.
Method
Participants
The sample included 312 teachers (84.6% women), Mage = 38.44 years, SD = 11.96. On average, participants had been teaching for 14.40 years (SD = 10.80), with 31.4% of participants working in primary schools, 20.8% working in lower secondary programs and 22.4% in high schools. Some participants (25.3%) taught at more than one educational level (e.g., both elementary and lower secondary programs). Most participants were affiliated to educational institutions located in urban areas (59.3%). A small number of participants in our sample (4.2%) were special education teachers (SpEd), whereas the rest of the sample worked in mainstream (MS) institutions.
Procedure
This study was approved by the institutional Ethics Committee (no. 593). Participants were invited to take part in this study by undergraduate students enrolled in a Work Psychology course in exchange for extra credit. Each student recruited one or two teachers. The potential participants received a short description of the study’s goals and informed consent was obtained from those who agreed to participate in the research. Participants filled out the scales online because of the COVID-19 outbreak restrictions.
Measures
Trait gratitude
Participants filled out the Gratitude Questionnaire-6 (6 items; McCullough et al., 2002). Items were rated on a 7- point scale, from 1 = strongly disagree to 7 = strongly agree. A total gratitude score was calculated by summing up the scores of all six items (α = 0.70).
Job demands
A 10-item scale was used to assess job demands on three dimensions. Time pressure (3 items; α = 0.67) and discipline problems (3 items; α = 0.90) were each assessed using items adapted from Skaalvik and Skaalvik (2011) and emotional job demands (4 items; α = 0.87) was measured using items adapted from Taris and Schreurs (2009). All items were scored on a 5-point scale (1 = strongly disagree to 5 = strongly agree). A CFA indicated good fit for a three-factor model, χ2 (32) = 109.04, p < 0.001; NFI = 0.93; CFI = 0.95; RMSEA = 0.08, 90% CI [0.07, 0.10]. An average score was computed separately for each type of job demand. These scales demonstrated good psychometric proprieties in other studies and were related to various outcomes such as employees’ intention to quit, depressed mood, or performance (e.g., Metin et al., 2016; Skaalvik & Skaalvik, 2018).
Job resources
Participants filled out a 15-item scale assessing two types of job resources (social and developmental job resources). Social resources were measured with 9 items adapted from Skaalvik and Skaalvik (2011) evaluating participants’ perceptions of supervisory support (α = 0.92), relations with their colleagues (α = 0.93), and relations with parents (α = 0.87) (each subscale comprising three items). Developmental job resources included feedback and opportunities for professional development. Feedback (α = 0.83) was assessed using three items from the Work Design Questionnaire (Morgeson & Humphrey, 2006), whereas opportunities for professional development (α = 0.90) were measured with three items designed specifically for this study (e.g., My job gives me the opportunity to learn new things). Items were rated from 1 = strongly disagree to 5 = strongly agree. A confirmatory factor analysis (CFA) indicated acceptable fit for a model whereby supervisory support, relations with colleagues, and relations with parents are combined into a higher-order factor (social job resources), whereas feedback and opportunities for professional development loaded onto the developmental job resources factor, χ2(81) = 279.45, p < 0.001; NFI = 0.92; CFI = 0.94; RMSEA = 0.07, 90% CI [0.07; 0.10]. Total average scores were separately computed for social job resources (α = 0.88) and developmental resources (α = 0.87). These scales were previously shown to be related to important outcomes in the workplace, including job satisfaction and employees’ well-being (e.g., Mishima-Santos et al., 2021; Skaalvik & Skaalvik, 2011).
Burnout
Burnout was measured with the Oldenburg Burnout Inventory (OLBI; Halbesleben & Demerouti, 2005). The 16-item scale assesses two dimensions of burnout: exhaustion (8 items) and disengagement (8 items). Items are scored on a 5-point scale, from 1 = strongly disagree to 5 = strongly agree. A confirmatory factor analysis (CFA) indicated poor model fit for a two-factor solution, χ2 (103) = 642.30, p < 0.001; NFI = 0.69; CFI = 0.72; RMSEA = 0.12, 90% CI [0.11, 0.13] and reversed items (i.e., positively framed items) had lower factor loadings. Because positively and negatively framed items of OLBI might convey different meanings (Sedlar et al., 2015), we decided to only use the negatively worded items (see Gruszczynska et al., 2021, for a similar approach). The CFA indicated that a one-factor model using negatively framed items had good fit, χ2 (18) = 54.16, p < 0.001; NFI = 0.94; CFI = 0.96; RMSEA = 0.08, 90% CI [0.05, 0.10]. A total score was therefore computed by averaging negatively worded items only (α = 0.86); higher scores indicate higher levels of burnout. The OLBI questionnaire was previously used to measure burnout in samples of teachers and it relates to their depressive and physical symptoms (e.g., Baka, 2015).
Work engagement
The short Utrecht Work Engagement Scale (9 items; Schaufeli et al., 2006) was used to assess work engagement. The questionnaire measures three dimensions of work engagement, i.e., vigor (α = 0.86), dedication (α = 0.84), and absorption (α = 0.76) (each scale including three items). Participants rated each item on a scale from 0 = never to 6 = always/ daily. Two CFAs indicated that a one-factor model, χ2 (25) = 82.55, p < 0.001; NFI = 0.95; CFI = 0.97; RMSEA = 0.08, 90% CI [0.06, 0.10], fitted the data better compared with a three-factor model, χ2 (19) = 196.07, p < 0.001; NFI = 0.90; CFI = 0.91; RMSEA = 0.15, 90% CI [0.13, 0.17], Δχ2 = 131.52, df = 6, p < 0.01. Therefore, a total score was computed by averaging scores across all items (α = 0.92). The instrument demonstrated good psychometric proprieties in different samples of Romanian employees (Vîrgă et al., 2009).
Socio-demographic and occupational variables
Participants were asked to report their gender, age and tenure (in years), and the type of school they taught in (MS or SpEd school).
Results
Overview of the analyses
First, preliminary analyses were conducted in order to check whether participants’ demographic and occupational variables (i.e., gender, tenure, and type of school) were related to their gratitude, work engagement, or burnout. We also assessed common method bias using Harman's single factor test (Podsakoff et al., 2003). In this statistical procedure, all variables used in a study are entered into an exploratory factor analysis and the unrotated factor matrix is then examined. Common method bias might be present when only one factor emerges or when a single factor accounts for the majority of the covariance in the data. Second, zero-order correlations among the main study variables were computed. Third, structural equation modeling (SEM) in AMOS Graphics 20 was employed to simultaneously test the direct relations of trait gratitude and job characteristics with work engagement and burnout, as well as the meditational hypothesis. To evaluate the model fit, the χ2 statistic, the normative fit index (NFI), the comparative fit index (CFI), and the root mean square error of approximation (RMSEA) were used. The CFI and NFI values ≥ 0.95 (0.90), and RMSEA < 0.06 indicate well-fitting models (Hu & Bentler, 1999). We used Tofighi and MacKinnon’s (2011) method to test the significance of mediation, in which the confidence intervals for the indirect effects are based on the estimated unstandardized path coefficients and their standard errors.
Preliminary analyses
Descriptive statistics for the study variables are presented in Table 1. Participants’ tenure was positively correlated with work engagement, r = 0.13, p = 0.01, and unrelated to burnout, r = 0.04, p > 0.05. SpEd teachers reported higher levels of burnout (M = 3.41, SD = 0.98) and lower levels of work engagement (M = 4.17, SD = 1.30) compared with MS teachers (M burnout = 2.67, SD = 0.82; M work engagement = 4.96, SD = 0.80), t(310) = 3.14 and—3.36, respectively, ps < 0.01. Participants working in SpEd schools (M = 33.84, SD = 4.68) also obtained lower gratitude scores than participants working in MS schools (M = 36.57, SD = 4.77), t(310) =—2.02, p = 0.04. There were no gender differences in work engagement or burnout.Table 1 Descriptive Statistics and Zero-Order Correlations between Main Study Variables
Variable 1 2 3 4 5 6 7 8 9 10 M SD
1. Trait gratitude 36.46 4.79
2. Social resources .36*** 5.71 0.97
3. Developmental resources .28*** .69*** 5.67 1.07
4. Time pressure -.13* -.12* -.02 4.86 1.37
5. Discipline problems -.20*** -.06 .03 .37*** 3.94 1.72
6. Emotional demands -.13* -.05 .10 .55*** .54*** 4.59 1.56
7. Work engagement .46*** .45*** .42*** -.13* -.21** -.11 4.93 0.84
8. Burnout -.42*** -.29*** -.18** .51*** .41*** .49*** -.45*** 2.70 0.83
9. Tenure .09 .06 -.02 .04 -.26*** .00 .13* -.04 14.40 10.80
10. Gender .14** .07 .08 .14** .00 .17** .07 .06 .10
11. Type of school (0 = MS) -.11* -.12* -.04 -.03 .05 .07 -.18** .17** -.03 .04
*p < .05; **p < .01; ***p < .001
To test the common method variance, Harman’s single factor test was used. Eight factors with eigenvalues greater than 1 were extracted, consistent with the eight different variables that were measured in our study. These factors accounted for 59.87% of the total variance, with the first factor explaining only 24.67% of the total variance. These results showed that common method variance does not threaten the validity of the conclusions drawn from the analyses reported below.
Associations among main study variables
Zero-order correlations among the study variable are presented in Table 1. Trait gratitude correlated positively with work engagement, r = 0.46, p < 0.001, and negatively with burnout, r =—0.42, p < 0.001. Gratitude was also negatively associated with time pressure, discipline problems, and emotional demands, rs = -0.13, -0.20, and -0.13, respectively, all ps < 0.05. Further, trait gratitude correlated positively with social and developmental job resources, rs = 0.36 and 0.28, respectively, ps < 0.001. Social and developmental job resources correlated positively with work engagement, rs = 0.45 and 0.42, respectively, ps < 0.001, while also correlating negatively with burnout, rs = -0.29 and -0.18, respectively, ps < 0.01. Time pressure, discipline problems, and emotional demands were positively related to burnout, rs = 0.51, 0.41, and 0.49, all ps < 0.001.
SEM analyses evaluating the study’s hypotheses
Participants’ type of school (MS vs. SpEd) was included in the model as a control variable seeing that it was found to be significantly related to both the independent variable (trait gratitude) and the dependent variables (work engagement and burnout), thus potentially becoming a confounder that could artificially inflate the strength of the relation between these variables (MacKinnon et al., 2000). The hypothesized model had a good fit to data, χ2 (20) = 55.46, p < 0.001, NFI = 0.93, CFI = 0.95, RMSEA = 0.07, 90% CI [0.05, 0.09].1 The model explained 36.2% of the variance of work engagement and 54.3% of the variance of burnout. Trait gratitude was positively related to job resources, β = 0.39, p < 0.001, and negatively related to job demands, β = -0.20, p < 0.001 (see Fig. 1). Further, job resources were positively related to work engagement, β = 0.39, p < 0.001, and negatively related to burnout, β =—0.16, p < 0.001. Job demands were positively related to burnout, β = 0.58, p < 0.001. Gratitude was positively related to work engagement, β = 0.30, p < 0.001, and negatively to burnout, β = -0.24, p < 0.001. Teacher’s type of school (MS vs. SpEd) was significantly related to both burnout, β = 0.10, p < 0.05, and work engagement, β =—0.11, p < 0.05. Job resources mediated the relations of trait gratitude with work engagement, Estimate (SE) = 0.24 (0.05), 95% CI [0.15, 0.35], and burnout, Estimate (SE) = -0.08 (0.03), 95% CI [-0.15, -0.03]. Further, job demands mediated the relations of gratitude with burnout, Estimate (SE) = -0.16 (0.04), 95% CI [-0.24, -0.07].Fig. 1 Results of Structural Equation Modeling Evaluating the Mediational Role of Job Demands and Resources. Note. Standardized path coefficients are reported. The error terms for work engagement and burnout were correlated (r =—.26, p < .001). Exogenous variables (gratitude and type of school) were permited to covary (r =—.11, p < .05). * p < .05; **p < .01; *** p < .001
Discussion
The present research aimed to investigate whether teachers’ trait gratitude is linked to their burnout and work engagement. Moreover, the study examined whether perceived job demands and job resources might explain the relations of trait gratitude with burnout and work engagement.
Our findings indicate that teachers who are more grateful also report higher work engagement and lower burnout. These results are in line with previous research showing that grateful employees are less likely to experience emotional exhaustion and depersonalization (e.g., Lee et al., 2018). To our knowledge, this is the first study to show that teachers who are higher in trait gratitude have the tendency to experience increased levels of work engagement.
Further, our findings showed that, similar to other personal resources (e.g., PsyCap; Grover et al., 2018), trait gratitude influences how teachers evaluate their work context. Grateful teachers reported that their schools provided them with more resources and that they had to deal with lower levels of job demands. These results support the theoretical view that gratitude is intertwined with a positive interpretation bias (Wood et al., 2008). For teachers who are more dispositionally thankful, even small positive changes in the workplace conditions will likely trigger appreciation. Contrastingly, employees who are low on gratitude probably feel entitled to receive even more benefits from their employer and will rapidly get used to the good things that are present in their work environment, a process called hedonic adaption (Lyubomirsky, 2011). While these benefits are taken for granted, the daily hassles and unavoidable shortcomings of life at work are more likely to stand out and affect their well-being. An alternative explanation for these results could be that grateful employees not only perceive more resources in the workplace, but build more resources themselves. First, gratitude may act as a moral motive, prompting people to behave prosocially towards their initial benefactor, as well as towards third-parties (McCullough et al., 2001). Therefore, expressing gratitude and helping others will in the long term benefit the grateful employees by strengthening their social network in the workplace, thus providing them with more social support in the future. In addition to building social resources, gratitude might also help employees consolidate and create other types of job resources (e.g., developmental resources). Gratitude was recently found to correlate with job crafting (Chen et al., 2021). It seems that grateful employees take more responsibility and initiative in the workplace, thus actively shaping their tasks in order to better align their job with their skills and goals. If gratitude determines employees to engage in job crafting behaviors, it should lead to increased job resources, according to the JD-R theory (Bakker & Demerouti, 2017). More work is needed in order to empirically test these relations.
In line with the JD-R theory (Bakker & Demerouti, 2017), job demands correlated with burnout, and job resources were related to both burnout and work engagement. These results bring further support to the idea that job demands and job resources initiate two separate processes – a health impairment process and a motivation process, respectively. Whereas job demands deplete employees’ energy resources, leading to exhaustion and disengagement, job resources help employees increase their levels of vigor, dedication, and absorption, thus enabling them to fulfill their work goals.
A key finding of our study is that job resources mediated the relation between teachers’ trait gratitude and their burnout and work engagement. It seems that teachers who are more thankful will be more likely to take notice of the resources that are available in their schools, which in turn will motivate them to stay engaged and will reduce their risk of developing burnout symptoms. Further, because teachers who are more grateful pay less attention to their job demands, this will also protect them from exhaustion and disengagement. These results align with other studies (Boudrias et al., 2011; Grover et al., 2018) suggesting that perceived work characteristics might explain the link between personal resources and various work outcomes, such as psychological health or work engagement. Future studies might examine other variables that could explain the relation between trait gratitude and employees’ outcomes. For instance, trait gratitude was shown to be a predictor of basic psychological need satisfaction (Reyes et al., 2022). In turn, research suggests that basic psychological need satisfaction influences a plethora of work-relevant variables, such as employees’ work engagement, organizational citizenship behaviors, or turnover intentions (Trépanier et al., 2015; Wörtler et al., 2020). Therefore, future studies might investigate whether basic psychological need satisfaction could be an explanatory mechanism in the relation between trait gratitude and employees’ outcomes.
Theoretical and practical implications
These results add to the literature on the JD-R model, as well as to the growing literature regarding the effects of gratitude in the workplace, by suggesting that thankfulness might be an important personal resource for educators. Our study advances the literature by showing that trait gratitude shapes the way employees perceive job demands and resources. Further, our research is the first to investigate whether perceived job characteristics may play a mediating role in the relation between trait gratitude, burnout, and work engagement. From a practical standpoint, our findings suggest that educational organizations should seek to cultivate employees’ gratitude, in addition to constantly striving to improve their work conditions. For instance, a count-your-blessings intervention might help teachers develop a new sense of appreciation for their work environment, thus positively influencing both work engagement and burnout. There is some evidence suggesting that such an intervention might indeed be effective. For instance, Chan (2011) found that an eight-week pretest/posttest count-your-blessings intervention was effective in reducing Chinese school teachers’ symptoms of emotional exhaustion and in increasing their life satisfaction. Future studies might explore whether the effect of the intervention is attributable to the changes in the way teachers perceive their job demands and resources.
Limitations and future directions
Despite investigating a previously underexplored yet important topic, this study is not without limitations. First, causal inferences cannot be drawn due to the cross-sectional and correlational design of the present research. It could be argued that job characteristics precede and determine teachers’ gratitude. That is, educators who have more resourceful and less stressful work environments have more reasons to be grateful. However, we measured trait gratitude, not work-specific gratitude. Although job resources and demands might have a direct influence on work-specific gratitude, it is unlikely that they will impact one’s disposition to experience gratitude in general. The imbalance in gender distribution is another limitation of the present research, restricting the generalizability of our results. However, our sample reflects gender distribution in this professional category, seeing that, at least in Romania, most teachers working in primary and secondary educational institutions are women. In order to further improve the generalizability of these results, future studies could examine the relations among trait gratitude, work engagement and burnout in other professions, which involve a different set of job demands and resources. Another limitation of the present work is that it did not take into account the distinction between hindrance and challenge job demands. Whereas hindrance demands are positively associated with exhaustion, challenge demands are positively related to vigor (Van den Broeck et al., 2010). Personal resources (such as professional self-efficacy) were shown to influence teachers’ perception of job demands. That is, teachers higher in self-efficacy perceived more challenge demands and fewer hindrance demands (Ventura et al., 2015). Gratitude could play a similar role. Scholars could explore the relation between gratitude and job demands in more depth, by testing whether gratitude has an effect on the way employees categorize job stressors as hindrances or challenges.
Conclusion
In summary, the present research shed some light on why thankful teachers are less vulnerable to burnout and more engaged. Gratitude seems to be an important personal resource which exerts a positive influence on how educators perceive job characteristics, thus protecting their health and improving their motivation. These relations should be examined in more depth by future studies using longitudinal designs. More research is needed to uncover other potential benefits of trait gratitude for the performance and well-being of teachers, as well as for the school communities they work in.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on request.
Declarations
The present study was carried out in accordance with the Declaration of Helsinki for research involving humans. Approval for this study was obtained from the Ethics Committee of the Faculty of Psychology and Education Sciences, Alexandru Ioan Cuza University of Iași.
Informed consent
Informed consent was obtained from all participants included in the study.
Competing interests
None.
1 Fit indices for the model that did not include participats’ type of school were very similar, χ2 (15) = 44.60, p < .001, NFI = .94, CFI = .95, RMSEA = .08, 90% CI [.05, .10].
Publisher's note
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References
Baka L Does job burnout mediate negative effects of job demands on mental and physical health in a group of teachers? Testing the energetic process of job demands-resources model International Journal of Occupational Medicine and Environmental Health 2015 28 2 335 346 10.13075/ijomeh.1896.00246 26182928
Bakker AB Bal MP Weekly work engagement and performance: A study among starting teachers Journal of Occupational and Organizational Psychology 2010 83 1 189 206 10.1348/096317909X402596
Bakker AB Demerouti E Job demands–resources theory: Taking stock and looking forward Journal of Occupational Health Psychology 2017 22 3 273 285 10.1037/ocp0000056 27732008
Bottiani JH Duran CA Pas ET Bradshaw CP Teacher stress and burnout in urban middle schools: Associations with job demands, resources, and effective classroom practices Journal of School Psychology 2019 77 36 51 10.1016/j.jsp.2019.10.002 31837727
Boudrias J-S Desrumaux P Gaudreau P Nelson K Brunet L Savoie A Modeling the experience of psychological health at work: The role of personal resources, social-organizational resources, and job demands International Journal of Stress Management 2011 18 4 372 395 10.1037/a0025353
Burić I Slišković A Penezić Z Understanding teacher well-being: A cross-lagged analysis of burnout, negative student-related emotions, psychopathological symptoms, and resilience Educational Psychology 2019 39 9 1136 1155 10.1080/01443410.2019.1577952
Cain IH Cairo A Duffy M Meli L Rye MS Worthington EL Jr Measuring gratitude at work The Journal of Positive Psychology 2019 14 4 440 451 10.1080/17439760.2018.1484936
Chan DW Burnout and life satisfaction: Does gratitude intervention make a difference among Chinese school teachers in Hong Kong? Educational Psychology 2011 31 7 809 823 10.1080/01443410.2011.608525
Chen, H., Yang, X., Xia, W., Li, Y., Deng, Y., & Fan, C. (2021). The relationship between gratitude and job satisfaction: The mediating roles of social support and job crafting. Current Psychology, 1–8. 10.1007/s12144-021-01658-y
Cho S Effects of social support and grateful disposition on employees’ psychological well-being The Service Industries Journal 2019 39 11–12 799 819 10.1080/02642069.2018.1444755
Cortini M Converso D Galanti T Di Fiore T Di Domenico A Fantinelli S Gratitude at work works! A mix-method study on different dimensions of gratitude, job satisfaction, and job performance Sustainability 2019 11 14 3902 10.3390/su11143902
Demerouti E Bakker AB Nachreiner F Schaufeli WB The job demands-resources model of burnout Journal of Applied Psychology 2001 86 3 499 512 10.1037/0021-9010.86.3.499 11419809
Demerouti E Bakker AB Vardakou I Kantas A The convergent validity of two burnout instruments: A multitrait-multimethod analysis European Journal of Psychological Assessment 2003 19 1 12 23 10.1027/1015-5759.19.1.12
Fernet C Austin S Trépanier SG Dussault M How do job characteristics contribute to burnout? Exploring the distinct mediating roles of perceived autonomy, competence, and relatedness European Journal of Work and Organizational Psychology 2013 22 2 123 137 10.1080/1359432X.2011.632161
García-Carmona M Marín MD Aguayo R Burnout syndrome in secondary school teachers: A systematic review and meta-analysis Social Psychology of Education 2019 22 1 189 208 10.1007/s11218-018-9471-9
Garg, N., Mahipalan, M., Poulose, S., & Burgess, J. (2022). Does Gratitude Ensure Workplace Happiness Among University Teachers? Examining the Role of Social and Psychological Capital and Spiritual Climate. Frontiers in Psychology, 13. 10.3389/fpsyg.2022.849412
Grover SL Teo STT Pick D Roche M Newton CJ Psychological capital as a personal resource in the JD-R model Personnel Review 2018 47 4 968 984 10.1108/PR-08-2016-0213
Gruszczynska E Basinska BA Schaufeli WB Within-and between-person factor structure of the Oldenburg Burnout Inventory: Analysis of a diary study using multilevel confirmatory factor analysis PLoS ONE 2021 16 5 e0251257 10.1371/journal.pone.0251257 33989326
Guan B Jepsen DM Burnout from emotion regulation at work: The moderating role of gratitude Personality and Individual Differences 2020 156 109703 10.1016/j.paid.2019.109703
Guglielmi D Bruni I Simbula S Fraccaroli F Depolo M What drives teacher engagement: A study of different age cohorts European Journal of Psychology of Education 2016 31 3 323 340 10.1007/s10212-015-0263-8
Halbesleben JR Demerouti E The construct validity of an alternative measure of burnout: Investigating the English translation of the Oldenburg Burnout Inventory Work & Stress 2005 19 3 208 220 10.1080/02678370500340728
Han J Yin H Wang J Zhang J Job demands and resources as antecedents of university teachers’ exhaustion, engagement and job satisfaction Educational Psychology 2020 40 3 318 335 10.1080/01443410.2019.1674249
Hobfoll SE Johnson RJ Ennis N Jackson AP Resource loss, resource gain, and emotional outcomes among inner city women Journal of Personality and Social Psychology 2003 84 3 632 643 10.1037/0022-3514.84.3.632 12635922
Høigaard R Giske R Sundsli K Newly qualified teachers’ work engagement and teacher efficacy influences on job satisfaction, burnout, and the intention to quit European Journal of Teacher Education 2012 35 3 347 357 10.1080/02619768.2011.633993
Hu LT Bentler PM Cutoff criteria for fit indexes in covariance structure analysis: Conventional criteria versus new alternatives Structural Equation Modeling: A Multidisciplinary Journal 1999 6 1 1 55 10.1080/10705519909540118
Lambert NM Graham SM Fincham FD Stillman TF A changed perspective: How gratitude can affect sense of coherence through positive reframing The Journal of Positive Psychology 2009 4 6 461 470 10.1080/17439760903157182
Lambert NM Fincham FD Stillman TF Gratitude and depressive symptoms: The role of positive reframing and positive emotion Cognition & Emotion 2012 26 4 615 633 10.1080/02699931.2011.595393 21923564
Lanham M Rye M Rimsky L Weill S How gratitude relates to burnout and job satisfaction in mental health professionals Journal of Mental Health Counseling 2012 34 4 341 354 10.17744/mehc.34.4.w35q80w11kgpqn26
Lau BHP Cheng C Gratitude and coping among familial caregivers of persons with dementia Aging & Mental Health 2017 21 4 445 453 10.1080/13607863.2015.1114588 26613417
Lee JY Kim SY Bae KY Kim JM Shin IS Yoon JS Kim SW The association of gratitude with perceived stress and burnout among male firefighters in Korea Personality and Individual Differences 2018 123 205 208 10.1016/j.paid.2017.11.010
Lesener T Gusy B Wolter C The job demands-resources model: A meta-analytic review of longitudinal studies Work & Stress 2019 33 1 76 103 10.1080/02678373.2018.1529065
Li M Wang Z Gao J You X Proactive personality and job satisfaction: The mediating effects of self-efficacy and work engagement in teachers Current Psychology 2017 36 1 48 55 10.1007/s12144-015-9383-1
Lyubomirsky S Folkman S Hedonic adaptation to positive and negative experiences The Oxford handbook of stress, health, and coping 2011 Oxford University Press 200 224
MacKinnon DP Krull JL Lockwood CM Equivalence of the mediation, confounding and suppression effect Prevention Science 2000 1 4 173 181 10.1023/A:1026595011371 11523746
Madigan DJ Kim LE Does teacher burnout affect students? A systematic review of its association with academic achievement and student-reported outcomes International Journal of Educational Research 2021 105 101714 10.1016/j.ijer.2020.101714
Madigan DJ Kim LE Towards an understanding of teacher attrition: A meta-analysis of burnout, job satisfaction, and teachers’ intentions to quit Teaching and Teacher Education 2021 105 103425 10.1016/j.tate.2021.103425
Maricuțoiu LP Sulea C Iancu A Work engagement or burnout: Which comes first? A meta-analysis of longitudinal evidence Burnout Research 2017 5 35 43 10.1016/j.burn.2017.05.001
Mazzetti, G., Robledo, E., Vignoli, M., Topa, G., Guglielmi, D., & Schaufeli, W. B. (2021). Work Engagement: A meta-Analysis Using the Job Demands-Resources Model. Psychological Reports, 00332941211051988. 10.1177/00332941211051988
McCullough ME Kilpatrick SD Emmons RA Larson DB Is gratitude a moral affect? Psychological Bulletin 2001 127 2 249 266 10.1037/0033-2909.127.2.249 11316013
McCullough ME Emmons RA Tsang JA The grateful disposition: A conceptual and empirical topography Journal of Personality and Social Psychology 2002 82 1 112 127 10.1037/0022-3514.82.1.112 11811629
Méndez I Martínez-Ramón JP Ruiz-Esteban C García-Fernández JM Latent profiles of burnout, self-esteem and depressive symptomatology among teachers International Journal of Environmental Research and Public Health 2020 17 18 6760 10.3390/ijerph17186760 32948075
Mérida-López S Extremera N Sánchez-Álvarez N The interactive effects of personal resources on teachers’ work engagement and withdrawal intentions: A structural equation modeling approach International Journal of Environmental Research and Public Health 2020 17 7 2170 10.3390/ijerph17072170 32218113
Metin UB Taris TW Peeters MCW van Beek I Van den Bosch R Authenticity at work—A job-demands resources perspective Journal of Managerial Psychology 2016 31 2 483 499 10.1108/JMP-03-2014-0087
Minghui L Lei H Xiaomeng C Potměšilc M Teacher efficacy, work engagement, and social support among Chinese special education school teachers Frontiers in Psychology 2018 9 648 10.3389/fpsyg.2018.00648 29867634
Mishima-Santos, V., Sticca, M. G., & Pérez-Nebra, A. R. (2021). Wellbeing and Work Design in Brazilian Teleworkers. Frontiers in Psychology, 4612. 10.3389/fpsyg.2021.733640
Morgeson FP Humphrey SE The Work Design Questionnaire (WDQ): Developing and validating a comprehensive measure for assessing job design and the nature of work Journal of Applied Psychology 2006 91 6 1321 1339 10.1037/0021-9010.91.6.1321 17100487
Ott AR Haun VC Binnewies C Negative work reflection, personal resources, and work engagement: The moderating role of perceived organizational support European Journal of Work and Organizational Psychology 2019 28 1 110 123 10.1080/1359432X.2018.1550076
Podsakoff PM MacKenzie SB Lee J-Y Podsakoff NP Common method biases in behavioral research: A critical review of the literature and recommended remedies Journal of Applied Psychology 2003 88 5 879 903 10.1037/0021-9010.88.5.879 14516251
Reyes V Unanue W Gómez M Bravo D Unanue J Araya-Veliz C Cortez D Dispositional Gratitude as an Underlying Psychological Process Between Materialism and the Satisfaction and Frustration of Basic Psychological Needs: A Longitudinal Mediational Analysis Journal of Happiness Studies 2022 23 2 561 586 10.1007/s10902-021-00414-0
Salvagioni DAJ Mesas AE Melanda FN González AD de Andrade SM Burnout and long-term sickness absence from the teaching function: A cohort study Safety and Health at Work 2022 3 2 201 206 10.1016/j.shaw.2022.01.006
Schaufeli WB Truss C Alfes K Delbridge R Shantz A Soane E What is engagement? Employee Engagement in Theory and Practice 2013 Routledge
Schaufeli WB Bakker AB Salanova M The measurement of work engagement with a short questionnaire: A cross-national study Educational and Psychological Measurement 2006 66 4 701 716 10.1177/0013164405282471
Sedlar N Šprah L Tement S Sočan G Internal structure of an alternative measure of burnout: Study on the Slovenian adaptation of the Oldenburg Burnout Inventory (OLBI) Burnout Research 2015 2 1 1 7 10.1016/j.burn.2015.02.001
Shibiti R Public school teachers’ satisfaction with retention factors in relation to work engagement SA Journal of Industrial Psychology 2020 46 1 1 9 10.4102/sajip.v46i0.1675
Shin H Noh H Jang Y Park YM Lee SM A longitudinal examination of the relationship between teacher burnout and depression Journal of Employment Counseling 2013 50 3 124 137 10.1002/j.2161-1920.2013.00031.x
Skaalvik EM Skaalvik S Teacher job satisfaction and motivation to leave the teaching profession: Relations with school context, feeling of belonging, and emotional exhaustion Teaching and Teacher Education 2011 27 6 1029 1038 10.1016/j.tate.2011.04.001
Skaalvik EM Skaalvik S Job demands and job resources as predictors of teacher motivation and well-being Social Psychology of Education 2018 21 5 1251 1275 10.1007/s11218-018-9464-8
Song JH Chai DS Kim J Bae SH Job performance in the learning organization: The mediating impacts of self-efficacy and work engagement Performance Improvement Quarterly 2018 30 4 249 271 10.1002/piq.21251
Taris TW Schreurs PJ Explaining worker strain and learning: How important are emotional job demands? Anxiety, Stress & Coping 2009 22 3 245 262 10.1080/10615800802460401 19253169
Tofighi D MacKinnon DP RMediation: An R package for mediation analysis confidence intervals Behavior Research Methods 2011 43 3 692 700 10.3758/s13428-011-0076-x 21487904
Trépanier SG Fernet C Austin S A longitudinal investigation of workplace bullying, basic need satisfaction, and employee functioning Journal of Occupational Health Psychology 2015 20 1 105 116 10.1037/a0037726 25151460
Van den Broeck A Vansteenkiste M De Witte H Lens W Explaining the relationships between job characteristics, burnout, and engagement: The role of basic psychological need satisfaction Work & Stress 2008 22 3 277 294 10.1080/02678370802393672
Van den Broeck A De Cuyper N De Witte H Vansteenkiste M Not all job demands are equal: Differentiating job hindrances and job challenges in the Job Demands-Resources model European Journal of Work and Organizational Psychology 2010 19 6 735 759 10.1080/13594320903223839
Van Droogenbroeck F Spruyt B Vanroelen C Burnout among senior teachers: Investigating the role of workload and interpersonal relationships at work Teaching and Teacher Education 2014 43 99 109 10.1016/j.tate.2014.07.005
Vargas Rubilar N Oros LB Stress and burnout in teachers during times of pandemic Frontiers in Psychology 2021 12 756007 10.3389/fpsyg.2021.756007 34899498
Ventura M Salanova M Llorens S Professional self-efficacy as a predictor of burnout and engagement: The role of challenge and hindrance demands The Journal of Psychology 2015 149 3 277 302 10.1080/00223980.2013.876380 25590343
Vera M Salanova M Lorente L The predicting role of self-efficacy in the Job Demands-Resources Model: A longitudinal study Estudios De Psicología 2012 33 2 167 178 10.1174/021093912800676439
Vîrgă D Zaborilă C Sulea C Maricuțoiu L Romanian adaptation of Utrecht Work Engagement Scale: The examination of validity and reliability Psihologia Resurselor Umane 2009 7 1 58 74 10.24837/pru.v7i1.402
Wang Y Huang J You X Personal resources influence job demands, resources, and burnout: A one-year, three-wave longitudinal study Social Behavior and Personality: An International Journal 2016 44 2 247 258 10.2224/sbp.2016.44.2.247
Wood AM Joseph S Linley PA Coping style as a psychological resource of grateful people Journal of Social and Clinical Psychology 2007 26 9 1076 1093 10.1521/jscp.2007.26.9.1076
Wood AM Maltby J Stewart N Linley PA Joseph S A social-cognitive model of trait and state levels of gratitude Emotion 2008 8 2 281 290 10.1037/1528-3542.8.2.281 18410201
Wood AM Froh JJ Geraghty AW Gratitude and well-being: A review and theoretical integration Clinical Psychology Review 2010 30 7 890 905 10.1016/j.cpr.2010.03.005 20451313
Wörtler B Van Yperen NW Barelds DP Do individual differences in need strength moderate the relations between basic psychological need satisfaction and organizational citizenship behavior? Motivation and Emotion 2020 44 2 315 328 10.1007/s11031-019-09775-9
Xanthopoulou D Bakker AB Demerouti E Schaufeli WB Reciprocal relationships between job resources, personal resources, and work engagement Journal of Vocational Behavior 2009 74 3 235 244 10.1016/j.jvb.2008.11.003
Yin H Huang S Wang W Work environment characteristics and teacher well-being: The mediation of emotion regulation strategies International Journal of Environmental Research and Public Health 2016 13 9 907 10.3390/ijerph13090907 27649216
| 0 | PMC9734782 | NO-CC CODE | 2022-12-14 23:28:30 | no | Curr Psychol. 2022 Dec 5;:1-10 | utf-8 | Curr Psychol | 2,022 | 10.1007/s12144-022-04086-8 | oa_other |
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Inflammopharmacology
Inflammopharmacology
Inflammopharmacology
0925-4692
1568-5608
Springer International Publishing Cham
36471190
1086
10.1007/s10787-022-01086-9
Review
Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases
http://orcid.org/0000-0001-5737-4626
Welcome Menizibeya O. [email protected]
1
Dogo Dilli 2
Nikos E. Mastorakis 3
1 grid.449465.e 0000 0004 4653 8113 Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Nile University of Nigeria, Plot 681 Cadastral Zone, C-00 Research and Institution Area, Jabi Airport Road Bypass, FCT, Abuja, Nigeria
2 grid.449465.e 0000 0004 4653 8113 Department of Surgery, Faculty of Clinical Sciences, College of Health Sciences, Nile University of Nigeria, Abuja, Nigeria
3 grid.6981.6 0000 0004 0438 9594 Technical University of Sofia, Klement Ohridksi 8, Sofia, 1000 Bulgaria
6 12 2022
129
2 8 2022
11 10 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Heart diseases and related complications constitute a leading cause of death and socioeconomic threat worldwide. Despite intense efforts and research on the pathogenetic mechanisms of these diseases, the underlying cellular and molecular mechanisms are yet to be completely understood. Several lines of evidence indicate a critical role of inflammatory and oxidative stress responses in the development and progression of heart diseases. Nevertheless, the molecular machinery that drives cardiac inflammation and oxidative stress is not completely known. Recent data suggest an important role of cardiac bitter taste receptors (TAS2Rs) in the pathogenetic mechanism of heart diseases. Independent groups of researchers have demonstrated a central role of TAS2Rs in mediating inflammatory, oxidative stress responses, autophagy, impulse generation/propagation and contractile activities in the heart, suggesting that dysfunctional TAS2R signalling may predispose to cardiac inflammatory and oxidative stress disorders, characterised by contractile dysfunction and arrhythmia. Moreover, cardiac TAS2Rs act as gateway surveillance units that monitor and detect toxigenic or pathogenic molecules, including microbial components, and initiate responses that ultimately culminate in protection of the host against the aggression. Unfortunately, however, the molecular mechanisms that link TAS2R sensing of the cardiac milieu to inflammatory and oxidative stress responses are not clearly known. Therefore, we sought to review the possible role of TAS2R signalling in the pathophysiology of cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. Potential therapeutic significance of targeting TAS2R or its downstream signalling molecules in cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction is also discussed.
Keywords
Cardiac bitter taste receptors
Cardiac inflammation
Contractile dysfunction
Arrhythmia
Novel therapeutics
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pmcIntroduction
Heart diseases are a global epidemic (Gianluigi Savarese 2017; Khan et al. 2020) that pose an immense public health concern with a prevalence of over 500 million, affecting all age groups (Ahern et al. 2011), including children (Musa et al. 2017). Heart diseases are the leading cause of death worldwide (Ahern et al. 2011; Roth et al. 2017). In 2015 alone, mortality due to heart diseases was estimated at about 18 million, representing 32% of all deaths in the world (Roth et al. 2017). Alas, billions of dollars are spent in the management of heart diseases, causing a huge burden to the sufferers, relatives, caregivers and the health care system (Muka et al. 2015; Gheorghe et al. 2018; Roth et al. 2020). Though scientific advances, preventive measures and campaigns against heart diseases (Khan et al. 2020) as well as health care system reforms in the cardiovascular setting (Obama 2016; Weintraub and Boden 2017; León-Cortés et al. 2019) may have brought about higher quality healthcare (Clarke et al. 2017), regrettably, the incidence and mortality of heart diseases have constantly increased over the past years (Gianluigi Savarese 2017; Khan et al. 2020; Emmons-Bell and Johnson 2022). Even so, the prevalence and mortality of heart diseases are projected to rise substantially in the next decades, if adequate measures are not taken to address the growing menace of these diseases on the society (Kelly and Donovan 1995).
Over the past few years, accumulating data have consistently implicated cardiac inflammation in etiopathogenetic mechanism of a range of heart diseases, including myocarditis (Lu et al. 2015; Tschöpe et al. 2021), pericarditis, Kawasaki syndrome (Jui et al. 2021), cardiac vessel endotheliitis (Maccio et al. 2021), infective endocarditis (Jui et al. 2021), myocardial infarction/ischaemic heart disease (Moreira et al. 2015), cardiomyopathies (Meraviglia et al. 2021; Tschöpe et al. 2021), angina pectoris (Lu et al. 2015), coronary artery disease/atherosclerotic heart disease (Moreira et al. 2015), cardiac arrhythmias (Shenasa and Shenasa 2017), congestive heart failure (Murphy et al. 2020), hypertensive heart disease (Shenasa and Shenasa 2017), rheumatic and non-rheumatic heart valve disease (Lars et al. 2007; Lee and Choi 2018; Passos et al. 2021), cardiac amyloidosis (Siegismund et al. 2018; McVeigh and Tennyson 2020), and human heart senescence (de Arellano et al. 2019). In addition, inflammatory response plays a pivotal role in the pathogenic mechanism that drives cardiac involvement in systemic diseases (Knockaert 2007; Veinot 2010). Cardiac inflammation is a cellular and tissue response to adverse stimuli due to the activation of signalling cascades that control the secretion of inflammatory mediators in resident immunocytes and cardiac cells as well as recruitment of inflammatory cells, triggered by microbial agents, toxins, cellular debris or toxigenic metabolites. Though inflammatory response constitutes a key defence mechanism against pathogenic aggression or adverse environmental stimuli (Furman et al. 2019), inadequate or chronic inflammatory response can potentially lead to harmful consequences resulting in the development of diseases (Williams et al. 2019; Tsampasian et al. 2021). Despite intense efforts and research investigation directed towards the identification of the pathogenetic basis of cardiac inflammation, the underlying cellular and molecular mechanisms responsible for triggering the inflammatory responses in the cells and tissues of the heart are yet to be fully understood.
Interestingly, inflammatory responses usually occur concurrently with oxidative stress in several pathophysiological conditions, including heart diseases (Neri et al. 2015; Dludla et al. 2019). Oxidative stress is an adverse cellular and tissue response due to dysbalance between the production of reactive species and the endogenous antioxidant defence system (Pizzino et al. 2017) resulting in cell and tissue damage (van der Pol et al. 2019). Indeed, independent research groups have demonstrated an association between proinflammatory responses and the generation of reactive species that promotes oxidative stress (Ji and Li 2016; Dludla et al. 2019). Correspondingly, progress in cardiac research has identified oxidative stress cascades as fundamental pathophysiological pathways in the development and progression of heart diseases (van der Pol et al. 2019). In the heart, oxidative stress induces cardiomyocyte hypertrophy, apoptosis and Ca2+ overload via oxidation of membrane phospholipids, proteins and DNA molecules (Shibata et al. 2021). Regrettably, however, the mechanisms of development of oxidative stress in heart diseases are not completely known, thereby substantiating the need to step up research investigation against this global epidemic and search for new frontiers that may lead to the development of novel therapeutics for some heart diseases.
The relatively recent finding that bitter taste receptor (TAS2R)-expressing cells play a critical role as innate immune sentinels (Lee and Cohen 2013a) has sparked research interest on the functional role and the molecular mechanisms of these nodal signalling units of the plasma membrane (Welcome 2020a; Welcome and Mastorakis 2021; Welcome et al. 2021). TAS2Rs are transmembrane proteins of the G-protein-coupled receptors that sense “bitter” molecules to initiate intracellular signalling downstream multiple cytoplasmic acceptors, mediating cellular responses that ultimately lead to elimination of the aggression or protection of the cell or tissue from damage (Welcome 2020a). So far, 25 TAS2Rs have been discovered in humans (Meyerhof et al. 2010), 35 TAS2Rs in rat and mice (Wu et al. 2005), 3 TAS2Rs in chicken and 50 TAS2Rs in frog (Di Pizio and Niv 2015). The amino acid sequence of TAS2Rs from different species share a similarity of about 23–86% (Chandrashekar et al. 2000; Shi et al. 2003; Wu et al. 2005). TAS2Rs are activated by hundreds of different substances, including denatonium, amarogentin, caffeine, chloroquine, quinine (Bayer et al. 2021), N-phenylthiourea, phenylthiocarbamide, cycloheximide (Meyerhof et al. 2010; Gradinaru et al. 2022), xanthohumol, dextromethorphan, methimazole, and glimepiride (D’Urso and Drago 2021). These taste receptors are ubiquitously expressed in many cells and tissues of the body. TAS2Rs were first identified in taste bud cells of the oral cavity and were thought to only detect and prevent the ingestion of potentially poisonous “bitter” molecules (Adler et al. 2000; Chandrashekar et al. 2000). Thereafter, TAS2Rs were discovered in other regions of the gut—stomach, ileum and colon (Rozengurt 2006; Vegezzi et al. 2014), which suggested that these nodal signalling units may play a number of essential roles other than detecting poisonous “bitter” molecules (Rozengurt 2006). TAS2Rs were also discovered in the upper respiratory tract, where they were shown to sense toxigenic and microbial molecules to mediate responses that ultimately lead to elimination of the pathogenic molecules (Gulbransen et al. 2008; Tizzano et al. 2011), in part, by activating the innate immune system to confer protection on the respiratory epithelium (Kinnamon and Finger 2019). TAS2Rs are expressed in blood monocytes or monocyte-derived macrophages (Grassin-Delyle et al. 2019), neutrophils (Maurer et al. 2015), keratinocytes (Wölfle et al. 2015), thymus (Panneck et al. 2014; Soultanova et al. 2015), vascular smooth muscles (Lund et al. 2013), pancreas (Gaida et al. 2016), brain (Singh et al. 2011), thyroid gland (Clark et al. 2015), testis (Xu et al. 2013), spermatozoa (Governini et al. 2020), prostate (Dupre and Martin 2017; Martin et al. 2019), vagina, cervix, endometrium, myometrium, placenta, ovary (Dupre and Martin 2017; Welcome 2020a), urethra, ureter, bladder (Welcome 2020a; Welcome et al. 2021), and kidney (Liu et al. 2015b). Relatively more recently, independent groups of researchers have identified the expression of TAS2Rs in cells and tissues of the heart (Foster et al. 2013, 2014; Manson et al. 2014), indicating that these receptors may be involved in mediating the inflammatory, oxidative stress responses, autophagy (Hamdard et al. 2019b), cardiac rhythm (Yuan et al. 2020) and contractile activities (Manson et al. 2014; Bloxham et al. 2020; Yuan et al. 2020) in this vital organ.
Indeed, several lines of evidence suggest that cardiac TAS2Rs may play a role in both cardiac and vascular diseases (Foster et al. 2015; D’Urso and Drago 2021; Kamila and Agnieszka 2021). The role of cardiac TAS2Rs in mediating reduction in spontaneous beating rate of the sinoatrial node and left ventricular relaxation (Yuan et al. 2020) indicates that dysfunction in cardiac TAS2Rs may necessarily affect impulse generation or propagation and mechanical efficiency of the heart, thereby predisposing to contractile dysfunction and arrhythmia. Comparable data have also been reported by Manson et al. (2014). Moreover, cardiac TAS2Rs can act as gateway surveillance units that detect pathogenic components, including the microbial quorum-sensing signal molecules. Thus, under normal condition, stimulation of TAS2R by microbial molecules results in downstream signalling that activates the intracellular acceptors responsible for protecting the cell via secretion of anti-inflammatory and -microbial mediators. However, dysfunctional cardiac TAS2R signalling or excessive action of the pathogenic or danger molecules can result in collateral tissue damage, predisposing to disease development (Foster et al. 2015; D’Urso and Drago 2021; Kamila and Agnieszka 2021).
Therefore, defects in cardiac TAS2R signalling can initiate inflammatory and oxidative stress responses, as well as disorder of cardiac rhythm and contractile force of the heart in cardiac diseases. Unfortunately, the molecular mechanisms that link TAS2R sensing of the cardiac milieu to inflammatory and oxidative stress responses are not clearly known. Hence, we sought to review the possible role of TAS2R signalling in the pathophysiology of cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. First, we discuss the contemporary view of the mechanisms of inflammation and oxidative stress and their roles in the development of heart diseases. Second, we discuss the expression of TAS2R, its ligands, functional roles and signal transduction mechanism in the heart. Third, we describe the role of dysfunctional TAS2R signalling in cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. Further, we attempt to delineate the molecular pathways, linking TAS2R sensing of microbial and toxigenic molecules with inflammatory, oxidative stress responses, arrhythmia and contractile dysfunction in heart diseases. Potential therapeutic significance of targeting TAS2R or its downstream signalling molecules in cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction is also discussed.
Contemporary view of the mechanisms of cardiac inflammation and oxidative stress and their roles in disruption of cardiac rhythm and contractility in heart diseases
Cardiac inflammatory and oxidative stress responses are triggered by multiple pathogenetic factors
The inflammatory and oxidative stress responses in the heart are triggered by multiple factors, which include pathogens (bacteria, viruses, fungi, parasites) (Zhang et al. 2020), gut microbiota disorder (Mesquita et al. 2021), tissue injury (Chen et al. 2018), acute emotional and chronic psychological stress (Wirtz 2017), toxins and irritants (Lu et al. 2015; Chen et al. 2018). These factors mediate the release of pathogenic and danger molecules that stimulate the pattern-recognition receptors on local and distant immunocytes (macrophages, leukocytes, natural killer and cytotoxic CD8+ T cells (Jui et al. 2021)) as well as cardiac cells to initiate the inflammatory and oxidative stress response (Mesquita et al. 2021). Therefore, gut microbiota disorder, for example, causes gut epithelial barrier leakage with corresponding increase in circulating microbial particles that promote chronic low-grade inflammatory response, which is considered as a central player in cardiac failure, diastolic dysfunction, arrhythmia, ageing, and fibrotic heart disease (Mesquita et al. 2021). Interestingly, multiple pathogenetic factors have been reportedly shown to trigger cardiac pathology via gut microbiota disorder (Mesquita et al. 2021).
Indeed, cardiac diseases are associated with numerous inflammatory mediators, including interleukin (IL)-1β, IL-6, tumour necrosis factor-α (TNF-α) (Lu et al. 2015; Chen et al. 2018), macrophage chemoattractant protein-1 (MCP-1), and C-reactive protein (Jui et al. 2021). Similarly, reactive species play a crucial role in the development and progression of many heart diseases (Pashkow 2011). In addition, secretion of alarmins such as matrix metalloprotease (MMP)-2, -9 (Jui et al. 2021), high-mobility group box 1 (HMGB-1), cardiac myosin, heat shock protein (HSP)-60, HSP-70, hyaluronic acid, fibronectin-extra domain A, extracellular adenosine triphosphate (ATP), circulating RNA, nuclear and mitochondrial DNA (Silvis et al. 2020), Ca2+-binding S100 proteins (S100A7, S100A8, S100A9 and S100A12) (Yan 2014; Lu et al. 2019; Silvis et al. 2020) also contribute to the signalling cascades that promote the development of heart diseases. Accordingly, Zhang et al. (2020) showed that these factors promote aberrant cardiac metabolism and mitochondrial dysfunction that further worsen the abnormalities of cardiac rhythm and contractility in heart diseases (Zhang et al. 2020). Thus, the inflammatory mediators, reactive species, and alarmins represent fundamental drivers of the pathogenetic processes in cardiac pathology (Wadley et al. 2013; Zhang et al. 2017a; Papaconstantinou 2019).
Though the mechanisms are not exactly clear, cardiac inflammatory signalling is closely associated with oxidative stress response in the heart (Ooi et al. 2017; Zhang et al. 2017a; Wu et al. 2021b). Recent investigation has implicated reactive isolevuglandin, a toxic lipid peroxidation byproduct and γ-ketoaldehyde, as a possible molecular switch, connecting cardiac inflammation to oxidative stress. Ngwenyama et al. (2021) showed that myocardial oxidative stress triggers the generation of reactive isolevuglandin molecules that act as cardiac antigens to stimulate the T cell receptor (Ngwenyama et al. 2021) to promote the development of heart failure (May-Zhang et al. 2018), cardiac senescence, atherosclerotic and hypertensive heart disorders (Aschner et al. 2021), including high salt-induced heart disease (Ruggeri Barbaro et al. 2021). Data from both animal and human research (Ruggeri Barbaro et al. 2021) have revealed that reactive isolevuglandin formation due to high salt diet (Ruggeri Barbaro et al. 2021), myocardial oxidative stress (Ngwenyama et al. 2021), pressure overload (Shang et al. 2019), and lipopolysaccharide (LPS)-induced inflammation in mice (Mayorov et al. 2019) can initiate the activation of monocytes, dendritic cell, and secretion of the proinflammatory cytokines TNF-α, IL-1β, IL-6, IL-17A (Dikalova et al. 2020; Ruggeri Barbaro et al. 2021), and reactive species (superoxide anions, and reactive nitrogen species) (Dikalova et al. 2020). Thus, isolevuglandin may serve as a therapeutic target in the treatment of certain heart diseases. Indeed, the isolevuglandin scavengers, 2-hydroxybenzylamine (Shang et al. 2019; Ngwenyama et al. 2021) and (4-(4-aminomethyl)-3-hydroxyphenoxy)butyl)-triphenylphosphonium (Mayorov et al. 2019; Dikalova et al. 2020) have been shown to attenuate the pathological sequelae of left ventricular hypertrophy and heart failure in both animal and human cell lines.
Pathological activation and phenotype switching of resident cardiac immunocytes are critical to inflammatory and oxidative stress responses in the heart
Macrophages are primary resident immunocytes involved in both inflammatory and oxidative stress responses in several disorders, including heart diseases (Hu et al. 2020). These resident immunocytes play a central role in initiating, maintaining, and resolving the inflammatory and oxidative stress responses through the secretion of cytokines, chemokines and growth factors (Liu et al. 2021). The pathogenic factors that initiate inflammatory and oxidative stress responses in the heart concomitantly cause pathological activation of the cardiac immunocytes, initiating the phenotype switching of non-activated macrophage (M0) to the proinflammatory subtype M1 that propagates the inflammatory processes (Orekhov et al. 2019). Research data have shown that generation of M1 macrophage is triggered by LPS or interferon-gamma (IFN-γ), whereas IL-4 and IL-13 mediate the polarisation of M2 macrophage (Liu et al. 2021). Investigators have reported that the proinflammatory cytokines/chemokines released in the heart following the action of pathological factors activate the cell surface receptors of the resting resident macrophages with increased generation of the M1 proinflammatory over the M2 anti-inflammatory phenotype (Hu et al. 2019). The activated M1 macrophage secretes proinflammatory factors such as IL-1β, IL-6, IL-12, IL-23, TNF-α, nitric oxide (NO), inducible NO synthase (iNOS), MCP-1, IFNγ, prostaglandins (PGE2), and MMPs to promote inflammation (Aimo et al. 2020; Liu et al. 2021). However, the M2 phenotype expresses the cluster of differentiation (CD) 14, CD80, CD163, CD200, and CD206 receptors and secretes anti-inflammatory factors, including IL-10, C–C motif chemokine ligand 17 (CCL17), CCL22, and CCL24 to blunt the inflammatory reactions, thereby enhancing tissue repair (Aimo et al. 2020; Kishore and Petrek 2021). Moreover, the macrophage precursors—monocytes can directly polarise into M1- or M2-like phenotypes or their respective isoforms to control inflammatory response (Orekhov et al. 2019; Lu et al. 2020).
Therefore, data from both animal (Hu et al. 2019) and human (Dai et al. 2021) studies have revealed that pathological processes resulting in heart diseases are associated with M1 macrophage polarisation, concomitantly with inhibition of M2 macrophage recruitment in the heart. For instance, Liu et al. (2015a, b) demonstrated M1 polarisation in a rat model of myocardial infarction along with disordered Ca2+ waves, which stimulated the extracellular Ca2+ receptor, CaSR, which in turn activated the NLRP3 (nucleotide-binding oligomerisation domain, leucine-rich repeats, pyrin domain-containing protein 3) inflammasome via phospholipase C (PLC)—inositol 1,4,5-triphosphate (IP3) pathway (Liu et al. 2015a). The authors also reported the secretion of collagen, α-SMA (alpha smooth muscle actin) and MMP-2/-9 (Liu et al. 2015a), which are implicated in cardiac fibrosis—a crucial process in the pathogenetic mechanism of myocardial infarction (Talman and Ruskoaho 2016; CHEN et al. 2021). In contrast, TIMP-2 (tissue inhibitor of matrix metalloproteinase) expression was downregulated in cardiac fibroblasts via IL-1β/IL-1 receptor (Liu et al. 2015a). TIMP-2 is highly expressed in the myocardium, and required for pro-MMP-2 activation and MMP-2 inhibition. TIMP-2 plays multiple roles in cardiac physiology, including electrical coupling among myocardial cells. For instance, Givvimani et al. (2013) showed decreased expression of myocardial connexin (Cx) 37 and 43 in TIMP-2 knockout mice compared with control animals (Givvimani et al. 2013). ((Cx43 is required for the maintenance of electrical and mechanical synchrony in the heart (vide infra)). In addition, MMP-2 and TIMP-2 dysbalance plays an important role in the development of cardiomyopathy (Li et al. 2010) and heart failure (Kobusiak-Prokopowicz et al. 2018) in both animals and humans. Thus, TIMP-2/MMP-2 axis may serve as an important molecular target in the treatment of some cardiac diseases.
Furthermore, the M1 phenotype within the myocardium can mediate inflammatory processes by internalising and accumulating oxidised low-density lipoprotein, leading to the formation of “foam cells” in atherosclerotic plaques of the coronary vessels, which in turn may cause myocardial ischaemia and necrosis (Bonetti et al. 2021). However, phenotype conversion between M1 and M2 has been documented and depends on the activity of the dominant signalling molecules. For instance, M1 conversion to M2 occurs by selective apoptosis of M1 macrophages and maybe induced by iNOS/NO (Albina et al. 1989; Mills 2012; Lu et al. 2020), TNF/TNF receptor 1, and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways (Lu et al. 2020). Interestingly, some pharmacological agents can attenuate cardiac inflammation and oxidative stress by promoting the polarisation of M2 over M1 phenotype or conversion of M1 to M2 phenotype. Correspondingly, Zhou et al. (2020) demonstrated specific inhibition of M1 polarisation by attenuating CD11c, iNOS, IL-6 and MCP-1 and augmenting CD206 and IL-10 expression in M2 via suppression of the nuclear factor κB (NF-κB) and Notch1 signalling upon treatment with recombinant human IL-37 in LPS- and IFN-γ-stimulated THP-1 monocytes (Zhou et al. 2020). Comparable results have been reported for other pharmacological agents (Zhou et al. 2015; Saqib et al. 2018; Davoodvandi et al. 2019), including drugs currently used in the clinic (He and Marneros 2014; He et al. 2021). For example, both preclinical (Garcia et al. 2007; Spaulding et al. 2018) and clinical (Cerisano et al. 2014) studies have shown that acute administration of the tetracycline-class antibiotic, doxycycline in myocardial infarction considerably ameliorates cardiac dysfunction by inhibiting the proinflammatory macrophage and mediators. In an open-label, randomised, phase II trial (ClinicalTrials.gov: NCT00469261), doxycycline (100 mg b.i.d. for 7 days) in addition to standard therapy substantially enhanced left ventricular function and reduced the infarct size in patients with acute ST-segment elevation myocardial infarction and low (< 40%) left ventricular ejection fraction (Cerisano et al. 2014). Several investigators have consistently shown that the beneficial effects of doxycycline on the heart are mainly due to the suppression of intracellular matrix metalloproteinase (MMP)-2 (Fan et al. 2014; Berry et al. 2015), MMP-9 (Fan et al. 2014), secretory phospholipase A2 activity (Berry et al. 2015), and M2-type macrophage polarisation (He and Marneros 2014b), while also upregulating and normalising the distribution of Cx43 in the infarct zone (Fan et al. 2014). (The role of Cx43 in cardiac physiology is discussed below). These data corroborate the essential role of this broad-spectrum antibiotic in abrogating the proinflammatory stress responses of the heart (Kandasamy et al. 2010).
Inflammatory and oxidative stress responses in the heart are responsible for disruption of cardiac rhythm and contractility via connexon and calcium signalling defects
Emerging data indicate that the detrimental effects of inflammation and oxidative stress in the heart are mediated via dysfunctional connexon, a major type of gap junction protein expressed in the heart. Research investigation has consistently shown that C×40, C×43, and C×45 are expressed in relative and distinct combination in different regions of the heart (Severs 2002; Severs et al. 2008). However, C×43 is the best characterised cardiac gap junction connexon protein with the most important role in cardiac physiology. In the myocardium of a healthy heart, the expression of C×43 is very high (Eckardt et al. 2004; Takanari et al. 2016), whereas in the cardiac conduction system, its expression is low (Eckardt et al. 2004). The myocardial Cx43 not only forms the gap junction that constitutes a critical component of the intercalated disc (Palatinus et al. 2012; Takanari et al. 2016), but also forms hemichannels, which represent crucial players in cardiac ionic homeostasis (Hirschhäuser et al. 2021). Therefore, myocardial Cx43 are required for direct cell-to-cell contact, movement of ions and signalling molecules to maintain cardiac electrical coupling (Takanari et al. 2016) and synchrony (Palatinus et al. 2012) that ensure a regulated contractile activity of the heart (Severs 2002).
Concomitantly with decreased C×43 protein expression in high glucose-stimulated AC16 human cardiomyocytes, Thakur et al. (2021) demonstrated upregulation of troponin-I, HSP-60, RAGE (receptor for advanced glycation endproducts), HMGB-1, toll-like receptor (TLR)-4, and CXC chemokine receptor (CXCR)-4 (Thakur et al. 2021). The reduction of Cx43 expression in left ventricular hypertrophy induced by type-2 diabetes mellitus in rats was associated with reduced expression of heme-oxygenase 1 (HO-1) and increased level of TNFα and asymmetric dimethylarginine (ADMA) (Leffler and Abdel-Rahman 2019, 2020). ADMA is a cardiac biomarker and risk factor for heart diseases that acts as an endogenous competitive inhibitor of NOS (Böger 2005; Hou et al. 2018), formed during proteolysis by protein methyl transferases via methylation of L-arginine sites of protein molecules (Bulau et al. 2007). ADMA has been demonstrated to inhibit the expression and heterogeneous localisation of C×43 (Jia et al. 2009; Tsang et al. 2013). Under normal condition, 10% of ADMA is formed daily and subsequently excreted in the urine. The remaining 90% is metabolised by dimethylarginine dimethylaminohydrolase (DDAH) to dimethylamine and L-citrulline (Tsikas 2020). Deficiency of DDAH due to cardiomyocyte injury or apoptosis is the primary cause of elevated circulating ADMA (Tsikas 2020). Interestingly, DDAH has been shown to attenuate left ventricular dysfunction after myocardial infarction by inhibiting oxidative stress and apoptotic biomarkers (Hou et al. 2018).
The secretion of inflammatory, oxidative stress and pro-fibrotic mediators due to C×43 dysfunction can trigger dysregulation of spontaneous generation of excitation by the cardiac pacemakers and impulse conduction via disruption of ionic homeostasis and redox potential, thereby predisposing to disorders of cardiac rhythm and contraction (Palatinus et al. 2012; Li et al. 2013; Andelova et al. 2021). Consistent with previous data (Takanari et al. 2016), several pieces of evidence have shown that C×43 breakdown, modification or remodelling in heart diseases essentially impairs the gap junction function through disruption of its charge, size, organisation and distribution—representing a distinct feature of cardiac arrhythmia in many heart diseases (Severs et al. 2008; Palatinus et al. 2012). Truly, several dysfunctions of the heart, including cardiac electrical instability have been associated with C×43 dysfunction in animal models of cardiac specific C×43 knockout (Gutstein et al. 2001; Eckardt et al. 2004). Similarly, a marked reduction in the expression of C×43 mRNA and protein levels in the left ventricle of ischaemic cardiomyopathy and idiopathic dilated cardiomyopathy was reported (Dupont et al. 2001). Though the mechanisms underlying connexon-induced elevation of proinflammatory, oxidative stress and pro-fibrotic molecules that subsequently results in cardiac pathology are not fully understood, researchers have previously demonstrated the association of endothelial C×43 knockout with hypotension, bradycardia, and elevation of angiotensin I and II in experimental animals (Liao et al. 2001). Indeed, the involvement of regional (organ-specific) angiotensin system in inflammatory and oxidative responses is extensively been discussed in the literature (Leung 2007; Rodriguez-Pallares et al. 2008; Labandeira-Garcia et al. 2017; Tsai et al. 2018; Milanesi et al. 2019). Regrettably, however, little is known about the role of intrinsic angiotensin system of the heart in cardiac inflammation, oxidative stress and fibrosis.
The cardiac C×43 also interacts with several ions, including Na+ (Delmar and Liang 2012) and Ca2+ (Takanari et al. 2016) to control cardiac rhythm via cross-talks in the ventricular cardiomyocytes. Thus, disorders in C×43 function can directly affect Na+ and Ca2+ transport across the sarcolemma (Delmar and Liang 2012; Takanari et al. 2016). Accordingly, dysfunctional Ca2+ signalling has been shown to mediate the detrimental effects of inflammatory and oxidative stress responses in the heart. Research data indicate that increased activity of Ca2+ signalling via calmodulin/Ca2+-calmodulin protein kinase II (CaM/CaMKII) regulates C×43 expression and impulse conduction in a diseased heart (Takanari et al. 2016). Dries et al. (2021) demonstrated CaMKII involvement in susceptibility to arrhythmia, via spontaneous Ca2+ release, in cryoinjured subendocardium of experimental rats (Dries et al. 2021). Therefore, investigators have reliably established that inhibition of CaMKII results in decreased tissue excitability (Procida et al. 2009) and susceptibility to arrhythmia (Dries et al. 2021). Similar findings were revealed by Takanari et al. (2016) who demonstrated augmentation of conduction velocity and C×43 expression in the intercalated disc of CaMKII knockout AC3-I mice subjected to pressure overload (Takanari et al. 2016). Researchers have demonstrated a heightened predisposition to inflammatory responses in the heart following experimental CaMKII activation. Thus, Suetomi et al. (2018) reported that CaMKIIδ actively participates in detection and transduction of pressure overload to trigger the activation of NF-κB and NLRP3 inflammasome (Suetomi et al. 2018). These molecular sensors of inflammation mediate an increased secretion of pro-fibrotic molecules, proinflammatory cytokines and chemokines in cardiomyocytes, along with macrophage activation, which predispose to arrhythmia and contractile dysfunction in heart diseases, including myocardial infarction (Suetomi et al. 2019). Similar findings are reported elsewhere (Ling et al. 2013; Willeford et al. 2018). As a matter of fact, inhibition of CaMKII reportedly attenuated the expression of proinflammatory and pro-fibrotic molecules (Suetomi et al. 2019). Likewise, Jiang et al. (2020) demonstrated attenuation of myocardial injury via inhibition of CaMKII by tilianin, a TAS2R agonist (Jiang et al. 2020). Though the role of CaMKII in cardiac pathology is not exactly clear, Gray and co-workers (2017) have previously demonstrated a differential regulation of CaMKII isoforms—CaMKIIδ, CaMKIIδB and CaMKIIδC in the development of myocardial ischaemia or infarction via NF-κB signalling (Gray et al. 2017). Further research on the role of specific isoforms of CaMKII in cardiac inflammation, oxidative stress, fibrosis and apoptotic cell death is important for understanding the underlying molecular mechanisms in some heart diseases.
Phosphorylation reactions at specific sites of the C×43 are also critical to the changes in its expression and functions in heart diseases (Procida et al. 2009). These reactions may be triggered by CaMKII (Procida et al. 2009), mitogen-activated protein kinase (MAPK) (Yang et al. 2019; Hirschhäuser et al. 2021), and protein kinase C (PKC) (Lampe et al. 2000; Hirschhäuser et al. 2021). Although certain phosphorylation of cardiac connexon may be protective, abnormal connexon phosphorylation can lead to serious abnormalities in electrical coupling and synchrony (Hirschhäuser et al. 2021). Thus, research on identification of novel pharmacological agents that can mediate favourable phosphorylation reactions of connexon in a region-dependent manner may provide important information for identification of new therapeutic options for some heart diseases. Correspondingly, a novel class of pharmacological agents—known as C×43 mimetic peptides, which stimulate favourable connexon phosphorylation are currently been developed for potential treatment of heart diseases. For instance, Jiang et al. (2019) reported a marked attenuation of left ventricular dysfunction and arrhythmia, accompanied by increased phosphorylation of C×43 at serine 368 by PKCε, following treatment with 25–amino acid α-carboxyl terminus 1 peptide (C×43 mimetic peptide αCT1) or a variant of αCT1 (known as αCT11) in a mouse model of myocardial ischaemia–reperfusion injury (Jiang et al. 2019).
Bitter taste receptors of the heart and their signal transduction mechanism
Cardiac bitter taste receptors: subtypes, ligands and functions
TAS2Rs were discovered in cardiomyocytes and fibroblasts of the rat and human heart by Foster and co-workers (Foster et al. 2013). The following year, same group of researchers established the expression of TAS2R subtypes 108, 137, and 143 in the mouse heart (Foster et al. 2014). Several subtypes of these receptors have been identified in the cells and tissues of both murine and human heart (Table 1).Table 1 Summary of bitter taste receptor expression in the heart
Cells and tissues of the heart Model Types of taste receptors Comments Reference
Whole heart tissue Mice TAS2R108, TAS2R137, TAS2R143 Concentration-dependent decrease in contraction (Foster et al. 2014)
Left ventricle, sinoatrial node and cardiomyocytes Rat TAS2R108 Concentration-dependent decrease in contraction (Yuan et al. 2020)
Aorta and pulmonary arteries Guinea-pig, mice, human TAS2R3, TAS2R4, TAS2R10, TAS2R14 Strong endothelium-independent relaxation (Manson et al. 2014)
Aortic smooth muscle tissue Rat TAS2R and gustducin Increased muscle tone (Manson et al. 2014)
Whole heart tissue Chinese Fast Yellow Chicken TAS2R – (Hamdard et al. 2019a)
Whole heart tissue Chinese fast yellow chicken TAS2R1, 2, 7, α-gustducin ↑PLCβ2, IP3R3, TRPM5, CALPN1, dyanin, GPX1, CAT, SOD1; ↓CASP, Bcl-2 (Bcl-2l1, Mcl, BID, NOXA), beclin-1* (Hamdard et al. 2019b)
Cardiac myocytes and fibroblasts Rat and human TAS2R – (Foster et al. 2013)
Whole heart tissue Human and mice TAS2R – (Foster et al. 2015)
Whole heart tissue Rodent TAS2R14 – (D’Urso and Drago 2021)
Note: *in acute administration at low-moderate doses (5 and 20 mg/kg), but not in chronic and large dose, Bcl-2 B cell lymphoma 2, Bcl-2l1 Bcl-2 like 1, BID—BH3-interacting domain death agonist, CALPN1 calpain 1, CASP caspase, CAT catalase, GPx1 glutathione peroxidase, Mcl Mantle cell lymphoma, NOXA NADPH (nicotinamide adenine dinucleotide phosphate) oxidase activator, SOD superoxide dismutase
The cardiac TAS2R mediates the sensation of bitter tasting (i.e. bitter tastants or bitterants), toxigenic or pathogenic molecules. There are thousands of TAS2R ligands. All currently known bitterants are available on the “database of bitter molecules”: BitterDB (http://bitterdb.agri.huji.ac.il) and PlantMolecularTasteDB (www.plantmoleculartastedb.org).
Similar to other extra-oral tissues, cardiac TAS2Rs may play multiple physiological roles, including immune defence against pathogens (D’Urso and Drago 2021) and local metabolic regulation, at least in part, by regulating cytoplasmic protein kinases and cyclic AMP levels (Manson et al. 2014; D’Urso and Drago 2021). TAS2Rs are also involved in the maintenance of endothelial homeostasis (D’Urso and Drago 2021).
Data also indicate a role of TAS2Rs in cardiac contractility (Foster et al. 2014; Bloxham et al. 2020) and vascular tone (Manson et al. 2014; Bloxham et al. 2020). Yuan et al. (2020) investigated the effect of the TAS2R agonists, quinine and chloroquine on Langendorff-perfused hearts in adult rat and demonstrated increased expression of TAS2R mRNA and α-gustducin in the left ventricle (Yuan et al. 2020). Furthermore, the researchers showed that stimulation of TAS2R with either quinine or chloroquine resulted in increased R-R interval and QRS duration (Yuan et al. 2020). Foster et al. (2014) demonstrated the involvement of mouse cardiac TAS2R 108, 137, and 143 in decreased force of ventricular contraction (Foster et al. 2014). Interestingly, previous investigation revealed this relaxation effect of TAS2R agonists in the two major arteries connecting the heart—aorta and pulmonary arteries (Manson et al. 2014). These results suggest that TAS2Rs may play an important role in the pathophysiology of cardiac and vascular diseases, including disorders of the coronary arteries (Manson et al. 2014; Foster et al. 2014).
Yuan et al. (2020) demonstrated increased expression of TAS2R and α-gustducin and reduced spontaneous beating rate in the sinoatrial node following treatment with the TAS2R agonists, quinine and chloroquine in Langendorff-perfused hearts of adult rats (Yuan et al. 2020), suggesting that cardiac TAS2R may play a crucial role in the regulation of cardiac rhythm. Furthermore, the involvement of cardiac TAS2R in the regulation of cardiac rhythm may be essential for the prevention of arrhythmia, in part, via regulation of C×43 activity (see “Bitter taste receptors, cardiac contractility and rhythm: bitter taste receptor agonists modulate cardiac contractility and pacemaker activity via Ca2+-, cyclic AMP- and PDE-dependent mechanisms” and “Molecular signalling pathways, linking bitter taste receptor sensing of pathogenic and toxigenic molecules with inflammatory, oxidative stress responses, arrhythmia and contractile dysfunction in heart diseases”).
The expression of TAS2Rs in the heart suggests that these nodal signalling units of the plasma membrane are critical for evaluating the chemical composition of blood and tissue fluid, serving as gateway surveillance units that sense and mobilise protective mechanisms against the transport of noxious or toxigenic molecules into the cells and tissues of the heart (D’Urso and Drago 2021). Thus, pharmacological agents that act on cardiac TAS2Rs can be harnessed for potential therapeutics in some cardiac diseases (Foster et al. 2015). Indeed, some phytochemicals and their derivatives acting as TAS2R agonists have been identified as promising therapeutic agents for potential treatment of several disorders, including heart diseases (vide infra) (Kamila and Agnieszka 2021). Therefore, research has revealed that denatonium benzoate, an agonist of TAS2R1, 2, 7, and α-gustducin, at low dose (5 mg/kg) and short period of treatment (i.e. 7 days) causes a decrease in the expression of apoptosis and autophagy-related genes—caspase (Casp) 2, Casp3, Casp7, Casp9, Bcl-2l1 (B cell lymphoma 2 like 1), Mcl (mantle cell lymphoma), Bid (BH3-interacting domain death agonist), and Noxa (NADPH oxidase activator), along with increased expression of antioxidant enzymes or mediators such as glutathione peroxidase 1 (Gpx1), catalase (CAT), superoxide dismutase 1 (SOD1) and calpain-1 in whole heart tissues of experimental animals (Hamdard et al. 2019b). However, at higher doses and chronic treatment with denatonium benzoate, Hamdard et al. (2019a, b) demonstrated increased expression of the apoptosis and autophagy-related genes, suggesting that TAS2R activation may be beneficial at low doses and acute treatment period (Hamdard et al. 2019b).
Furthermore, Burt and coauthors demonstrated that treatment of HL-1 mouse cardiac myocytes with flufenamic acid (10 μM) decreases Ca2+ oscillations followed by an overall increase in intracellular Ca2+ level as well as depolarisation of the mitochondrial membrane (Burt et al. 2013). Flufenamic acid is a TAS2R14 agonist (Meyerhof et al. 2010) and a member of the anthranilic acid derivative class of nonsteroidal anti-inflammatory drugs (Chi et al. 2011). Though it is not exactly clear whether the anti-inflammatory effect of flufenamic acid is due to its stimulatory action on TAS2R, available data suggest that this TAS2R14 agonist can modulate the expression of COX-2 gene via interaction with the NF-κB pathway (vide infra) or NADH oxidase signalling (Hamdard et al. 2019b). Indeed, activation of TAS2R1, 8, 10, 13, 14, and 38 by the human gut microbiota-derived quorum-sensing signal molecule, 3-oxo-C12:2-HSL in LPS- and IFNγ-stimulated RAW264.7 macrophages reportedly resulted in decreased expression of the proinflammatory cytokines IL-1β and TNFα via modulation of the NF-κB, Janus kinases/Signal transducer and activator of transcription (JAK/STAT) and TNF signalling pathways (Coquant et al. 2022). Similar cardioprotective effects have been reported for the TAS2R agonists genistein in preclinical studies (Bai and Wang 2019; Chen et al. 2019) and clinical trial (ClinicalTrials.gov: NCT00287690), and epigallocatechin-3-gallate in preclinical studies (Xuan and Jian 2016; Reddy et al. 2020), and clinical trials (ClinicalTrials.gov: NCT02015312; aus dem Siepen et al. 2015). However, it is not exactly clear how these agonists exert their protective effects on the heart via TAS2R-activated intracellular signalling.
Besides the TAS2R agonists, a few molecules have been identified to act as TAS2R antagonists in taste receptor-expressing cells. Probenecid ((p-(dipropylsulfamoyl)benzoic acid)) is an inhibitor of the multidrug resistance protein 1 transporter, approved by the United States Food and Drug Administration, and clinically used for the treatment of gout in humans. Probenecid was identified to inhibit the human type TAS2R16, -38, and -43 through an allosteric mechanism of action (Greene et al. 2011). Roland et al. (2014) demonstrated that 6,3'-dimethoxyflavanone, 4'-fluoro-6-methoxyflavanone, and 6-methoxyflavanone inhibit denatonium benzoate- and epigallocatechin-3-gallate-mediated activation of TAS2R14 and -39 by reversible insurmountable antagonism (Roland et al. 2014). Antagonists of TAS2Rs also include homoeriodictyol (TAS2R14, 39 and 43) (Tiroch et al. 2021), eriodictyol (TAS2R14, 39) (Ley et al. 2006), enterodiol (TAS2R10) (Ley et al. 2006, 2012), 2,4-dihydroxybenzoic acid vanillylamide (unknown TAS2R subtype) (Ley et al. 2006), [2]-gingerdione and its homologue [3]-gingerdione (unknown TAS2R subtype) (Ley et al. 2008), sakuranetin, 6-methoxysakuranetin, and jaceosidin (TAS2R31) (Fletcher et al. 2011). Research is required to explore and clarify the mechanisms of TAS2R antagonism, its implication on cellular signalling, the clinical significance and potential therapeutic effects of TAS2R antagonists in cardiac diseases.
It should be mentioned that the mechanism of TAS2R–ligand interactions is yet to be fully elucidated and the pharmacology of TAS2R is poorly defined (Devillier et al. 2015; Jaggupilli et al. 2016; Medapati et al. 2022). There is severe lack of data on the mechanism of deactivation of TAS2R after it has been activated by a noxious stimulant. Notwithstanding, available data indicate that the activation of TAS2R causes a conformational change in the receptor (Jaggupilli et al. 2016), which may lead to its deactivation, thereby preventing its continued stimulation. It is currently not clear whether the activation of this taste receptor causes it to subsequently undergo proteolysis or other mechanisms of deactivation. It is also not clear whether a feedback mechanism is involved in the control of TAS2R activity. Therefore, further research is required to unravel the pharmacology of TAS2R–ligand interactions.
Signal transduction mechanism of cardiac bitter taste receptors
Upon activation by certain metabolites, toxigenic or microbial molecules, TAS2Rs relay their signal downstream the cytoplasm (Fig. 1), which under normal condition, is required to resolve cellular or tissue injury (Welcome 2020a; Welcome and Mastorakis 2021). However, disordered signalling or excessive activation of TAS2Rs by pathological molecules can initiate cellular or tissue damage, characterised by proinflammatory and oxidative stress responses (Welcome 2020a; Welcome and Mastorakis 2021; Welcome et al. 2021). Notwithstanding, however, there are peculiarities in the responses or mechanisms of signal transduction of TAS2Rs in some regions of the body. Therefore, in addition to activation and recruitment of macrophages and other immunocytes in the heart, the cardiac TAS2Rs respond to stimuli via transduction cascades involving the activation of phosphodiesterase (PDE)-dependent pathways and downregulation of cyclic AMP. The pathways of signal transduction of cardiac TAS2Rs are summarised in Fig. 1.Fig. 1 Signal transduction mechanisms of cardiac bitter taste receptors (TAS2R). The pathogenic or toxigenic molecules activate TAS2R (Freund et al. 2018) to trigger the dissociation of α-gustducin from the βγ subunit. The former stimulates the membrane bound enzyme, adenylate cyclase (AC). This enzyme produces cyclic adenosine monophosphate (AMP) in the presence of adenosine triphosphate (ATP) (Jeon et al. 2011; Workman et al. 2018; Xie et al. 2018). Cyclic AMP activates some ion channels and intracellular enzymes, including protein kinase A (PKA), which phosphorylates its downstream targets. However, cyclic AMP is hydrolysed by phosphodiesterases (PDE3, -4) to form 5’AMP, thereby decreasing the level of activated PKA (Foster et al. 2014). The βγ subunit stimulates phospholipase Cβ (PLCβ), which mediate the formation of diacylglycerol (DAG) and 1,4,5-inositol trisphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). IP3 stimulates IP3 receptor (IP3R) to mediate cytosolic release of Ca2+. The increase in cytosolic Ca2+ activates transient receptor potential cation channel, subfamily M, member 5 (TRPM5), calcium homeostasis modulator 1 (CALHM1), and ryanodine receptor 2 (RyR2) of the sarcoplasmic reticulum (SR) (Chandrashekar et al. 2000; Jeon et al. 2011; Workman et al. 2018; Xie et al. 2018). Elevation of cytosolic Ca2+ may cause ATP secretion via P2XY channel (Welcome et al. 2015). However, increase in Ca2+ level is only transient and not able to cause contraction of the muscle cell. DAG activates protein kinase C (PKC), which phosphorylates other intracellular proteins and membrane receptors such as Ca2+-calmodulin protein kinase II (CaMKII), angiotensin II receptor (Ang IIR), connexins (Cx) (Manson et al. 2014; Welcome et al. 2015)
Emerging role of cardiac bitter taste receptors in cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction: cellular and molecular mechanisms
Data have consistently shown that TAS2Rs can act as immune sensors by detecting not only the danger-associated molecular patterns, but also microbial components to mobilise protective measures against the pathogenic invasion or aggression (Manson et al. 2014; Hamdard et al. 2019b; Welcome 2020a; D’Urso and Drago 2021; Welcome and Mastorakis 2021). Accordingly, TAS2Rs are now considered as integral components of the sensory (Palmer 2007; Barham et al. 2013) and innate immune system (Gulbransen et al. 2008; Tizzano et al. 2011). Therefore, cardiac TAS2Rs may function as immune cystocytes or sentinels that effectively monitor and maintain the cardiac immediate environment to ensure uninterrupted functioning of the heart. Furthermore, previous studies have revealed a potential role of these receptors as critical mediators of inflammatory and oxidative stress responses (Hamdard et al. 2019b; Welcome 2020a; Welcome and Mastorakis 2021). Very recent data suggest a possible role of cardiac TAS2Rs in the pathophysiology of arrhythmia and contractile dysfunction in heart diseases (vide infra).
Cardiac bitter taste receptors sense the “quorum” to mobilise defensive mechanisms against pathogenic aggression
Research has shown that TAS2Rs can sense the “quorum” to regulate the activities of pathogens by detecting the quorum-sensing signal molecules (Gulbransen et al. 2008; Tizzano et al. 2011). Quorum-sensing signal molecules are substances produced by pathogens that enable them communicate with each other, share information about cell density and adjust to gene expression until sufficient quantity of the pathogens is available to counteract the host defence mechanisms (Rajput et al. 2016). Quorum-sensing signal molecules are essential in secretion of virulence factors, biofilm formation, motility, etc. (Rajput et al. 2016). As a matter of fact, the virulence of pathogens, in part, depends on the quantity of quorum-sensing signal molecules synthesised in the host (Wu et al. 2021a). All currently identified quorum-sensing signal molecules are available in specialised repositories, namely SigMol Database (http://bioinfo.imtech.res.in/manojk/sigmol), which harbours about 1380 molecules (Rajput et al. 2016), and QSIdb (http://qsidb.lbci.net/), a quorum-sensing interference (QSI) database with several hundreds of quorum-sensing signal molecules (Wu et al. 2021a). Table 2 shows some quorum-sensing signal molecules produced by cardiotrophic pathogens.Table 2 Pathogens (bacteria, and parasites and viruses) and their quorum sensing signal molecules and evidence about their involvement in cardiac infection
Pathogen Genera/types Quorum-sensing signal molecule Evidence of involvement in cardiac infection
Gram-positive bacteria Bacillus sp. (e.g. Bacillus cereus), Listeria sp., Enterococcus sp., Streptococcus pordonii, and Staphylococcus sp. (e.g. S. aureus) Oligopeptides, thiolactone, PlcR, Npr, and PapR (autoinducing peptides) [166,167, 168] Endocarditis (Fernández Guerrero et al. 2007; Guerrero et al. 2009; Thomas et al. 2012; Ferrand et al. 2013; Lamond et al. 2021); myocarditis (McGee et al. 2018; Strnadel et al. 2018)
Gram-negative bacteria Escherichia coli Autoinducer (AI)-3 (Zhou et al. 2016) Endocarditis (Quiring and Burke 2021)
Stenotrophomonas Maltophilia (Xanthomonas maltophilia and Pseudomonas maltophilia), X. campestris Homologue of farnesoic acid: cis-11-methyl-2-dodecenoic acid, α,β unsaturated fatty acid (diffusible signal factor, DSF) [178,179] Endocarditis (Mehta et al. 2000)
Acinetobacter sp. (A. baumannii), Aeromonas hydrophyla, Pseudomonas sp., Serratia marcescens, and Yersinia sp. N-acyl-L-homoserine lactone, N-(3-oxoacyl)-L-homoserine lactone, N-(3-hydroxyacyl)-L-homoserine lactone; AI-1 (Deep et al. 2011; Zhou et al. 2016) Endocarditis (Suri et al. 1971; Rodríguez-Hernández et al. 2004; Pugliese et al. 2016; Gürtler et al. 2019; Ioannou et al. 2021), myocarditis (Del-Pozo et al. 2011; Ranjani et al. 2015)
Pseudomonas aeruginosa Butyryl-homoserine lactone; AI-1(Deep et al. 2011; Zhou et al. 2016) Endocarditis (Gürtler et al. 2019), myocarditis (Ranjani et al. 2015)
Escherichia coli Furanosyl borate diester (AI-2) (Li et al. 2007; Zhou et al. 2016) Endocarditis (Quiring and Burke 2021)
Escherichia coli, Salmonella enterica, and Shigella flexneri 2-Methy-2,3,3,4-tetrahydroxytetrahydrofuran (AI-2) (Li et al. 2007; Zhou et al. 2016) Endocarditis (Fernández Guerrero et al. 2004; Quiring and Burke 2021), pericarditis (Fernández Guerrero et al. 2004), myocarditis (Chehab et al. 2020), pancarditis (Guerrero Ortiz et al. 2003)
Pseudomonas aeruginosa 2-heptyl-3-hydroxy-4 quinolone, 3-oxododecanoyl-l-homoserine lactone (Rennemeier et al. 2009) Vide supra
Neisseria gonorrhoeae NgAI-2 (AI) (Anderson et al. 2016; Edwards et al. 2016) Endocarditis (Olayemi et al. 2017)
Treponema pallidum TpAI-2 (AI) (Babb et al. 2005; von Lackum et al. 2006; Arnold et al. 2015) Endocarditis (Hijikata et al. 2019), septic cardiomyopathy (Guo and Guo 2021)
Chlamydia trachomatis CtAI, certain fatty acids (AI) (Bergsson et al. 1998; Barczak and Hung 2009; Rabin et al. 2015; Simon et al. 2015) Endocarditis (Brearley and Hutchinson 1981), myocarditis (Ringel et al. 1982)
Legionella sp. (e.g. Legionella pneumophila) LAI-1 (Legionella autoinducer) (3-hydroxypentadecane-4-one—an α-hydroxyketone) (Tiaden and Hilbi 2012; Simon et al. 2015) Endocarditis (Pearce et al. 2011), pericarditis, myocarditis (Burke et al. 2009)
Vibrio vulnificus cyclo-(l-Phe-l-Pro) (Kim et al. 2018) Endocarditis (Truwit et al. 1987)
Parasites Candida albicans, C. auris, Aspergillus fumigatus, Cryptococcus Farnesol, tyrosol, 3(R)-hydroxy-tetradecaenoic acid (β-oxidation metabolite of linoleic acid), phenylethanol, tryptophol (Rennemeier et al. 2009; Deep et al. 2011; Nigam et al. 2011) Pacemaker site infection, cardiac failure (COHEN et al. 1991; Mullick et al. 2006)
Viruses Coronaviruses (e.g. SARS-CoV-2), coxsackievirus, parvovirus B19, Epstein–Barr virus, cytomegalovirus, and varicella-zoster virus, human herpesvirus 6, etc Rap-Phr, AimR-AimP, AimR-AimP-like, etc. (Bernard et al. 2021) Endocarditis (Ouarradi et al. 2021), myocarditis (Martens and Accornero 2021)
Note: QSS quorum-sensing signal, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, Gram-negative bacteria are called autoinducers, whereas Gram-positive bacteria produce autoinducing peptides
Under normal condition, the quorum-sensing signal molecules activate the TAS2Rs to initiate intracellular signalling that culminate in protection of the host against microbial invasion, at least in part, by suppressing the host immune responses (Grassin-Delyle et al. 2019; Kinnamon and Finger 2019). Though the mechanisms of suppression of the host immune system is not completely known, Lee et al. (2018) showed that quorum-sensing signal molecules subvert the host anti-viral, -bacteria and -fungi defences mainly by abrogating interferon (IFN)-β production via pathogen interaction with the activation of retinoic-acid-inducible gene-I (Lee et al. 2018). More so, evidence indicates that pathogens use quorum-sensing signal molecules to actively suppress the production of inflammatory cytokines, reactive species, including NO via inhibition of κB (IκB) kinase (IKK) phosphorylation, IκBα degradation, and nuclear translocation of NF-κB (Kim et al. 2015). In addition to activation of NF-κB, cardiotrophic quorum-sensing signal molecules (including those of the severe acute respiratory syndrome coronavirus 2) (Freeman and Swartz 2020; Kandasamy 2021) initiate intracellular signalling via TAS2Rs (Barham et al. 2021; Parsa et al. 2021; Sharma et al. 2021) to activate the cytoplasmic sensor of inflammatory signal—NLRP3 inflammasome (Freeman and Swartz 2020; Kandasamy 2021). However, under normal condition, cardiac TAS2Rs counteract these quorum-sensing signal molecules by binding to them and mediating responses that eventually result in the prevention of the pathogenic aggression, suggesting that TAS2Rs may serve as a novel type of pattern-recognition receptors (Lee et al. 2018; Zhou et al. 2021). Interestingly, recent data showed that TAS2R16 activation effectively suppresses LPS-induced secretion of proinflammatory cytokines (Zhou et al. 2021). Therefore, cardiac TAS2Rs detect quorum-sensing signal molecules to initiate microbicidal and other responses that lead to elimination of the pathogens. Nevertheless, dysfunctional signalling of TAS2Rs can predispose to pathologies (Welcome 2020a). Thus, investigating the mechanisms of detection of quorum-sensing signal molecules or other pathogenic molecules by TAS2Rs and their signal transduction cascades in health and disease can provide useful information for identification of novel frontiers in the treatment of some heart diseases.
Nitric oxide secretion contributes to the anti-inflammatory effects of cardiac bitter taste receptor activation
The synthesis and secretion of NO is a key mechanism involved in the anti-inflammatory effects of TAS2R activation. Kim et al. (2015) showed that pathogens use quorum-sensing signal molecules to actively suppress the production of NO (Kim et al. 2015). Indeed, NO has been repeatedly shown to exhibit a microbicidal effect on cardiotropic pathogens (Akaike and Maeda 2000; Uehara et al. 2015). TAS2Rs of the endocardium or cardiac vessel endothelium respond to quorum-sensing signal molecules, potentially dangerous microbial metabolites, toxins, pharmacological agents such as acetaminophen, chloramphenicol, chloroquine, quinine, noscapine (Tables 1 and 2) [BitterDB (http://bitterdb.agri.huji.ac.il)], and phytochemicals such as genistein and polyphenols (Gradinaru et al. 2022) to trigger NO secretion via the canonical pathway of taste receptor transduction (Gopallawa et al. 2021; Carey et al. 2021). Accordingly, in the canonical pathway, the microbicidal effects of activation of cardiac endothelial TAS2Rs are largely due to the rise in intracellular Ca2+, which forms complexes with CaM, and in turn activates CaM-dependent protein kinases to stimulate eNOS (endothelial NOS). eNOS is the enzyme that catalyses the formation of L-citrulline and NO from L-arginine (Welcome 2020a). Upon stimulation of α-gustducin by a higher concentration of bitterants or microbial quorum-sensing signal molecules in TAS2R-expressing endothelial cells, a rise in cytosolic Ca2+ activates a greater NO generation in a dose-dependent manner, thereby inducing substantial microbicidal effects on the pathogens (Gopallawa et al. 2021). Consistently, Grekov et al. (2017) reported significant destruction of Leishmania promastigotes, the parasite that causes leishmaniasis, following treatment with calcimycin (a calcium ionophore) via activation of NO secretion (Grekov et al. 2017). Comparable data are discussed elsewhere (Jeandroz et al. 2013).
Bitter taste receptors, cardiac contractility and rhythm: bitter taste receptor agonists modulate cardiac contractility and pacemaker activity via Ca2+-, cyclic AMP- and PDE-dependent mechanisms
Since TAS2R signalling is associated with changes in cardiomyocyte cytosolic Ca2+ and cyclic AMP along with other signalling molecules (Manson et al. 2014; D’Urso and Drago 2021), activation of TAS2Rs will elicit corresponding changes in cardiac mechanics and pacemaking. Accordingly, administration of TAS2R108 and 137 agonists in Langendorff-perfused heart of C57BL/6 mice revealed a ∼40% decrease in left ventricular pressure and increase in the aortic pressure, respectively (Foster et al. 2014). However, these responses were abolished in the presence of pertussis toxin and gallein, which are, respectively, inhibitors of Gαi and Gβγ subunits of the G-protein, indicating a negative inotropic effect of TAS2R agonists on the heart (Foster et al. 2014). Thus, activation of cardiac TAS2Rs leads to negative ionotropy (Fig. 2).Fig. 2 The negative ionotropic effect of TAS2R activation in cardiac muscle cell. TAS2R activation initiates downstream signaling that culminates in reduced formation of cyclic AMP (adenosine monophosphate) in a PDE-dependent manner. This reduces the activity of protein kinase A (PKA) along with deregulated activity of protein kinase C (PKC) resulting in decreased phosphorylation of its targets (Foster et al. 2014; Manson et al. 2014; Welcome et al. 2015). These protein kinases reduce their stimulatory effect of Ca2+-calmodulin protein kinase II (CaMKII), thereby decreasing the activity of ion channels/receptors such as 1,4,5-inositol trisphosphate receptor (IP3R), transient receptor potential cation channel, subfamily M, member 5 (TRPM5), ryanodine receptor 2 (RyR2), CaATPase, angiotensin II receptor (AngIIR), adrenoreceptor (AR), etc. (Chandrashekar et al. 2000; Jeon et al. 2011; Workman et al. 2018; Xie et al. 2018). The resultant effect is reduced cytosolic calcium waves, decreased phosphorylation of the motor proteins that promote relaxation of the cardiac muscles (negative inotropy). Other abbreviations are similar to those in Fig. 1
In a relatively recent study, Yuan et al. (2020) demonstrated a negative chronotropic effect of quinine and chloroquine on the sinoatrial node, which was abrogated via inhibition of TAS2R108 with abscisic acid. In addition, both TAS2R agonists suppressed the isoprenaline-induced tachycardia on the sinoatrial node (Yuan et al. 2020). In the same study, the authors showed that inhibition of phosphodiesterases (PDE3 and PDE4) with 3-isobutyl-1-methylxanthine resulted in a negative chronotropic effect on the sinoatrial node (Yuan et al. 2020). Thus, TAS2R agonists suppress the pacemaker activity of the sinoatrial node via PDE-induced cyclic AMP reduction (Fig. 3), suggesting that dysfunctional signalling of TAS2R may play a role in the development of cardiac arrhythmia via disordered generation of impulse.Fig. 3 The negative chronotropic effect of TAS2R activation on the sinoatrial node. The reduced activity of protein kinase A (PKA) and protein kinase C (PKC) leads to downregulation of the activity of Ca2+-calmodulin protein kinase II (CaMKII), funny (f) channel, L-type Ca channel, T-type Ca channel, 1,4,5-inositol trisphosphate receptor (IP3R), transient receptor potential cation channel, subfamily M, member 5 (TRPM5), ryanodine receptor 2 (RyR2), CaATPase, angiotensin II receptor (AngIIR), glucagon-like peptide 1 receptor (GLP1-R), adrenoreceptor (AR), etc. However, certain phosphorylation may increase channel activity (e.g. K channel). The overall effect is associated with increase in the slow depolarising (pacemaker) potential (negative chronotropic effect) mainly due to reduced if current, reduced Ca2+ waves, and increased K+ current (Foster et al. 2014; Manson et al. 2014; Welcome et al. 2015). Other abbreviations are similar to those in Fig. 1
Molecular signalling pathways, linking bitter taste receptor sensing of pathogenic and toxigenic molecules with inflammatory, oxidative stress responses, arrhythmia and contractile dysfunction in heart diseases
Accumulating research data have consistently shown that TAS2Rs participate in inflammatory and oxidative stress responses (Hamdard et al. 2019b; Welcome 2020a; Welcome et al. 2021; Welcome and Mastorakis 2021). Furthermore, available data indicate that TAS2Rs are involved in modulation of cardiac excitability and contractile activities, suggesting that disorders in TAS2R signalling might predispose to cardiac diseases, which are characterised by inflammation, oxidative stress, contractile dysfunction and possibly arrhythmia (Manson et al. 2014; Hamdard et al. 2019b; Yuan et al. 2020). Data also indicate a critical role of NLRP3 and NF-κB in mediating and establishing a molecular bridge between the immune-inflammatory system and TAS2R dysfunction (Welcome 2020a; Welcome and Mastorakis 2021). These molecular sensors of the immune system and inflammatory responses are responsible for cardiac inflammation due to defective TAS2R signalling.
The NF-κB and NLRP3 inflammasome are the primary regulators of inflammatory responses (Welcome 2020a; Welcome and Mastorakis 2021) and have been widely implicated in cardiac inflammation (Lu et al. 2015; Chen et al. 2018; Jui et al. 2021) and taste receptor signalling defects (Zhou et al. 2018; Welcome 2020a). In addition, it is widely acknowledged that the master oxidative stress sensor, Nrf-2 (nuclear factor erythroid 2-like 2) connects the inflammatory signalling cascades to oxidative stress responses and vice versa (Jui et al. 2021). Indeed, the Nrf-2 has been consistently implicated in the pathogenic mechanism of cardiac disorders (Jui et al. 2021). Thus, Nrf-2 may be responsible for mediating the signalling cascades that link oxi-inflammatory stress with taste receptor dysfunction (Hamdard et al. 2019b). Hence, an extensive cross-talk occurs between the inflammatory sensors (NLRP3 and NF-κB) and Nrf-2 to regulate the homeostasis of the immune system, inflammatory and oxidative stress profiles of the cells and tissues of the heart.
NF-κB signalling
The NF-κB is a transcription factor that regulates the expression of over 550 genes (nf-kb.org) involved in immune, inflammatory, oxidative stress responses, cell proliferation, differentiation, growth, survival, apoptosis and other cellular processes (Collins et al. 2016). The mammalian proteins of the NF-κB family consist of p105 (precursor protein of p50), p100 (precursor of p52), RelA (p65), RelB and c-Rel (Thu and Richmond 2010). The NF-κB signalling pathway is stimulated by pathogenic factors, cytokines, ROS, and reactive nitrogen species. Therefore, oxidative stress molecules such as ROS or the proinflammatory cytokine, IL-1β, produced by dysfunctional taste receptors (Zhou et al. 2018; Welcome and Mastorakis 2021) can activate the NF-κB signalling through the IκB kinase or TLR, respectively. In addition, abnormal stimulation of TAS2R by pathogenic components or quorum-sensing signal molecules can also activate the NF-κB (Welcome 2020a).
The NF-κB is abundantly expressed in cardiac endothelial cells, fibroblasts and cardiomyocytes (Sangeetha et al. 2011; Yin et al. 2021). This molecular sensor of inflammation is present in the cytosol of cardiac cells as an inactive protein bound to IκB to form the NF-κB/IκB complex. Upon activation by pathological stimuli, the IκB kinase phosphorylates the inhibitory kappa B (IκBs) protein of the cytoplasmic complex NF-κB/IκB to cause degradation of IκB and release of NF-κB protein heterodimers to translocate into the nucleus to activate gene transcription (Fig. 4). The IκB kinase is a primary target of reactive species, proinflammatory mediators such as IL-1β, TNFα and other pathogenic signals (Gloire and Legrand-Poels 2006; Thu and Richmond 2010; Collins et al. 2016; Jimi et al. 2019). Even so, a non-classical (non-canonical) or alternative pathway exists for the activation of NF-κB. The pathway involves activation of the NF-κB-inducing kinase (NIK) (Jimi et al. 2019; Pflug and Sitcheran 2020). In the alternative pathway, NIK is stimulated by ligands such as TNF receptor superfamily member 5 (CD40) ligand and TNF-related weak inducer of apoptosis (Thu and Richmond 2010) resulting in cleavage of the p100 to produce p52 with subsequent dimerisation of the latter with RelB. The complex formed translocates into the nucleus to initiate gene transcription (Thu and Richmond 2010). Recent evidence indicates that the NIK protein can interact with the canonical NF-κB pathway by activating the IκB kinase (Woronicz et al. 1997; Thu and Richmond 2010). The activated NF-κB induces the expression of caspase-1, IL-1β and NLRP3 (Welcome and Mastorakis 2021). NLRP3 is discussed in the next subsection.Fig. 4 NF-κB/IκB and NLRP3 signaling in TAS2R dysfunction in cardiac cell. Dysfunctional signaling or pathological activation of TAS2R can trigger the activation of NLRP3 (NLR Family Pyrin Domain Containing 3) (Murakami et al. 2012; Zhong et al. 2016; Welcome and Mastorakis 2021) and nuclear factor κB (NF-κB) signaling, which mediate the production of proinflammatory cytokines and alarmins that cause inflammation, pyroptosis and fibrosis—constitute critical pathological processes in several heart diseases (Zhong et al. 2016; Chen et al.2017; Li et al. 2018). NF-κB/IκB and NLRP3 signaling in TAS2R dysfunction is also accompanied by Ca2+ overload, which worsens cardiac functions. The secreted interleukins can trigger proinflammatory responses in neighbouring cardiac cells and immunocytes. (See further explanation in text). TLR toll-like receptor, IL interleukin, MMPs Matrix metalloproteinases, TIMP tissue inhibitor of metalloproteinases, PYD pyrin domain, CARD caspase activation and recruitment domains, LRR leucine-rich repeat, ASC apoptosis-associated speck-like protein containing a caspase activation and recruitment domain—CARD, NACHT domain present in NAIP, CIITA, HETE and TP1. Other abbreviations are similar to those in Figs. 1 and 2
Though the exact mechanisms are not known, emerging data suggest that NF-κB activation is linked to TAS2R signalling. As a matter of fact, increased expression of taste receptors has been reported in inflammatory conditions (Shin et al. 2010), suggesting that taste receptor dysfunction can predispose to inflammatory conditions. Consistent with these findings, independent groups of researchers (Cui et al. 2019; Wu et al. 2020) have demonstrated the involvement of disorders of the bitter taste sensor, TRPM5 (transient receptor potential cation channel subfamily M member 5) in hypertensive heart disease. Zhou et al. (2021) reported that TAS2R16 activation by salicin effectively suppressed the release of LPS-induced proinflammatory cytokines, in part, by inhibiting the increase in cytosolic cyclic AMP and nuclear translocation of NF-κB p65 in human fibroblasts (Zhou et al. 2021). Though NF-κB p65 activation can mediate the secretion of alarmins and pore-forming proteins, which result in pyroptosis (a form of cell death ensuing from the formation of pores in the plasma membrane), evidence indicates that under normal condition, taste receptor signalling also leads to inhibition of autophagy in the heart through the activation of the mammalian rapamycin complex 1 (mTORC1) (Kokabu et al. 2015). In fact, rodents lacking taste receptors displayed increased rate of autophagy in the heart (Kokabu et al. 2015). Apparently, NF-κB activation provides a critical molecular nexus between inflammatory cascades and mTORC1 activity via interaction with IκBα. Moreover, the activation of mTORC1 is considered as a downstream event of NF-κB activation in immortalised NPE cells (Zhu et al. 2016). Therefore, NF-κB and mTORC1 exhibit an extensive cross-talk with each other (Li et al. 2019) and are both involved in regulating the inflammatory and host defence system against pathogenic aggression (Bao et al. 2015; Li et al. 2019).
Several pharmacological compounds activate the TAS2Rs to mediate downstream signalling that leads to the inhibition of NF-κB. For instance, the anti-microbial, -inflammatory and immunomodulatory activities of flavones are mediated via TA2R14 activation, which suppresses the release of proinflammatory cytokines (Hariri et al. 2017). Flavone-induced taste receptor activation also increases the TA2R14-driven Ca2+ flux that subsequently stimulate NO production in response to multiple inflammatory stimuli, in part, through inhibition of PKC, receptor tyrosine kinase (Hariri et al. 2017) and NF-κB (Panche et al. 2016; Yahfoufi et al. 2018; Choy et al. 2019). Some flavones may also activate a functional TA2R38 isoform, which closely co-localises with TA2R14 to mediate the anti-inflammatory effects of this class of phytochemicals (Hariri et al. 2017). Consistent with the findings of previous authors (Hariri et al. 2017), a recent investigation by Tiroch et al. (2021) revealed that the anti-inflammatory effect of trans-resveratrol was mediated via the activation of TAS2R50 as treatment with the TAS2R antagonist homoeriodictyol or small interfering RNA-mediated TAS2R50 knockdown completely abolished the anti-inflammatory effect of trans-resveratrol in LPS-induced IL-6 secretion in an in vitro model of human fibroblasts (Tiroch et al. 2021). Interestingly, the flavone and stilbenoid subclasses of polyphenolic compounds possess cardioprotective properties, which highlight a possible adjunct therapeutic role of these phytochemicals in heart diseases (Akinwumi et al. 2017; Khan et al. 2021).
NLRP3 signalling
The NLRP3 is a cytoplasmic sensor that detects pathogenic (Swanson et al. 2019; Ciążyńska et al. 2020) and endogenous danger molecules as well as environmental toxins, including ultraviolet radiation (Liu et al. 2014; Ciążyńska et al. 2020) resulting in the formation of the NLRP3 inflammasome (Swanson et al. 2019). The NLRP3 is also activated by metabolic toxins, extracellular ATP, reactive species, K+ efflux (Liu et al. 2014; Swanson et al. 2019; Wang et al. 2020) and disordered gut microbiota (Henao-Mejia et al. 2013).
Inflammasomes are cytosolic oligomeric multiprotein complexes of the innate immune system that assemble in response to pathogenic signals to mediate inflammatory responses via the activation of caspase-1, resulting in proteolytic cleavage of pro-IL-1β, -IL-18 and gasdermin-D into their active forms with corresponding initiation of proinflammatory responses and pyroptosis (Mariathasan et al. 2004; de Zoete et al. 2014; Broz and Dixit 2016). Out of the 22 proteins of the NLR ((nucleotide-binding oligomerisation domain (NOD) like receptor)) family currently discovered in humans, only 8 have been reported to form an inflammasome: NLRP-1, -2, -3, -6, -7, -12, NLRC4 (Nod-like receptor Card domain-containing protein 4), and AIM2 (Absent In Melanoma 2) (de Zoete et al. 2014). However, the NLRP3 is the most widely studied and best characterised inflammasome (Swanson et al. 2019).
The NLRP3 is normally autoinhibited in the absence of danger or pathogenic signals (Sharma and De Alba 2021). The presence of pathogenic signal leads to the activation of NF-κB to promote the transcription of NLRP3, pro-IL1β, pro-IL-18, and a 53-kDa gasdermin-D through a process known as priming (Brownlee et al. 2020). The signal subsequently activates the NLRP3 (Brownlee et al. 2020) to promote the formation of active NLRP3 (i.e. NLRP3 inflammasome), involving the assembly or oligomerisation of the inactive upstream sensor (NLRP3), the adapter protein ASC (apoptosis-associated speck-like protein), and the downstream effector procaspase-1 (Henao-Mejia et al. 2013; Brownlee et al. 2020). The formation of the inflammasome triggers an autocleavage of procaspase-1 to caspase-1, which mediates the proteolytic cleavage, maturation and release of IL-1β and IL-18 (Broz and Dixit 2016; Swanson et al. 2019). The downstream effector of the NLRP3 inflammasome also mediates the cleavage of gasdermin-D to produce a 22-kDa C-terminal and a 31-kDa N-terminal fragment. The latter mediates the formation of membrane pores resulting in a greater secretion of proinflammatory molecules and alarmins (Wang et al. 2020) and eventually, pyroptotic cell death (Broz and Dixit 2016; Swanson et al. 2019). Apart from caspase-1, other caspases (e.g. caspase-11 in rodents, caspase 4 and caspase 5 in humans) can cause the activation of inflammasome via the non-canonical pathway by direct sensing of microbial components (e.g. bacterial LPS) in the cytosol (Broz and Dixit 2016).
Under normal condition, the NLRP3 is expressed in the cytosol at low levels in healthy heart tissues (Huang et al. 2014; Ye et al. 2015). Liu et al. (2014) demonstrated sparse expression of NLRP3 in cardiomyocytes, but increased expression of the protein in cardiac microvascular endothelial cells, which may indicate a greater role of the cardiac endothelium in inflammatory and immune response (Liu et al. 2014). Correspondingly, the authors showed increased NLRP3 inflammasome activation in cardiac ischaemia/reperfusion injury in cardiac microvascular endothelial cells, but not in cardiomyocytes (Liu et al. 2014). New data indicate a fundamental role of the cardiac microvascular endothelial cells in triggering cardiomyocyte injury (Zhang et al. 2021). Consistent with these data, Mezzaroma et al. (2011), Sandanger et al. (2013), and Liu et al. (2014) previously showed high NLRP3 expression in myocardial leukocytes, fibroblasts, and endothelial cells in myocardial ischaemia. Similar findings have been reported in a recent investigation (Mesquita et al. 2021). Increased expression of NLRP3 has also been confirmed in heart failure and cardiomyopathy (Wang et al. 2020). This pathogenic sensor is believed to be a critical molecular target for some existing medications, including agents used for the treatment of cardiovascular diseases (Wang et al. 2020). The NLRP3 is also expressed in dendritic cells, monocytes, macrophages and neutrophils (Wang et al. 2018, 2020).
On the basis of available evidence, indicating that taste receptors are crucial components of the innate immune system, inflammatory (Gulbransen et al. 2008; Tizzano et al. 2011; Lee and Cohen 2013b) and oxidative stress (Hamdard et al. 2019b) responses, as well as data suggesting a critical role of taste receptor signalling in neuroinflammation (Welcome and Mastorakis 2021), respiratory tract infection (Lee and Cohen 2013b), gastrointestinal infection (Liszt et al. 2022) and urinary and reproductive tract inflammation (Welcome et al. 2021), we therefore suggest that activation of NLRP3 by reactive species and abnormal Ca2+ signal is involved in the proinflammatory and oxidative stress responses of dysfunctional taste receptor signalling in the heart (Fig. 4). The activation of NLRP3 contributes to several cardiac disorders, including atherosclerotic heart disease, hypertensive heart disease, myocardial infarction, cardiac infection, cardiomyopathy, heart failure (Wang et al. 2018), and ageing (Mesquita et al. 2021). Indeed, the NLRP3 inflammasome and elevated cytosolic ROS along with decreased intracellular Ca2+ level have been associated with taste receptor dysfunction involving downregulation of α-gustducin, TRPM5, and phospholipase C β2 (Zhou et al. 2018). In mammals, TRPM5 is coexpressed with phospholipase C β2 in taste receptor cells, and both molecules are essential elements in the signal transduction mechanism of TAS2R (Pérez et al. 2002). Again, disorders of these taste receptor components are involved in inflammation and cardiac disorders. For instance, it has been reported in animal and humans studies that TRPM5 dysfunction is associated with cardiac inflammation (Koc et al. 2022; Virginio et al. 2022) and conduction disorders (Syam et al. 2014), suggesting that specific cardiac isoforms of TRPM may serve as useful therapeutic targets in heart diseases. Accordingly, there is a growing interest on the use of pharmacological agents for targeting the TRPM in pathological conditions (Virginio et al. 2022). Therefore, Simard et al. (2012) demonstrated that 9-phenanthrol, an aromatic alcohol derived from phenanthrene and an inhibitor of TRPM4, substantially reduces the frequency of early afterdepolarisations in a mouse model of cardiac hypoxia/re-oxygenation injury (a model of cardiac ischaemia/arrhythmia), suggesting that 9-phenanthrol can act as an anti-arrhythmogenic agent (Simard et al. 2012). (Early afterdepolarisations are essential cause of life-threatening ventricular arrhythmias, which are associated with sudden cardiac death. The limited efficacy of current antiarrhythmic therapy and the associated toxicity Bhat et al. 2022; Zeppenfeld et al. 2022) substantiates the need to search for novel therapeutic agents for the treatment of ventricular arrhythmias). Furthermore, the phenanthrene-derived TRPM4 inhibitor has been demonstrated to abrogate cardiac contractile dysfunction and oxidative stress in preclinical studies. Wang et al. (2013) showed that treatment of isolated Langendorff-perfused rat hearts with 9-phenanthrol resulted in a dramatic recovery of contractile function, significant decrease in infarct size and ischaemia–reperfusion injury (Wang et al. 2013). The authors also revealed that 9-phenanthrol substantially reduced the activity of lactate dehydrogenase (LDH) (Wang et al. 2013), an important oxidative stress marker implicated in a range of cardiac diseases (Lin et al. 1991; Kopel et al. 2012; Dai et al. 2020). In contrast, control hearts had reduced contractile function, increased size of the infarct area and LDH activity (Wang et al. 2013). Piao et al. (2015) also reported that prior treatment with 9-phenanthrol or TRPM4 silencing substantially decreased the level of reactive species in ROS-induced injury in H9c2 cardiomyocytes subjected to hydrogen peroxide treatment (Piao et al. 2015). Flufenamic acid can also inhibit the TRPM4. Using a mouse model of cardiac hypoxia/re-oxygenation injury, Simard et al. (2012) showed that administration of flufenamic acid abolished cardiac arrhythmias and significantly improved cardiac contractility (Simard et al. 2012). The sulfonylurea antidiabetic drug, glibenclamide at a concentration of 100 μM completely inhibited TRPM4 activity in sinoatrial node cells (Demion et al. 2007). Interestingly, both flufenamic acid (Chi et al. 2011; Hamdard et al. 2019b) and glibenclamide (Zhang et al. 2017b; Hou et al. 2020) possess anti-inflammatory and antioxidative properties. However, only 9-phenanthrol specifically inhibits TRPM4 activity (Grand et al. 2008; Burris et al. 2015) as flufenamic acid and glibenclamide can also inhibit Ca2+ and ATP-dependent K+ channels, respectively (Ozhathil et al. 2018).
Research investigation with animal models has demonstrated cross-signalling between the NLRP3 inflammasome and cytosolic Ca2+ level, suggesting that Ca2+ is a critical modulator of inflammasome activity (Lee et al. 2012). Interestingly, the activation of TAS2Rs elicits a brief rise in cytosolic Ca2+ level (Tomás et al. 2016; Duarte et al. 2020), followed by a fall (Suetomi et al. 2018) in cardiac muscle cells. Notwithstanding, however, dysfunctional taste receptor signalling may result in an excessive increase in cytosolic Ca2+ level with associated cytotoxicity due to Ca2+-induced activation of inflammatory and apoptotic signalling cascades. Recent investigations have shown that the Ca2+-dependent protein kinase, CaMKIIδ plays a central role in initiating inflammatory responses through its interaction with the NLRP3 inflammasome in cardiomyocytes in response to pressure overload, thereby upregulating NLRP3, caspase-1, IL-1β, IL-18, and MCP-1 to trigger macrophage recruitment (Suetomi et al. 2018). These pathological processes are associated with cardiac fibrosis, apoptosis, necrosis along with ventricular dilation and contractile dysfunction in heart diseases (Suetomi et al. 2018). Thus, CaMKIIδ acts as an intracellular molecular switch that controls cardiac Ca2+ flux, contractility, and inflammation via interaction with NLRP3 (Suetomi et al. 2018) and NF-κB (Martin et al. 2018).
Moreover, ROS (Suetomi et al. 2018) and toxigenic metabolites formed during taste receptor disorder (Hamdard et al. 2019b) can activate the NLRP3 signalling pathway (Kong et al. 2016). Data obtained from animal experiment have shown that toxigenic metabolites induce the expression and release of peri- and intracellular degrading enzymes such as MMP-1, -3, -8, and -9 (Lee et al. 2012). Interestingly, MMP-3, -8, or -9 reportedly increased the cytosolic levels of ROS, NO, IL-1β, TNF-α, expression of NF-κB and protease-activated receptor-1 (Lee et al. 2010). Notably, MMPs have been shown to degrade cellular components by targeting proteinases, cell adhesion molecules, extracellular matrix proteins and cell surface receptors, including TAS2Rs (Sternlicht and Werb 2001). The secreted proinflammatory molecules promote inflammatory responses, oxidative stress, and downregulate the expression of connexon gap junction, anti-inflammatory mediators, pro-oxidants and antioxidant enzymes (Welcome 2020b; Welcome and Mastorakis 2020).
Nrf-2 signalling
The Nrf-2 is a transcription factor that acts as an oxidative stress sensor, which upon activation, translocates into the nucleus to bind with the antioxidant response element, stimulating a battery of cytoprotective, detoxifying and antioxidant genes (Fig. 5) (Vomund et al. 2017). Nrf-2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (Li and Jia 2019) and protein kinases such as glycogen synthase kinase 3 beta and PI3K (Wu et al. 2014; Li and Jia 2019).Fig. 5 Nrf-2 and TAS2R signalling in cardiac cell. TAS2R dysfunction triggers the formation of intracellular molecules that inhibit the nuclear translocation of Nrf-2 to downregulate the synthesis and secretion of protective and detoxifying enzymes (see further explanation in text). Akt protein kinase B (PKB), ARE antioxidant response element, ERK extracellular signal-regulated kinase, Keap1 Kelch-like ECH-associated protein 1, Maf MAF transcription factor, Nrf-2 nuclear factor erythroid-derived 2-like 2, PI3K phosphoinositide 3-kinase, SOD superoxide dismutase, CAT catalase, GSH glutathione, GR glutathione reductase, GPx glutathione peroxidase, GSH-ST glutathione-S-transferase, NQO1 dehydrogenase quinone1, XOR xanthine oxidoreductase, TrxR thioredoxin reductase, IDD iodothyronine deiodinases, GCLC glutamate-cysteine ligase catalytic subunit. (See explanation in text)
The Nrf-2 transcription factor plays a major role in regulating the equilibrium between formation and removal of reactive species (Qin and Hou 2017). Nrf-2 interacts with inflammatory signalling pathways to increase the expression of anti-inflammatory mediators (Vomund et al. 2017). Thus, Nrf-2 activation is required to abrogate the progression of inflammatory and oxidative stress responses (Ahmed et al. 2017; Hennig et al. 2018). Truly, the Nrf-2 exhibits cross-talks with the NLRP3 (Ahmed et al. 2017; Hennig et al. 2018) and NF-κB signalling pathways (Lampiasi and Montana 2018). The IκB kinase mediates the molecular interaction between Nrf-2 and the proinflammatory NLRP3 and NF-κB. As an integration point, activation of the IκB kinase stimulates both Nrf-2 and NLRP3, and also serves as a potential mechanism for the activation of antioxidant enzymes such as SOD, CAT, GPx, glutathione, glutathione reductase, glutathione-S-transferase, dehydrogenase quinone1 (Tinggi 2008; Lampiasi and Montana 2018; Cecerska-Heryć et al. 2021), xanthine oxidoreductase, thioredoxin reductase, iodothyronine deiodinases, and glutamate-cysteine ligase catalytic subunit (Tinggi 2008; Cecerska-Heryć et al. 2021).
Regrettably, however, there is a severe scarcity of data on the interaction between TAS2Rs and Nrf-2. Nevertheless, it can be suggested that TAS2R signalling may activate downstream cytoplasmic acceptors that interact with this transcription factor. Indeed, TAS2R signalling has been associated with several oxidative stress markers (Hamdard et al. 2019b). Furthermore, several activators of TAS2R have been shown to interact with the Nrf-2 to mediate downregulation of oxidative stress and proinflammatory mediators (Zhai et al. 2018; Hamdard et al. 2019b; Welcome and Mastorakis 2021). For instance, salicin activates TAS2R to exert its anti-inflammatory and anti-oxidant effects by promoting Nrf-2 nuclear translocation, HO-1 expression and inhibition of p65 phosphorylation to reduce ROS, IL-6, TNF-α, MMP-1, and -3 in animal model of inflammation (Zhai et al. 2018).
Conclusion
Cardiac inflammatory and oxidative stress responses represent central pathophysiological processes in several diseases of the heart and are associated with dysfunctional cardiac TAS2R signalling. Under normal condition, cardiac TAS2R is required for endocardial and myocardial homeostasis, including regulation of impulse generation and propagation, cardiac rhythm, and contractile functions of the heart primarily via the activities of PDE3, PDE4, protein kinases, and Cx43. However, defects in cardiac TAS2R signal transduction essentially activate the molecular switches that connect cardiac inflammation and oxidative stress to contractile dysfunction and arrhythmia via Ca2+-calmodulin protein kinase II, NLRP3, NF-κB, and Nrf-2 signalling cascades. These molecular signalling pathways mediate the secretion of inflammatory, oxidative stress, apoptotic and fibrotic mediators, activation and recruitment of immunocytes as well as monocyte/macrophage polarisation, which initiate the development of cardiac arrhythmia and contractile dysfunction in heart diseases. Cardiac TAS2Rs also act as gateway surveillance units that monitor and detect toxigenic or pathogenic molecules, including microbial components, and initiate responses that ultimately culminate in protection of the host against pathogenic aggression. Several pharmacological agents can act as TAS2R agonists to attenuate cardiac inflammation, oxidative stress responses, apoptosis and fibrosis, thereby abrogating cardiac arrhythmia and contractile dysfunction via activation of Nrf-2 and inhibition of NLRP3 and NF-κB signalling cascades.
Future directions
Since TAS2R signalling defects are involved in the pathophysiology of heart diseases, investigating the molecular switches that connect cardiac inflammation and oxidative stress to contractile dysfunction and arrhythmia may provide important information for identifying the molecular culprits of some heart diseases. In addition, investigation of specific molecular bridges that link cardiac TAS2R signalling defects to cardiac inflammation, oxidative stress, contractile dysfunction and arrhythmia in heart diseases may lead to identification of novel molecular targets for potential therapeutics of heart diseases. There is need to investigate the potential therapeutic roles of pharmaceuticals in cardiac TAS2R dysfunction, inflammation, oxidative stress, fibrosis, and pyroptotic cell death in heart diseases.
Funding
Funding is not available for this paper.
Data availability
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Declarations
Conflict of interest
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References
Adler E Hoon MA Mueller KL A novel family of mammalian taste receptors Cell 2000 10.1016/S0092-8674(00)80705-9
Ahern RM Lozano R Naghavi M Improving the public health utility of global cardiovascular mortality data: The rise of ischemic heart disease Popul Health Metr 2011 10.1186/1478-7954-9-8
Ahmed SMU Luo L Namani A Nrf2 signaling pathway: Pivotal roles in inflammation Biochim Biophys Acta Mol Basis Dis 2017 1863 585 597 10.1016/j.bbadis.2016.11.005 27825853
Aimo A Castiglione V Borrelli C Oxidative stress and inflammation in the evolution of heart failure: From pathophysiology to therapeutic strategies Eur J Prev Cardiol 2020 27 494 510 10.1177/2047487319870344 31412712
Akaike T Maeda H Nitric oxide and virus infection Immunology 2000 10.1046/j.1365-2567.2000.00142.x
Akinwumi BC Raj P Lee DI Disparate effects of stilbenoid polyphenols on hypertrophic cardiomyocytes in Vitro vs. in the spontaneously hypertensive heart failure rat Molecules 2017 10.3390/molecules22020204
Albina JE Caldwell MD Henry WL Mills CD Regulation of macrophage functions by L-arginine J Exp Med 1989 10.1084/jem.169.3.1021
Andelova K Benova TE Bacova BS Cardiac connexin-43 hemichannels and pannexin1 channels: Provocative antiarrhythmic targets Int J Mol Sci 2021 22 260 10.3390/ijms22010260
Anderson MT Byerly L Apicella MA Steven Seifert H Seminal plasma promotes Neisseria gonorrhoeae aggregation and biofilm formation J Bacteriol 2016 10.1128/JB.00165-16
de Arellano MLB, Pozdniakova S, Kühl AA, et al (2019) Sex differences in the aging human heart: Decreased sirtuins, proinflammatory shift and reduced anti-oxidative defense. Aging (Albany NY). 10.18632/aging.101881
Arnold WK Savage CR Antonicello AD Stevenson B Apparent role for Borrelia burgdorferi LuxS during mammalian infection Infect Immun 2015 10.1128/IAI.00032-15
Aschner M Nguyen TT Sinitskii AI Isolevuglandins (isoLGs) as toxic lipid peroxidation byproducts and their pathogenetic role in human diseases Free Radic Biol Med 2021 162 266 273 10.1016/j.freeradbiomed.2020.10.024 33099003
aus dem Siepen F, Buss SJ, Andre F, et al (2015) Extracellular remodeling in patients with wild-type amyloidosis consuming epigallocatechin-3-gallate: preliminary results of T1 mapping by cardiac magnetic resonance imaging in a small single center study. Clin Res Cardiol 10.1007/s00392-015-0826-3
Babb K Von Lackum K Wattier RL Synthesis of autoinducer 2 by the lyme disease spirochete Borrelia Burgdorferi J Bacteriol 2005 10.1128/JB.187.9.3079-3087.2005
Bai Z Wang Z Genistein protects against doxorubicin-induced cardiotoxicity through Nrf-2/HO-1 signaling in mice model Environ Toxicol 2019 10.1002/tox.22730
Bao W Wang Y Fu Y mTORC1 regulates flagellin-induced inflammatory response in macrophages PLoS ONE 2015 10.1371/journal.pone.0125910
Barczak AK Hung DT Productive steps toward an antimicrobial targeting virulence Curr Opin Microbiol 2009 12 490 496 10.1016/j.mib.2009.06.012 19631578
Barham HP Cooper SE Anderson CB Solitary chemosensory cells and bitter taste receptor signaling in human sinonasal mucosa Int Forum Allergy Rhinol 2013 10.1002/alr.21149
Barham HP Taha MA Broyles ST Association between bitter taste receptor phenotype and clinical outcomes among patients with COVID-19 JAMA Netw Open 2021 10.1001/jamanetworkopen.2021.11410
Bayer S Mayer AI Borgonovo G Chemoinformatics view on bitter taste receptor agonists in food J Agric Food Chem 2021 10.1021/acs.jafc.1c05057
Bergsson G Arnfinnsson J Karlsson SM In vitro inactivation of Chlamydia trachomatis by fatty acids and monoglycerides Antimicrob Agents Chemother 1998 10.1128/aac.42.9.2290
Bernard C, Li Y, Lopez P, Bapteste E (2021) Large-scale identification of viral quorum sensing systems reveal convergent evolution of density-dependent sporulation-hijacking in bacteriophages. bioRxiv 33
Berry E Hernandez-Anzaldo S Ghomashchi F Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever J Am Heart Assoc 2015 10.1161/JAHA.115.001868
Bhat SA Gambril JA Azali L Chen ST Rosen L Palettas M Wiczer T Kalathoor S Zhao Q Rogers KA Kittai AS Grever MR Awan FT Ruz P Byrd JC Woyach JAAD Ventricular arrhythmias and sudden death events following acalabrutinib initiation Blood 2022 10.1182/blood.2022016953
Bloxham CJ Foster SR Thomas WG A bitter taste in your heart Front Physiol 2020 11 431 10.3389/fphys.2020.00431 32457649
Böger RH Asymmetric dimethylarginine (ADMA) and cardiovascular disease: Insights from prospective clinical trials Vasc Med 2005 10.1191/1358863x05vm602oa
Bonetti J Corti A Lerouge L Phenotypic modulation of macrophages and vascular smooth muscle cells in atherosclerosis-nitro-redox interconnections Antioxidants 2021 10.3390/antiox10040516
Brearley BF Hutchinson DN Endocarditis associated with Chlamydia trachomatis infection Br Heart J 1981 10.1136/hrt.46.2.220
Brownlee M, Lloyd P Aiello, Jennifer K Sun, Mark E Cooper, Eva L Feldman JP, AJMB (2020) Complications of Diabetes Mellitus. In: Melmed S (ed) Williams Textbook of Endocrinology, 37th edn. Elsevier, pp 1438–1524.e23
Broz P Dixit VM Inflammasomes: mechanism of assembly, regulation and signalling Nat Rev Immunol 2016 16 407 420 10.1038/nri.2016.58 27291964
Bulau P Zakrzewicz D Kitowska K Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA Am J Physiol Lung Cell Mol Physiol 2007 10.1152/ajplung.00076.2006
Burke PT Shah R Thabolingam R Saba S Suspected legionella-induced perimyocarditis in an adult in the absence of pneumonia: A rare clinical entity Texas Hear Inst J 2009 36 601
Burris SK Wang Q Bulley S 9-Phenanthrol inhibits recombinant and arterial myocyte TMEM16A channels Br J Pharmacol 2015 10.1111/bph.13077
Burt R Graves BM Gao M 9-Phenanthrol and flufenamic acid inhibit calcium oscillations in HL-1 mouse cardiomyocytes Cell Calcium 2013 10.1016/j.ceca.2013.06.003
Cecerska-Heryć E Surowska O Heryć R Are antioxidant enzymes essential markers in the diagnosis and monitoring of cancer patients – A review Clin Biochem 2021 93 1 8 10.1016/j.clinbiochem.2021.03.008 33773993
Cerisano G Buonamici P Valenti R Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: The TIPTOP trial Eur Heart J 2014 10.1093/eurheartj/eht420
Chandrashekar J Mueller KL Hoon MA T2Rs function as bitter taste receptors Cell 2000 10.1016/S0092-8674(00)80706-0
Chehab O McGuire E Wani RLS Acute myopericarditis caused by Salmonella enterica serovar Enteritidis: A case report Eur Hear J - Case Reports 2020 10.1093/ehjcr/ytaa173
Chen SP Qin T Seidel JL Inhibition of the P2X7-PANX1 complex suppresses spreading depolarization and neuroinflammation Brain 2017 10.1093/brain/awx085
Chen L, Deng H, Cui H, et al (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9:7204-7218 10.18632/oncotarget.23208
Chen M Samuel VP Wu Y Dang M Lin Y Sriramaneni R Sah SK Chinnaboina GKZG Nrf2/HO-1 mediated protective activity of genistein against doxorubicin-induced cardiac toxicity J Env Pathol Toxicol Oncol 2019 38 143 152 10.1615/JEnvironPatholToxicolOncol.2019029341 31679277
Chen R Chen W Huang X RUI Q, Tanshinone IIA attenuates heart failure via inhibiting oxidative stress in myocardial infarction rats Mol Med Rep 2021 10.3892/mmr.2021.12043
Chi Y Li K Yan Q Nonsteroidal anti-inflammatory drug flufenamic acid is a potent activator of AMP-activated protein kinase J Pharmacol Exp Ther 2011 10.1124/jpet.111.183020
Choy KW Murugan D Leong XF Flavonoids as natural anti-inflammatory agents targeting nuclear factor-kappa B (NFκB) signaling in cardiovascular diseases: A mini review Front Pharmacol 2019 10.3389/fphar.2019.01295
Ciążyńska M Bednarski IA Wódz K NLRP1 and NLRP3 inflammasomes as a new approach to skin carcinogenesis (Review) Oncol Lett 2020 19 1649 1656 32194656
Clark AA Dotson CD Elson AET TAS2R bitter taste receptors regulate thyroid function FASEB J 2015 10.1096/fj.14-262246
Clarke JL Bourn S Skoufalos A An innovative approach to health care delivery for patients with chronic conditions Popul Health Manag 2017 10.1089/pop.2016.0076
Cohen TJ Pons VG Schwartz J Griffin JC Candida Albicans pacemaker site infection Pacing Clin Electrophysiol 1991 10.1111/j.1540-8159.1991.tb05081.x
Collins PE Mitxitorena I Carmody RJ The ubiquitination of NF-κB subunits in the control of transcription Cells 2016 5 23 10.3390/cells5020023 27187478
Coquant G Aguanno D Brot L Belloir C Delugeard J Roger N Pham HP Briand L Moreau M de Sordi L Carrière V Grill JP Thenet SSP 3-oxo-C12:2-HSL, quorum sensing molecule from human intestinal microbiota, inhibits pro-inflammatory pathways in immune cells via bitter taste receptors Sci Rep 2022 12 9440 10.1038/s41598-022-13451-3 35676403
Cui Y Wu H Li Q Impairment of bitter taste sensor transient receptor potential channel M5-mediated aversion aggravates high-salt intake and hypertension Hypertension 2019 10.1161/HYPERTENSIONAHA.119.13358
D’Urso O Drago F Pharmacological significance of extra-oral taste receptors Eur J Pharmacol 2021 910 174480 10.1016/j.ejphar.2021.174480 34496302
Dai C Li Q May HI Lactate dehydrogenase a governs cardiac hypertrophic growth in response to hemodynamic stress Cell Rep 2020 10.1016/j.celrep.2020.108087
Dai J Liu J Zhang Q Cathepsin C is involved in macrophage M1 polarization via p38/MAPK pathway in sudden cardiac death Cardiovasc Ther 2021 10.1155/2021/6139732
Davoodvandi A Sahebnasagh R Mardanshah O Medicinal plants as natural polarizers of macrophages: phytochemicals and pharmacological effects Curr Pharm Des 2019 10.2174/1381612825666190829154934
de Rossi BP García C Alcaraz E Franco M Stenotrophomonas maltophilia interferes via the DSF-mediated quorum sensing system with Candida albicans filamentation and its planktonic and biofilm modes of growth Rev Argent Microbiol 2014 10.1016/s0325-7541(14)70084-7
de Zoete MR Palm NW Zhu SFR Inflammasomes Cold Spring Harb Perspect Biol 2014 10.1101/cshperspect.a016287
Deep A Chaudhary U Gupta V Quorum sensing and bacterial pathogenicity: from molecules to disease J Lab Physicians 2011 10.4103/0974-2727.78553
Delmar M Liang FX Connexin43 and the regulation of intercalated disc function Hear Rhythm 2012 10.1016/j.hrthm.2011.10.028
Del-Pozo J Girling S Pizzi R Severe Necrotizing Myocarditis caused by Serratia marcescens Infection in an Axolotl (Ambystoma mexicanum) J Comp Pathol 2011 10.1016/j.jcpa.2010.11.001
Demion M Bois P Launay P Guinamard R TRPM4, a Ca2+-activated nonselective cation channel in mouse sino-atrial node cells Cardiovasc Res 2007 10.1016/j.cardiores.2006.11.023
Devillier P Naline E Grassin-Delyle S The pharmacology of bitter taste receptors and their role in human airways Pharmacol Ther 2015 155 11 21 10.1016/j.pharmthera.2015.08.001 26272040
Di Pizio A Niv MY Promiscuity and selectivity of bitter molecules and their receptors Bioorgan Med Chem 2015 10.1016/j.bmc.2015.04.025
Dikalova A Mayorov V Xiao L Mitochondrial isolevuglandins contribute to vascular oxidative stress and mitochondria-targeted scavenger of isolevuglandins reduces mitochondrial dysfunction and hypertension Hypertension 2020 10.1161/HYPERTENSIONAHA.120.15236
Dludla PV Nkambule BB Jack B Inflammation and oxidative stress in an obese state and the protective effects of gallic acid Nutrients 2019 11 23 10.3390/nu11010023
Dries E Bardi I Nunez-Toldra R Camkii inhibition reduces arrhythmogenic ca2+ events in subendocardial cryoinjured rat living myocardial slices J Gen Physiol 2021 10.1085/jgp.202012737
Duarte AC Rosado T Costa AR The bitter taste receptor TAS2R14 regulates resveratrol transport across the human blood-cerebrospinal fluid barrier Biochem Pharmacol 2020 10.1016/j.bcp.2020.113953
Dupont E Matsushita T Kaba RA Altered connexin expression in human congestive heart failure J Mol Cell Cardiol 2001 10.1006/jmcc.2000.1308
Dupre DJ Louis Martin MN Expression and functionality of bitter taste receptors in ovarian and prostate cancer FASEB J 2017 10.1096/fasebj.31.1_supplement.992.2
Eckardt D Theis M Degen J Functional role of connexin43 gap junction channels in adult mouse heart assessed by inducible gene deletion J Mol Cell Cardiol 2004 10.1016/j.yjmcc.2003.10.006
Edwards JL Jennings MP MAA& KLS, Is gonococcal disease preventable? The importance of understanding immunity andpathogenesis in vaccine development Crit Rev Microbiol 2016 42 928 941 10.3109/1040841X.2015.1105782 26805040
Emmons-Bell S Johnson CRG Prevalence, incidence and survival of heart failure: a systematic review Heart 2022 10.1136/heartjnl-2021-320131
Fan XZ Zhu HJ Wu X Effects of doxycycline on cx43 distribution and cardiac arrhythmia susceptibility of rats after myocardial infarction Iran J Pharm Res 2014 10.1136/heartjnl-2013-303992.093
Fernández Guerrero ML Aguado JM Arribas A The spectrum of cardiovascular infections due to Salmonella enterica: a review of clinical features and factors determining outcome Medicine (baltimore) 2004 83 123 10.1097/01.md.0000125652.75260.cf 15028966
Fernández Guerrero ML Goyenechea A Verdejo C Enterococcal endocarditis on native and prosthetic valves: A review of clinical and prognostic factors with emphasis on hospital-acquired infections as a major determinant of outcome Medicine (baltimore) 2007 86 363 10.1097/MD.0b013e31815d5386 18004181
Ferrand J Hadou T Selton-Suty C Cardiac device-related endocarditis caused by Paenibacillus glucanolyticus J Clin Microbiol 2013 10.1128/JCM.00864-13
Fletcher JN Kinghorn AD Slack JP In vitro evaluation of flavonoids from Eriodictyon californicum for antagonist activity against the bitterness receptor hTAS2R31 J Agric Food Chem 2011 10.1021/jf204359q
Foster SR Porrello ER Purdue B Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart PLoS ONE 2013 10.1371/journal.pone.0064579
Foster SR Blank K See Hoe LE Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart FASEB J 2014 10.1096/fj.14-256305
Foster SR Porrello ER Stefani M Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation Naunyn Schmiedebergs Arch Pharmacol 2015 10.1007/s00210-015-1118-1
Freeman TL Swartz TH Targeting the NLRP3 inflammasome in severe COVID-19 Front Immunol 2020 11 1518 10.3389/fimmu.2020.01518 32655582
Freund JR Mansfield CJ Doghramji LJ Activation of airway epithelial bitter taste receptors by pseudomonas aeruginosa quinolones modulates calcium, cyclic-amp, and nitric oxide signaling J Biol Chem 2018 10.1074/jbc.RA117.001005
Furman D Campisi J Verdin E Chronic inflammation in the etiology of disease across the life span Nat Med 2019 10.1038/s41591-019-0675-0
Gaida MM, Mayer C, Dapunt U, et al (2016) Expression of the bitter receptor T2R38 in pancreatic cancer: Localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. Oncotarget. 10.18632/oncotarget.7206
Garcia RA Go KV Villarreal FJ Effects of timed administration of doxycycline or methylprednisolone on post-myocardial infarction inflammation and left ventricular remodeling in the rat heart Mol Cell Biochem 2007 10.1007/s11010-006-9379-0
Gheorghe A Griffiths U Murphy A The economic burden of cardiovascular disease and hypertension in low- and middle-income countries: A systematic review BMC Public Health 2018 10.1186/s12889-018-5806-x
Gianluigi Savarese LHL (2017) Global public health burden of heart failure. Card Fail Rev 3:7–11. 10.15420/cfr.2016:25:2
Givvimani S Kundu S Narayanan N TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure Arch Physiol Biochem 2013 10.3109/13813455.2012.755548
Gloire G Legrand-Poels SPJ NF-kappaB activation by reactive oxygen species: fifteen years later Biochem Pharmacol 2006 72 1493 1505 10.1016/j.bcp.2006.04.011 16723122
Gopallawa I Freund JR Lee RJ Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling Cell Mol Life Sci 2021 10.1007/s00018-020-03494-y
Governini L Semplici B Pavone V Expression of taste receptor 2 subtypes in human testis and sperm J Clin Med 2020 10.3390/jcm9010264
Gradinaru TC Petran M Dragos DGM PlantMolecularTasteDB: a database of taste active phytochemicals Front Pharmacol 2022 12 751712 10.3389/fphar.2021.751712 35095484
Grand T Demion M Norez C 9-Phenanthrol inhibits human TRPM4 but not TRPM5 cationic channels Br J Pharmacol 2008 10.1038/bjp.2008.38
Grassin-Delyle S Salvator H Mantov N Bitter taste receptors (TAS2Rs) in human lung macrophages: receptor expression and inhibitory effects of TAS2R agonists Front Physiol 2019 10.3389/fphys.2019.01267
Gray CBB Suetomi T Xiang S CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α J Mol Cell Cardiol 2017 10.1016/j.yjmcc.2017.01.002
Greene TA Alarcon S Thomas A Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin PLoS ONE 2011 10.1371/journal.pone.0020123
Grekov I Pombinho AR Kobets T Calcium ionophore, calcimycin, kills Leishmania promastigotes by activating parasite nitric oxide synthase Biomed Res Int 2017 10.1155/2017/1309485
Guerrero Ortiz M, Manrique Legaz A, Díaz Izquierdo L (2003) Pancarditis por salmonella entérica. Diagnóstico de localización mediante exploración con 67galio. Rev Esp Med Nucl 10.1157/13044680
Guerrero MLF López JJG Goyenechea A Endocarditis caused by staphylococcus aureus a reappraisal of the epidemiologic, clinical, and pathologic manifestations with analysis of factors determining outcome Medicine (baltimore) 2009 88 1 22 10.1097/MD.0b013e318194da65 19352296
Gulbransen BD Clapp TR Finger TE Kinnamon SC Nasal solitary chemoreceptor cell responses to bitter and trigeminal stimulants in vitro J Neurophysiol 2008 10.1152/jn.00066.2008
Guo S Guo Q Syphilis-associated septic cardiomyopathy: case report and review of the literature BMC Infect Dis 2021 10.1186/s12879-020-05722-z
Gürtler N Osthoff M Rueter F Prosthetic valve endocarditis caused by Pseudomonas aeruginosa with variable antibacterial resistance profiles: a diagnostic challenge BMC Infect Dis 2019 10.1186/s12879-019-4164-3
Gutstein DE Morley GE Vaidya D Heterogeneous expression of gap junction channels in the heart leads to conduction defects and ventricular dysfunction Circulation 2001 10.1161/hc3601.093990
Hamdard E Lv Z Jiang J Responsiveness expressions of bitter taste receptors against denatonium benzoate and genistein in the heart, spleen, lung, kidney, and bursa fabricius of chinese fast yellow chicken Animals 2019 10.3390/ani9080532
Hamdard E Shi Z Lv Z Denatonium benzoate-induces oxidative stress in the heart and kidney of chinese fast yellow chickens by regulating apoptosis, autophagy, antioxidative activities and bitter taste receptor gene expressions Animals 2019 10.3390/ani9090701
Hariri BM McMahon DB Chen B Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor J Biol Chem 2017 10.1074/jbc.M116.771949
Hawver LA Jung SA Ng WL Specificity and complexity in bacterial quorum-sensing systemsa FEMS Microbiol Rev 2016 40 738 752 10.1093/femsre/fuw014 27354348
He L Marneros AG Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization J Biol Chem 2014 10.1074/jbc.M113.535765
He L Jhong JH Chen Q Huang KY Strittmatter K Kreuzer J DeRan M Wu X Lee TY Slavov N Haas WMA Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors Cell Rep 2021 37 109955 10.1016/j.celrep.2021.109955 34731634
Henao-Mejia J Elinav E Thaiss CA Flavell RA The intestinal microbiota in chronic liver disease Adv Immunol 2013 117 73 97 10.1016/B978-0-12-410524-9.00003-7 23611286
Hennig P Garstkiewicz M Grossi S The crosstalk between Nrf2 and inflammasomes Int J Mol Sci 2018 19 562 10.3390/ijms19020562 29438305
Hijikata S Hongo I Nakayama S Infective endocarditis due to treponema pallidum: a case diagnosed using polymerase chain reaction analysis of aortic valve Can J Cardiol 2019 10.1016/j.cjca.2018.11.009
Hirschhäuser C Lissoni A Görge PM Connexin 43 phosphorylation by casein kinase 1 is essential for the cardioprotection by ischemic preconditioning Basic Res Cardiol 2021 10.1007/s00395-021-00861-z
Hou L Guo J Xu F Cardiomyocyte dimethylarginine dimethylaminohydrolase1 attenuates left-ventricular remodeling after acute myocardial infarction: involvement in oxidative stress and apoptosis Basic Res Cardiol 2018 10.1007/s00395-018-0685-y
Hou L Yang J Li S Glibenclamide attenuates 2,5-hexanedione-induced neurotoxicity in the spinal cord of rats through mitigation of NLRP3 inflammasome activation, neuroinflammation and oxidative stress Toxicol Lett 2020 10.1016/j.toxlet.2020.06.002
Hu C Zhang X Wei W Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway Acta Pharm Sin B 2019 10.1016/j.apsb.2019.03.003
Hu C Zhang X Zhang N Osteocrin attenuates inflammation, oxidative stress, apoptosis, and cardiac dysfunction in doxorubicin-induced cardiotoxicity Clin Transl Med 2020 10.1002/ctm2.124
Huang ZZ Yu M Tong S Tissue-specific expression of the NOD-like receptor protein 3 in BALB/c mice J Vet Sci 2014 10.4142/jvs.2014.15.2.173
Ioannou P Vougiouklakis G Baliou S Infective endocarditis by yersinia species: A systematic review Trop Med Infect Dis 2021 6 19 10.3390/tropicalmed6010019 33540800
Jaggupilli A Howard R Upadhyaya JD Bitter taste receptors: Novel insights into the biochemistry and pharmacology Int J Biochem Cell Biol 2016 10.1016/j.biocel.2016.03.005
Jeandroz S Lamotte O Astier J Rasul S Trapet P Besson-Bard A Bourque S Nicolas-Francès V Ma W Gerald A Berkowitz DW Focus issue on calcium signaling there’s more to the picture than meets the eye: nitric oxide cross talk with Ca2+ signaling Plant Physiol 2013 163 459 470 10.1104/pp.113.220624 23749853
Jeon TI Seo YK Osborne TF Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK Biochem J 2011 10.1042/BJ20110009
Ji H, Li XK (2016) Oxidative stress in atopic dermatitis. Oxid Med Cell Longev
Jia SJ Zhou Z Zhang BK Asymmetric dimethylarginine damages connexin43-mediated endothelial gap junction intercellular communication Biochem Cell Biol 2009 10.1139/O09-042
Jiang J Hoagland D Palatinus JA Interaction of α carboxyl terminus 1 peptide with the connexin 43 carboxyl terminus preserves left ventricular function after ischemia-reperfusion injury J Am Heart Assoc 2019 10.1161/JAHA.119.012385
Jiang H Xing J Fang J Tilianin protects against ischemia/reperfusion-induced myocardial injury through the inhibition of the Ca2+/calmodulin-dependent protein kinase II-dependent apoptotic and inflammatory signaling pathways Biomed Res Int 2020 10.1155/2020/5939715
Jimi E Fei H Nakatomi C Nf-κb signaling regulates physiological and pathological chondrogenesis Int J Mol Sci 2019 20 6275 10.3390/ijms20246275 31842396
Jui E Singampalli KL Shani K The immune and inflammatory basis of acquired pediatric cardiac disease Front Cardiovasc Med 2021 10.3389/fcvm.2021.701224
Kamila T Agnieszka K An update on extra-oral bitter taste receptors J Transl Med 2021 19 1 33 33397399
Kandasamy AD Chow AK Ali MAM Schulz R Matrix metalloproteinase-2 and myocardial oxidative stress injury: Beyond the matrix Cardiovasc Res 2010 85 413 423 10.1093/cvr/cvp268 19656780
Kandasamy M NF-κB signalling as a pharmacological target in COVID-19: potential roles for IKKβ inhibitors Naunyn Schmiedebergs Arch Pharmacol 2021 10.1007/s00210-020-02035-5
Kelly TM Donovan K Cardiac rehabilitation in the time of health-care reform AACN Clin Issues 1995 10.1097/00044067-199508000-00008
Khan MA Hashim MJ Mustafa H Global epidemiology of ischemic heart disease: results from the global burden of disease study Cureus 2020 10.7759/cureus.9349
Khan J Deb PK Priya S Dietary flavonoids: Cardioprotective potential with antioxidant effects and their pharmacokinetic, toxicological and therapeutic concerns Molecules 2021 26 4021 10.3390/molecules26134021 34209338
Kim K Kim NJ Kim SY Cyclo(Phe-Pro) produced by the human pathogen Vibrio vulnificus inhibits host innate immune responses through the NF-κB pathway Infect Immun 2015 10.1128/IAI.02878-14
Kim IH Kim SY Park NY Cyclo-(L-Phe-L-Pro), a quorum-sensing signal of Vibrio vulnificus, induces expression of hydroperoxidase through a ToxR-LeuO-HU-RpoS signaling pathway to confer resistance against oxidative stress Infect Immun 2018 10.1128/IAI.00932-17
Kinnamon SC, Finger TE (2019) Recent advances in taste transduction and signaling. F1000Research 8:2117 10.12688/f1000research.21099.1
Kishore A Petrek M Roles of macrophage polarization and macrophage-derived mirnas in pulmonary fibrosis Front Immunol 2021 12 678457 10.3389/fimmu.2021.678457 34489932
Knockaert DC Cardiac involvement in systemic inflammatory diseases Eur Heart J 2007 28 1797 1804 10.1093/eurheartj/ehm193 17562669
Kobayashi J Lifestyle-mediated nitric oxide boost to prevent SARS-CoV-2 infection: A perspective Nitric Oxide Biol Chem 2021 115 55 61 10.1016/j.niox.2021.08.001
Kobusiak-Prokopowicz M Krzysztofik J Kaaz K MMP-2 and TIMP-2 in patients with heart failure and chronic kidney disease Open Med 2018 10.1515/med-2018-0037
Koc G Soyocak A Duzgun Ergun D Association of TRPM5 Asn235Ser polymorphism and trace elements/minerals in chronic gastritis patients: a case-control study Biol Trace Elem Res 2022 10.1007/s12011-021-03002-8
Kokabu S Lowery JW Toyono T Muscle regulatory factors regulate T1R3 taste receptor expression Biochem Biophys Res Commun 2015 10.1016/j.bbrc.2015.10.142
Kong F Ye B Cao J Curcumin represses NLRP3 inflammasome activation via TLR4/MyD88/NF-κB and P2X7R signaling in PMA-induced macrophages Front Pharmacol 2016 10.3389/fphar.2016.00369
Kopel E Kivity S Morag-Koren N Relation of serum lactate dehydrogenase to coronary artery disease Am J Cardiol 2012 10.1016/j.amjcard.2012.08.005
Labandeira-Garcia JL Rodríguez-Perez AI Garrido-Gil P Brain renin-angiotensin system and microglial polarization: Implications for aging and neurodegeneration Front Aging Neurosci 2017 9 129 10.3389/fnagi.2017.00129 28515690
Lamond NM McMullen PD Paramasvaran D Cardiotropic isolates of listeria monocytogenes with enhanced vertical transmission dependent upon the bacterial surface protein InlB Infect Immun 2021 10.1128/IAI.00321-20
Lampe PD TenBroek EM Burt JM Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication J Cell Biol 2000 10.1083/jcb.149.7.1503
Lampiasi N Montana G An in vitro inflammation model to study the Nrf2 and NF-κB crosstalk in presence of ferulic acid as modulator Immunobiology 2018 10.1016/j.imbio.2017.10.046
Lars W Thora S Mats B Role of inflammation in nonrheumatic, regurgitant heart valve disease. A comparative, descriptive study regarding apolipoproteins and inflammatory cells in nonrheumatic heart valve disease Cardiovasc Pathol 2007 10.1016/j.carpath.2006.10.004
Lee E-J Woo M-S Moon P-G α-Synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1 J Immunol 2010 10.4049/jimmunol.0903480
Lee GS Subramanian N Kim AI The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP Nature 2012 492 123 127 10.1038/nature11588 23143333
Lee RJ Cohen NA The emerging role of the bitter taste receptor T2R38 in upper respiratory infection and chronic rhinosinusitis Am J Rhinol Allergy 2013 10.2500/ajra.2013.27.3911
Lee SH Choi JH Involvement of inflammatory responses in the early development of calcific aortic valve disease: lessons from statin therapy Animal Cells Syst 2018 22 390 399 10.1080/19768354.2018.1528175
Lee W Lee SH Kim M Vibrio vulnificus quorum-sensing molecule cyclo(Phe-Pro) inhibits RIG-I-mediated antiviral innate immunity Nat Commun 2018 10.1038/s41467-018-04075-1
Leffler KE Abdel-Rahman AA Estrogen-dependent disruption of adiponectin-connexin43 signaling underlies exacerbated myocardial dysfunction in diabetic female rats J Pharmacol Exp Ther 2019 10.1124/jpet.118.254029
Leffler KE Abdel-Rahman AA Restoration of adiponectin-connexin43 signaling mitigates myocardial inflammation and dysfunction in diabetic female rats J Cardiovasc Pharmacol 2020 10.1097/FJC.0000000000000789
León-Cortés JL Leal Fernández G Sánchez-Pérez HJ Health reform in Mexico: Governance and potential outcomes Int J Equity Health 2019 18 1 6 10.1186/s12939-019-0929-y 30606218
Leung PS The physiology of a local renin-angiotensin system in the pancreas J Physiol 2007 580 31 37 10.1113/jphysiol.2006.126193 17218353
Ley JP Blings M Paetz S New bitter-masking compounds: Hydroxylated benzoic acid amides of aromatic amines as structural analogues of homoeriodictyol J Agric Food Chem 2006 10.1021/jf0617061
Ley JP Paetz S Blings M Structural analogues of homoeriodictyol as flavor modifiers. Part III: Short chain gingerdione derivatives J Agric Food Chem 2008 10.1021/jf8006536
Ley JP Dessoy M Paetz S Identification of enterodiol as a masker for caffeine bitterness by using a pharmacophore model based on structural analogues of homoeriodictyol J Agric Food Chem 2012 10.1021/jf301335z
Li J Attila C Wang L Quorum sensing in Escherichia coli is signaled by AI-2/LsrR: effects on small RNA and biofilm architecture J Bacteriol 2007 10.1128/JB.00014-07
Li Q Wang Y Sun SZ Effects of benazepril on cardiac fibrosis in STZ-induced diabetic rats Acta Cardiol 2010 10.2143/AC.65.4.2053902
Li Y Ge S Peng Y Chen X Inflammation and cardiac dysfunction during sepsis, muscular dystrophy, and myocarditis Burn Trauma 2013 1 3 2321 3868
Li L Feng X Zhou Z Stress accelerates defensive responses to looming in mice and involves a locus coeruleus-superior colliculus projection Curr Biol 2018 10.1016/j.cub.2018.02.005
Li R Zhenquan Jia HZ Regulation of Nrf2 Signaling React Oxyg Species 2019 8 312 322
Li Y Yang L Dong L Crosstalk between the Akt/mTORC1 and NF-κB signaling pathways promotes hypoxia-induced pulmonary hypertension by increasing DPP4 expression in PASMCs Acta Pharmacol Sin 2019 10.1038/s41401-019-0272-2
Liao Y Day KH Damon DN Duling BR Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice Proc Natl Acad Sci USA 2001 10.1073/pnas.171305298
Lin L Sylvén C Åström H Myocardial lactate dehydrogenase and its isoenzyme activities in transplanted human hearts Scand Cardiovasc J 1991 10.3109/14017439109098083
Ling H Gray CBB Zambon AC Ca2+/calmodulin-dependent protein kinase ii δ mediates myocardial ischemia/reperfusion injury through nuclear factor-κb Circ Res 2013 10.1161/CIRCRESAHA.112.276915
Liszt KI Wang Q Farhadipour M Segers A Thijs T Nys L Deleus E Van der Schueren B Gerner C Neuditschko B Ceulemans LJ Lannoo M DI Tack J Human intestinal bitter taste receptors regulate innate immune responses and metabolic regulators in obesity J Clin Invest 2022 132 e144828 10.1172/JCI144828 34784295
Liu Y Lian K Zhang L TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury Basic Res Cardiol 2014 10.1007/s00395-014-0415-z
Liu W Zhang X Zhao M Activation in M1 but not M2 macrophages contributes to cardiac remodeling after myocardial infarction in rats: A critical role of the calcium sensing receptor/NRLP3 inflammasome Cell Physiol Biochem 2015 10.1159/000374048
Liu X Gu F Jiang L Expression of bitter taste receptor Tas2r105 in mouse kidney Biochem Biophys Res Commun 2015 10.1016/j.bbrc.2015.01.089
Liu J Zong Z Zhang W Nicotinamide mononucleotide alleviates LPS-induced inflammation and oxidative stress via decreasing COX-2 expression in macrophages Front Mol Biosci 2021 10.3389/fmolb.2021.702107
Lu L Sun R Liu M Zheng YZP The inflammatory heart diseases: causes, symptoms, and treatments Cell Biochem Biophys 2015 72 851 855 10.1007/s12013-015-0550-7 25682012
Lu H Zhang Z Barnie PA Su Z Dual faced HMGB1 plays multiple roles in cardiomyocyte senescence and cardiac inflammatory injury Cytokine Growth Factor Rev 2019 47 74 82 10.1016/j.cytogfr.2019.05.009 31129019
Lu H Chen R Barnie PA Fibroblast transdifferentiation promotes conversion of M1 macrophages and replenishment of cardiac resident macrophages following cardiac injury in mice Eur J Immunol 2020 10.1002/eji.201948414
Lund TC Kobs AJ Kramer A Bone marrow stromal and vascular smooth muscle cells have chemosensory capacity via bitter taste receptor expression PLoS ONE 2013 10.1371/journal.pone.0058945
Maccio U Zinkernagel AS Shambat SM SARS-CoV-2 leads to a small vessel endotheliitis in the heart EBioMedicine 2021 10.1016/j.ebiom.2020.103182
Manson ML Säfholm J Al-Ameri M Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle Eur J Pharmacol 2014 10.1016/j.ejphar.2014.07.005
Mariathasan S Hewton K Monack DM Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf Nature 2004 10.1038/nature02664
Martens CR Accornero F Viruses in the heart: Direct and indirect routes to myocarditis and heart failure Viruses 2021 13 1924 10.3390/v13101924 34696354
Martin TP McCluskey C Cunningham MR CaMKIIδ interacts directly with IKKβ and modulates NF-κB signalling in adult cardiac fibroblasts Cell Signal 2018 10.1016/j.cellsig.2018.07.008
Martin LTP Nachtigal MW Selman T Bitter taste receptors are expressed in human epithelial ovarian and prostate cancers cells and noscapine stimulation impacts cell survival Mol Cell Biochem 2019 10.1007/s11010-018-3464-z
Maurer S Wabnitz GH Kahle NA Tasting Pseudomonas aeruginosa biofilms: Human neutrophils express the bitter receptor T2R38 as sensor for the quorum sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone Front Immunol 2015 10.3389/fimmu.2015.00369
Mayorov V Uchakin P Amarnath V Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation Redox Biol 2019 10.1016/j.redox.2019.101300
May-Zhang LS Yermalitsky V Huang J Modification by isolevuglandins, highly reactive γ-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function J Biol Chem 2018 10.1074/jbc.RA117.001099
McGee M Shiel E Brienesse S Staphylococcus aureus Myocarditis with Associated Left Ventricular Apical Thrombus Case Reports Cardiol 2018 10.1155/2018/7017286
McVeigh T Tennyson C Understanding and recognizing cardiac amyloidosis JAAPA 2020 33 16 20 10.1097/01.JAA.0000697236.11386.3a
Medapati MR Bhagirath AY Singh N Chelikani P Pharmacology of T2R mediated host-microbe interactions Handbook Experim Pharmacol 2022 10.1007/164_2021_435
Mehta NJ Khan IA Mehta RN Gulati A Stenotrophomonas maltophilia endocarditis of prosthetic aortic valve: Report of a case and review of literature Hear Lung J Acute Crit Care 2000 10.1067/mhl.2000.108362
Meraviglia V Alcalde MCO BM, Inflammation in the pathogenesis of arrhythmogenic cardiomyopathy: secondary event or active driver? Front Cardiovasc Med 2021 8 784715 10.3389/fcvm.2021.784715 34988129
Mesquita T Lin YN Ibrahim A Chronic low-grade inflammation in heart failure with preserved ejection fraction Aging Cell 2021 10.1111/acel.13453
Meyerhof W, Batram C, Kuhn C, et al (2010) The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors Present address : Department of Physiology Building 58, University of Saarland, Medical Chem Senses
Mezzaroma E Toldo S Farkas D The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse Proc Natl Acad Sci USA 2011 10.1073/pnas.1108586108
Milanesi S Verzola D Cappadona F Uric acid and angiotensin II additively promote inflammation and oxidative stress in human proximal tubule cells by activation of toll-like receptor 4 J Cell Physiol 2019 10.1002/jcp.27929
Mills CD M1 and M2 macrophages: Oracles of health and disease Crit Rev Immunol 2012 10.1615/CritRevImmunol.v32.i6.10
Moreira DM da Silva RL Vieira JL Role of vascular inflammation in coronary artery disease: potential of anti-inflammatory drugs in the prevention of atherothrombosis: inflammation and anti-inflammatory drugs in coronary artery disease Am J Cardiovasc Drugs 2015 10.1007/s40256-014-0094-z
Muka T Imo D Jaspers L The global impact of non-communicable diseases on healthcare spending and national income: a systematic review Eur J Epidemiol 2015 30 251 277 10.1007/s10654-014-9984-2 25595318
Mullick A Leon Z Min-Oo G Cardiac failure in C5-deficient A/J mice after Candida albicans infection Infect Immun 2006 10.1128/IAI.00159-06
Mulya E Waturangi DE Screening and quantification of anti-quorum sensing and antibiofilm activity of Actinomycetes isolates against food spoilage biofilm-forming bacteria BMC Microbiol 2021 10.1186/s12866-020-02060-7
Murakami T Ockinger J Yu J Critical role for calcium mobilization in activation of the NLRP3 inflammasome Proc Natl Acad Sci U S A 2012 10.1073/pnas.1117765109
Murphy SP Kakkar R McCarthy CP Januzzi JL Inflammation in heart failure: JACC state-of-the-art review J Am Coll Cardiol 2020 75 1324 1340 10.1016/j.jacc.2020.01.014 32192660
Musa NL Hjortdal V Zheleva B The global burden of paediatric heart disease Cardiol Young 2017 27 S3 S8 10.1017/S1047951117002530
Neri M Fineschi V Paolo M Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction Curr Vasc Pharmacol 2015 10.2174/15701611113119990003
Ngwenyama N Kirabo A Aronovitz M Isolevuglandin-modified cardiac proteins drive CD4+ T-cell activation in the heart and promote cardiac dysfunction Circulation 2021 10.1161/CIRCULATIONAHA.120.051889
Nigam S Ciccoli R Ivanov I On mechanism of quorum sensing in candida albicans by 3(R)-hydroxy-tetradecaenoic acid Curr Microbiol 2011 10.1007/s00284-010-9666-6
Obama B United States health care reform: Progress to date and next steps JAMA 2016 316 525 532 10.1001/jama.2016.9797 27400401
Olayemi G Oferczak M Elagizi A El-Abbassi I Eschete MCJ Gonococcal endocarditis: The gift that stops giving! An uncommon presentation of a common disease J La State Med Soc 2017 169 47
Ooi BK Goh BH Yap WH Oxidative stress in cardiovascular diseases: Involvement of Nrf2 antioxidant redox signaling in macrophage foam cells formation Int J Mol Sci 2017 18 2336 10.3390/ijms18112336 29113088
Orekhov AN, Orekhova VA, Nikiforov NG, et al (2019) Monocyte differentiation and macrophage polarization. Vessel Plus 10.20517/2574-1209.2019.04
Ouarradi AE, Kantri A, Agrad K, Bensahi I, Merzouk F, Guennoun Z, Makani S, Jebbari Y, Elkettani CSM (2021) Infective endocarditis following COVID-19 pneumonia: about two cases. Pan Afr Med J 40:152. 10.11604/pamj.2021.40.152.32071
Ozhathil LC Delalande C Bianchi B Identification of potent and selective small molecule inhibitors of the cation channel TRPM4 Br J Pharmacol 2018 10.1111/bph.14220
Palatinus JA Rhett JM Gourdie RG The connexin43 carboxyl terminus and cardiac gap junction organization Biochim Biophys Acta Biomembr 2012 1818 1831 1843 10.1016/j.bbamem.2011.08.006
Palmer RK The pharmacology and signaling of bitter, sweet, and umami taste sensing Mol Interv 2007 7 87 10.1124/mi.7.2.9 17468389
Panche AN, Diwan AD, Chandra SR (2016) Flavonoids: An overview. J Nutr Sci 5
Panneck AR Rafiq A Schütz B Cholinergic epithelial cell with chemosensory traits in murine thymic medulla Cell Tissue Res 2014 10.1007/s00441-014-2002-x
Papaconstantinou J The role of signaling pathways of inflammation and oxidative stress in development of senescence and aging phenotypes in cardiovascular disease Cells 2019 8 1383 10.3390/cells8111383 31689891
Parsa S Mogharab V Ebrahimi M COVID-19 as a worldwide selective event and bitter taste receptor polymorphisms: An ecological correlational study Int J Biol Macromol 2021 10.1016/j.ijbiomac.2021.02.070
Pashkow FJ Oxidative stress and inflammation in heart disease: do antioxidants have a role in treatment and/or prevention? Int J Inflam 2011 10.4061/2011/514623
Passos LSA Nunes MCP Aikawa E Rheumatic heart valve disease pathophysiology and underlying mechanisms Front Cardiovasc Med 2021 10.3389/fcvm.2020.612716
Pearce MM Theodoropoulos N Noskin GA Native valve endocarditis due to a novel strain of Legionella J Clin Microbiol 2011 10.1128/JCM.01066-11
Pérez CA Huang L Rong M A transient receptor potential channel expressed in taste receptor cells Nat Neurosci 2002 10.1038/nn952
Pflug KM Sitcheran R Targeting NF-κB-inducing kinase (NIK) in immunity, inflammation, and cancer Int J Mol Sci 2020 10.3390/ijms21228470
Piao H Takahashi K Yamaguchi Y Transient receptor potential melastatin-4 is involved in hypoxia-reoxygenation injury in the cardiomyocytes PLoS ONE 2015 10.1371/journal.pone.0121703
Pizzino G, Irrera N, Cucinotta M, et al (2017) Oxidative stress: harms and benefits for human health. Oxid Med Cell Longev
Procida K Jørgensen L Schmitt N Phosphorylation of connexin43 on serine 306 regulates electrical coupling Hear Rhythm 2009 10.1016/j.hrthm.2009.07.043
Pugliese ME Falcone M Oliva A Aeromonas hydrophila endocarditis with ruptured mycotic aneurysm of right renal artery Infect Dis Rep 2016 10.4081/idr.2016.6515
Qin S Hou DX The biofunctions of phytochemicals and their applications in farm animals: The Nrf2/Keap1 system as a target Engineering 2017 10.1016/J.ENG.2017.03.011
Quiring R Burke V Escherichia coli prosthetic valve endocarditis from a non-genitourinary source Idcases 2021 10.1016/j.idcr.2021.e01329
Rabin N Zheng Y Opoku-Temeng C Agents that inhibit bacterial biofilm formation Future Med Chem 2015 7 493 512 10.4155/fmc.15.6 25875875
Rajput A Kaur K Kumar M SigMol: Repertoire of quorum sensing signaling molecules in prokaryotes Nucleic Acids Res 2016 10.1093/nar/gkv1076
Ranjani J Pushpanathan M Mahesh A Pseudomonas aeruginosa PAO1 induces distinct cell death mechanisms in H9C2 cells and its differentiated form J Basic Microbiol 2015 10.1002/jobm.201500037
Reddy AT Lakshmi SP Maruthi Prasad E Epigallocatechin gallate suppresses inflammation in human coronary artery endothelial cells by inhibiting NF-κB Life Sci 2020 10.1016/j.lfs.2020.118136
Rennemeier C Frambach T Hennicke F Microbial quorum-sensing molecules induce acrosome loss and cell death in human spermatozoa Infect Immun 2009 10.1128/IAI.00586-09
Ringel RE Brenner JI Rennels MB Serologic evidence for Chlamydia trachomatis myocarditis Pediatrics 1982 10.1542/peds.70.1.54
Rodríguez-Hernández MJ Jiménez-Mejias ME Pichardo C Colistin efficacy in an experimental model of Acinetobacter baumannii endocarditis Clin Microbiol Infect 2004 10.1111/j.1469-0691.2004.00910.x
Rodriguez-Pallares J Rey P Parga JA Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS Neurobiol Dis 2008 10.1016/j.nbd.2008.03.003
Roland WSU Gouka RJ Gruppen H 6-Methoxyflavanones as bitter taste receptor blockers for hTAS2R39 PLoS ONE 2014 10.1371/journal.pone.0094451
Roth GA Johnson C Abajobir A Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015 J Am Coll Cardiol 2017 10.1016/j.jacc.2017.04.052
Roth GA Mensah GA Johnson CO Global burden of cardiovascular diseases and risk factors, 1990–2019: Update From the GBD 2019 Study J Am Coll Cardiol 2020 76 2982 3021 10.1016/j.jacc.2020.11.010 33309175
Rozengurt E Taste receptors in the gastrointestinal tract. I. Bitter taste receptors and α-gustducin in the mammalian gut Am J Physiol Gastrointest Liver Physiol 2006 291 G171 G177 10.1152/ajpgi.00073.2006 16710053
Ruggeri Barbaro N Van Beusecum J Xiao L Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation Cardiovasc Res 2021 10.1093/cvr/cvaa207
Ryan M. Carey, Benjamin M. Hariri, Nithin D. Adappa, James N. Palmer RJL (2021) HSP90 modulates T2R bitter taste receptor nitric oxide production and innate immune responses in human airway epithelial cells and macrophages. bioRxiv. 10.1101/2021.11.16.468387
Sandanger Ø Ranheim T Vinge LE The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury Cardiovasc Res 2013 10.1093/cvr/cvt091
Sangeetha M Pillai MS Philip L NF-κB inhibition compromises cardiac fibroblast viability under hypoxia Exp Cell Res 2011 10.1016/j.yexcr.2010.12.024
Saqib U Sarkar S Suk K Phytochemicals as modulators of M1–M2 macrophages in inflammation Oncotarget 2018 9 17937 17950 10.18632/oncotarget.24788 29707159
Severs NJ (2002) Gap junctions and connexin expression in human heart disease. In: Heart cell coupling and impulse propagation in health and disease. Basic Science for the Cardiologist, vol. 12. Springer, Boston, MA, pp 321–334
Severs NJ Bruce AF Dupont E Rothery S Remodelling of gap junctions and connexin expression in diseased myocardium Cardiovasc Res 2008 80 9 19 10.1093/cvr/cvn133 18519446
Shang L Weng X Wang D Isolevuglandin scavenger attenuates pressure overload-induced cardiac oxidative stress, cardiac hypertrophy, heart failure and lung remodeling Free Radic Biol Med 2019 10.1016/j.freeradbiomed.2019.06.029
Sharma M De Alba E Structure, activation and regulation of NLRP3 and AIM2 inflammasomes Int J Mol Sci 2021 10.3390/ijms22020872
Sharma P McAlinden KD Ghavami S Deshpande DA Chloroquine: Autophagy inhibitor, antimalarial, bitter taste receptor agonist in fight against COVID-19, a reality check? Eur J Pharmacol 2021 10.1016/j.ejphar.2021.173928
Shenasa M Shenasa H Hypertension, left ventricular hypertrophy, and sudden cardiac death Int J Cardiol 2017 10.1016/j.ijcard.2017.03.002
Shi P Zhang J Yang H Zhang Y ping, Adaptive diversification of bitter taste receptor genes in mammalian evolution Mol Biol Evol 2003 10.1093/molbev/msg083
Shibata A Izumiya Y Yamaguchi Y Increased oxidative stress during exercise predicts poor prognosis in patients with acute decompensated heart failure ESC Hear Fail 2021 10.1002/ehf2.13538
Shin YJ Park JH Choi JS Enhanced expression of the sweet taste receptors and alpha-gustducin in reactive astrocytes of the rat hippocampus following ischemic injury Neurochem Res 2010 10.1007/s11064-010-0223-2
Siegismund CS Escher F Lassner D Intramyocardial inflammation predicts adverse outcome in patients with cardiac AL amyloidosis Eur J Heart Fail 2018 10.1002/ejhf.1039
Silvis MJM, Kaffka genaamd Dengler SE, Odille CA, et al (2020) Damage-associated molecular patterns in myocardial infarction and heart transplantation: The Road to Translational Success. Front Immunol 11:599511
Simard C Sallé L Rouet R Guinamard R Transient receptor potential melastatin 4 inhibitor 9-phenanthrol abolishes arrhythmias induced by hypoxia and re-oxygenation in mouse ventricle Br J Pharmacol 2012 10.1111/j.1476-5381.2011.01715.x
Simon S Schell U Heuer N Inter-kingdom signaling by the legionella quorum sensing molecule LAI-1 modulates cell migration through an IQGAP1-Cdc42-ARHGEF9-dependent pathway PLoS Pathog 2015 10.1371/journal.ppat.1005307
Singh N Vrontakis M Parkinson F Chelikani P Functional bitter taste receptors are expressed in brain cells Biochem Biophys Res Commun 2011 10.1016/j.bbrc.2011.02.016
Soultanova A Voigt A Chubanov V Cholinergic chemosensory cells of the thymic medulla express the bitter receptor Tas2r131 Int Immunopharmacol 2015 10.1016/j.intimp.2015.06.005
Spaulding K Takaba K Collins A Short term doxycycline treatment induces sustained improvement in myocardial infarction border zone contractility PLoS ONE 2018 10.1371/journal.pone.0192720
Sternlicht MD Werb Z How matrix metalloproteinases regulate cell behavior Annu Rev Cell Dev Biol 2001 10.1146/annurev.cellbio.17.1.463
Strnadel M Hnátek T Havlíček R Listerial myocarditis as a complication of Listerial meningoencephalitis Cor Vasa 2018 10.1016/j.crvasa.2017.02.004
Suetomi T Willeford A Brand CS Inflammation and NLRP3 Inflammasome activation initiated in response to pressure overload by Ca2+/calmodulin-dependent protein kinase II δ signaling in cardiomyocytes are essential for adverse cardiac remodeling Circulation 2018 10.1161/CIRCULATIONAHA.118.034621
Suetomi T Miyamoto S Brown JH Inflammation in nonischemic heart disease: Initiation by cardiomyocyte CaMKII and NLRP3 inflammasome signaling Am J Physiol Hear Circ Physiol 2019 317 H877 H890 10.1152/ajpheart.00223.2019
Suri RK Selby DA Hawks GH Baker CB Serratia marcescens endocarditis. A report of a case involving Cross-Jones mitral valve prosthesis, with a review of the literature Can Med Assoc J 1971 104 1013 4930398
Swanson KV Deng M Ting JPY The NLRP3 inflammasome: molecular activation and regulation to therapeutics Nat Rev Immunol 2019 19 477 489 10.1038/s41577-019-0165-0 31036962
Syam N Rougier JS Abriel H Glycosylation of TRPM4 and TRPM5 channels: Molecular determinants and functional aspects Front Cell Neurosci 2014 10.3389/fncel.2014.00052
Takanari H Bourgonje VJA Fontes MSC Calmodulin/CaMKII inhibition improves intercellular communication and impulse propagation in the heart and is antiarrhythmic under conditions when fibrosis is absent Cardiovasc Res 2016 10.1093/cvr/cvw173
Talman V Ruskoaho H Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration Cell Tissue Res 2016 10.1007/s00441-016-2431-9
Thakur V Alcoreza N Cazares J Chattopadhyay M Changes in stress-mediated markers in a human cardiomyocyte cell line under hyperglycemia Int J Mol Sci 2021 10.3390/ijms221910802
Thomas BS Bankowski MJ Lau WKK Native valve Bacillus cereus endocarditis in a non-intravenous-drug-abusing patient J Clin Microbiol 2012 10.1128/JCM.00657-11
Thu YM Richmond A NF-κB inducing kinase: A key regulator in the immune system and in cancer Cytokine Growth Factor Rev 2010 10.1016/j.cytogfr.2010.06.002
Tiaden A Hilbi H α-hydroxyketone synthesis and sensing by Legionella and Vibrio Sensors 2012 10.3390/s120302899
Tinggi U (2008) Selenium: Its role as antioxidant in human health. In: Environmental Health and Preventive Medicine
Tiroch J Sterneder S Di Pizio A Bitter sensing TAS2R50 mediates the trans -resveratrol-induced anti-inflammatory effect on interleukin 6 release in HGF-1 cells in culture J Agric Food Chem 2021 10.1021/acs.jafc.0c07058
Tizzano M Cristofoletti M Sbarbati A Finger TE Expression of taste receptors in Solitary Chemosensory Cells of rodent airways BMC Pulm Med 2011 10.1186/1471-2466-11-3
Tomás J Santos CRA Quintela T Gonçalves I “Tasting” the cerebrospinal fluid: Another function of the choroid plexus? Neuroscience 2016 10.1016/j.neuroscience.2016.01.057
Truwit JD Badesch DB Savage AM Shelton M Vibrio vulnificus bacteremia with endocarditis South Med J 1987 10.1097/00007611-198711000-00032
Tsai HJ Liao MH Shih CC Angiotensin-(1–7) attenuates organ injury and mortality in rats with polymicrobial sepsis Crit Care 2018 10.1186/s13054-018-2210-y
Tsampasian V Swift AJ Assadi H Myocardial inflammation and energetics by cardiac MRI: a review of emerging techniques BMC Med Imaging 2021 21 1 9 10.1186/s12880-021-00695-0 33407190
Tsang H Leiper J Lao KH Role of asymmetric methylarginine and connexin 43 in the regulation of pulmonary endothelial function Pulm Circ 2013 10.1086/674440
Tschöpe C Ammirati E Bozkurt B Myocarditis and inflammatory cardiomyopathy: current evidence and future directions Nat Rev Cardiol 2021 21 1 9
Tsikas D Urinary dimethylamine (DMA) and its precursor asymmetric dimethylarginine (ADMA) in clinical medicine, in the context of nitric oxide (no) and beyond J Clin Med 2020 9 6 1843 10.3390/jcm9061843 32545708
Uehara EU de Shida B S, de Brito CA, Role of nitric oxide in immune responses against viruses: beyond microbicidal activity Inflamm Res 2015 10.1007/s00011-015-0857-2
van der Pol A van Gilst WH Voors AA van der Meer P Treating oxidative stress in heart failure: past, present and future Eur J Heart Fail 2019 10.1002/ejhf.1320
Vegezzi G Anselmi L Huynh J Diet-induced regulation of bitter taste receptor subtypes in the mouse gastrointestinal tract PLoS ONE 2014 10.1371/journal.pone.0107732
Veinot K-LC JP, Cardiac Involvement by Systemic Diseases Anatomic Basis of Echocardiographic Diagnosis 2010 London Springer 439 454
Virginio C Aldegheri L Nola S Brodbeck D Brault L Raveglia LF Barilli A Sabat MMR Identification of positive modulators of TRPM5 channel from a high-throughput screen using a fluorescent membrane potential assay SLAS Discov 2022 27 55 64 10.1016/j.slasd.2021.10.004 35058176
Vomund S Schäfer A Parnham MJ Nrf2, the master regulator of anti-oxidative responses Int J Mol Sci 2017 18 2772 10.3390/ijms18122772 29261130
von Lackum K Babb K Riley SP Functionality of Borrelia burgdorferi LuxS: The Lyme disease spirochete produces and responds to the pheromone autoinducer-2 and lacks a complete activated-methyl cycle Int J Med Microbiol 2006 10.1016/j.ijmm.2005.12.011
Wadley AJ Veldhuijzen Van Zanten JJCS Aldred S The interactions of oxidative stress and inflammation with vascular dysfunction in ageing: The vascular health triad Age (omaha) 2013 10.1007/s11357-012-9402-1
Wang LH He Y Gao Y A bacterial cell-cell communication signal with cross-kingdom structural analogues Mol Microbiol 2004 10.1046/j.1365-2958.2003.03883.x
Wang J Takahashi K Piao H 9-Phenanthrol, a TRPM4 inhibitor, protects isolated rat hearts from ischemia-reperfusion injury PLoS ONE 2013 10.1371/journal.pone.0070587
Wang Z Hu W Lu C Targeting NLRP3 (nucleotide-binding domain, leucine- rich-containing family, pyrin domain-containing-3) inflammasome in cardiovascular disorders Arterioscler Thromb Vasc Biol 2018 38 2765 2779 10.1161/ATVBAHA.118.311916 30571177
Wang Y Liu X Shi H NLRP3 inflammasome, an immune-inflammatory target in pathogenesis and treatment of cardiovascular diseases Clin Transl Med 2020 10.1002/ctm2.13
Weintraub WS Boden WE Making cardiovascular care more responsive to societal needs Am J Med 2017 130 1259 1261 10.1016/j.amjmed.2017.07.018 28797644
Welcome MO, Mastorakis NE, Pereverzev VA (2015) Sweet taste receptor signaling network: Possible implication for cognitive functioning. Neurol Res Int
Welcome MO The bitterness of genitourinary infections: Properties, ligands of genitourinary bitter taste receptors and mechanisms linking taste sensing to inflammatory processes in the genitourinary tract Eur J Obstet Gynecol Reprod Biol 2020 247 101 110 10.1016/j.ejogrb.2020.02.015 32088528
Welcome MO Cellular mechanisms and molecular signaling pathways in stress-induced anxiety, depression, and blood–brain barrier inflammation and leakage Inflammopharmacology 2020 28 643 665 10.1007/s10787-020-00712-8 32333258
Welcome MO Mastorakis NE Stress-induced blood brain barrier disruption: Molecular mechanisms and signaling pathways Pharmacol Res 2020 10.1016/j.phrs.2020.104769
Welcome MO Mastorakis NE The taste of neuroinflammation: Molecular mechanisms linking taste sensing to neuroinflammatory responses Pharmacol Res 2021 167 105557 10.1016/j.phrs.2021.105557 33737243
Welcome M Jeremiah A Allagoa D Etiopathogenesis of reproductive tract infections and the emerging role of bitter taste receptors: A scoping review Asian Pacific J Reprod 2021 10 145 10.4103/2305-0500.321122
Willeford A Suetomi T Nickle A CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis JCI Insight 2018 10.1172/jci.insight.97054
Williams DWP Koenig J Carnevali L Heart rate variability and inflammation: A meta-analysis of human studies Brain Behav Immun 2019 10.1016/j.bbi.2019.03.009
Wirtz PH, von KR (2017) Psychological stress, inflammation, and coronary heart disease. Curr Cardiol Rep 19:111. 10.1007/s11886-017-0919-x
Wölfle U Elsholz FA Kersten A Expression and functional activity of the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes Skin Pharmacol Physiol 2015 10.1159/000367631
Workman AD Maina IW Brooks SG The role of quinine-responsive taste receptor family 2 in airway immune defense and chronic rhinosinusitis Front Immunol 2018 10.3389/fimmu.2018.00624
Woronicz JD Gao X Cao Z IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK [see comments] Science 1997 80–s 278
Wu SV Chen MC Rozengurt E Genomic organization, expression, and function of bitter taste receptors (T2R) in mouse and rat Physiol Genom 2005 10.1152/physiolgenomics.00030.2005
Wu J Williams D Walter GA Estrogen increases Nrf2 activity through activation of the PI3K pathway in MCF-7 breast cancer cells Exp Cell Res 2014 10.1016/j.yexcr.2014.08.030
Wu H Cui Y He C Activation of the bitter taste sensor TRPM5 prevents high salt-induced cardiovascular dysfunction Sci China Life Sci 2020 10.1007/s11427-019-1649-9
Wu S Liu C Feng J QSIdb: Quorum sensing interference molecules Brief Bioinform 2021 10.1093/bib/bbaa218
Wu X Huang L Liu J Relationship between oxidative stress and nuclear factor-erythroid-2-related factor 2 signaling in diabetic cardiomyopathy (Review) Exp Ther Med 2021 10.3892/etm.2021.10110
Xie C Wang X Young RL Role of intestinal bitter sensing in enteroendocrine hormone secretion and metabolic control Front Endocrinol 2018 10.3389/fendo.2018.00576
Xu J Cao J Iguchi N Functional characterization of bitter-taste receptors expressed in mammalian testis Mol Hum Reprod 2013 10.1093/molehr/gas040
Xuan F Jian J Epigallocatechin gallate exerts protective effects against myocardial ischemia/reperfusion injury through the PI3K/Akt pathway-mediated inhibition of apoptosis and the restoration of the autophagic flux Int J Mol Med 2016 10.3892/ijmm.2016.2615
Yahfoufi N Alsadi N Jambi M Matar C The immunomodulatory and anti-inflammatory role of polyphenols Nutrients 2018 10.3390/nu10111618
Yan L (2014) Chronic sustained inflammation links to left ventricular hypertrophy and aortic valve sclerosis: a new link between S100/RAGE and FGF23. Inflamm Cell Signal 10.14800/ics.279
Yang Y Yan X Xue J Connexin43 dephosphorylation at serine 282 is associated with connexin43-mediated cardiomyocyte apoptosis Cell Death Differ 2019 10.1038/s41418-019-0277-x
Ye J Yu M Zhang K Tissue-specific expression pattern and histological distribution of NLRP3 in Chinese yellow chicken Vet Res Commun 2015 10.1007/s11259-015-9641-6
Yin C Ye Z Huang C Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction SSRN Electron J 2021 10.2139/ssrn.3861570
Yuan G Jing Y Wang T The bitter taste receptor agonist-induced negative chronotropic effects on the Langendorff-perfused isolated rat hearts Eur J Pharmacol 2020 10.1016/j.ejphar.2020.173063
Zeppenfeld K Tfelt-Hansen J de Riva M Winkel BG Behr ER Blom NA Charron P Corrado D Dagres N de Chillou C Eckardt L Friede T Haugaa KH Hocini M Lambiase PD Marijon E Merino JL Peichl P Priori SG Reichlin T Schulz-Menger J Sticherling VMESDG ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death Eur Hear J 2022 10.1093/eurheartj/ehac262
Zhai KF Duan H Khan GJ Salicin from Alangium chinense ameliorates rheumatoid arthritis by modulating the Nrf2-HO-1-ROS pathways J Agric Food Chem 2018 10.1021/acs.jafc.8b02241
Zhang B Shen Q Chen Y Myricitrin alleviates oxidative stress-induced inflammation and apoptosis and protects mice against diabetic cardiomyopathy Sci Rep 2017 10.1038/srep44239
Zhang G Lin X Zhang S A protective role of glibenclamide in inflammation-associated injury Mediat Inflamm 2017 10.1155/2017/3578702
Zhang L Tian J Diao S GLP-1 receptor agonist liraglutide protects cardiomyocytes from IL-1β-induced metabolic disturbance and mitochondrial dysfunction Chem Biol Interact 2020 10.1016/j.cbi.2020.109252
Zhang X Qu H Yang T Regulation and functions of NLRP3 inflammasome in cardiac fibrosis: Current knowledge and clinical significance Biomed Pharmacother 2021 143 112219 10.1016/j.biopha.2021.112219 34560540
Zhong Z Umemura A Sanchez-Lopez E NF-κB restricts inflammasome activation via elimination of damaged mitochondria Cell 2016 10.1016/j.cell.2015.12.057
Zhou Y Zhang T Wang X Curcumin modulates macrophage polarization through the inhibition of the toll-like receptor 4 expression and its signaling pathways Cell Physiol Biochem 2015 10.1159/000430126
Zhou J Lyu Y Richlen ML Quorum sensing is a language of chemical signals and plays an ecological role in algal-bacterial interactions CRC Crit Rev Plant Sci 2016 10.1080/07352689.2016.1172461
Zhou L Huang W Xu Y Sweet taste receptors mediated ROS-NLRP3 inflammasome signaling activation: Implications for diabetic nephropathy J Diabetes Res 2018 10.1155/2018/7078214
Zhou P Li Q Su S Interleukin 37 suppresses M1 macrophage polarization through inhibition of the Notch1 and nuclear factor Kappa B pathways Front Cell Dev Biol 2020 10.3389/fcell.2020.00056
Zhou Z Xi R Liu J Peng X Zhao L Zhou X Li J Xin Zheng XX TAS2R16 activation suppresses LPS-induced cytokine expression in human gingival fibroblasts Front Immunol 2021 12 726546 10.3389/fimmu.2021.726546 34975834
Zhu DD Zhang J Deng W Significance of NF-κB activation in immortalization of nasopharyngeal epithelial cells Int J Cancer 2016 10.1002/ijc.29850
| 36471190 | PMC9734786 | NO-CC CODE | 2022-12-14 23:28:30 | no | Inflammopharmacology. 2022 Dec 6;:1-29 | utf-8 | Inflammopharmacology | 2,022 | 10.1007/s10787-022-01086-9 | oa_other |
==== Front
J Psychopathol Behav Assess
J Psychopathol Behav Assess
Journal of Psychopathology and Behavioral Assessment
0882-2689
1573-3505
Springer US New York
10007
10.1007/s10862-022-10007-7
Article
Young Adult Routines Inventory (YARI): Development and Initial Validation
Grinnell Morgan 12
http://orcid.org/0000-0003-3033-504X
Piscitello Jennifer [email protected]
3
Kelley Mary Lou 1
1 grid.64337.35 0000 0001 0662 7451 Department of Psychology, Louisiana State University, Baton Rouge, LA USA
2 Silber Psychological Services, P.A., Raleigh, NC USA
3 grid.65456.34 0000 0001 2110 1845 Center for Children and Families, Florida International University, Academic Health Center 1, 11200 SW 8th Street, Miami, FL 33129 USA
6 12 2022
112
9 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Young adulthood is characterized by important life transitions (e.g., college, employment, relocation, marriage), where time management skills and routines help promote positive adjustment. Routines are observable, repetitive behavior that are context specific and automate aspects of daily life (e.g., personal hygiene, health, occupational, academic). Although measures of routines exist for children, adolescents, and older adults, similar measures assessing young adult routines are lacking. The purpose of this study was to develop and initially validate The Young Adult Routines Inventory (YARI). Analyses revealed a four-factor measure reflecting daily routines, social routines, time management, and procrastination. The YARI demonstrates good internal consistency, construct, and convergent validity, and was positively correlated with measures of emotional well-being and perceived life satisfaction. The YARI was negatively correlated with self-reported symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) and successfully distinguished individuals with and without ADHD symptomatology. Preliminary evidence suggests the YARI is a promising measure of young adult routines.
Keyword
Routines
Time management
Young adults
Rating scale
Assessment
http://dx.doi.org/10.13039/100000026 National Institute on Drug Abuse T32DA043449 Piscitello Jennifer
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pmcRoutines are defined as observable behavior that occur in about the same order, at the same place and around the same time, on a consistent (e.g., daily, or weekly) basis (Jensen et al., 1983; Sytsma et al., 2001). Routines are context specific, repetitive, and conserve cognitive and physical resources by automating aspects of daily life (Zisberg et al., 2007). Routines can provide a sense of stability and predictability for children and adults alike (Kiser et al., 2005; Lindstedt & Umb-Carlsson, 2013). Typical routines for adults include those involving sleep, meals, social relationships, personal hygiene, and health, chores as well as those necessary for meeting occupational or academic demands (e.g., studying, task management, arriving on time and with necessary materials).
The benefits of routines are well documented in the literature. Routines are thought to strengthen family bonds; promote self-esteem, improve emotional stability, and enhance well-being (Koome et al., 2012; Zisberg, et al., 2009). Routines have been shown to serve as a protective factor against mental illness; and are an indicator of overall functioning throughout the lifespan (Barton et al., 2019; Koome et al., 2012; Zisberg et al., 2009). Increased frequency and consistency of routines are often recommended to parents seeking advice for mitigating their child’s psychological or behavioral concerns and may even account for differences in symptom severity (Kiser et al., 2005; Lanza & Drabick, 2011). Emerging work during the current COVID-19 pandemic has also revealed that routines, such as increased family meals, have a positive impact on psychological well-being for young adults (Berge et al., 2021), as well as for children and adolescents (Dvorsky et al., 2021; McRae et al., 2020). Several comprehensive measures of routines exist for children and adolescents (e.g., Jensen et al., 1983; Piscitello et al., 2019; Sytsma et al., 2001); however, similar measures for young adults are non-existent.
As young adults progress through their 20 s and 30 s, they typically experience life-changing events such as moving from the family home, attending college, entering the workforce, getting married, and having children that may disrupt rhythms of daily living. Previous research has defined young adulthood in a variety of ways. Some researchers (e.g., Arnett, 2000) conceptualize young adults as those aged 18 to 25, while others (e.g., Atwood & Scholtz, 2008; Bentley, 2007) have extended the range to capture individuals in their 30 s and up to 40 years of age. Defining young adulthood as ages 18 to 35 allowed the current research to capture a wide range of nuanced stages of transition within the phase of early adulthood (e.g., single/in a relationship/married, with/without children, college/career).
Young adults are expected to care for themselves and their belongings, prioritize commitments, and manage their time effectively. However, these skills can prove difficult to develop and maintain in the absence of external structure provided by authority figures (e.g., parents, teachers, and coaches). Mirsa and McKean (2000) found, for example, that effective time management had a greater buffering effect on anxiety and academic stress in college students than did increased leisure activities. Further, the use of time management strategies was associated with academic achievement and personal success in college (Britton & Tesser, 1991; George et al., 2008), rendering the skill set valuable for the well-being of young adults.
Time management, a method of monitoring and controlling time expenditure with the goal of increasing task efficiency, is necessary for successful adherence to routines. In turn, managing time efficiently requires skills in goal setting, prioritizing, and self-regulation (Claessens et al., 2007). These concepts intersect with the broader construct of executive functioning (EF). EF processes are necessary to plan and execute goal-directed behavior, to adapt to novel situations, and to self-regulate. As such, EF processes boast expansive influence over the daily lives of individuals. Poorer EF has been related to health difficulties such as obesity, poor treatment adherence, and substance abuse (Diamond, 2013; Stilley et al., 2010); whereas better EF is associated with improved quality of life and greater success in school and work (Diamond, 2013; Dvorsky & Langberg, 2014). Such deficits in EF are common among individuals with Attention-Deficit/Hyperactivity Disorder (Barkley, 1997; Barkley et al., 1997, 2001; Nigg, 2013a, b; Willcutt et al., 2005) and other psychological disorders.
The impact of maintaining daily routines on psychological and physical health in adults is widely recognized (Margraf et al., 2016). For example, Lindstedt and Umb-Carlsson (2013) evaluated the benefits of cognitive assistive technology products (e.g., key or object finders, pill dispensers, weekly schedules, electronic planning devices, and watches or alarm clocks) for adults with ADHD across daily environments. Of the products tested, weekly schedules and watches were found to be the most valuable to participants, which are items frequently employed in time management and adherence to routines (Lindstedt & Umb-Carlsson, 2013). Despite the importance of routines and time management, research related to young adult self-regulatory activities is limited. In part, this may be due to the fact that few assessment tools have been developed specifically to measure routines and time management skills in young adult populations.
Many of the existing measures of routines for young adults are retrospective or ask individuals to report on routines related to their family of origin (e.g., The Stability of Activities in the Family Environment (SAFE); Israel et al., 2002), which inadequately accounts for current routines away from the family home. Other measures include daily diaries (e.g., Social Rhythm Metric (SRM); Monk et al., 1990), which can be time intensive and burdensome for participants. For example, the SRM requires daily recording for two weeks, which is impractical or unnecessary for obtaining a valid assessment of routines. Further, the SRM does not account for less frequent routines such as paying bills or attending meetings.
Other measures related to time management and routines include The Barkley Deficits in Executive Functioning Scale (Barkley, 2011), a measure used to assess commonly cited constructs of EF in adults (i.e., inhibition, working memory, organization, problem solving, time management, and self-regulation of emotions; Barkley, 2011, 2012). Similarly, Duggan et al. (2018) developed a valid and reliable screener of EF in young adults based on the college version of the Behavioral Assessment System for Children (Reynolds & Kamphaus, 2004). The screener assesses EF behaviors such as problem solving, attentional control, behavioral control, and emotional control. Although these are strong measures of functional impairment caused by EF deficits in adults, they do not capture specific daily routines that can be utilized in intervention planning and treatment monitoring.
Additionally, there are several measures that specifically assess time management, but do not address specific daily routines. These measures include the Time Management Questionnaire (TMQ; Britton & Tesser, 1991), Time Management Behavior Scale (TMB; Macan et al., 1990), and Time Structure Questionnaire (TSQ; Bond & Feather, 1988). The TMQ and the TMB, for example, are limited in that these measures were developed for use with college students and thus, do not include items relevant to young adults who are not students. Additionally, the TMB’s inconsistent factor structure and low subscale reliability estimates are significant limitations to this measure (Hellsten, 2012; Mudrack, 1997).
Current Study
The goal of the current study was to address the gap in the literature by developing a measure of common routines and time management activities in young adults: The Young Adult Routines Inventory (YARI). Similar to measures of routines in younger samples (e.g., Harris et al., 2013; Piscitello et al., 2019; Sytsma et al., 2001), we hoped this measure would have a secondary benefit in differentiating adults with and without ADHD thus providing useful information for targeted interventions. Based on measures of routines in adolescents (i.e., Adolescent Routines Questionnaire; Piscitello et al., 2019) and older adults (i.e., Scale of Older Adults’ Routines; Zisberg et al., 2009) which both resulted in a five-factor structure, we predicted that the current measure would also consist of five factors. Predicted factors included: Daily Living Routines (e.g., sleep/wake schedule, meals, hygiene), Organizational/Instrumental Routines (e.g., chores, vehicle maintenance, managing money), Health Related Activities (e.g., exercise, medical appointments, substance use), Social/Leisure Routines (e.g., talking with family or friends, engaging in outside activities), and Time Management Routines (e.g., attending events on time, prioritizing important activities, scheduling).
Additionally, it was predicted that the frequency of routines endorsed by young adults would be positively correlated with time management, perceived life satisfaction, and positive mental health. Also, the frequency of routines endorsed by the participants is expected to be negatively correlated with ADHD symptoms. As such, we predicted that adults with self-reported ADHD would endorse fewer routines and less frequent use of time management strategies than those without ADHD. Similarly, it was expected that the YARI scores would distinguish those with self-reported ADHD from those without ADHD.
Phase I: Item Generation and Measure Development
Procedure
A pool of items was generated with the goal of capturing typical routines for young adults, including both students and working adults. The item pool was produced using descriptive reports from young adults, reworded items extracted from existing scales measuring routines in adolescents and older adults, and a review of the relevant literature. Item generation utilized theorized dimensions of routines based on previous literature, along with time management-related routines and resulted in 80 items. After removing items which applied only to students, 72 items remained.
Experts were recruited to judge the content and face validity of the item pool (Clark & Watson, 1995; Netemeyer et al., 2003). Based on initial feedback from a professor and two advanced graduate students in clinical psychology, similar items were combined, and several irrelevant or redundant items were deleted, reducing the pool to 67 items. After being briefed on the rationale for the measure, seven additional graduate students and a professor reexamined the item pool. This group suggested revisions, items to delete due to redundancy, and recommended additional items. Reviewers rated items based on the extent to which they agreed the content was relevant and suitable to the construct (i.e., whether the item represented a routine experienced by young adults), on a scale of 1 (Strongly Disagree) to 5 (Strongly Agree). Items with below average ratings (i.e., less than 3) were eliminated. This resulted in 54 items total, with between seven and sixteen items retained to account for each hypothesized factor.
Phase II: Initial Factor Structure and Reliability
Participants
After receiving IRB approval, participants were recruited through undergraduate psychology classes, social media, word-of-mouth, and websites which allow advertisement of research studies (e.g., Craigslist). Participants included 492 adults aged 18 to 35. Of those, 389 participants (79%) completed the questions and passed the embedded validity checks included in the survey. Attrition and careless responding are well-documented risks when using online surveys and may be attributable to fatigue from long survey instruments, or increased anonymity and distraction (Huang et al., 2012; Ward et al., 2017). Therefore 103 participants were removed from the final sample due to attrition and careless responding. There were no significant differences on demographic variables between those who were included and those who were excluded. The sample was considered sufficiently large enough to conduct the analyses, as a sample size of 300 is often recommended (Clark & Watson, 1995; DeVellis, 2017).
The final sample (N = 389) was predominately female (77.6%) and White (85.9%), with 5.9% identifying as African American/Black, 4.4% Asian/Pacific Islander, and 3.9% other. The mean age for the sample was 24.17 (SD = 5.43); 59.4% were students. The majority of the sample (66.8%) reported no previous psychological diagnoses, with the most common self-reported disorders being anxiety-related disorders (9.0%), ADHD (6.7%), and mood-related disorders (3.6%). The majority of the sample reported working parttime (37.8%) or full time (35.5%) and a minority were employed (26.7%). The sample was diverse in terms of income, as a majority (68%) of the sample reported making less than $50,000 USD/year, with 11.1% reported making between $50,000-$74,999, 8.0% made between $75,000 and $99,999, and 12.6 reported making over $100,000/year. Participants reported a range of educational backgrounds with < 1% reported having less than high school, 22.4% reported completing high school, 30.1% had some college, 2.6% received an Associate Degree, 24.9% received a Bachelor Degree, and 19.6% received a graduate or professional degree.
Measures
Demographic Questionnaire
Participants completed a questionnaire which asked for basic information related to age, sex, marital/relationship status, education level, job/academic status, income, and mental health diagnoses.
Young Adult Routines Inventory (YARI) – Initial Version
Participants were presented with written definition of routines and time management (i.e., “Routines are events that occur regularly: at about the same time, in the same order, or in the same way every time. Routines are closely related to time management which is defined as behavior aimed at achieving an effective use of time while performing goal-oriented activities. Time management behaviors include those related to assessing, planning, and monitoring time use”). The definitions were provided to ensure the participants rated behavior they routinely engaged in, not simply activities that occur. Participants were asked to rate the 54 items retained in Phase I based on how often they engaged in the behavior over the last month, on a scale of 0 (Never) to 4 (Almost always).
Procedure
Prior to beginning the questionnaires, participants were presented with information about the study and completed informed consent procedures. Participants completed questionnaires using Qualtrics online survey software. Individuals recruited through the psychology department research recruitment pool received course credit for participation. All other participants were given the option of entering a raffle to win a gift card ($20) for their participation.
Statistical Analyses
All analyses were conducted in R (R Core Team, 2017) primarily using the psych package developed by Revelle (2017). Prior to conducting data analysis, items were screened for normality, skewness, and kurtosis. This examination showed that several items were skewed and kurtotic; however, these items were retained in analyses with no corrections, as some basic routines (e.g., hygiene routines, attending work) are not expected to be normally distributed in a community (i.e., mostly non-clinical) sample. Of note, the skewed and kurtotic items were ultimately eliminated during the factor analysis procedure because they also failed to load significantly onto any factor. Further, several participants were multivariate outliers based on their significant Malhalanobis distance scores. However, the participants were retained for analyses as it is expected that some adults have far more or far fewer routines and time management skills than others. Exploratory Factor Analysis (EFA) was conducted to determine the factor structure of the YARI and a parallel analysis was conducted to identify the maximum number of factors representing the data (Floyd & Widaman, 1995). Most of the data fell within the assumption of the normal distribution, so the chosen factor extraction method for both the parallel analysis and subsequent EFA was maximum likelihood (ML), which is a robust model fitting procedure (Costello & Osborne, 2005; Fabrigar et al., 1999). The results of the parallel analysis suggested the data could support up to twelve factors.
Results
Item Analysis
Initial item analyses included examination of item frequencies, item means, and inter-item correlations. Items that were endorsed infrequently (i.e., less than 15% of the time) or had item means which did not approach the median value for responses were considered for elimination (DeVellis, 2017). One item related to tobacco use was eliminated due to low frequency. Several items (e.g., I attend work/school obligations) had high means but were retained for further analyses because of their possible theoretical importance (Clark & Watson, 1995). Inter-item correlations were examined to evaluate redundant items. No items were eliminated as the correlation coefficients for item pairs were less than .7. Several items were reverse scored. Item-total correlations were also reviewed for correlation coefficients of items with the remainder of the scale if the individual item was dropped (DeVellis, 2017; Floyd & Widaman, 1995). This review highlighted several items that did not correlate highly with the overall scale; however, these items were retained to investigate how they may cluster and influence the exploratory factor analysis.
Exploratory Factor Analysis
Using the results of the parallel analysis, the remaining 53 items were factor analyzed using a 12-factor solution with ML extraction method and a promax rotation, a form of oblique rotation which allows factors to be correlated with one another. Multiple criteria have been suggested for determining the optimal number of factors to retain in a solution, including factor loadings above .3 or .4, simple structure, and retaining factors with three or more items per factor (Costello & Osborne, 2005; Fabrigar et al., 1999; Floyd & Widaman, 1995). The resulting 12-factor solution had several factors with only two to three items loaded, several items which cross-loaded onto multiple factors, and was not interpretable.
All possible factor solutions with fewer than twelve factors were examined for comprehensiveness, and to determine which solution produced the most theoretically and empirically sound structure. Factor solutions with more than seven factors were found to be uninterpretable and possessed factors with few items as well as cross-loaded items. An additional two items were deleted due to not being theoretically cohesive with the remainder of the items, thus additional analyses were conducted after deleting these items. After examining the interpretability and item loadings of the remaining factor solutions, the most theoretically sound and interpretable solutions were 3-factor and 4-factor solutions.
The items that failed to load or loaded onto multiple factors for each of the remaining factor solutions were removed and the analyses were re-run with the reduced number of items. Again, the 3-factor and 4-factor solutions produced the most stable loadings with the fewest cross-loadings. The internal consistency for each factor, overall alpha values, and variance accounted for were compared between the 3-factor and 4-factor solutions. Although both solutions were very similar statistically, the 4-factor solution fit better with theoretical predictions, had a greater quantity of items loading onto each factor, and the relationship between factors was more cogent. As a result, a 25-item, 4-factor solution was chosen as the best fit for the data. This final structure accounted for 34.2% of the variance with Eigenvalues ranging from 1.47 to 2.46.
Factor loadings are presented in Table 1. Factor 1, Daily Routines, consists of seven items which represent routines that are daily regulatory activities, such as sleeping and eating. The internal consistency for the Daily Routines factor was α = .79 (ω = .76, 95% CI [.70, .80]). Factor 2, Social Routines, consists of seven items measuring communication, responsiveness, and participation in social activities. The Social Routines factor demonstrated adequate internal consistency (α = .73; ω = .76, 95% CI [.70, .81]). Factor 3, Time Management, consisted of five items related to timeliness and planning, which had adequate to good internal consistency (α = .72; ω = .83, 95% CI [.79, .86]). Of note this factor had one item that also loaded onto the Daily Routines factor, albeit weaker. Finally, Factor 4 was made up of six items related to productive activities and inversely scored items related to interference activities and was labeled Procrastination. For example, “I procrastinate on tasks I should complete” and “I put off doing laundry.” This factor demonstrated questionable internal consistency (α = .64; ω = .65, 95% CI [.59, .71]).; however, based on the developmental stage of the YARI no further items were deleted so as not to reduce the potential utility of the measure. The overall YARI demonstrated good internal consistency reliability (α = .81; ω = .79, 95% CI [.73, .83]) and the Tucker Lewis Index was equal to .829. Scale and composite means and standard deviations are reported in Table 2. Bivariate correlations between the subscales and composite ranged from weak to strong positive correlations (.12 < Pearson’s r < .74).Table 1 Factors and factor loadings for young adult routines inventory
Factor
Item description 1 2 3 4
I eat meals at the same time every day .68 −.08 .01 −.15
I plan my meals/snacks .68 −.01 −.15 .02
I have a predictable schedule .57 −.06 .15 −.08
I wake up around the same time every day .50 −.08 .13 −.04
I go to bed at a time which allows an adequate amount of sleep .46 −.18 .11 .12
I spend time planning my days or week .46 .19 −.05 .15
I monitor my caloric intake or weight .40 .15 −.22 .00
I spend time with friends or family regularly −.09 .76 −.02 .08
I plan and/or participate in fun weekend activities −.10 .70 −.03 .04
I talk to friends daily (in person or via phone/internet) −.16 .63 .04 −.14
I talk with my parents or family members regularly −.04 .49 .17 .01
I respond to calls in a timely manner .01 .45 .11 .15
I participate in clubs or organizations .04 .42 −.06 −.09
I volunteer my time or talents regularly .16 .36 .01 −.08
I arrive on time for scheduled events with others −.06 .06 .76 −.03
I arrive on time to obligations (e.g., class, meetings, work, appointments) .01 .06 .74 .02
I am late for meetings or appointments* −.11 −.03 .71 .02
I get dressed and ready in a timely manner .24 .04 .45 .03
I wake up with enough time to get ready for the daya .36 .02 .43 .00
I procrastinate on tasks I should complete* .13 .03 .04 .62
Video games, internet, or television get in the way of my productivity* −.01 .00 .06 .56
I put off doing laundry* .15 −.05 −.07 .40
I depend on another adult for reminders (e.g., to make appointments or run errands)* −.12 .00 .07 .38
I complete chores regularly .19 .22 −.03 .38
Eigenvalue 2.46 2.40 2.22 1.47
% Variance 9.8 9.6 8.9 5.9
Factor 1 = Daily Routines; Factor 2 = Social Routines; Factor 3 = Time Management; Factor 4 = Procrastination
*indicates reverse-scored items
aindicates item which loaded onto two factors
Bolded font indicates items loadings >.30
Table 2 Descriptive statistics of the YARI
Scale Items Min., Max M SD Skew Kurtosis α ω
Daily Routines 7 7, 29 19.31 4.47 −.15 −.38 .79 .76
Social Routines 7 10, 35 26.23 4.88 −.58 .23 .73 .76
Time Management 5 10, 25 20.93 3.47 −.79 .08 .72 .83
Procrastination 6 7, 28 17.74 3.83 .05 −.29 .64 .65
YARI Total 25 49, 109 84.21 11.13 −.26 −.32 .81 .79
Min., Max. Minimum and maximum observed scale scores, YARI Young Adult Routines Inventory
Phase III: Initial Validity Analyses
Participants
Participants for this phase were a subset of those described in Phase II, who had completed all measures to satisfaction. The participants were 370 individuals between the ages of 18 and 35. The descriptive statistics for this sample do not meaningfully differ from those in Phase II.
Measures
Time Structure Questionnaire (TSQ; Bond & Feather, 1988)
The TSQ is a 26-item self-report measure that assesses the level to which individuals use their time in a structured and purposeful manner. Items are rated on a seven-point scale ranging from Yes, always to No, never. Some items are reverse scored, so that higher scores on the TSQ indicates more time structure. The TSQ items map onto five factors: structured routine, sense of purpose, present orientation, effective organization, and persistence. Items include questions such as “Do you find during the day that you are often not sure what to do next?” and “Do you think you do enough with your time?” The TSQ has been shown to demonstrate high internal consistency and is adequate stability over time (Bond & Feather, 1988). Reliability of the TSQ for this study was comparable that of other reports (α = .77; Mudrack, 1997).
Satisfaction with Life Scale (SWLS; Diener et al., 1985
The SWLS measures global cognitive judgements of satisfaction with a person’s life. The scale contains five items measured on a seven-point scale, ranging from Strongly Disagree to Strongly Agree. An exemplar from the measure is, “I am satisfied with my life.” All items are totaled and interpreted so higher scores indicate greater life satisfaction. The SWLS has been translated into over 30 languages and was initially developed using two college student samples and a geriatric sample. The scale has one factor which accounts for 66% of the variance and has demonstrated good internal consistency (Diener et al., 1985). This measure has good test–retest reliability (Diener et al., 1985; Pavot & Diener, 2008). For the current study, reliability was estimated to be good (α = .89).
RAND 36-Item Health Survey 1.0 (SF-36; Hays et al., 1993)
The SF-36 is a self- report measure of overall health status and health-related quality of life. The SF-36 has eight subscales which measure: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to emotional problems, social functioning, emotional well-being, energy/fatigue, health perceptions, and one item which measures perceived change in health status over the last year. The measure was designed to be self-administered by individuals aged 14 and older and has adequate to excellent reliability (Hays et al., 1995; McHorney et al., 1994). The Emotional Well-Being scale was utilized for the present study, which consists of five items that measure symptoms associated with depression and anxiety (M = 70.38, SD = 21.97, α = .90; Hays et al., 1993). Reliability estimates for the current study were good (α = .81).
Adult ADHD Self-report Scale (ASRS; Kessler et al., 2005)
The ASRS was used to screen ADHD-related symptoms. This 18-item diagnostic checklist of current symptoms is based on DSM-IV-TR ADHD criteria and has two underlying subscales. Nine items assess inattention, and nine items measure hyperactivity/impulsivity. The symptom frequency is rated on a five-point scale from 0 (Never) to 4 (Very Often). The questionnaire takes approximately five minutes to complete, and answers can be categorized dichotomously with a cut-off score of nine out of eighteen items, or scored as a continuous variable (Taylor et al., 2011). The internal consistency for the ASRS is between .75 and .89, and the sensitivity and specificity are 56% and 98%, respectively, with a total classification accuracy of 96% (Adler et al., 2006; Kessler et al., 2005; Taylor et al., 2011). Reliability for the current sample was similar to that of previous studies (α = .88).
Procedure
Data collection was the same as Phase II.
Statistical Analyses
Data were analyzed using R software, including the Psych package (Revelle, 2017). Pearson correlations were conducted to test construct validity of the YARI with existing measures of time management, satisfaction with life, emotional well-being, and ADHD symptoms. Further, t-tests were utilized to test convergent validity of the YARI to determine if the measure successfully differentiated individuals with self-reported ADHD and those without ADHD.
Results
To test the hypotheses about the convergent and construct validity of the YARI, Pearson correlations were conducted. Less than 2% of the variables were missing data. To prevent additional data loss, the sample mean for the variable was imputed in each of these few cases. Then, correlations were conducted between each subscale and composite scores of the YARI and the total score for the TSQ, SWLS, ASRS, and the Emotional Well-being scale of the RAND SF-36. The Pearson correlation coefficients for these analyses are displayed in Table 3. A Bonferroni correction was used to account for multiple comparisons.Table 3 Correlations between YARI and related measures
Measure/Scale name Daily routines Social routines Time management Procrastination YARI
Total score
TSQ .51** .37** .42** .58** .69**
SWLS .33** .40** .24** .32** .49**
ASRS −.19** −.14 −.30** −.45** −.39**
SF-36: Emotional Well Being .18* .31** .22** .30** .38**
TSQ Time Structure Questionnaire, SWLS Satisfaction with Life Scale, ASRS Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale, SF-36 RAND 36-item Health Survey 1.0, YARI Young Adult Routines Inventory
* p < .05 with a Bonferroni correction; ** p < .03 with a Bonferroni correction
As predicted, there was a strong correlation between the overall YARI scores and the scores on the TSQ, r(368) = 0.69, p < .001. Further, there were moderate correlations between the TSQ and each of the scales of the YARI. As predicted, there also was a moderate positive correlation between the SWLS and YARI composite score, r(368) = .49, p < .001, as well as the subscales. Interestingly, aside from the total YARI composite score, the Social Routines scale score had the strongest correlation with the SWLS, r(368) = 0.40, p < .001. The Emotional Well-being scale of the RAND SF-36 was positively correlated with the YARI composite, r(368) = 0.38, p < .001, as predicted. ADHD symptoms as measured by the ASRS produced a moderate negative correlation with the YARI composite score, as predicted in the fifth hypothesis, r(368) = -0.39, p < .001, with an even stronger negative correlation with the Procrastination items on the YARI, r(368) = -0.45, p < .001.
In addition to correlational analyses, we were interested in whether the YARI would distinguish individuals with ADHD from those without, as other measures of routines did so in younger individuals (e.g., Harris et al., 2013). For this test, the ADHD group included participants who had self-reported a diagnosis of ADHD, which included participants who reported only a diagnosis of ADHD (n = 25) and those who reported a diagnosis of ADHD along with other disorders (n = 16) for total of 41 participants with ADHD. To confirm that a self-reported ADHD diagnosis was an appropriate criterion to use for delineating the groups, we verified that the ASRS scores measuring ADHD symptoms for the ADHD (n = 41) and non-ADHD (n = 329) groups were significantly different using a Welch’s t-test. Welch’s more robust version of the t-test is recommended for use, especially when sample sizes are unequal, as it calculates separate variances (Zimmerman, 2004). The results of the Welch’s t-test showed that the ADHD group had significantly higher ASRS scores than the non-ADHD group (t (53.89) = 6.93, p < .001, d = 1.04, 95% CI [7.47, 13.55]). Following this confirmation, the YARI total scores for the ADHD group were compared to the YARI scores for the non-ADHD group using the same statistical test. The YARI scores for the ADHD group were significantly lower than those for the non-ADHD group (t (47.79) = -.2.25, p = .03, d = 0.42, 95% CI [-8.71, -0.48]), which is indicative of fewer routines overall. Thus, the YARI was able to differentiate adults with and without ADHD and showed a small to moderate practical significance evidenced by the effect size. The mean and standard deviation for each group for the ASRS as well as the scales and composite scores of the YARI are presented in Table 4.Table 4 Descriptive statistics of ADHD and Non-ADHD groups
ADHD (n = 41) Non-ADHD (n = 329)
M SD M SD Welch’s
t-test
ASRS 38.86 9.01 28.35 10.29 6.93**
Daily Routines 18.39 5.19 19.43 4.37 −1.23
Social Routines 25.78 5.07 26.28 4.86 −0.60
Time Management 19.56 4.23 21.10 3.33 −2.25**
Procrastination 16.39 3.94 17.90 3.79 −2.34**
YARI Total 80.12 12.52 84.72 10.85 −2.25**
ASRS = ** p < .03, with a Bonferroni correction. Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale
YARI Young Adults Routines Inventory
Finally, additional analyses were conducted to examine the convergent validity of the individual scales of the YARI. Like the analyses above, Welch’s t-tests were conducted to examine the differences for the ADHD and non-ADHD groups for each scale. The difference was nonsignificant between the two groups on the Daily Routines scale (t (47.33) = -1.23, p = .23, d = 0.23, 95% CI [-2.74, 0.66]), and on the Social Routines scale (t (49.61) = -0.60, p = .55, d = 0.10, 95% CI [-2.18, 1.18]). However, the ADHD group had scores significantly lower than the non-ADHD group on Time Management (t (46.404) = -2.25, p = .03, d = 0.45, 95% CI [ -2.92, -0.16]). Also, a significant difference was found on the Procrastination scales (t (49.683) = -2.34, p = .02, d = 0.40, 95% CI [-2.82, -0.21]) where individuals with ADHD endorsed more procrastination and fewer productive routines than individuals without ADHD. These results suggest that Time Management and Procrastination may be especially important factors and areas of difficulty for individuals with ADHD in the sample, evidenced by the effect sizes which indicate small to moderate practical significance.
General Discussion
The purpose of the current study was to develop a measure of routines and time management practices in young adults. Routines and time management strategies are considered beneficial because they provide stability, structure, and a sense of control and are associated with numerous mental and physical health benefits. Lack of routines are associated with numerous physical and psychological health outcomes (e.g., substance use, ADHD, obesity). Although there are measures of routines in children, families, adolescents, and older adults, there was a paucity of measures for young adults.
Initial factor analyses suggested that the most promising factor solutions were the 3- and 4-factor solutions. Ultimately, the 4-factor, 25-item solution was chosen as it was the most theoretically cogent. The factors were, Daily Routines, related to daily tasks such as sleeping, eating, and scheduling, Social Routines, that included communication and participation in social or community activities. Time Management with items relating to planning and timeliness and Procrastination consisted of items related to interfering activities, as well as productive activities primarily in the home context.
Three of the four subscales of the YARI demonstrated adequate internal consistency, while the Procrastination scale exhibited questionable internal consistency. The overall YARI composite demonstrated good internal consistency. All scales had moderate intercorrelations with one another, except for Procrastination and Social Routines which showed a weak correlation, although a weak relationship between these two constructs is theoretically foreseeable. All four factors had strong correlations with the overall YARI composite, making it the best overall assessment of routines and time management, while each of the scales provide unique information which may be important to areas of particular interest or intervention within related areas of routines and time management.
To establish construct and convergent validity, the YARI was compared to the TSQ which is an established measure of time structure, closely related to routines and time management. As hypothesized, the YARI showed a strong positive association with time structure (i.e., TSQ). Similarly, all subscales of the YARI were moderately correlated with the total scores on the TSQ. Results provided initial evidence of construct validity of the YARI.
Research has shown that establishing and adhering to routines is associated with greater life satisfaction and sense of well-being; in contrast, a lack of routines is associated with an array of negative mental and physical health outcomes (Margraf et al., 2016). For example, as hypothesized the YARI was correlated positively with measures of well-being (i.e., RAND SF-36) and life satisfaction (i.e., SWLS). These relationships suggest that with increased routines and time management, individuals report higher levels of life satisfaction, lower levels of depression/anxiety.
One of the more common disorders where impaired routines and time management are often observed is ADHD. Previous measures of routines have been able to distinguish children and adolescents with ADHD from those without ADHD (Sytsma et al., 2001). As such, we aimed to explore the utility of the YARI in differentiating adults with and without self-reported ADHD. As hypothesized the YARI correlated negatively with higher levels of endorsed ADHD symptoms, suggesting that participants who reported more symptoms of ADHD also reported less frequent or consistent routines and time management practices. The YARI total score also differentiated a sample of adults with self-reported diagnoses of ADHD from individuals without the diagnosis. This finding provides initial support for the YARI’s value in differentiating individuals with and without ADHD and aligns with previous findings for measures of routines in younger populations (Sytsma et al., 2001).
Additional analyses were conducted to explore whether the individual YARI subscales distinguished ADHD and non-ADHD participants as well. The results indicated that there was a statistically significant relationship between the YARI and the Time Management and Procrastination scales. However, the Daily Routines and Social Routines scales were not significantly different across the two groups. The findings suggest that the Time Management and Procrastination scales may be better measures of behaviors that are impacted by ADHD symptoms. Overall, the convergent validity of the YARI was supported in the analyses comparing the items of the new measure to existing assessments as well as through comparing subgroups of participants.
Taken together, the results of this study provide preliminary evidence that the YARI is a practical, theoretically supported, and valid measure of multidimensional routines and time management in younger adults. It was developed using a sample of adults aged 18–35, with characteristics ranging from high school graduate to post-graduate degree recipient, unemployed to fully employed, and single to married. Overall, the YARI appears to be an adequate instrument for use in its intended population. The YARI items and scale scores may be useful in identifying target behaviors when working with adults with ADHD or other individuals who lack adequate routines and purposeful behavior. Further, the instrument could be used to monitor progress in individuals who are working to improve their routines and time management. Thus, the measure has considerable practical applications.
Limitations and Future Directions
Despite the strengths of the results, the current study has several limitations. One chief concern was the biased nature of the sample. Although this study captured a variety of ages and lifestyles (e.g., related to employment, relationship status, and education), the participants in this study were predominantly White and female. Student participants from the university’s psychology participant pool were expected to be mostly female, given the typical demographics of the major. Therefore, the current sample’s homogeneity may have affected the frequency and variability of items endorsed and may not be as representative of males or non-White individuals. Future studies aiming to refine the development of the YARI should seek to obtain reliability and validity data using a more heterogeneous sample regarding race, ethnicity, and gender. Similarly, the sample size was too small to explore additional psychometric inquiries of interest, such as testing measurement invariance using formal multigroup analyses or examining developmental differences in older and younger samples. Recruiting a larger, highly diverse sample, would allow for examination of item invariance with regard to various participant characteristics (e.g., gender, age, income, education-level, etc.) an important and necessary next step in understanding the utility of the YARI.
Online survey attrition and careless responding are known risks to online survey data and thus, can introduce respondent bias (Huang et al., 2012; Ward et al., 2017). We attempted to address this problem by offering incentives for completion, and by removing participants who did not pass included attention checks. As a result, the number of participants who provided useable data was considerably fewer than the number of participants who began the study. Future studies employing the YARI may address this shortcoming by using different recruitment techniques (e.g., in person, or using online survey companies which assure quality responses).
Another limitation of the current study involves the psychometrics of the YARI factors. The fourth factor derived from the data, Procrastination, exhibited questionable internal consistency. This factor was ultimately included because it approached acceptable internal consistency, and because the current study goal was to develop the YARI rather than validate its structure. Thus, it was retained for future studies which should work towards confirming the factor structure. Furthermore, the YARI scales together accounted for a limited amount of the variance in the population (i.e., 34.2%). Despite this, findings are similar to previous measures in the initial development phase. For example, the Adolescent Routines Questionnaire (ARQ; Piscitello et al., 2019) found 35.32% and 42.10% of the variance was accounted for by the parent-report and adolescent self-report versions of the ARQ respectively. Additional validation studies are needed to improve the psychometric properties of the YARI. For example, while the 4-factor solution was chosen because it performed slightly better with the current data, the 3-factor solution was similar in many ways. Thus, it may be beneficial to include items other than the 25 remaining items to consider both a three and four factor solution. This may help to address limitations in proportion of variance explained and internal consistency in future participant samples.
The YARI was successful in distinguishing those with ADHD from those without ADHD; however, the subsample of participants with self-reported ADHD was small and the diagnosis was not formally verified. Future studies should gather a more clinical and rigorously diagnosed sample with the goal of establishing interpretation guidelines and cutoff scores for the YARI. Nevertheless, the YARI in its current form can provide clinical utility informally through the identification of different areas of routine which may be compromised in individuals with ADHD or other disorders. The YARI may be used by practitioners to identify and target maladaptive or absent routines to use in progress monitoring measure.
Overall, many of these limitations can and should be addressed in future studies to refine and validate the factor structure of the YARI. The age range of this population is difficult to assess in the area of routines due to the diversity of lifestyles at this developmental stage. However, despite the aforementioned limitations of this study, the YARI appears to provide otherwise unmeasured information related to routines and time management practices in younger adults.
Conclusions
In summary, results of the study provide initial support for the YARI as a sound measurement tool with good internal consistency, and construct and convergent validity. The YARI adds to the literature, a useful tool for researchers and clinicians to examine functional impairment related to routines and time management, which is common among many mental health concerns. For example, this measure can be utilized when conducting initial assessment or impairment of routines and for progress monitoring in treatment contexts. In its current state, the YARI represents a sorely needed update in measures assessing routines and related behaviors in young adults, a population neglected by similar measures in the past.
Author Contributions
Drs. Morgan Grinnell and Mary Lou Kelley contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Dr. Morgan Grinnell. Dr. Jennifer Piscitello assisted with data processing and analyses. The first draft of the manuscript was written by Drs. Morgan Grinnell and Piscitello. Dr. Mary Lou Kelley provided feedback on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Dr. Jennifer Piscitello’s post-doctoral position at Florida International University is funded through National Institute on Drug Abuse (T32DA043449) during the preparation of this work. No other funds, grants, or other support was received to conduct this research.
Data Availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Declarations
Ethics Approval
Approval was obtained from the ethics committee of Louisiana State University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Conflict of Interest
Morgan Grinnell, Jennifer Piscitello and Mary Lou Kelley have no relevant financial or non-financial interests to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Adler LA Spencer T Faraone SV Kessler RC Howes MJ Biederman J Secnik K Validity of pilot adult ADHD self-report scale (ASRS) to rate adult ADHD symptoms Annals of Clinical Psychiatry 2006 18 3 145 148 10.1080/10401230600801077 16923651
Arnett JJ Emerging adulthood: A theory of development from the late teens through the twenties American Psychologist 2000 55 5 469 480 10.1037/0003-066X.55.5.469 10842426
Atwood JD Scholtz C The quarter-life time period: An age of indulgence, crisis or both? Contemporary Family Therapy: An International Journal 2008 30 4 233 250 10.1007/s10591-008-9066-2
Barkley RA Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD Psychological Bulletin 1997 121 65 94 10.1037/0033-2909.121.1.65 9000892
Barkley RA The Barkley deficits in executive functioning scale 2011 Guilford Press
Barkley RA Distinguishing sluggish cognitive tempo from attention-deficit/hyperactivity disorder in adults Journal of Abnormal Psychology 2012 121 978 990 10.1037/a0023961 21604823
Barkley RA Koplowitz S Anderson T McMurray MB Sense of time in children with ADHD: Effects of duration, distraction, and stimulant medication Journal of the International Neuropsychological Society 1997 3 359 369 10.1017/S1355617797003597 9260445
Barkley RA Murphy KR Bush T Time perception and reproduction in young adults with attention deficit hyperactivity disorder Neuropsychology 2001 15 351 360 10.1037/0894-4105.15.3.351 11499990
Barton AW Brody GH Yu T Kogan SM Chen E Ehrlich KB The profundity of the everyday: Family routines in adolescence predict development in young adulthood Journal of Adolescent Health 2019 64 3 340 346 10.1016/j.jadohealth.2018.08.029
Bentley E Adulthood 2007 Routledge
Berge JM Hazzard VM Larson N Hahn SL Emery RL Neumark-Sztainer D Are there protective associations between family/shared meal routines during COVID-19 and dietary health and emotional well-being in diverse young adults? Preventive Medicine Reports 2021 24 101575 10.1016/j.pmedr.2021.101575 34631398
Bond MJ Feather NT Some correlates of structure and purpose in the use of time Journal of Personality and Social Psychology 1988 55 2 321 329 10.1037/0022-3514.55.2.321
Britton BK Tesser A Effects of time-management practices on college grades Journal of Educational Psychology 1991 83 3 405 410 10.1037/0022-0663.83.3.405
Claessens BJ Van Eerde W Rutte CG Roe RA A review of the time management literature Personnel Review 2007 36 2 255 276 10.1108/00483480710726136
Clark LA Watson D Constructing validity: Basic issues in objective scale development Psychological Assessment 1995 7 3 309 319 10.1037/1040-3590.7.3.309
Costello AB Osborne JW Best practices in exploratory factor analysis: Four recommendations for getting the most from your analysis Practical Assessment, Research & Evaluation 2005 10 7 1 9 10.4135/9781412995627.d8
DeVellis RF Scale development: Theory and applications 2017 4 Sage Publications
Diamond A Executive functions Annual Review of Psychology 2013 64 135 168 10.1146/annurev-psych-113011-143750
Diener E Emmons RA Larsen RJ Griffin S The satisfaction with life scale Journal of Personality Assessment 1985 49 71 75 10.1207/s15327752jpa4901_13 16367493
Duggan EC Garcia-Barrera MA Müller U Derivation, replication, and validity analyses of a screener for the behavioral assessment of executive functions in young adults Assessment 2018 25 7 867 884 10.1177/1073191116670511 27655970
Dvorsky, M. R., Breaux, R., Cusick, C. N., Fredrick, J. W., Green, C., Steinberg, A., ... & Becker, S. P. (2021). Coping with COVID-19: Longitudinal Impact of the Pandemic on Adjustment and Links with Coping for Adolescents with and without ADHD. Research on Child and Adolescent Psychopathology, 1-15. 10.1007/s10802-021-00857-2
Dvorsky MR Langberg JM Predicting impairment in college students with ADHD Journal of Attention Disorders 2014 10.1177/1087054714548037
Fabrigar LR Wegener DT MacCallum RC Strahan EJ Evaluating the use of exploratory factor analysis in psychological research Psychological Methods 1999 4 3 272 299 10.1037/2F1082-989X.4.3.272
Floyd FJ Widaman KF Factor analysis in the development and refinement of clinical assessment instruments Psychological Assessment 1995 7 286 299 10.1037/2F1040-3590.7.3.286
George D Dixon S Stansal E Gelb SL Pheri T Time diary and questionnaire assessment of factors associated with academic and personal success among university undergraduates Journal of American College Health 2008 56 6 706 715 10.3200/JACH.56.6.706-715 18477529
Harris AN Stoppelbein L Greening L Becker SP Luebbe A Fite P Child routines and parental adjustment as correlates of internalizing and externalizing symptoms in children diagnosed with ADHD Child Psychiatry & Human Development 2013 45 2 243 253 10.1007/s10578-013-0396-4
Hays RD Sherbourne CD Mazel RM The RAND 36-item health survey 1.0 Health Economics 1993 2 217 227 10.1002/hec.4730020305 8275167
Hays RD Sherbourne CD Mazel RM User's manual for the Medical Outcomes Study (MOS) core measures of health-related quality of life 1995 Rand Corporation
Hellsten, L. A. M. (2012). What do we know about time management? A review of the literature and a psychometric critique of instruments assessing time management. Time Management, Todor Stoilov , IntechOpen, 1–28. 10.5772/37248
Huang JL Curran PG Keeney J Poposki EM DeShon RP Detecting and deterring insufficient effort responding to surveys Journal of Business and Psychology 2012 27 1 99 114 10.1007/s10869-011-9231-8
Israel AC Roderick HA Ivanova MY A measure of the stability of activities in a family environment Journal of Psychopathology and Behavioral Assessment 2002 24 2 85 95 10.1023/A:1015336707701
Jensen EW James SA Boyce WT Hartnett SA The family routines inventory: Development and validation Social Science & Medicine 1983 17 4 201 211 10.1016/0277-9536(83)90117-X 6844952
Kessler, R. C., Adler, L., Ames, M., Demler, O., Faraone, S., Hiripi, E., & ... Walters, E. E. (2005). The World Health Organization adult ADHD self-report scale (ASRS): A short screening scale for use in the general population. Psychological Medicine, 35(2), 245–256. 10.1017/S0033291704002892
Kiser LJ Bennett L Heston J Paavola M Family ritual and routine: Comparison of clinical and non-clinical families Journal of Child and Family Studies 2005 14 3 357 372 10.1007/s10826-005-6848-0
Koome F Hocking C Sutton D Why routines matter: The nature and meaning of family routines in the context of adolescent mental illness Journal of Occupational Science 2012 19 312 325 10.1080/14427591.2012.718245
Lanza HI Drabick DA Family routine moderates the relation between child impulsivity and oppositional defiant disorder symptoms Journal of Abnormal Child Psychology 2011 39 1 83 94 10.1007/s10802-010-9447-5 20690009
Lindstedt H Umb-Carlsson Õ Cognitive assistive technology and professional support in everyday life for adults with ADHD Disability and Rehabilitation: Assistive Technology 2013 8 5 402 408 10.3109/17483107.2013.769120 23992459
Macan TH Shahani C Dipboye RL Phillips AP College students' time management: Correlations with academic performance and stress Journal of Educational Psychology 1990 82 4 760 10.1037/0022-0663.82.4.760
Margraf J Lavallee K Zhang X Schneider S Social rhythm and mental health: A cross- cultural comparison PLoS ONE 2016 11 3 e0150312 10.1371/journal.pone.0150312 26954568
McHorney CA Ware JE Jr Lu JR Sherbourne CD The MOS 36-item Short-Form Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups Medical Care 1994 32 1 40 66 10.1097/00005650-199401000-00004 8277801
McRae E Stoppelbein L O’Kelley S Fite P Smith S Comorbid internalizing and externalizing symptoms among children with ADHD: The influence of parental distress, parenting practices, and child routines Child Psychiatry & Human Development 2020 51 5 813 826 10.1007/s10578-020-01019-z 32607913
Mirsa R McKean M College students' academic stress and its relation to their anxiety, time management, and leisure satisfaction American Journal of Health Studies 2000 16 1 41 51
Monk TK Flaherty JF Frank E Hoskinson K Kupfer DJ The Social Rhythm Metric: An instrument to quantify the daily rhythms of life Journal of Nervous and Mental Disease 1990 178 2 120 126 10.1097/00005053-199002000-00007 2299336
Mudrack PE The structure of perceptions of time Educational and Psychological Measurement 1997 57 2 222 240 10.1177/0013164497057002003
Netemeyer RG Bearden WO Sharma S Scaling procedures: Issues and applications 2003 Sage Publications
Nigg JT Beauchaine TP Hinshaw SP Attention-deficit/hyperactivity disorder Child and adolescent psychopathology 2013 2 Wiley 377 409
Nigg JT Attention-deficit/hyperactivity disorder and adverse health outcomes Clinical Psychology Review 2013 33 2 215 228 10.1016/j.cpr.2012.11.005 23298633
Pavot W Diener E The satisfaction with life scale and the emerging construct of life satisfaction The Journal of Positive Psychology 2008 3 2 137 152 10.1080/17439760701756946
Piscitello J Cummins RN Kelley ML Meyer K Development and initial validation of the adolescent routines questionnaire: Parent and self-report Journal of Psychopathology and Behavioral Assessment 2019 41 2 208 220 10.1007/s10862-018-9707-1
R Core Team. (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/
Revelle, W. (2017) psych: Procedures for Personality and Psychological Research, Northwestern University, Evanston, Illinois, USA. https://CRAN.Rproject.org/package=psych Version = 1.7.8.
Reynolds CR Kamphaus RW Behavior assessment system for children 2004 2 Pearson
Stilley CS Bender CM Dunbar-Jacob J Sereika S Ryan CM The impact of cognitive function on medication management: Three studies Health Psychology 2010 29 1 50 55 10.1037/a0016940 20063935
Sytsma SE Kelley ML Wymer JH Development and initial validation of the Child Routines Inventory Journal of Psychopathology and Behavioral Assessment 2001 23 4 241 251 10.1023/A:1012727419873
Taylor A Deb S Unwin G Scales for the identification of adults with attention deficit hyperactivity disorder (ADHD): A systematic review Research in Developmental Disabilities 2011 32 3 924 938 10.1016/j.ridd.2010.12.036 21316190
Ward MK Meade AW Allred CM Pappalardo G Stoughton JW Careless response and attrition as sources of bias in online survey assessments of personality traits and performance Computers in Human Behavior 2017 76 417 430 10.1016/j.chb.2017.06.032
Willcutt EG Doyle AE Nigg JT Faraone SV Pennington BF Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review Biological Psychiatry 2005 57 1336 1346 10.1016/j.biopsych.2005.02.006 15950006
Zimmerman, D. W. (2004). A note on preliminary tests of equality of variances. British Journal of Mathematical and Statistical Psychology, 57(1), 173-181. 10.1348/000711004849222
Zisberg A Young HM Schepp K Zysberg L A concept analysis of routine: Relevance to nursing Journal of Advanced Nursing 2007 57 4 442 453 10.1111/j.1365-2648.2007.04103.x 17291208
Zisberg A Young HM Schepp K Development and psychometric testing of the scale of older adults' routine Journal of Advanced Nursing 2009 65 3 672 683 10.1111/j.1365-2648.2008.04901.x 19222665
| 0 | PMC9734787 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Psychopathol Behav Assess. 2022 Dec 6;:1-12 | utf-8 | J Psychopathol Behav Assess | 2,022 | 10.1007/s10862-022-10007-7 | oa_other |
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Research Paper
The impact of polypharmacy on 30-day COVID-related mortality in nursing home residents: a multicenter retrospective cohort study
http://orcid.org/0000-0003-3505-4335
Visser Anne G. R. [email protected]
13
Winkens Bjorn 2
Schols Jos M. G. A. 3
Janknegt Rob 3
Spaetgens Bartholomeus 4
1 Zuyderland Elderly Care, Sittard, The Netherlands
2 grid.5012.6 0000 0001 0481 6099 Department of Methodology and Statistics, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
3 grid.5012.6 0000 0001 0481 6099 Present Address: Departments Health Services Research and Family Medicine, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
4 grid.5012.6 0000 0001 0481 6099 Section Geriatric Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
9 12 2022
17
13 6 2022
15 11 2022
© The Author(s), under exclusive licence to European Geriatric Medicine Society 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Key summary points
Aim
The impact of polypharmacy on 30-day COVID-related mortality in nursing home residents was assessed after adjustment for age, sex, CCI, BMI and vaccination status.
Findings
A significant positive association between a higher total number of medications and 30-day COVID-related mortality in NH residents was found. However, this association was attenuated when adjusted for dementia and use of PPI, vitamin D, antipsychotics and antithrombotics.
Supplementary Information
The online version contains supplementary material available at 10.1007/s41999-022-00723-4.
Purpose
Both the coronavirus (COVID-19) disease and polypharmacy pose a serious threat to nursing home (NH) residents. This study aimed to assess the impact of polypharmacy on 30-day COVID-related mortality in NH residents with COVID-19.
Methods
Multicenter retrospective cohort study including NH residents from 15 NHs in the Netherlands. The impact of polypharmacy on 30-day COVID-related mortality was evaluated and assessed using multivariable logistic regression analyses with correction for age, sex, CCI, BMI and vaccination status.
Results
In total, 348 NH residents were included, with a mean age of 84 years (SD = 8); 65% were female, 70% lived in a psychogeriatric ward, with a main diagnosis of dementia. 30-day COVID-related mortality was 27.3%. We found a significant, positive association between the total number of medications and 30-day COVID-related mortality (OR 1.09; 95% CI 1.001–1.20, p = 0.046), after adjustment for age, sex, Charlson Comorbidity Index (CCI), Body Mass Index (BMI) and vaccination status. After additional correction for dementia (model 2) and use of PPI, vitamin D, antipsychotics and antithrombotics (model 3), this effect remained positive, but was no longer significant.
Conclusion
Nursing home residents with a higher number of medications and who were not vaccinated, had a higher 30-day COVID-related mortality. These findings have important implications for the management of COVID-19 in the frail NH population. As such they underline the importance of deprescribing on the one hand, but also of improving vaccination rates on the other.
Supplementary Information
The online version contains supplementary material available at 10.1007/s41999-022-00723-4.
Keywords
Polypharmacy
COVID-19
Nursing home residents
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pmcIntroduction
The Coronavirus Disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), still disproportionately affects nursing home (NH) populations all over the world due to the high proportion of frail older adults with underlying chronic conditions, resulting in substantial morbidity and mortality [1, 2]. In this frail population, there is a high prevalence of polypharmacy, i.e., the concomitant use of 5 or more medications, which in itself is already associated with poor outcomes, such as unplanned hospitalizations, reduced functional capacity and increased all-cause mortality [3]. Since both COVID-19 and polypharmacy pose a threat to NH residents, it is important to gain insight into the impact of polypharmacy on clinical outcomes in NH residents with COVID-19.
Previous research has shown that increasing multimorbidity and polypharmacy are associated with a higher risk of developing COVID-19 [4]. Conversely, being diagnosed with COVID-19 also contributes to polypharmacy by increasing the average number of medications by an average of 2 (range 1–13), even 30 days post-COVID-19 [5]. According to some studies, polypharmacy seems to be associated with poor clinical outcomes, such as adverse drug reactions, acute kidney injury, developing severe COVID-19 (compared to non-severe COVID) and mortality, while other studies reported no significant differences between survivors and non-survivors [6–10]. One of the studies that showed that polypharmacy increased the risk of developing severe COVID-19 also showed that this increased risk was promoted by specific medications, such as proton pump inhibitors (PPIs) or antipsychotics, such as haloperidol, risperidon or clozapine [10].
On the other hand, several medications were found to possibly prevent severe COVID-19 or COVID-19-related mortality. Tang et al. found that anticoagulants could decrease mortality in patients with severe COVID-19 [11]. A retrospective case series of Brouns et al. on nursing home residents showed that oral antithrombotics were associated with a lower mortality in the univariable analysis. However, this difference was attenuated after additional adjustments for sex, age and comorbidity [12].
While these studies examined the impacts of polypharmacy on COVID-19 patients in general, little is known about the impact of polypharmacy on COVID-19 survival among residents of nursing homes. Understanding the impact of polypharmacy on COVID-19-related outcome might help to improve the care and treatment of this frail population.
The aim of this multicenter retrospective cohort study was to determine the impact of polypharmacy on 30-day COVID-related mortality in nursing home residents in the Netherlands.
Methods
Between March 2020 and December 2021, a multicenter retrospective cohort study of nursing home residents with COVID-19 was performed in 15 nursing homes of the nursing home organization Zuyderland in Sittard, the Netherlands. During these months, there were 4 coronavirus exacerbation waves. The Alfa variant was dominant from February 2020 until May 2020, from September until December 2020, and from March until June 2021, while the Delta variant was dominant from September 2021 until December 2021. In the Netherlands, the vaccination program started on 6 January 2021, and the first to be vaccinated were residents of nursing homes.
In the Netherlands, admission to a nursing home is only possible if permanent disabilities and comorbidities have led to severe care dependency for activities of daily living (ADL) and instrumental activities of daily living (iADL) and 24-h long-term institutional care is needed. The participating NHs have somatic wards for residents with physical diseases as well as psychogeriatric wards, which are primarily inhabited by residents with dementia. These NHs range from small scale homes with 30 beds to large-scale homes with 150 beds, adding up to a total capacity of 1459 beds.
NH residents were included if they lived in a long stay ward and had a laboratory-confirmed diagnosis of COVID-19, represented by a positive result on the reverse-transcriptase polymerase chain reaction (rRT-PCR) assay for SARS-CoV-2. There were no exclusion criteria.
All included residents received the same medical care for COVID-19, in accordance with national guidelines, including oxygen therapy, dexamethasone, antibiotics in case of a bacterial superinfection and/or low-molecular-weight heparin in patients without anticoagulants. Patients who were likely to die from COVID-19 received palliative care within the NHs.
Data collection
The following data were retrospectively obtained from the medical records: age, sex, nursing home ward (somatic or psychogeriatric), medical history, body mass index (BMI), medication use and date of death (if applicable). Based on the participants’ medical histories, the comorbidity levels were assessed by calculating the Charlson Comorbidity Index (CCI). The primary outcome of this study was 30-day COVID-related mortality. All data were treated confidentially and stored securely.
Data analysis
Primary outcome was COVID-related mortality 30 days after a positive rRT-PCR test. The characteristics of survivors and non-survivors were compared using independent-samples t-tests for numerical variables and the chi-square test or Fisher’s exact test for categorical variables. Numerical variables were expressed as mean with standard deviation (SD), while categorical variables were expressed as number and percentage of residents. The effects of the total number of medications used at time of a positive COVID PCR test on mortality were calculated with multivariable logistic regression analyses. The effects are presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs), correcting for three sets of potential confounders (models 1–3). Model 1 included age, sex, CCI, BMI, and the vaccination status (fully, partially, or not vaccinated) as potential confounders, while model 2 additionally included dementia; model 3 included the same variables as model 2, but also corrected for some of the medication groups that are prescribed most frequently for NH residents: PPI, vitamin D, antipsychotics, antithrombotics [13].
As the effects of the total number of medications used might depend on vaccination status and dementia, two-way interaction terms were included and tested in all three models. A top-down procedure was applied on these interaction terms, i.e., removing the least significant interaction term (highest p value) if it was not significant. In addition, the results of the final models 1, 2 and 3 were compared using likelihood ratio tests. The same models were analyzed using logistic mixed models and generalized estimating equations (GEE), accounting for the correlation between residents within the same NH. As the intra-class correlation (ICC) could not be estimated reliably (close to 0, but negative), it was set equal to 0, which reduces these analyses to logistic regression analyses. All analyses were performed using SPSS Statistics for Windows (version 26.0, Armonk, N.Y., USA, IBM Corp.). A two-sided p value of p ≤ 0.05 was considered statistically significant. This study was approved by the medical ethical review board of Zuyderland. (METC-Z Z2021109).
Results
In total 348 nursing home residents who suffered from COVID-19 were included, 227 of whom (65%) were female. The mean age was 84 years (SD = 8). Of the participating residents, 242 (70%) lived in psychogeriatric wards with a main diagnosis of dementia, and the remaining 106 (30%) residents lived in a somatic ward with a main diagnosis of post-stroke status, chronic obstructive pulmonary disease (COPD), heart failure, Parkinson’s disease, or other neurodegenerative diseases. The mean CCI was 7 (SD = 2), the mean BMI was 24.2 (SD = 5.1) and the mean total number of medications used was 6 (SD = 3). On the day of the positive rRT-PCR test result, 109 (31%) residents were fully vaccinated, 23 (7%) were partially vaccinated and 216 (62%) were not vaccinated. Of the unvaccinated residents, 4 residents had refused vaccination and 212 residents were infected with COVID-19 before vaccination was available. None of the participating residents were hospitalized during their COVID-19 infection. See also Table 1.Table 1 Characteristics of nursing home residents with COVID-19
Baseline Total (N = 348) Non-survivor (N = 95) Survivor (N = 253) p value
Women, n (%) 227 (65%) 54 (57%) 173 (68%) 0.044
Men, n (%) 121 (35%) 41 (43%) 80 (32%)
Age, mean (SD), y 84 (8) 86 (8) 84 (7) 0.066
Ratio ward 0.423
Psychogeriatric, n (%) 242 (70%) 63 (66%) 179 (71%)
Somatic, n (%) 106 (30%) 32 (34%) 74 (29%)
Main diagnosis 0.724
Dementia, n (%) 246 (71%) 64 (67%) 182 (72%)
CVA, n (%) 51 (15%) 16 (17%) 35 (14%)
Parkinson’s disease, n (%) 14 (4%) 6 (6%) 8 (3%)
COPD, n (%) 12 (3%) 3 (3%) 9 (4%)
Heart failure, n (%) 12 (3%) 3 (3%) 9 (4%)
Other, n (%) 14 (4%) 4 (4%) 10 (4%)
Vaccination 0.019
Full, n (%) 109 (31%) 24 (25%) 85 (34%)
Partial, n (%) 23 (7%) 2 (2%) 21 (8%)
None, n (%) 216 (62%) 69 (73%) 147 (58%)
CCI, mean (SD) 7 (2) 7.4 (2.1) 6.6 (1.8) < 0.001
BMI, mean (SD) 24.2 (5.1) 24.4 (5.3) 24.2 (5.0) 0.709
Medication use
Total number of medicines, mean (SD) 6 (3) 6.9 (2.8) 6.1 (3.0) 0.013
Vitamin D, n (%) 122 (35%) 32 (34%) 90 (36%) 0.742
PPI, n (%) 154 (44%) 54 (57%) 100 (40%) 0.004
Antipsychotics, n (%) 86 (25%) 23 (24%) 63 (25%) 0.894
Antithrombotics, n (%) 210 (60%) 64 (67%) 146 (58%) 0.101
VKA, n (%) 23 (7%) 7 (7%) 16 (6%) 0.727
DOAC, n (%) 60 (17%) 12 (13%) 48 (19%) 0.163
APT, n (%) 125 (36%) 43 (45%) 82 (32%) 0.026
LMWHa, n (%) 5 (1%) 3 (3%) 2 (1%) 0.128
Data collected on the day of the positive rRT-PCR test
Statistical significant values (p < 0.005) are presented in bold
APT antiplatelet therapy, BMI body mass index, CCI Charlson Comorbidity Index, COPD chronic obstructive pulmonary disease, CVA cardiovascular accident, DOAC direct oral anticoagulant, LMWH low-molecular-weight heparin, No number of, PPI proton pump inhibitor, rRT-PCR real-time reverse-transcriptase polymerase chain reaction, SD standard deviation, VKA vitamin K antagonist, y year
aFisher’s exact test
COVID-related mortality within 30 days after a positive rRT-PCR-test was 27.3% (95 out of 348). All non-survivors died from COVID-19, as confirmed by the nursing home physician. Most demographic characteristics were similar between survivors and non-survivors. Of the non-survivors, more were male (p = 0.044) and not fully vaccinated (not vaccinated or partially vaccinated, p = 0.019), more used a higher number of medications (p = 0.013) and more received a PPI or antiplatelet therapy (APT) (p = 0.004 and p = 0.026 resp.).
Of the three models that were considered in the multivariable logistic regression analyses, model 1 showed a significant positive association between a higher total number of medications and higher 30-day COVID-related mortality (OR 1.09; 95% CI 1.001–1.20, p = 0.046), after adjustment for age, sex, CCI, BMI and vaccination status. As shown in model 2, after adjusting for the diagnosis dementia, this association was similar, but not statistically significant anymore (OR 1.09; 95% CI 0.995–1.20, p = 0.063). Note that in model 2, the association between dementia and 30-day COVID-related mortality was not statistically significant (OR 0.94; 95% CI 0.53–1.67, p = 0.846).
Model 3 showed no statistically significant association between the use of PPI, vitamin D, antipsychotics or antithrombotics and 30-day COVID-related mortality. Based on likelihood ratio tests, model 1 was preferred, as the more complex models 2 and 3 did not fit the data significantly better than model 1 (p = 0.846 and p = 0.594, respectively).
Table 2 shows that in all three models, COVID-19 vaccination was associated with lower 30-day COVID-related mortality in nursing home residents (model 1, fully versus not vaccinated: OR 0.56; 95% CI 0.32–0.97, p = 0.039; partially versus not vaccinated: OR 0.20; 95% CI 0.04–0.88, p = 0.034).Table 2 Three models of multivariable logistic regression analyses to explore the association between clinical characteristics and 30-day COVID-related mortality in nursing home residents with COVID-19
Characteristics Model 1 OR (95% CI)a p value Model 2 OR (95% CI)a p value Model 3 OR (95% CI)a p value
Age (years) 1.04 (1.004–1.08) 0.031 1.04 (1.004–1.08) 0.031 1.04 (1.005–1.08) 0.027
Sex—female 0.67 (0.39–1.14) 0.138 0.67 (0.39–1.14) 0.138 0.65 (0.38–1.13) 0.125
Male Reference Reference Reference
CCI (unit) 1.14 (0.99–1.30) 0.065 1.14 (0.99–1.30) 0.065 1.13 (0.98–1.30) 0.095
BMI (unit) 1.00 (0.95–1.05) 0.967 1.00 (0.95–1.05) 0.977 1.003 (0.95–1.05) 0.905
Vaccination status 0.019 0.020 0.021
Fully vaccinated 0.56 (0.32–0.97) 0.039 0.56 (0.32–0.99) 0.046 0.56 (0.32–0.99) 0.045
Not vaccinated Reference Reference Reference
Partially vaccinated 0.20 (0.04–0.88) 0.034 0.20 (0.04–0.88) 0.033 0.20 (0.04–0.90) 0.036
No. of medications (unit) 1.09 (1.001–1.20) 0.046 1.09 (0.995–1.20) 0.063 1.08 (0.97–1.21) 0.157
Dementia
Yes 0.94 (0.53–1.67) 0.846 0.97 (0.54–1.76) 0.927
No Reference Reference
PPI use
Yes 1.61 (0.89–2.91) 0.118
No Reference
Vitamin D use
Yes 0.74 (0.43–1.29) 0.295
No Reference
Antipsychotics use
Yes 1.09 (0.59–2.00) 0.792
No Reference
Antithrombotics use
Yes 0.82 (0.44–1.51) 0.519
No Reference
Interactions were not significant, therefore not included in final models that are presented
Model 1: vaccination status with no. of medications p = 0.275
Model 2: vaccination status with no. of medications p = 0.187; no. of medications with dementia p = 0.779
Model 3: vaccination status with no. of medications p = 0.243; no. of medications with dementia p = 0.816
Statistical significant values (p < 0.005) are presented in bold
APT antiplatelet therapy, BMI body mass index, CCI Charlson Comorbidity Index, DOAC direct oral anticoagulant, No number of, PPI proton pump inhibitor, OR odds ratio, VKA vitamin K antagonist
aLikelihood ratio tests—model 3 vs 2: p = 0.454; model 2 vs 1: p = 0.846; model 3 vs 1: p = 0.594
Also, a higher age was associated with a higher 30-day COVID-related mortality (p = 0.031, 0.031, 0.027 respectively). This association did not attenuate after adjustment for sex, CCI, BMI, vaccination status, total number of medications, diagnosis of dementia and the different medication groups (OR 1.04; 95% CI 1.005–1.08, p = 0.027).
Discussion
This multicenter retrospective cohort study is the first to show the impact of polypharmacy on 30-day COVID-related mortality in nursing home residents (n = 348). We found a significant, positive association between the total number of medications and 30-day COVID-related mortality, which persisted after adjustment for age, sex, CCI, BMI and vaccination status. After adjustment for dementia and other potential confounders, this association was similar, but not statistically significant anymore, which could be related to the relatively small sample size. An interesting additional finding was the observation that non-survivors were more often unvaccinated, and this association was not attenuated after adjustment for age, sex and other potential confounders.
Our finding that polypharmacy is associated with poor outcome in the NH population is in line with the findings of studies on other populations, which showed that severe COVID-19 was associated with polypharmacy and also that patients in NH facilities are potentially more exposed to polypharmacy and thus to medication-related errors [5, 10]. A recent study by Blaszczyk et al. also showed that 1 in 5 NH residents with a COVID-19 diagnosis developed a new, potentially dangerous drug-drug interaction [14]. This finding further emphasizes the importance of our study.
In addition to the number of medications, specific medication classes are of particular importance. These medications are among the most prescribed in NHs and are well-known indicators of overprescribing. Also, these medication classes have specific side effects that might increase the risk of adverse outcomes. For example, following the onset of the COVID-19 pandemic, previous studies have shown that NH residents were increasingly prescribed psychotropic, anticonvulsant, and opioid medications [15, 16]. This is probably due to the fact that otherwise favorable non-pharmacological interventions were deemed less appropriate due to isolation measures or had lower priority in times of limited resources, including lack of staff [16]. This potentially excessive prescribing behavior may pose an important threat to NH residents’ health, as it might lead to increased confusion, sedation or falls [17].
Another medication class of particular interest are antithrombotics, as our univariable analysis showed that the use of PPI and APT was more common among non-survivors. Currently, there is conflicting evidence regarding the benefit of anticoagulant therapy in general and of APT in particular, as studies in different populations yielded mixed results [18, 19].
The finding that a higher percentage of non-survivors were unvaccinated may also explain why the COVID-related mortality found in this study (27.3%) was lower than expected. Given the greater frailty and older age of the multimorbid NH residents in our study, we expected a higher mortality [13]. Our findings support the hypothesis that vaccination reduced the risk of COVID-19-related mortality in NHs.
The present study offers relevant insights into the impact of polypharmacy and COVID-19 on NH residents and shows the importance of vaccination in NH residents. Nevertheless, a note of caution is due since there are several study limitations, such as the retrospective design and the observational nature of the study. Also, data for this study were collected between March 2020 and December 2021, hence they most likely did not include the novel omicron variant of SARS-CoV-2. This new variant appears to be associated with a reduced risk of hospital admission and mortality. It is unclear whether these study results also apply on this new omicron variant.
Despite these limitations, our study provides relevant information and insight into the impact of polypharmacy on 30-day COVID-related mortality in NH residents. Additional studies are needed to evaluate the impact of different kinds of medication groups on mortality within the NH population, as an approach to reduce mortality due to COVID-19 among NH residents.
Conclusion and implications
Nursing home residents with a higher number of medications and who were not vaccinated, had a higher 30-day COVID-related mortality. These findings have important implications for the management of COVID-19 in the frail NH population. As such they underline the importance of deprescribing on the one hand, but also of improving vaccination rates on the other.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file 1 (XLSX 43 kb)
Acknowledgements
There are no contributions of others who did not merit authorship.
Author contributions
Study concept and design: AGRV, JMGAS, BS, RJ and BW. Acquisition of data: AV. Analysis and interpretation of data: AGRV, BW, JMGAS, BS and RJ. Drafting of the manuscript: AGRV, BS, BW, JMGAS and RJ. Critical revision of the manuscript for important intellectual content: JMGAS, BS, BW, RJ, and AGRV.
Funding
This research did not receive any funding from agencies in the public, commercial, or not-for-profit sectors.
Data availability
The authors declare that the data supporting the findings of this study are available within the article and its supplementary files.
Declarations
Conflict of interest
The authors have no conflict of interest to report, financial or otherwise.
Ethical approval
All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
For this type of study formal consent is not required.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Fisman DN Bogoch I Lapointe-Shaw L Risk factors associated with mortality among residents with coronavirus disease 2019 (COVID-19) in long-term care facilities in Ontario, Canada JAMA Netw Open 2020 10.1001/jamanetworkopen.2020.15957
2. McMichael TM Currie DW Clark S Epidemiology of Covid-19 in a long-term care facility in King County, Washington N Engl J Med 2020 10.1056/NEJMoa2005412
3. Page AT Clifford RM Potter K The feasibility and effect of deprescribing in older adults on mortality and health: a systematic review and meta-analysis Br J Clin Pharmacol 2016 10.1111/bcp.12975
4. McQueenie R Foster HME Jani BD Multimorbidity, polypharmacy, and COVID-19 infection within the UK Biobank cohort PLoS ONE 2020 10.1371/journal.pone.0238091
5. Sandlin K Hernandez L Bader H Observations of polypharmacy and interactions on varying COVID-19 medications regimens in nursing home residents J Am Med Dir Assoc 2021 10.1016/j.jamda.2021.01.053
6. Sun J Deng X Chen X Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System Clin Pharmacol Ther 2020 10.1002/cpt.1866
7. Taher A Alalwan AA Naser N Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain Cureus 2020 10.7759/cureus.9693
8. Poblador-Plou B Carmona-Pírez J Ioakeim-Skoufa I Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain Int J Environ Res Public Health 2020 10.3390/ijerph17145171
9. de Smet R Mellaerts B Vandewinckele H Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study J Am Med Dir Assoc 2020 10.1016/j.jamda.2020.06.008
10. McKeigue PM Kennedy S Weir A Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case–control study BMC Med 2021 10.1186/s12916-021-01907-8
11. Tang N Bai H Chen X Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy J Thromb Haemost 2020 10.1111/jth.14817
12. Brouns SH Brüggemann R Linkens AEMJH Mortality and the use of antithrombotic therapies among nursing home residents with COVID-19 J Am Geriatr Soc 2020 10.1111/jgs.16664
13. Pasina L Novella A Cortesi L Drug prescriptions in nursing home residents: an Italian multicenter observational study Eur J Clin Pharmacol 2020 10.1007/s00228-020-02871-7
14. Blaszczyk AT Sandlin K Mirza S Hernandez L Bader H Hall RG Potential for drug interactions and polypharmacy from treatment of COVID-19 in long-term care J Am Med Dir Assoc 2022 10.1016/j.jamda.2022.03.016
15. Stall NM Zipursky JS Rangrej J Assessment of psychotropic drug prescribing among nursing home residents in Ontario, Canada, during the COVID-19 pandemic JAMA Intern Med 2021 10.1001/jamainternmed.2021.0224
16. Campitelli MA Bronskill SE Maclagan LC Comparison of medication prescribing before and after the COVID-19 pandemic among nursing home residents in Ontario, Canada JAMA Netw Open 2021 10.1001/jamanetworkopen.2021.18441
17. Van der Cammen TJM Rajkumar C Onder G Drug cessation in complex older adults: time for action Age Aging 2014 10.1093/ageing/aft166
18. Ten Cate H Surviving Covid-19 with heparin? N Engl J Med 2021 10.1056/NEJMe2111151
19. Spaetgens B Nagy M ten Cate H Antiplatelet therapy in patients with COVID-19—more is less? JAMA 2022 10.1001/jama.2021.23866
| 36484958 | PMC9734791 | NO-CC CODE | 2022-12-14 23:28:30 | no | Eur Geriatr Med. 2022 Dec 9;:1-7 | utf-8 | Eur Geriatr Med | 2,022 | 10.1007/s41999-022-00723-4 | oa_other |
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International Journal of Economic Policy Studies
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10.1007/s42495-022-00097-2
Research Article
The effect of management practices on the performance of bus enterprises
Kawasaki Kazuyasu [email protected]
1
Inui Tomohiko 2
Miyagawa Tsutomu 2
1 grid.443595.a 0000 0001 2323 0843 Chuo University, Tokyo, Japan
2 grid.472046.3 0000 0001 1230 0180 Research Institute of Economy, Trade and Industry and Gakushuin University, Tokyo, Japan
6 12 2022
129
26 10 2022
6 11 2022
© Japan Economic Policy Association (JEPA) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Bloom and Van Reenen (Quarterly Journal of Economics 122:1351–1408, 2007) examined the relationship between firm management practices and performance and demonstrated that management scores had a positive impact on firm performance. While they focus on the impact of firm management practices on its performance in the manufacturing sector, we examine how firm management practices are related to its performance in the bus industry in Japan, where both private and public companies exist, and these firms are regulated by the government. We find that public companies have better management practices than private companies. The gross output index is taken as the dependent variable with a significant coefficient of the management practice score. However, if the dependent variable is a value-added index, no significant coefficient is obtained. Because the bus industry is regulated, they cannot expect to increase their profits by providing better services. Finally, we find that organizational management practices are more positively related to the firm performance than human resource management practices.
Supplementary Information
The online version contains supplementary material available at 10.1007/s42495-022-00097-2.
Keywords
Management practice
Public service
Public–private partnership
Privatization
JEL Classification
R4
H4
D2
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pmcIntroduction
Since Bloom and Van Reenen [2] first showed that firm management practices are positively related to firm performance, research on the relationship between firm management and performance has developed greatly. First, they extend their study to not only advanced countries but also the development of the country, as in Bloom and Van Reenen [3], because their pioneering work focused on the US and main European countries, such as the UK, France, and Germany. Second, they also analyze the service sector because their first study focused on the manufacturing firms. However, as Morikawa [13, 14] pointed out, it is difficult to measure output and value added in the service sector because in the service sector, the quality of the services offered differs greatly. As a result, in the field of medical care services, performance is measured by factors such as mortality among emergency patients and during emergency surgery and the length of hospital waiting lists [4]. In the case of educational services, performance is measured by factors, such as students’ test scores, grade point average, and school evaluation [5].
Considering both the manufacturing and service sectors in Japan and South Korea, Lee et al. [11] calculated the management practice scores of Japanese and Korean firms by applying the method developed by Bloom and Van Reenen [2] and examined the relationship with firm performance. In their study, service sector performance was measured in the same manner as manufacturing, with nominal output (sales value) adjusted using an industry-level deflator, but the quality of the service was by no means adequately considered.
Based on previous studies on management practices, our study focuses on the relationship between firm performance, considering several outcome measures in addition to standard output and value-added measures, and its management practices in a specific service industry. This study analyzes this relationship in the Japanese passenger bus business. The business differs from oft-analyzed manufacturing in three ways. First, the “number of passengers” can be used as an indicator of the real performance of the business. Second, like those in medical care and educational services, companies in the passenger bus business can be both privately and publicly operated, making it possible to compare the management quality of these two types of companies. Dealing with a sector with differing operational formats not only allows us to investigate whether differences in management quality depend on operational format, but also provides an opportunity to consider the quality of service after privatization.1 The final factor is the existence of the regulations. Because passenger bus operators must run their businesses with due regard to road safety and also receive subsidies from the government, they are subject to heavy regulations even if they belong to the private sector. Additionally, there is a licensing system for bus routes, and although participation is regulated, the determination of fares is also restricted. Bloom et al. [4, 5] considered the relationship between management quality and service quality in the health care and educational service sectors, which are also heavily regulated. Therefore, we also intend to consider the issues of management quality and performance while controlling for the existence of regulations.
We raise discussions from not only the viewpoint of productivity analysis, but also from the viewpoint of social welfare policies, that is, the importance of bus transport policies in an aging society. As shown in “Overview of regular passenger bus business in Japan” section, the number of bus users has clearly declined since Japan’s period of high growth. However, given the aging society, the use of busses as a means of everyday transport is likely to be reviewed amid increasing concerns about elderly people driving themselves. In this case, because the elderly are the main users, offering services that take full account of safety is likely to become important. Furthermore, we propose a hitherto unconsidered angle, in that our study deals with management practices as a means of improving service quality.
The remainder of this paper is organized as follows. “Literature review” section presents a review of previous research on management practices and quality improvements in such service sectors. “Overview of regular passenger bus business in Japan” section provides an overview of the bus businesses in Japan. Our survey of management practices for bus operators is outlined in “Overview of the survey” section. In “Management practice and performance” section, we analyze the survey results. The analysis was broadly divided into two phases. First, there is a comparison of the survey results for private- and public-sector companies and management practices at metropolitan and local bus enterprises, which provides an overview of the characteristics of bus operators’ management practices. Second, using simple quantitative analysis, we investigate some features of the relationship between the evaluation of management practices (as obtained from the survey results) and various management performance indicators of bus enterprises. In the final section, strategic problems are discussed, as well as a summary of the results of the analysis.
Literature review
Previous research on this topic has covered three fields. The first is related to the impact of management practices and relevant investment on productivity. Bender et al. [1] investigated whether management practices affect productivity directly or via human capital, that is, via managers and employees. Their analysis revealed that in addition to contributing directly to a rise in the level of a company’s total factor productivity (TFP), management practices also contribute to such a rise, as companies with excellent management practices employ excellent managers. Bloom et al. [6] investigated whether the delay in IT introduction and stagnation in the rate of TFP improvement in Europe are attributable to the nature of management practices or to the wider economic environment, such as the scale of the market in the US and Europe. They compared the impact of IT investment on productivity in domestic companies and in U.S.-owned multinationals with a base in Europe. Their analysis clarified that IT investment has a significant impact on productivity in US-owned multinationals and in companies with US capital participation, suggesting that it is highly likely that management practices play an important role in ensuring that IT investment is effective.
The second is based on the management practices in the public service sector. While the studies mentioned have far focused on manufacturing and the market economy, the studies below focus on the impact of management practices in public-sector services, namely schools and hospitals. Bloom et al. [5] analyzed the relationship between management practices and school performance at 1800 schools in the United Kingdom, Sweden, Canada, the United States, Germany, Italy, Brazil, and India. Their research ascertained that pupils’ results are excellent at schools with excellent management practices. Furthermore, they found that among government-run schools, management practices were superior in schools, independent of local government control. Bloom et al. [4] found that in hospitals in the United Kingdom with excellent management practices (i) medical treatment performance is strong with low patient mortality rates, for example; and (ii) competition between hospitals contributes to improvement in management practices.
The third field is an analysis of the impact of companies’ ownership format (i.e., whether they are in the private or public sector) on their performance. Brown et al. [7] analyzed the effect of privatization in Hungary, Romania, Russia, and Ukraine. They found that privatization contributed to an improvement in TFP. Chen et al. [8] analyzed the impact of privatization on TFP while considering the impact of differentiation within the privatization policy of the Chinese government (i.e., that government involvement would continue for large-scale state enterprises, while small-scale state enterprises would be privatized). Hence, their study also revealed that privatization contributes to an improvement in TFP. Mizutani and Urakami’s [12] research relates to the efficiency of the regular passenger bus business in Japan, comparing privately operated and publicly operated bus businesses in terms of the cost and wage functions. They found that the costs for publicly operated bus businesses were 20.2% higher than those for privately operated bus businesses, even when controlling for various operational conditions surrounding bus businesses. Furthermore, even after controlling for workers’ length of service, years in post, etc., they were 14.5% higher.
As outlined above, although there has been progress in research into firm performance, management practices, and ownership formats, our study is the first to mix private- and public-sector companies and test the relationship between management practices and firm performance in the heavily regulated market in which services are provided.
Overview of regular passenger bus business in Japan
The regular passenger bus business in Japan has faced declining demand over a long period but has shown a sideways trend in recent years. The number of passengers carried approximately halved to 5.939 billion in 2004, peaking at 10.144 billion in 1968. The decline continued thereafter, and the figure has been approximately 4.2 billion in recent years. There were both private- and public-sector operators, and there were 2192 private-sector operators and 25 public-sector operators in the financial year 2016, as shown in Table 1. Looking at their scale, the majority are small- and medium-sized operators with 30 or fewer busses accounting for 83.8% of operators. The picture is similar when looking at the number of employees, with 74.9% of the operators having 30 or fewer employees.Table 1 Overview of route bus transport in Japan
Source: Ministry of land, infrastructure and transport
F.Y. 2013 2014 2015 2016 2017
Private Public Private Public Private Public Private Public Private Public
Number of passengers (millions) 2984 923 2,995 914 3031 924 3061 914 3061 934
Number of operators 1956 35 2,090 30 2092 28 2192 25 N.A. N.A.
Revenue (billion yen) 562.3 152.7 560.4 151.5 568.4 152.6 572.7 152.6 577.7 155.2
Cost (billion yen) 584.8 166.0 583.5 164.0 583.0 160.5 583.0 160.5 601.2 165.0
Profit (billion yen) − 22.5 − 13.3 − 23.1 − 12.5 − 14.6 − 7.9 10.3 − 7.9 − 23.5 − 9.8
The numbers in revenue, cost and profits are for operators owing more than 30 vehicles
Table 2 shows trends in the number of passengers carried by private- and public-sector operators with 30 or more busses from 2013 to 2017 and their income and expenditure. The number of passengers carried by public-sector operators and private-sector operators has trended at just above 900 million and around 3 billion, respectively. A comparison of the average number of passengers carried per operator shows that the figure for private-sector operators was 13.53 million in financial year 2017, while that for public-sector operators was around four times larger, at 51.89 million. The income is around 570 billion JPY for private-sector operators and just over 150 billion JPY for public-sector operators. Similar to the comparative number of passengers carried, the income per public-sector operator is large at 8.6 billion JPY while it is 2.6 billion JPY per private-sector operator. A lot of companies, both private- and public-sector operators, are operating in deficit, with the expenditure exceeding the income. The current profit/income ratio in the financial year 2017 is 96.1% for private-sector operators and is a little lower for public-sector operators at 94.1%. However, the ratio of recurring income to recurring expenses has improved since the financial year 2013, having been 78.3% in the financial year 2000. As shown in Table 3, the majority of private- and public-sector operators are operating in the red and only 32.3% of all private-sector operators and 11.1% of all public-sector operators are operating in the black in the financial year 2017.Table 2 Size distribution of bus operator in Japan in FY 2016
Source: Ministry of land, infrastructure and transport
By vehicle By employees By capital
Number of vehicle Number of operator (%) Number of employees Number of operator (%) Capital (million yen) Number of operator (%)
− 10 1559 (70.3%) − 10 1247 (56.2%) − 10* 1282 (57.8%)
11–30 300 (15.5%) 11–30 415 (18.7%) 11–30 404 (18.2%)
31–50 96 (4.3%) 31–50 135 (6.1%) 31–50 195 (8.8%)
51–100 97 (4.4%) 51–100 132 (6.0%) 51–100 214 (9.7%)
101– 165 (7.4%) 101–300 160 (7.2%) 101– 97 (4.4%)
300–500 128 (5.8%) Public 25 (1.1%)
Total 2217 (100%) Total 2217 (100%) Total 2217 (100%)
The item “less than 10 million in capital (*)” includes individual ownership operators (50 operators)
Table 3 Fiscal situation of route bus operators
Source: Ministry of land, infrastructure and transport
F.Y. 2013 2014 2015 2016 2017
Private Public Private Public Private Public Private Public Private Public
Number of deficit operators 160 20 161 17 145 15 142 15 153 16
Number of surplus operators 65 2 63 3 76 4 78 3 73 2
The numbers are for operators owing more than 30 vehicles
Table 4 shows trends in income and costs per vehicle kilometer from the financial year 2013 to the financial year 2017 for private- and public-sector operators. The income per vehicle kilometer is improving for both the operators and it rose from 381 to 409 JPY and from 606 to 654 JPY for the private and public sector, respectively. Over the same period, the costs per vehicle kilometer also increased, rising from 397 to 426 JPY in the private sector and from 658 to 696 JPY in the public sector. When comparing the breakdown of costs in the private and public sector, in the financial year 2018, in addition to labor costs per vehicle kilometer in the public sector is 381 JPY, which is 55% higher than 246 JPY for the private sector and miscellaneous “other” costs per vehicle kilometer in the public sector are 275 JPY, which is 89% higher than 146 JPY for the private sector.Table 4 Average revenue and cost in yen per vehicle kilometer
Source: Ministry of land, infrastructure and transport
F.Y. 2013 2014 2015 2016 2017
Private Public Private Public Private Public Private Public Private Public
Revenue 318.3 605.5 384.2 615.7 392.2 624.5 399.8 638.7 408.8 654.6
Cost 397.1 658.1 400.1 666.2 402.3 656.6 411.5 678.2 425.9 696.2
Labour cost 224.4 357.6 228.1 359.5 233.1 358.4 223.0 361.2 245.7 381.0
Fuel oil cost 43.1 50.1 41.2 49.6 31.8 38.2 30.3 33.9 34.6 39.8
Other cost 129.6 250.5 130.8 257.0 137.4 259.9 158.2 283.1 145.7 275.4
The numbers are for operators owing more than 30 vehicles
Table 5 shows the trends in income and costs per vehicle kilometer from 2013 to 2017 for metropolitan and other (local) areas. As the table shows, income per vehicle kilometer is slightly above expenditure in metropolitan areas, with operations in the black. When comparing income and costs per vehicle kilometer in the financial year 2017, although the income in metropolitan areas is 88% higher (593 JPY) than the income for other areas (315 JPY), costs in metropolitan areas are 578 JPY compared to 386 JPY in other areas, meaning that metropolitan costs are 58% higher than those for other areas. Furthermore, when looking at the current profit/income ratio, while for metropolitan operators shows a slight improvement from 101% in 2013 to 102% in 2017, while for the operators in other areas have deteriorated from 88 to 56% over the same period.Table 5 Average revenue and cost in yen per vehicle kilometer
Source: Ministry of land, infrastructure and transport
F.Y. 2013 2014 2015 2016 2017
Metropolitan Local Metropolitan Local Metropolitan Local Metropolitan Local Metropolitan Local
Revenue 560.7 289.3 562.4 295.4 570.1 301.6 579.4 307.8 592.6 314.5
Cost 555.8 330.4 554.9 340.1 552.3 341.6 561.7 352.3 578.4 365.6
Labour cost 310.5 189.0 312.0 192.3 314.1 197.0 305.4 188.4 329.4 209.0
Fuel oil cost 47.4 34.9 45.9 39.5 35.4 30.4 32.9 29.0 38.0 33.1
Other cost 198.0 106.5 197.1 108.4 202.7 114.2 223.4 134.9 211.0 123.5
The numbers are for operators owing more than 30 vehicles
Overview of the survey
In this section, we explain the survey results on the management practices of passenger bus operators.
The aim of the survey, and the scoring method
First, we revise questionnaires of our survey developed by Bloom and Van Reenen [2] and Lee et al. [11]. Discussing with the Ministry of Land, Infrastructure, Transport, and Tourism, the Japan Bus Association (Nihon Bus Association, NBA), and the Development Bank of Japan Inc., we added or removed some questionnaires to fit our survey with the operations of the Japanese bus companies.
Bloom and Van Reenen [2] categorized their survey questions into the four category headings of “operations,” “target-setting,” “monitoring,” and “incentives” and developed a scoring system of management practices in the manufacturing firms. For each question, a judgment was given on the situation at the company on a five-point scale ranging from (1) no structured management practice in place to (5) strong management practice in place, and the average score for each category was used in our empirical analysis.
In the “operations” category, surveyed companies are asked whether the latest production techniques and manufacturing processes have been introduced and whether these have been rationalized or improved, for example. In the “target-setting” category, they are asked about company-wide targets, targets for each place of business, and the extent to which targets are shared among employees, etc. In the “monitoring” category, they are asked how key performance indicators are measured and managed, who monitors them, and how the results of monitoring are shared, etc. In the “incentives” category, they are asked about their response, related to promotion, wage increases, or bonuses, to strong performance by employees and their response to employees who perform badly, among other factors.
Lee et al. [11] added an “organizational reform” category and conducted a survey via interviews. However, the evaluation in their survey was conducted on a four-point scale ranging from 1 to 4.
Furthermore, based on the conditions currently surrounding the bus business, we added items related to operational control, such as the introduction of smartcards and timetable reform, and deleted items typical of manufacturing, such as technological innovation and items where monitoring of achievement was unlikely to be frequent. This process resulted in fewer questions than Bloom and Van Reenen [2] and Lee et al. [11], prompting us to combine the “target-setting” and “monitoring” categories in our questionnaire.
We used the same four-grade evaluation as Lee et al. [11] and added points according to the “yes” or “no” reply to each question. Regarding categories, such as “operations” and “target management and monitoring,” we took the average value for the relevant questions as the category score. Please note that the questions and scoring systems are provided in Kawasaki et al. [10].
Summary of survey and responses
We conducted our survey in November 2018 by mailing 779 passenger bus operators who were members of the Nihon Bus Association. Among these, 23 public enterprises were included in the study.
Valid responses were obtained from 132 firms, with a response rate of 16.9%. Among them, 15 were public enterprises, representing a response rate of 65.2%. Furthermore, the TSR-van2 database from Tokyo Shoko Research, Ltd. was used to fill in the gaps for companies that omitted financial data where possible. Descriptive statistics of the results are presented in Tables 6 and 7.Table 6 Descriptive statistics: management practice score
Number of sample Average Standard deviation Minimum Maximum
Q1. Your company’s business philosophy 124 2.50 1.38 1 4
Q2. The organization’s targets 128 2.73 1.41 1 4
Q3. Monitoring the achievement of targets 128 2.59 1.28 1 4
Q4. Organizational responses after the monitoring 130 2.88 0.75 1 4
Q5. Organizational responses when monitoring of the operation of organizational targets shows that a unit has not achieved its targets 81 2.47 1.08 1 4
Q6. Organizational responses when, in contrast to the last category, targets are achieved 129 2.13 1.35 1 4
Q7. Information transmission within the organization other than formal communication such as at meetings 129 1.59 0.85 1 4
Q8. Implementation of organizational reform 110 1.79 1.24 1 4
Q9. Timetable reform 128 2.61 1.34 1 4
Q10. Operational control 128 1.53 0.98 1 4
Q11. The promotion system and the remuneration system 126 1.92 1.07 1 4
Q12. Means of improving motivation 118 2.11 0.77 1 4
Q13. Treatment of employees whose performance is not good 125 1.78 1.02 1 4
Q14. Treatment of workers with strong performance 122 2.46 1.31 1 4
Q15. The securing of excellent members of staff 122 2.17 0.70 1 4
Q15. The loss of excellent member 125 2.15 0.61 1 3
Q16. Evaluation of managers’ staff management 124 1.52 0.94 1 4
Q17. Training personnel 122 2.24 0.92 1 4
Q18. OJT 121 2.60 1.10 1 4
Whole 130 2.19 0.49 1.20 3.13
Operations 130 2.09 0.53 1.00 3.25
Target and Monitoring 130 2.45 0.82 1.00 4.00
Incentive 129 2.10 0.47 1.00 3.57
Organization reform 130 2.24 0.66 1.25 3.88
Table 7 Descriptive statistics: financial and business data
Unit Number of sample Average Standard deviation Minimum Maximum
Operating profit million JPY 96 138 2933 (10,978) 26,374
Recurring profit million JPY 97 446 3598 (2803) 35,041
Sales million JPY 101 5289 22,811 5.00 224,141
Labour costs million JPY 83 2013 7259 6.00 63,432
Depreciation million JPY 80 1060 5694 0.78 48,460
Add value million JPY 82 3586 16,454 (5.00) 146,933
Capital million JPY 101 7506 51,606 1.00 504,976
Fixed assets million JPY 99 23,538 158,713 2.00 1,548,916
The number of bus driver person 108 274 1226 1 12,575
Length of routes in operation Km 112 29,659 225,136 13 2,276,641
No. of routes in operation 111 63 96 1 520
Km travelled per annum Km 112 4,928,752 8,726,770 6830 46,561,501
Passengers carried 112 10,058,052 31,324,666 600 231,212,000
Dummy of metropolitan area 131 0.28 0.45 0.00 1.00
Populations (log) 131 14.75 0.83 13.44 16.44
Dummy of public sector 131 0.11 0.32 0.00 1.00
Profit rate (operating profit/sales) 94 − 0.12 0.52 − 3.09 0.97
Profit rate (recurring profit/sales) 79 0.03 0.64 − 1.13 3.09
Revised time table 127 2.61 1.34 1.00 4.00
IC card 127 1.52 0.98 1.00 4.00
Passenger bus sales million JPY 93 2448 6086 0.60 41,512
Passenger bus operating revenue million JPY 88 2334 5826 0.60 39,196
No. of passenger bus driver 109 162 362 1.00 2480
Profit rate of passenger bus 85 − 0.50 1.15 − 5.86 1.00
Public capital contribution ratio % 130 14.66 33.90 0.00 100.00
TFP(log) 71 1.01 0.86 − 2.13 2.80
Management practice and performance
In this section, we examine the relationship between bus operators’ performance and the management practice scores derived from our survey results. The analysis can be broadly divided into two parts. First, to provide an overview of the characteristics of bus operators’ management practices, we compare two types of management scores: the first is private companies vs. public companies, and the second compares companies operating in metropolitan areas and those in regional areas. Second, we investigate the relationship between management practice evaluations obtained from the survey results and various management performance indicators using a simple empirical analysis.
Comparison of data distribution
We present the kernel density estimation results of the management practice scores derived from the survey results and their distribution. First, we estimated the overall management practice scores (obtained by averaging all scores in each questionnaire) and average score for each category, as shown in Fig. 1.Fig. 1 Management practice score (Kernel density estimation)
Overall, the operators were clustered around two on the four-grade evaluation scale. As shown in Table 6, the average score was 2.19. This finding suggests that management in the bus industry is not necessarily highly qualified. Looking at the individual categories, although the average score for “operations” is 2.09. Because the distribution tail is thick when the score is higher, it is likely that many companies are engaged in higher-level practice. An interesting category is “target and monitoring”. The distributions of management scores for the “target and monitoring” and “organization reform” have two peaks which means that there are two types of firms: one with highly qualified management practices and the other with no monitoring mechanism. Regarding organizational reform, we find a similar distribution of scores to that of the target and monitoring.
We undertook the same comparison for public- and private-sector enterprises. Table 8 shows the descriptive statistics for public- and private-sector enterprises, and Fig. 2 shows the kernel density estimation results of the management practice scores for each category.Table 8 Descriptive statistics: management practice score (public vs. private)
Management practice Operations Target and monitoring Incentive
Public Private Public Private Public Private Public Private
Observation 15 115 15 115 15 115 15 114
Average 2.40 2.16 2.36 2.06 2.67 2.42 2.18 2.08
STD 0.47 0.49 0.57 0.52 0.60 0.85 0.50 0.47
Min 1.39 1.20 1.38 1.00 1.67 1.00 1.50 1.00
Max 3.11 3.13 3.25 3.25 3.50 4.00 3.22 3.57
Fig. 2 Management practice score (public vs. private)
Overall, the average for the public sector was 2.4 and that for the private sector was 2.16. Although this does not seem to be a large difference, it can be seen from the distribution that more public sector operators have high scores (i.e., engage in solid management practices). The data for the individual categories showed special characteristics more clearly. In the “target & monitoring” category, many private-sector operators do not engage in such practice at all, whereas the public-sector operators engage in such management practices at a relatively high level. Although private enterprises have high management scores, the average management score in private enterprises is lower than that in public enterprises because private enterprises have low scores. Especially, in the category of “target and monitoring” and “organizing reform,” public sector’s peak is relatively high and private sector’s peak is relatively low.
We also undertook the same comparison for metropolitan and local operators; descriptive statistics are shown in Table 9, and Fig. 3 shows the kernel density estimation of the relevant management practice scores for each category. Here, metropolitan operators are those whose head offices are located in the Tokyo area (Saitama Prefecture, Chiba Prefecture, Tokyo, and Kanagawa Prefecture), Nagoya area (Gifu Prefecture, Aichi Prefecture, and Mie Prefecture), or Osaka area (Kyoto, Osaka, Hyogo Prefecture, and Nara Prefecture), and operators whose head office is located in areas outside the metropolitan areas are deemed to be local operators.Table 9 Descriptive statistics: management practice score (metropolitan vs. local)
Management practice Operations Target and monitoring Incentive Organization reform
Metropolitan Local Metropolitan Local Metropolitan Local Metropolitan Local Metropolitan Local
Observation 37 93 37 93 37 93 36 93 37 93
Average 2.37 2.12 2.31 2.01 2.67 2.36 2.17 2.07 2.49 2.14
STD 0.47 2.12 0.52 2.01 0.79 2.36 0.42 2.07 0.69 2.14
Min 1.39 1.20 1.25 1.00 1.67 1.00 1.44 1.00 1.25 1.25
Max 3.11 3.13 3.25 3.25 4.00 4.00 3.22 3.57 3.88 3.75
Fig. 3 Management practice score (metropolitan vs. local)
Overall, the management practice scores for metropolitan operators tended to be higher than those for local operators. In the “target-setting and monitoring” category, polarization into two clear groups can be seen in terms of management practice scores among local operators, with some hardly engaging in such practices and some engaging at a high level. In the “organizational reform” category, we identified a tendency for metropolitan operators to be relatively active and for local operators to be polarized in this category.
Management practice score and firm performance
We conducted an empirical analysis to investigate the relationship between the management practice scores obtained from the questionnaire results and various management performance indicators for bus operators. Following Lee et al. [11], we selected variables suitable for the analysis of bus operators.1 y=β0+β1MPS+γkX
where y represents each variable expressing firm performance, MPS represents the relevant management practice score, and X represents controlling variables. For y, we used profit margin (operating balance/sales), bus profit margin (profit margin limited to bus operations), value-added (labor costs + recurring balance + depreciation), sales from bus operations, annual number of passengers carried/number of drivers, and annual passenger kilometers/number of drivers. Profit margins and sales were chosen as powerful indicators of a company’s financial performance. In addition to value-added, we used the annual number of passengers carried per driver and annual passenger kilometers per driver to capture output as a performance indicator. The data were obtained through a questionnaire survey. These and other control variables were included in 2018.
Some bus operators only provide bus services, while others are involved in regional transport and provide services, such as taxis and rail transport. We restricted our analysis to operators who provided financial information relating only to the bus business, and it should be noted that the number of data points was therefore reduced. Regarding the number of data points in Table 7, there are only 93 data points for sales limited to passenger bus operations, whereas there are 101 sales data points. Generally, companies involved in more than one business are large companies, even when they are local operators, and it should be noted that their data have been reduced. Conversely, although whole-company data for such companies were obtained, it is possible that the figures are greatly influenced by businesses other than busses. For this reason, we decided to include capital scale (denoted as “capital”) among the controlling variables. Furthermore, because it can be assumed that the scale of the market in the area of operation will have an impact on firm performance, we also included the population of the prefecture or city in which the operator’s head office is located (denoted as “POP”). Please note that the population of the prefecture or city was taken from “population and number of households in the basic resident register” data as of January 1, 2019, published by the Statistics Bureau of Japan. Another controlling variable was the public-sector dummy variable (denoted as “pub”; public-sector enterprise = 1, private-sector enterprise = 0). If raising the level of management practices improves firm performance, the β1 coefficient is likely to be significant.
We conducted an OLS estimation, the results are shown in Table 10.Table 10 Estimation result 1
Profit rate
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
Average MP 0.101 (0.88) 0.102 (0.87) 0.146 (1.53) 0.101 (1.15) 0.047 (0.85) 0.114 (1.24) 0.063 (0.90)
pub − 0.103 (− 0.66) − 0.174 (− 1.32) − 0.174 (− 1.31) − 0.168 (− 1.26) − 0.163 (− 1.24) − 0.172 (− 1.29)
lnPOP 0.021 (0.33) 0.034 (0.64) 0.036 (0.69) 0.041 (0.78) 0.037 (0.71) 0.042 (0.80)
Capital 0.000 (0.54) 0.000 (0.55) 0.000 (0.65) 0.000 (0.69) 0.000 (0.53)
_cons − 0.350 (-1.33) − 0.652 (− 0.70) − 0.896 (− 1.17) − 0.824 (− 1.08) − 0.793 (− 1.03) − 0.866 (− 1.13) − 0.832 (− 1.08)
Observation 94 94 91 91 91 91 91
F-value 0.78 0.42 1.16 0.91 0.75 0.96 0.77
R-Sq 0.0084 0.0138 0.0514 0.0404 0.0337 0.0426 0.0347
Passenger bus profit rate
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
Average MP 0.408 (1.70)* 0.290 (1.18) 0.370 (1.47) 0.338 (1.44) − 0.027 (− 0.18) 0.381 (1.61) 0.116 (0.60)
pub 0.220 (0.65) 0.212 (0.57) 0.210 (0.56) 0.296 (0.79) 0.249 (0.68) 0.254 (0.67)
lnPOP 0.263 (1.81)* 0.281 (1.87)* 0.282 (1.88)* 0.324 (2.15) ** 0.289 (1.95)* 0.308 (2.04)**
Capital 0.000 (-0.30) 0.000 (− 0.33) 0.000 (− 0.26) 0.000 (− 0.16) 0.000 (− 0.30)
_cons − 1.406 (− 2.56)** − 5.055 (− 2.39)** − 5.498 (− 2.52)** − 5.409 (− 2.49)** − 5.242 (− 2.38)** − 5.596 (− 2.57)** − 5.348 (− 2.43)**
Observation 85 85 79 79 79 79 79
F-value 2.89* 2.28 1.98 1.96 1.41 2.1 1.5
R-Sq 0.0337 0.0779 0.0968 0.0958 0.0709 0.1019 0.075
Add value
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
Average MP 4980.854 (1.38) 2295.227 (0.66) 886.214 (1.62) 650.048 (1.27) 232.723 (0.73) 575.360 (1.11) 631.811 (1.54)
pub 13,972.230 (3.07)
***
702.063 (0.93) 683.065 (0.89) 742.661 (0.97) 761.644 (1.00) 669.619 (0.88)
lnPOP 3852.805 (1.94)* 839.326 (2.64)** 857.040 (2.67)*** 900.180 (2.80)*** 905.944 (2.87)*** 855.688 (2.70)***
Capital 0.279 (55.44)*** 0.279 (55.04)*** 0.280 (54.81)*** 0.280 (55.08)*** 0.279 (55.14)***
_cons − 7660.876 (− 0.91) − 60,714.950 (− 2.13)** − 13,431.110 (− 2.94)*** − 13,109.740 (− 2.86)*** − 12,932.090 (− 2.80)*** − 13,653.320 (− 2.95)*** − 13,140.600 (− 2.88)***
Observation 82 82 80 80 80 80 80
F-value 1.89 5.93*** 947.62*** 934.91*** 921.36*** 930.23*** 944.22***
R-Sq 0.0231 0.1857 0.9806 0.9803 0.9801 0.9802 0.9805
Bus sales
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
Average MP 4484.389 (3.47)*** 1999.895 (1.81)* 1730.305 (2.23)** 2193.790 (3.23)*** 290.906 (0.69) 606.120 (0.83) 1362.522 (2.45)**
pub 8414.300 (6.07)*** 4079.478 (3.98)*** 3933.262 (3.95)*** 4339.011 (4.14)*** 4348.262 (4.17)*** 4016.887 (3.93)***
lnPOP 2029.254 (3.38)*** 1354.958 (3.22)*** 1249.706 (3.07)*** 1577.518 (3.75)*** 1555.600 (3.69)*** 1401.597 (3.41)***
Capital 0.066 (9.99)*** 0.066 (10.22)*** 0.067 (9.76)*** 0.067 (9.79)*** 0.066 (9.91)***
_cons − 7595.512 (− 2.58)** − 33,152.060 (− 3.91)*** − 22,667.010 (− 3.84)*** − 21,972.540 (− 3.83)*** − 22,837.110 (− 3.76)*** − 23,056.910 (− 3.80)*** − 22,635.280 (− 3.86)***
Observation 93 93 86 86 86 86 86
F-value 12.06*** 23.31*** 57.37 *** 62.31*** 53.29*** 53.5*** 58.28***
R-Sq 0.117 0.44 0.7391 0.7547 0.7246 0.7254 0.7421
No. of passenger/no. of bus driver
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
Average MP 27,408.850 (3.83)*** 14,893.790 (2.79)*** 12,873.880 (2.32)** 17,024.160 (3.43)*** 1506.199 (0.44) 6111.839 (1.14) 10,845.470 (2.53)**
pub 69,971.860 (8.82)*** 56,544.680 (6.55)*** 55,036.140 (6.60)*** 59,076.430 (6.68)*** 58,811.500 (6.71)*** 55,735.480 (6.47)***
lnPOP 9461.022 (2.85)*** 9953.340 (2.84)*** 9590.360 (2.84)*** 11,055.070 (3.08)*** 10,583.560 (2.94)*** 10,352.190 (2.99)***
Capital 0.099 (1.76)* 0.093 (1.72)* 0.103 (1.78)* 0.106 (1.85)* 0.092 (1.64)
_cons − 35,080.030 (− 2.18)** − 156,583.300 (− 3.22)*** − 158,107.100 (− 3.10)*** − 160,398.500 (− 3.26)*** − 149,977.100 (− 2.85)*** − 152,025.500 (− 2.91)*** − 160,128.700 (− 3.15)***
Observation 100 100 85 85 85 85 85
F-value 14.69*** 39.91*** 24.53*** 27.86*** 21.83*** 22.4*** 25.06***
R-Sq 0.1304 0.555 0.5509 0.5821 0.5219 0.5283 0.5561
(No. of passenger*km)/no. of bus driver(log)
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
Average MP 2.267 (4.40)*** 2.006 (3.82)*** 1.988 (3.97)*** 2.052 (4.53)*** 0.775 (2.46)** 0.835 (1.64) 1.753 (4.63)***
pub 1.587 (2.06)** 1.365 (1.75)* 1.281 (1.68)* 1.622 (1.99)** 1.726 (2.08)** 1.213 (1.60)
lnPOP 0.124 (0.38) 0.280 (0.89) 0.278 (0.90) 0.406 (1.23) 0.388 (1.14) 0.336 (1.10)
Capital 0.000 (0.58) 0.000 (0.48) 0.000 (0.73) 0.000 (0.74) 0.000 (0.36)
_cons 9.791 (8.40)*** 8.312 (1.76)* 6.035 (1.31) 6.099 (1.36) 6.601 (1.36) 7.045 (1.42) 5.636 (1.26)
Observation 98 98 85 85 85 85 85
F-value 19.36*** 8.15*** 7.06*** 8.4*** 4.32*** 3.37** 8.67***
R-Sq 0.1678 0.2064 0.2609 0.2958 0.1778 0.1441 0.3025
The estimation result shows there are positive coefficients on the management score for profit margin and value-added, but it is not statistically significant. In contrast, significant positive coefficients on the management score are obtained for bus sales, the number of passengers carried per driver, and passenger kilometers per driver. This is likely to be linked to the fact that bus fares are regulated as “public utility charges,” and to the existence of a licensing system for the setting of fares. Previous research focusing on manufacturing [2] reports that management practices have a beneficial impact on company finances. This could be partly attributable to a positive impact on profit margin, sales, etc., as a higher evaluation of product quality is reflected in price. However, it is likely that high product quality does not automatically lead to high fares, because charges are regulated for public utility operations, such as bus services. Against this background, the results suggest that strong management practices are linked to productivity in terms of output.
Furthermore, although a significant coefficient is obtained for the management practice score relating to “operations,” no such result was obtained for the management practice score relating to “incentives.” This suggests that organizational initiatives, such as operational control and timetable reform, have a larger beneficial impact on performance than the evaluation of driver performance.
The results of our analysis show that management practices in a regulated industry impact output performance more than profits and value-added and that operational control across the organization as a whole is more important than the efforts of individual employees.
Management practice score and productivity
Following Bloom and Van Reenen [2], we estimate the production function and investigate the impact of management practice scores on productivity. For the production function framework, we used the management practice score and controlling variables, as investigated in the preceding section, to conduct the OLS estimation.2 lnY=β0+α1lnL+α2lnK+β1MPS+γkX
Here, L represents the number of drivers, K is fixed capital, MPS is the management practice score, and X is the controlling variable. For Y, we used value-added per driver and passenger kilometers per driver. The results of the OLS estimation are presented in Table 11.Table 11 Estimation result 2
lnY/L
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
lnK/L 0.455 (7.28)*** 0.416 (6.56)*** 0.420 (6.13)*** 0.419 (6.17)*** 0.397 (5.86)*** 0.412 (5.87)*** 0.407 (6.03)***
MP − 0.268 (-1.31) − 0.382 (− 1.84)* − 0.383 (− 1.83)* − 0.383 (− 2.05)** − 0.240 (− 2.04)** − 0.135 (− 0.69) − 0.315 (− 2.04)**
pub 0.493 (1.79)* 0.504 (1.76)* 0.524 (1.84)* 0.500 (1.76)* 0.457 (1.57) 0.536 (1.87)*
lnPOP 0.165 (1.37) 0.169 (1.36) 0.170 (1.38) 0.162 (1.33) 0.128 (1.02) 0.161 (1.32)
Capital 0.000 (− 0.15) 0.000 (− 0.10) 0.000 (− 0.17) 0.000 (− 0.17) 0.000 (0.01)
Constant 1.591 (3.36)*** − 0.586 (− 0.34) − 0.649 (− 0.37) − 0.699 (− 0.40) − 0.747 (− 0.42) − 0.602 (− 0.33) − 0.638 (− 0.36)
Observation 71 71 71 71 71 71 71
F 26.48*** 15.33*** 12.09*** 12.39*** 12.39*** *** ***
Rsq 0.4378 0.4817 0.4819 0.4881 0.488 0.459 0.488
(No. of passenger*km)/no. of bus driver(log)
MPS Whole Whole Whole Operations Target and monitoring Incentive Organization reform
lnK/L 0.346 (2.33)** 0.292 (1.93)* 0.302 (1.90)* 0.324 (2.07)** 0.341 (2.05)** 0.329 (1.91)* 0.333 (2.18)**
MP 2.159 (4.45)*** 1.956 (3.97)*** 1.990 (4.04)*** 1.981 (4.45)*** 0.878 (2.84)*** 0.849 (1.69)* 1.790 (4.88)***
pub 1.085 (1.48) 1.124 (1.47) 1.057 (1.41) 1.320 (1.66) 1.462 (1.78)* 0.940 (1.27)
lnPOP 0.297 (0.98) 0.308 (0.99) 0.315 (1.04) 0.425 (1.32) 0.412 (1.23) 0.364 (1.23)
Capital 0.000 (− 0.04) 0.000 (− 0.19) 0.000 (0.07) 0.000 (0.10) 0.000 (− 0.35)
Constant 9.333 (8.35)*** 5.377 (1.22) 5.069 (1.12) 5.097 (1.14) 5.441 (1.14) 6.061 (1.24) 4.520 (1.03)
Observation 84 84 83 83 83 83 83
F 13.98*** 8*** 6.67*** 7.48*** 4.71*** *** ***
Rsq 0.2567 0.2882 0.3023 0.327 0.2342 0.1844 0.3539
Similar to the analysis of performance, in the analysis of manufacturing focusing on value-added, for example, results that are in line with theory are obtained. However, in our study of bus operations, it is often observed that the management practice score has a negative significant coefficient or no significant coefficient. In contrast, regarding passenger kilometers per driver (an indicator of output), the management practice score has a significant positive coefficient. Furthermore, we did not obtain a significant result for the management practice score relating to “incentives,” and the interpretation shown in the performance analysis could also be applied here.
Conclusion
Finally, we present the analysis results obtained in this study and provide its policy implications. Using our survey on management practices, we applied the management practice scores created by Bloom and Van Reenen [2] to bus operators. First, in an overview of the distribution of such scores, it was found that bus operators are not engaged in high-level management practices. In several categories, companies were polarized into two distinct separate groups: those who implemented strong management practices and those that engaged in hardly any management practices.
A comparison of the distribution among public- and private-sector enterprises reveals that management practices are at a relatively high level in public sector enterprises. Some private sector enterprises also implement high-level management practices, but quite a few implement hardly any management practices, throwing the spotlight on the problems of private sector operators. We compare metropolitan and local operators in a similar manner and find that metropolitan operators tend to have relatively better management practices than local operators. We consider the consequences that public enterprises in metropolitan areas survived as a result of market competition. Meanwhile, among local operators, it is not guaranteed that private sector enterprises will engage in strong management practices. These results imply that a competitive environment matters for good management.
We conducted a simple empirical analysis to investigate the impact of these management practice scores on firm performance and productivity. Unlike in the case of manufacturing firms’ analysis, we cannot obtain a stable coefficient when we use financial output as the explained variable, such as the profit rate add value. However, we can obtain a relatively stable, positive, and significant coefficient when we use the explained variable of physical output, such as bus sales and passenger times kilometers divided by bus drivers.
This is likely to relate to bus fares being regulated as public utility charges and adopting a permit system for fare setting. Even if providers set a high price, it was expected that high-quality products would be sold in the manufacturing sector. However, bus enterprises cannot charge a high fare for customers, even if they provide high-quality services, because fares are regulated by authorities. As a result, we cannot observe a correlation between management practice scores and financial output, such as added value and profit rate. In contrast, there is a positive correlation with quantitative output indicators, suggesting a link between strong management practices and improvement in output performance. These results suggest that a high-quality service does not always lead to financial profit in sticky price settings as a public utility. In addition, as Bloom et al. [4, 5] show, our study also shows that the industry-specific productivity measure is positively related to management scores.
Looking at each category separately, the coefficients on “operation” score are statistically significant, but those of “incentive” scores are not significant. These results suggest that organizational initiatives such as operational control and timetable reform have a more beneficial impact on performance than the evaluation of driver performance and that operational control across the entire organization is more important than that related to individual employees.
Our results showed that the relationship between management practices and performance of bus operators differs slightly from that in manufacturing. Our research suggests that privatization alone does not improve performance, but that organizational management practice is an important element.
Although we have analyzed the relation to financial performance indicators such as value-added and profit margin, and to output performance indicators such as passenger kilometers, there has been no discussion relating to the quality of public service. This might cause bus enterprises regulated by the authority to be evaluated by a quantitative output instead of a qualitative output.
Our study suggests that privatization of public enterprises may not always improve firm performance because management scores related to firm performance in private bus enterprises, are not high. Our study shows that firm performance, represented by financial data, does not provide sufficient information for management quality in the bus industry. Owing to the COVID-19 pandemic, the bus industry faces a further decrease in the number of passengers. Our study implies that we need better performance measures to evaluate service quality and management quality for government’s support for the revitalization of the bus industry.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (XLSX 74 KB)
Acknowledgements
The authors are grateful for helpful comments and suggestions by Makoto Yano (RIETI), Masayuki Morikawa (RIETI), Kyoji Fukao (Hitotsubashi University) and Discussion Paper seminar participants at RIETI. We also thank helpful comments and suggestions by Shigemichi Kanasaka (Konan University), Daisuke Fujii (Tokyo College of Transport Study), and participants at the Spring Conference of the Japan Economic Association in 2021 and JEPA 2022. Kawasaki acknowledges the financial support from the Japan Society for the Promotion of Science’s Grant-in-Aid for Scientific Research (No. 17K03715) and Chuo University Grant for Special Research. We would like to thank Editage (www.editage.com) for English language editing
1 Inui et al. [9] conducted a survey into how improvement in the quality of management of not-for-profit enterprises such as those in the public sector is linked to improvement in the quality of service.
This paper is the revised version of Kawasaki et al. [10] (Institute of Economic Research Chuo University Discussion Paper 375). Originally, this study is conducted as a part of the “Research on Productivity-improving Capital Investments” project undertaken at the Research Institute of Economy, Trade, and Industry (RIETI).
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References
1. Bender S Bloom N Card D Van Reenen J Wolter S Management practices, workforce selection, and productivity Journal of Labor Economics 2018 36 S1 S371 S409 10.1086/694107
2. Bloom N Van Reenen J Measuring and explaining management practices across firms and countries Quarterly Journal of Economics 2007 122 1351 1408 10.1162/qjec.2007.122.4.1351
3. Bloom N Van Reenen J Why do management practices differ across firms and countries? Journal of Economic Perspectives 2010 24 203 224 10.1257/jep.24.1.203
4. Bloom N Propper C Seiler S Van Reenen J The impact of competition on management quality: Evidence from public hospitals Review of Economic Studies 2015 82 457 489 10.1093/restud/rdu045
5. Bloom N Lemos R Sadun R Van Reenen J Does management matter in schools? Economic Journal 2015 125 647 674 10.1111/ecoj.12267
6. Bloom N Sadun R Van Reenen J Americans do IT better: US multinationals and the productivity miracle American Economic Review 2012 102 1 167 201 10.1257/aer.102.1.167
7. Brown JD Earle JS Telegdy Á The productivity effects on privatization: Longitudinal estimates from Hungary, Romania, Russia, and Ukraine Journal Political Economy 2006 114 1 61 99 10.1086/499547
8. Chen, Y., Igami, M., Sawada, M., & Xiao, M. (2018). Privatization and Productivity in China. Available at SSRN: https://ssrn.com/abstract=2695933 or 10.2139/ssrn.2695933
9. Inui, T., Ito, Y., Miyagawa, T., & Sato, K. (2017). Survey on Management Score and Quality Adjustment in Medical and Nursing Services. RIETI Policy Discussion Paper Series 17-P-022. (in Japanese)
10. Kawasaki, K., Inui, T., Miyagawa, T. (2022). The effect of management practices on the performance of bus enterprises. Institute of Economic Research Chuo University Discussion Paper, 375.
11. Lee K Miyagawa T Kim Y Edamura K Comparing the management practices and productive efficiency of Korean and Japanese firms: An interview survey approach Seoul Journal of Economics 2016 29 1 41
12. Mizutani F Urakami T A private-public comparison of bus service operators International Journal of Transport Economics 2003 30 2 167 185
13. Morikawa M Service oriented nation (Service Rikkoku Ron) 2016 NIKKEI Press
14. Morikawa M Productivity: Misperception and Truth 2018 NIKKEI Press
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==== Front
Oper. Res. Forum
Operations Research Forum
2662-2556
Springer International Publishing Cham
176
10.1007/s43069-022-00176-2
Methodology
Discrete Stochastic Optimization for Public Health Interventions with Constraints
Li Zewei [email protected]
1
Spall James C. [email protected]
2
1 grid.16753.36 0000 0001 2299 3507 Northwestern University, Evanston, USA
2 grid.474430.0 0000 0004 0630 1170 The Johns Hopkins University Applied Physics Laboratory, Laurel, USA
9 12 2022
2022
3 4 6823 9 2022
3 11 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Many public health threats exist, motivating the need to find optimal intervention strategies. Given the stochastic nature of the threats (e.g., the spread of pandemic influenza, the occurrence of drug overdoses, and the prevalence of alcohol-related threats), deterministic optimization approaches may be inappropriate. In this paper, we implement a stochastic optimization method to address aspects of the 2009 H1N1 and the COVID-19 pandemics, with the spread of disease modeled by the open-source Monte Carlo simulations, FluTE, and Covasim, respectively. Without testing every possible option, the objective of the optimization is to determine the best combination of intervention strategies so as to result in minimal economic loss to society. To reach our objective, this application-oriented paper uses the discrete simultaneous perturbation stochastic approximation method (DSPSA), a recursive simulation-based optimization algorithm, to update the input parameters in the disease simulation software so that the output iteratively approaches minimal economic loss. Assuming that the simulation models for the spread of disease (FluTE for H1N1 and Covasim for COVID-19 in our case) are accurate representations for the population being studied, the simulation-based strategy we present provides decision makers a powerful tool to mitigate potential human and economic losses from any epidemic. The basic approach is also applicable in other public health problems, such as opioid abuse and drunk driving.
Keywords
Discrete optimization
Gradient-free
Simultaneous perturbation (SPSA)
Stochastic optimization
H1N1
COVID-19
issue-copyright-statement© Springer Nature Switzerland AG 2022
==== Body
pmcIntroduction
Numerous public health problems (e.g., global pandemic influenza, prescription drug overdoses, and obesity) continuously threaten people’s lives, and finding optimal intervention strategies for many of these threats can be formulated as an optimization problem. As an example, by limiting the amount of opioids prescribed, regulating drug prices, and lecturing about the dangers of overdosing, professionals aim to find values that minimize costs related to opioid overdoses. Moreover, public safety entities can optimize speed limits on highways, locations of traffic lights, and traffic light cycles to find settings that minimize motor vehicle accidents. Solving public health optimization problems presents several challenges, including devising objective functions to compare the effectiveness of different strategies and utilizing suitable algorithms to optimize results under noisy measurement values since the inherent randomness involved. The main goal of this paper is to demonstrate some applications of a discrete stochastic optimization algorithm in determining optimal intervention strategies to yield minimal economic losses in the face of public health threats. Our focus below is on two infectious diseases: influenza and COVID-19.
Researchers in the field of epidemiology have attempted to solve optimization problems related to pandemics in several ways. Prosser et al. [1] evaluated the cost-effectiveness of the H1N1 vaccination across the USA in terms of the incremental cost-effectiveness ratio (ICER) and reported that vaccinating only children and working-age adults is more cost-effective compared to other vaccination strategies. Khazeni et al. [2] measured the cost-effectiveness of H1N1 vaccinations for New York City by infections, death averted, and qualified adjusted life-years, revealing that early vaccination is more cost effective relative to late vaccination. Piguillem and Shi [3] understood the optimal response to COVID-19 as a welfare maximization problem of a planner, and observed that extreme measures like mandatory quarantines seemed optimal for various curvatures of the welfare function. They also found that testing is a very close substitute of quarantine and can substantially reduce the need for indiscriminate quarantines. Hoertel et al. [4] evaluated the potential impact of quarantine duration, quarantine lifting type, post-quarantine screening, and use of a hypothetical effective treatment against COVID-19 with a microsimulation model. They projected that a two-step lifting of a quarantine according to age substantially lowered cumulative mortality and incidence. Charpentier et al. [5] conducted a tractable quantitative analysis of the impact of lockdowns and detection interventions using an extended SIR model (susceptible, infectious, and recovered compartment model) for COVID-19, identifying the optimal lockdown policy to be an intervention structured in four successive phases.
In the studies reviewed above, researchers mainly conducted sensitive analyses over a small range of candidate intervention strategies chosen on the basis of their prior knowledge and then selected the optimal one. Some researchers implemented a numerical algorithm to find the optimal set of intervention parameters, but that was based on a model with transmission dynamic of the pandemic governed by some known deterministic functions [6]. As discrete event simulation (DES) models can test assumptions at low cost and observe potential outcomes of decisions prior to implementation [7], they can be useful tools for our goal to develop improvement strategies. Among them, stochastic agent-based simulations can incorporate individual characteristics and person-to-person contact networks. Deterministic optimization algorithm will no longer be proper for such models as we only observe noisy measurement values and the dynamics can be complex and unknown. Paleshi et al. [8] implemented an agent-based model to simulate the spread of disease and optimized with a ranking and selection procedure called NSGS [9] to find a strategy on school closure and home confinement that minimized the effects of pandemic influenza. However, with the development of computational epidemiology, more factors can be taken into consideration in the construction of agent-based models. Simulating every feasible solution in ranking and selection algorithms becomes too computationally costly for high dimensional problems. Therefore, we employ a stochastic model and stochastic optimization method to estimate the optimal strategy among all possible options without testing every single one.
Our goal to determine the optimal strategy motivates the question of how to measure the performance of an intervention strategy. We use a dynamic model built by [10] in our application concerning 2009 H1N1 and an agent-based model developed by [11] in our application concerning COVID-19. These two models simulate the spread of those two infectious diseases in a given population using transmission parameters estimated from historical data. The performance of each input intervention strategy is evaluated by its respective simulation outcome. The models are Monte Carlo simulations to reflect the uncertainties surrounding the transmission of infectious disease. Therefore, optimization of these kinds of problems can only be performed with noisy measurements of the actual performance. In addition, because the decision variables are discretely valued, the discrete simultaneous perturbation stochastic approximation method (DSPSA) is suitable for this problem. An early study conducted by [12] obtained the optimal intervention strategy by using DSPSA in simplified settings. In contrast, one modification of this report is the manner in which the intervention parameters are transformed in order to achieve better convergence in a relative small number of iterations. We also use an improved approach for computing the influenza-related cost and update the values into dollars of current purchasing power aligned with the Consumer Price Index [13]. As noted in [14], non-constrained cases are rare in stochastic optimization, so we address the constraints with appropriate projection functions. We will discuss the projection function that is used to address the parameter constraints in Section 2 of this paper.
Our paper is organized as follows. First, we describe the DSPSA algorithm and discuss how to choose the gain sequence in a discrete high noise setting. Next, we introduce an application of the algorithm to the 2009 H1N1 pandemic, including the choice of simulator, the construction of the loss function, the transformation of input parameters, and some numerical results. Then, we show a second application of the algorithm to the COVID-19 pandemic in the same manner. Finally, we discuss the potential real-world interpretation of the final solution and offer ideas about how similar approaches can be applied in analyzing the optimal intervention strategy for other public health problems. While this paper is not oriented toward breaking new methodological ground, it does demonstrate some of the nontrivial considerations involved in the application of a powerful method in stochastic optimization in an important real-world problem.
Constrained DSPSA Algorithm
The DSPSA algorithm was introduced to solve discrete stochastic optimization problems in [15]. Suppose θ∈Zp, where Z={⋯,-1,0,1,⋯}. Our goal is to find a parameter θ that minimizes the loss function L(θ), given some constrained domain Θ; i.e.,1 minθ∈ΘL(θ)
Adding a restriction is equivalent to adding a projection function that maps the original θ to a subset Θ⊂Zp. When the constraint is a well-defined range, we can easily define the projection Ψ as a piecewise linear function. For example, when each component of θ=(t1,t2,…,tp)T has a lower bound and an upper bound, li≤ti≤ui,i=1,…,p, the projection can be represented as2 Ψ(ti)=liti<litili≤ti<uiui-τti≥ui
where τ>0 is a very small number, and is used to ensure the correctness of the DSPSA algorithm. Suppose y(θ) is a noisy measurement of L(θ); i.e., y(θ)=L(θ)+ϵ(θ), ϵ(θ) is the noise. The DSPSA method uses y(θ) to find the minimum of L(θ). Wang [14] gives a complete description of the theory and extends DSPSA to the case of a bounded domain. The algorithm is described below: Step 1: Pick an initial guess θ^0∈Zp, and set k=0.
Step 2: Generate the random perturbation vector Δk=(Δk1,Δk2,⋯,Δkp)T, where the Δki are independent Bernoulli random variables taking values ±1, each with probability 1/2, in this project. (Certain non-Bernoulli discrete distributions for Δk may also be used as long as θ^k± in step 4 takes on valid integer values.)
Step 3: Let π(θ^k)=⌊Ψ(Θ^k)⌋+1p/2, where 1p is a p-dimensional vector with all components being unity, and ⌊Ψ(θ^k)⌋ denotes the floor of all components (round down to nearest integer). Note that π(θ^k) is the middle point of a hypercube that contains θ^k with all corner points lying in Zp
Step 4: Evaluate y at the points θ^k±=π(θ^k)±Δk/2, and form the estimate of the sub-gradient g^k(θ^k) such that 3 g^k(θ^k)=(y(θ^k+)-y(θ^k-))Δk-1,
where Δk-1=(Δk1-1,Δk2-1,⋯,Δkp-1)T and [·] is the round operator applied to all components of the argument vector.
Step 5: Update θ^k+1 according to 4 θ^k+1=θ^k-akg^k(θ^k)
where ak=a/(1+A+k)α is the gain sequence, a>0,A≥0, and 0.5<α≤1. Either terminate the algorithm or set k=k+1 and return to step 2.
Step 6: After the terminal iteration (say, k=M), set the approximated optimal solution to be [Ψ(θ^M)].
Suppose that θ∗ is the unique minimal point of L(θ). By [15], under some common conditions of stochastic approximation algorithms, strong convergence of θ^k to θ∗ holds for the algorithm described above. Therefore, given a credible Monte Carlo simulation, we can obtain the optimal intervention strategy that minimizes the societal cost from the algorithm even though we only have noisy measurement values from a simulation.
Application to 2009 H1N1
Choice of Epidemic Model
In this application, we use a real-time agent-based influenza model (FluTE) developed by [10] to simulate the spread of influenza across major metropolitan areas. An agent-based model focuses on individual behavior. Individual agents with different demographic characteristics are programmed to behave and interact with other individuals in different ways, which makes the model more realistic than models based on aggregated responses.
FluTE is freely available at https://www.cs.unm.edu/~dlchao/flute/. It provides high flexibility over a variety of factors, including pre-existing immunity, vaccine efficacy, response delay, vaccination fraction, and antiviral policy, among other factors. The relationship of these factors to one another is of such complexity that real-time simulation models offer a better approach to investigate the population-level effects of mitigation strategies in comparison to analytic models.
In order to obtain the noisy measurement y, we first run FluTE with the perturbations of current estimate θ^k, which produces a summary in text format. The summary contains demographic features of the simulated population, a record of the chosen intervention strategies, and the outcome statistics, including the number of vaccines and antiviral agents used and the total number of symptomatic individuals corresponding to different age and risk groups. We then calculate monetary loss using these outcomes.
Choice of Optimization Parameters and Transformation
We choose the optimization parameters to be vaccination fraction (F), vaccination priorities (a row vector, P), antiviral policy (A), and school closure weeks (S). As DSPSA only works with integer vectors, we discretize and map the decision parameters θ=(F,P,A,S)T into integer vectors. Vaccination fraction (F) is a scalar parameter taking real values between 0 and 1 and corresponding to the fraction of people to be vaccinated among each population group that is assigned vaccines. For economic efficiency, we test for values of this fraction less than 1 as we hope to achieve herd immunity by vaccinating only a fraction of population. We discretize the interval [0,1] into 0, 0.1, 0.2, … , 1.0, divide the values by 0.1, and convert them into integers 0, 1, 2, … , 10. This parameter will be mapped back to the feasible domain of [0,1] when we run FluTE. Vaccine priorities (P) are a row vector of five integers, representing the vaccine priority for five categories of individuals. Though FluTE enables differential vaccine priorities’ setup for at most thirteen groups of individuals, some groups are included as part of other groups; for example, the pregnant women group is a subset of the young adults group (ages 19–29) and the older adults group (ages 30–64). Such overlap violates the basic assumption for the convergence of DSPSA, which requires L(θ) to have a unique minimal point. Also for the goal of understanding which age group affects the efficiency of the intervention strategy the most, we only focus on the five non-overlapping categories that are grouped solely based on age, setting no specific priority for the other eight categories, which corresponds to setting their priorities as 0 by the software. To facilitate convergence, we have 3 indicate the highest priority, 2 be the next-highest priority, 1 indicates the third-highest priority, and 0 represent no vaccination for that group. For antiviral policy (A) and school closure weeks (S), we use the same rule as that of [15], where A∈{0,1,2,3} (0: “none,” 1: “treatment only,” 2: “HHTAP100,” 3:“HHTAP,” where HHTAP means that household members all get prescribed drugs if one member is ascertained and HHTAP100 to be a special option for LA county: drugs can go to the first 100 households that have a member ascertained), S∈{0,1,⋯} represents the number of weeks for school closure.
Loss Function
Although vaccination, antiviral medicines, and school closure are all effective for influenza prevention and mitigation, we must also consider the cost they incur. This guides us in the construction of loss function, which should contain the investment on prevention and treatment and health benefit loss incurred from infection as well as the possible hidden loss (e.g., cost from side effects of vaccines). We formulate the loss function in the following general format:L(θ)=E[Medication Cost(θ)+Vaccination Cost(θ)+Antiviral Cost(θ)+School Closure Cost(θ)+Death Cost(θ)]
Note that at a fixed value of θ, the argument inside the [·] above is random due to the inherent unpredictability in cost response. The expectation operator forms the average over these random costs at the specified value of θ. Medication consists of two parts: non-hospitalized and hospitalized medications for influenza and its complications. Non-hospitalized medication cost is defined to be the summation of the cost of over-the counter (OTC) medications, physician visit cost for uncomplicated influenza (cost for prescription drugs included), physical visit cost for otitis media, and physician visit cost for non-hospitalized pneumonia, where otitis and pneumonia are complications of influenza. We assume both that all symptomatic individuals will use OTC medicine and that the age distribution in our synthetic city is proportional to the 2000 US census [16], on which FluTE is based and which differs no more than 2.5% from the population makeup in the 2010 census [17] for our age groups of interest. The probabilities of the above four types of non-hospitalization medication and their corresponding costs of each age group are available in Tables S1 and Table S2 of [1]. These tables also provide different percentages of infection and costs for high-risk and low-risk people. We follow their guidelines accordingly, but some of their age group categories are different from that of the FluTE. Therefore, we transform the data provided in [1], with age categories adjusted according to the age distribution provided by [16].
We calculate the hospitalized medication cost as the expectation of the total expense for all infected people who required hospital or ICU care. Chao et al. [18] suggest the division of each age group of symptomatic people into two risk-based subgroups: high risk and low risk, where symptomatic high-risk individuals have a higher rate of being hospitalized. We employ the hospitalization ratio shown in Web Table 7 of [18] and follow [2]’s estimate that hospitalized individuals required 5 days of hospital care and that 10% of hospitalized patients required 10 days of ICU care. According to Table 1 in [2], the average costs of hospitalization and ICU are $2430 and $4960 per day per person, respectively, when adjusted to 2019 dollars by multiplying the dollar amount by the ratio of 2019 CPI for medical care and that of the year when the referenced amount is based [13].
Vaccination cost includes the cost of vaccines and the cost of vaccination-related adverse events. The cost of vaccines is estimated as $40 (in 2019 dollars) per dose [12]. On the other hand, vaccines can also incur medication costs from vaccination-related adverse events, including systematic reactions, injection site reactions, anaphylaxis, and Guillain-Barr syndrome [1]. The probability and cost of each event are estimated in Tables S1 and Table S2 of [1]. The adjustment procedure is similar to what we did to the non-hospitalized medication cost.
The total cost of antiviral agents is equal to the antiviral cost per dose times the number of doses used. The antiviral cost per dose includes the production cost and dispensing cost, which is approximately $74 (in 2019 dollars) per course [19]. The simulator outputs the total number of antiviral agents used into the summary file. Multiplying this number by 74 gives the antiviral treatment cost.
School closure cost is defined to include the cost of making up classes and the cost of the parents’ lost wages to take care of their children. We employ the cost for school closure per day per students given by [19], which is $23 (in 2019 dollars), as the cost for making up classes. For the cost incurred on parents’ lost wages, Halder et al. [19] estimate the average wage of one person to be $980 (in 2019 dollars) weekly and Araz et al. [20] estimate the number of days of work missed to be 2.5 for couples and 5 for single parents. Therefore, school closure cost per student per day is calculated using the following formula:SchoolClosureCost=CostofMakeUpClasses+DailyWageofParent×Days Work Missed×15
The final school closure cost per student per day is calculated to be $123 (after adjusting to 2019 dollars). We then multiply this number by the number of students in each community and by 5 to get the weekly school closing cost per community. Chao et al. [10] specify the number of students in each community in FluTE. The number of communities can be retrieved from the simulation summary file. The resulting school closing cost per week per community is $221,804, in 2019 dollars after we adjust the dollar amount by the ratio of 2019 General CPI to that of the year when the referenced amount is based [13]; therefore, we expect the optimal school closing days to be very close or equal to 0 weeks (0 days).
We define the mortality loss to be the expected death cost, which has the following formula:Mortality Loss=Number of Symptomatic Individuals×Fatality Ratio of Symptomatic Individual×Death Cost
The simulator outputs the total number of symptomatic individuals by age and the number of symptomatic high-risk individuals by age into the summary file; both are vectors. By subtracting the latter from the former, we can get the number of symptomatic non-high-risk individuals by age. Chao et al. [18] give the fatality ratio by age and risk group in Web Table 7. This table also shows that high-risk individuals have a higher fatality ratio than non-risk individuals.
Molinari et al. [21] give the mortality loss in terms of both the value of a statistical life (VSL) and the present value of future earnings. The VSL estimates the number of dollars people are willing to pay for a certain number of reductions in mortality risks, whereas the present value of future earnings reflects how much output society loses in dollar terms when death occurs. In our context, the present value of future earnings better represents the definition of death costs as it reflects the economic loss to society. Therefore, we employ the data provided in Table 2 of [21], which are the present values of future earnings in 2003 dollars, and we adjust it to 2019 dollar values using historical CPI provided by [13].
Numerical Results
In this section, we present the numerical results of the performance of DSPSA algorithm. The general setup is as follows. Our synthetic population consists of 99,617 people from 20 contiguous tracts of central Los Angeles County. To facilitate the possible duplication of our experiment, we list the FIPS codes for the relevant tracts (FIPS codes specify the tract within Los Angeles County chosen for the simulation) in the Appendix. For vaccine availability, Chao et al. [18] give a detailed US pandemic H1N1 vaccine supply in its Web Table 3. We follow their assumption that Los Angeles County receives 3.195% of the total supply for the USA and that vaccine allocations after November 27, 2009, should be ignored. In addition, we assume that the vaccine supply for our synthetic city is proportional to the Los Angeles supply by population. We also set the initial inventory for all of the nine vaccines to be 0. Chao et al. [18] argue that all vaccines will be available in Los Angeles County 9 days after the US supply date. Thus, we construct a detailed delayed daily vaccine supply table for our synthetic city, assuming that the simulation starts on September 1, 2009, and ends 175 days (25 weeks) later.
The initial value for the optimization process is that no intervention policy is needed. This value is expressed as θ^0=(2,0,0,0,0,0,0,0)T, which is equivalent to (0.5,0,0,0,0,0,none,0)T in terms of FluTE input. Following principles in section 7.5 of [22], section 3.3 of [14] provides the guidelines for coefficient selection in the gain sequence ak=a/(1+A+k)α. A is recommended as 10% of the total number of iteration; α is recommended to take a value approximately as small as formally allowed, and the value of a can be found numerically by making the multiplication of a and the average magnitude of g^0(θ^0) equal to the desired magnitude of change of θ^k in early iterations. We set our number of iterations to be 10,000 and, following the guidelines above, we set A=1000 and α=0.501. For coefficient a, we find an initial estimate a=1.5.
Before running the algorithm for a large number of iterations, we test the common random numbers (CRN) variance reduction technique [22] for a small number of iterations to determine whether it can improve the performance. Plots of trials reveal no significant improvement when using the CRNs. The lack of effectiveness aligns with separate numerical experiments showing that no statistically significant positive correlation exists between y(θ^k+) and y(θ^k-) when using the same random number seed, a result that renders the CRNs ineffective. A lack of synchronization in the two outputs y(θ^k+), y(θ^k-) from FluTE may be a possible reason for the lack of correlation. To bring this to light, after some number of iterations, θ^k+ may indicate that only one age group is prioritized in receiving vaccines, while θ^k- indicates that two groups are prioritized. Then by the design of the model, we need different numbers of random variables in their simulations and fixing the same seed can only ensure partial alignment. Besides, we do not have the contribution of the perturbation vector Δk converging to zero in DSPSA, which is one of the conditions that guarantee that CRNs aid in continuous variable versions of the SPSA algorithm. As a result of little synchronization and the perturbation size not converging to zero, we do not incorporate the CRN technique into DSPSA in this application.
We first check the reasonableness of applying the DSPSA algorithm by examining the trends in total loss over the iterations. Figure 1 illustrates the tendency of total loss over 10000 iteration steps averaged over 10 Monte Carlo trials. As there is an approximately 60% decrease in total loss relative to a strategy of no intervention, the DSPSA algorithm is demonstrated to be suitable for seeking an optimal resource allocation in the epidemiological problem of interest here.
We then check the sensitivity of our simulation. In each trial, the solution greatly reduced the total monetary cost from the initial guess. However, as the algorithm is based on noisy measurement of L(θ), the noise level largely determines the reliability of the result. Figure 2 shows the fluctuation of a single trial, from which we can see that precise interpretation of the result is a problem with a high-noise setting. If one strategy has a loss value L only slightly below that of another strategy, such superiority might not be detected by the algorithm in limited iterations. As a result, we may only obtain a set of good choice strategies, but it is difficult to discern the best strategy.Fig. 1 Change of cost averaged over 10 runs versus number of iterations
Fig. 2 Change of cost in one run versus number of iterations
From the trials, we find that the optimal vaccination strategy is to vaccinate solely the school-age children and to vaccinate all of them. This result agrees with the conclusion of [23], where vaccinating school-age children is the most effective way to reduce the overall influenza attack rate as well as the overall number of deaths. The result is derived as follows, given the condition that pre-school, young adults, older adults, and the elderly will receive no vaccine and that only school age children will receive vaccines, then we should target to vaccinate 100% of them. Our purpose of setting a vaccination fraction is to vaccinate only a proportion of the population to achieve herd immunity. Therefore, we want to verify whether this proportion number follows the basic herd immunity threshold formula. From [18], we know that the basic reproductive number R0 of H1N1 is 1.3, then the herd immunity threshold for total population can be calculated as:1-1R0=1-11.3=23.1%
This number means that 23.1% of the total population should be vaccinated to achieve herd immunity. Comparing to the optimal value above, the proportion of population that actually gets vaccinated in the simulation of Fig. 2 is:number of school age childrentotal number of population=21,97699,617=22.1%
The simulation optimization result is close to the analytical solution. We see that this is the particular case when the school-age population is the dominating factor of H1N1 influenza transmission in a small population setup, and the optimal proportion of population to vaccinate is that entire age group. This agrees with the argument in [24] that pushing high vaccination coverage on school-age children is essential to building herd immunity for H1N1 influenza. Among four possible choices of antiviral policy, the optimal solution should be HHTAP. This result is consistent with the result in [12], where they also assume an unlimited antiviral agent supply. For school closure days, our initial guess of 0 weeks (0 days) is the optimal solution as closing school cost is significant compared to other parameters.
To determine the robustness of our solution, we carry out 500 independent Monte Carlo simulation trials to get the noisy loss function values at the terminal iterate. Then, we estimate the mean and the variance of the terminal loss function value with the sample mean and sample variance, and build an estimated 95% confidence interval for the mean loss function value from it, which is [3.75×106,3.87×106]. Across the 500 trials, the minimum noisy loss value is about 2.16 million, and the maximum noisy loss value is about 5.73 million. Then, we compare the sample mean with average loss function values of optimal intervention strategies suggested by other public health papers applied to the same L.A. tracts. Halder et al. [19] supposed that a combination of antiviral policy (HHTAP) and 2 weeks school closure was effective for mitigating a pandemic influenza with 2009 H1N1 characteristics, and we compute the average noisy loss function value with such strategy from 500 simulations, which is larger than $30.00 million. Prosser et al. [1] suggested that vaccinating school age children and adults of age 30–40 would be most cost-effective, and the average loss function value for that strategy is about $4.41 million. Pasquini-Descomps et al. [25] summarized that at least 60% of the population should be vaccinated, and we get the average measurement value to be about $5.76 million. Khazeni et al. [2] claimed that vaccinating 40% of population would be cost-saving; then, we compute that the average cost for such is about $5.14 million. Though strategies suggested by other papers are not based on the same assumptions, we can see through the comparison that the optimal solution from DSPSA has significantly lower cost, which indicate that it is a reasonably good solution in the setting of this paper. This comparison provides additional confidence about the quality of our optimal solution.
Application to COVID-19
Choice of Epidemic Model
We now consider the application of the above approach to COVID-19 prior to the availability of vaccines. We use an agent-based simulator (Covasim) developed by [11] to model the spread of the COVID-19 pandemic throughout a population. The model is freely available at https://www.github.com/InstituteforDiseaseModeling/covasim, and it has some advantages over other available models for the COVID-19 pandemic. Covasim incorporates randomness in its simulation output, so it better captures the stochastic nature of the virus spread compared to popular deterministic epidemic models like the SIR model. Covasim includes demographic information on age structure and population size, and it builds a transmission network with multiple social layers, including households, schools, workplaces, and communities to reflect individual contact in reality. Covasim also supports an extensive set of interventions, which works for our goal to explore scenarios under different combination of intervention strategies (pre-vaccine).
To obtain the noisy measurement y, we first run Covasim with the current estimate θ^k. Next, we collect some summary statistics from the simulation output, including the total number of diagnostic testing performed and cumulative number of symptomatic individuals. We will then use these statistics to calculate the economic cost of the scenario, with all cost values listed in 2020 US dollars.
Choice of Optimization Parameter and Transformation
There are recent developments that would likely lead to future studies related to COVID-19. First, vaccines for the COVID-19 have been developed and are serving as powerful tools against the pandemic in many countries. Second, variants of the coronavirus (delta, omicron, etc.) have also spread throughout the world. Additionally, general strategies related to masking, social distancing, quarantining, and so on have been refined over time as public health authorities learn more about the disease. These changes affect our goal of making a factual representation of the current situation in the model. Therefore, for the evaluation of the simulation optimization method, we restrict our attention to the pre-vaccine scenario and do not include vaccination as an intervention strategy. In that sense, one may consider this a “proof of concept” study, with vaccines and other interventions left for future study.
In this project, we choose optimization parameters that relate to four types of intervention strategies: social distancing (D, including closure of workplace and cancellation of public events), school closure (S), testing (T), and contact tracing (C). For each type of intervention, there are three parameters: the start and end day of the intervention and percentage level of intensity of the policy. Because DSPSA works only with integer vectors, we discretize the input vector θ=(D,S,T,C)T and map each parameter into integer values (each of D,S,T,C are row vectors). Note that dim(θ)=12. The percentage level of intensity for each intervention strategy takes a real value between 0 and 100. We discretize the level [0,100] into 0, 10, 20, ⋯, 100; divide the values by 10; and convert them into integers 0,1,2,⋯, 10. These parameters will be mapped back to percentage levels in [0,100] when we run Covasim. The start and end day for each intervention strategy should be kept within the range of days of the simulation, so we make their lower bounds li in the projection function (2) to be 1 and their upper bounds ui to be the length of days of the simulation. Under this setup, the number of possible interventions in Θ would be about 1017. Taking into consideration the fact that the start day of one intervention should not be later than its end day, we add one more step following the projection function (2) in the algorithm: we set the start day to be 1 day before the end day whenever the end day of any policy turns out to be earlier than its start day after the projection function (2) in the algorithm.
Loss Function
All four types of intervention strategies mentioned above are effective in helping control the spread of COVID-19. To determine the optimal combination of strategies, we construct a function to compute the socio-economic cost of each scenario. We formulate the loss function as follows:L(θ)=E[social distancing cost(θ)+school closure cost(θ)+testing cost(θ)+contact tracing cost(θ)+treatment cost(θ)+death cost(θ)]
All of the above costs are cumulative over the time period of interest. For the cost of social distancing, Strong and Welburn [26] estimate the percentage decrease in weekly household income for each state in the USA under several social distancing scenarios. Below we consider scenario 5B, which includes closing schools, bars, and restaurants, banning large events, closing nonessential businesses, and quarantining the most vulnerable. Thunstrom et al. [27] assume that a set of social distancing measures similar to scenario 5B leads to an average 38% decrease in individual contact rate, a measure to reflect the transmission probability between an infected individual and a susceptible individual. Using the estimates of the reduction in contact rate and decrease in household income, we assume a linear relationship between the percentage level of intensity for social distancing and percentage decrease in weekly household income. Next, we collect census data about the population and number of households [28] to estimate the number of households for our synthetic population in simulation. Then, we use the average weekly household income from the census data [28] to compute the social distancing cost by formula:Social Distancing Cost=Percentage level of intensity38×Total household income×Percentage decrease in weekly household income×Duration of the policy in weeks.
The total school closure cost is computed to be the sum of the cost of making up classes and the cost of the lost wages for parents to take care of their children. We estimate the cost for making up classes with the school closure cost per day per student given by [19], which is $23, in 2020 US dollars. For the cost incurred on parents’ lost wages, Halder et al. [19] estimate the average wage of one person to be $992 (in 2020 dollars) weekly and Araz et al. [20] estimate the number of days of work missed to be 2.5 for couples and 5 for single parents. Using these estimates, the total school closure cost per student per day is calculated to be $125 (after adjusting to 2020 dollars). Next, we use data from [29] to estimate the total number of students in our synthetic population. Using the closure cost per student and the total number of students, we get the daily school closure cost in our population under a complete school shutdown. Then, the cost of the intervention policy is computed by multiplying the respective percentage level of intensity.
Though COVID-19 tests are currently free for individuals in the USA, they will incur a cost to health insurance companies or the government. We employ the cost of a test performed by the CDC as given by [30], which is $36. Then, we compute the total cost for testing by multiplying it by the total number of tests performed, which is collected from the simulation output.
As for the cost of contact tracing, Watson et al. [31] claim that 100,000 tracers would be needed nationwide at an annual cost of $3.6 billion. We then compute the number of tracers needed in our synthetic population and their sum cost by proportion. The total cost will finally be multiplied by the percentage level of intensity to obtain the cost of contact tracing policy.
For the treatment cost, Bartsch et al. [32] estimate the medical costs for non-hospitalized patients with COVID-19 symptomatic infections to be $3994 and Cohen et al. [33] estimate the average cost to treat a hospitalized patient with coronavirus to be about $30,000. We assume that people who are symptomatic but have no severe or critical symptoms require no hospitalization, while those who have severe symptoms or critical symptoms, as well as those who die, all require hospitalization. Then, we follow the previous estimates and compute their treatment costs correspondingly.
To compute the cost of death, we use the value of statistical life (VSL). Eichenbaum et al. [34] estimate that the average VSL for a person in the USA to be $9.3 million, and we multiply their estimate by the total number of deaths from the simulation output to obtain the sum of death costs from the COVID-19 pandemic.
Numerical Results
In this section, we present some numerical results relating to the application of the DSPSA algorithm. The general setup for our simulation is as follows. Our synthetic population consists of 100,000 people with the same age structure as the state of Maryland, as revealed by the census data [28]. We use the hybrid contact network in Covasim for our simulation, which will be suitable to represent the realistic contact network of Maryland people in general [11]. For parameters about the disease progression and transmission such as the recovery time for severe cases, we use the default values in Covasim as denoted in Section 2.2 and 2.3 of [11]. We set the start day of the simulation to be March 1, 2020, and the length of the simulation to be 60 days, with the initial number of infected people being 50. As a measure of lack of sensitivity to the initial number, the length of time for social distancing in the results changes by less than 3 days on average when the number of initial infected people varies between 5 and 500.
The initial value for the optimization process is that no intervention policy is implemented. This value is expressed as θ^0=(1,2,0,1,2,0,1,2,0,1,2,0)T. We follow the guidelines provided in Section 3.3 of [14] and set the gain sequence to be ak=a/(1+A+k)α, where A is 10% of the total number of iterations and α is 0.501. The value of a can be found numerically by making the multiplication of a0 and the average magnitude of g^0(θ^0) equal to the desired magnitude of change of θ^k in early iterations. We set our number of iterations to be 5000 and follow the guidelines to find an initial estimate a=0.08.
Before running the algorithm for a large number of iterations, we perform some tests on the common random numbers (CRN) variance reduction technique [22]. Numerical experiments indicate the existence of statistically significant positive correlation between y(θ^k+) and y(θ^k-) when using the same random number seeds, one condition that renders the effectiveness of the CRNs. Plots of trials also reveal improvement when using CRNs. As a result, we incorporate CRNs into the algorithm in this application.
We first determine the reasonableness of applying the DSPSA algorithm in finding the optimal solution to this simulation by examining the fluctuation of total noisy loss y(θ) over the iterations (the true loss L(θ) is not available). Figure 3 shows the tendency of total loss over the first 2500 steps in a single trial. As there is approximately a 90% decrease in total noisy loss, DSPSA appears to be suitable for seeking optimal intervention strategy for COVID-19 in this simulation.Fig. 3 Change of cost in one run versus number of iterations
Next, we check the sensitivity of our simulation results to alternative solutions. In each trial, the solution greatly reduced the total monetary cost from our initial guess. While the algorithm is based on noisy measurements of L(θ), the noise level largely determines the reliability of the result. From Fig. 3, we can see that the level of fluctuation decreases through the iterations. Therefore, we have confidence that the solution we get from the algorithm is a reasonable solution. However, due to the scale of the plot, there is a reasonable chance that one strategy might be superior to another by a tiny margin and such superiority may not be detected by the algorithm in limited iterations. It is, therefore, possible that the solution we find is only one from a set of good choice strategies, but perhaps not the best one. From Fig. 3, we also notice that after some number of iterations, the magnitude of fluctuation upward seems to be greater than that downward. This asymmetry appears to be related to the transmission dynamics of the disease. When the input intervention strategies are close to some optimal ones after some iterations, slight improvement in the intervention strategies is no longer able to significantly reduce the total number of infected people. However, slight deterioration of the strategies may cause asymmetrically more people to get infected by the end of the simulation through the high transmission rate of the SARS-CoV-2. Such increase in the number of symptomatic individuals increases the societal cost of the disease substantially, which determines the pattern in Fig. 3.
From the trials, we find that the terminal solution is θ^5000=[4,18,10,1,2,0,1,20,10,1,2,0]T. The solution is interpreted to impose a social distancing policy with an extremely aggressive level of intensity (percentage level 100) for about 2 weeks starting from day 4 of the simulation and to also implement massive testing of the general population (goal to test 100% of the population) starting from the first day for about 20 days. Then, tests are performed to individuals who are symptomatic for the rest of the 2 months, and those who are tested positive are required to have 2-week-home-based-quarantine. This solution relies on the fact that the length of time after exposure before an individual is infectious is set to have a mean of 4.6 days in Covasim [11], and it corresponds to suggestions from the CDC that the timeframe for self-quarantine of suspected COVID-19 cases should be about 14 days [35]. The recommendation of massive testing is also consistent with the results from [3] that testing generates sizable welfare gains. As for the suggested level of intensity for the social distancing policy, though it may not be possible to reach the extreme (100%) level of intensity, and the number itself does not provide concrete ideas about specific measures that the government should impose, we can seek some guidance from the effect of established policies of other countries and nations. According to [36], the average number of contacts per individual in Wuhan, China decreased by about 86.3% through the duration of the social distancing policy imposed by the Chinese government, which corresponds to a social distancing policy of about 86 percent level of intensity by our definition. As their levels of intensity are close, we can learn that the desired social distancing policy suggested by the optimal solution should be close to that of Wuhan, China. Therefore, the government should impose similar measures including, but not limited to, compulsory wearing of masks in public areas, banning large events, and closing all nonessential business, among other measures [37].
Conclusions
In this paper, we considered two infectious-disease-related problems with the goal of finding optimal mitigation strategies using the DSPSA method of multi-dimensional stochastic optimization for discrete problems. Numerical results reveal that the algorithm results in a significant decrease in loss after a reasonable number of iterations, which illustrates that the DSPSA algorithm is a good approach to solving optimization problems with noisy loss.
Many previous public health studies analyze only a small set of candidate intervention strategies; such approaches require prior knowledge on the likely solution and are conducted on a case-by-case basis. Applications in this paper present a new approach that enables researchers to optimize over the whole set of available intervention strategies without the conceptual idea of a possible optimal strategy. This paper also sheds light on public health optimization analysis by considering not only the goal of public health but also the aim of minimal societal cost. Steps presented in this paper such as the loss function setup and the transformation of parameters can provide guidance in analyzing other types of public health problems, such as drug abuse (e.g., opioid) or further COVID developments (vaccines, antivirals, etc.) or variants of COVID (delta, omicron, etc.).
We may also conduct the same type of study on a modification of the DSPSA algorithm called the mixed simultaneous perturbation stochastic approximation (MSPSA), which applies to a mixture of discrete and continuous input parameters [38]. Because MSPSA is similar to DSPSA, only slight modifications are needed for applications from this paper, such as allowing the vaccine fraction (F) to range from [0,1] continuously. By the nature of the two algorithms, we expect that the solution will converge to an optimal solution in a similar manner as applications in this paper, and we leave the implementation for future study. As MSPSA formally allows for both continuous and discrete parameters, it can adapt to a broader range of public health problems.
In summary, this paper is in response to a need to enhance response to public health threats at regional or larger scale. While current models can support decision makers by measuring the expected impact of factors such as school closures, vaccination campaigns, vaccine fractions, and antiviral treatment strategies, they do not automatically provide an optimal combination of the variables to achieve cost-effective societal aims. This paper demonstrated that a formal stochastic optimization method, DSPSA, combined with a user-selected Monte Carlo simulation of disease transmission and economic impact can provide solutions that are both practically realistic and potentially better than current ad hoc solutions. Results presented in this paper can also motivate us to apply the SPSA family (DSPSA or MSPSA) of algorithms in future public health mitigation studies such as developing countermeasure for bioterrorism. In the long term, the DSPSA/MSPSA-based approach can also adapt to improved simulation models, real-time data sources, better biological understanding, and new candidate intervention strategies (e.g., the current availability of vaccines for COVID-19) to help local and national authorities make better decisions.
Appendix
Since all the 20 tracts we picked are located within California State and Los Angeles County, the State FPIS code and county FIPS code are 06 and 037 respectively for all tracts. The tract FIPS codes for the selected 20 tracts are 101110, 101120, 101210, 101220, 101300, 101400, 102101, 102102, 103101, 103102, 103200, 103300, 103400, 104103, 104104, 104105, 104106, 104107, 104201, and 104202.
Acknowledgements
We thank Yan Zhou and Mengdan Zhang (the Johns Hopkins University) for all the preliminary work done during the course of this research.
Author Contribution
JS encouraged ZL to investigate the application of stochastic optimization in public health and supervised the findings of this work. Both authors were involved in developing the methods and algorithms. ZL performed the numerical simulations and analysis. Both authors discussed the results. ZL wrote the final manuscript under the guidance of JS.
Data Availability
The datasets generated during the current study are available from the corresponding author on reasonable request.
Code Availability
Codes are available from the corresponding author on reasonable request.
Declarations
Ethics Approval
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Consent to Participate
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Consent for Publication
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Conflict of Interest
The authors declare no competing interests.
Publisher’s Note
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References
1. Prosser LA Lavelle TA Fiore AE Bridges CB Reed C Jain S Dunham KM Meltzer MI Cost-effectiveness of 2009 pandemic influenza A(H1N1) vaccination in the United States PloS One 2011 6 7 e22308 10.1371/journal.pone.0022308 21829456
2. Khazeni N Hutton DW Garber AM Hupert N Owens DK Effectiveness and cost-effectiveness of vaccination against pandemic influenza (H1N1) 2009 Ann Intern Med 2009 151 12 829 839 10.7326/0000605-200912150-00157 20008759
3. Piguillem F, Shi L (2020) Optimal COVID-19 quarantine and testing policies. CEPR Discuss Pap Ser: DP14613
4. Hoertel N, Blachier M, Blanco C, Olfson M, Massetti M, Limosin F, Leleu H (2020) Facing the COVID-19 epidemic in NYC: a stochastic agent-based model of various intervention strategies. MedRxiv
5. Charpentier A, Elie R, Laurière M, Tran V (2020) COVID-19 pandemic control: balancing detection policy and lockdown intervention under ICU sustainability. Math Model Nat Phenom 15(57)
6. Souza PA Dias CM Arruda EF Optimal control model for vaccination against H1N1 flu Semin Ciênc Exatas Tecnol 2020 41 1 105 114 10.5433/1679-0375.2020v41n1p105
7. Hamrock E Paige K Parks J Scheulen J Levin S Discrete event simulation for healthcare organizations: a tool for decision making J Healthc Manag 2013 58 2 110 125 23650696
8. Paleshi A Bae KH Evans G Heragu S A simulation-based optimization approach for mitigation of pandemic influenza IISE Trans. Healthc Syst Eng 2017 7 2 107 120 10.1080/24725579.2017.1302525
9. Nelson BL Swann JL Goldsman D Song WT Simple procedures for selecting the best simulated system when the number of alternatives is large Oper Res 2001 49 950 963 10.1287/opre.49.6.950.10019
10. Chao DL Halloran ME Obenchain VJ Longini IM Jr FluTE, a publicly available stochastic influenza epidemic simulation model PLoS Comput Biol 2010 6 1 e1000656 10.1371/journal.pcbi.1000656 20126529
11. Kerr C Stuart R Mistry D Abeysuriya R Hart G Rosenfeld K Selvaraj P Nunez RC Hagedorn B George L Izzo A Palmer A Delport D Bennette C Wagner B Chang S Cohen J Panovska-Griffiths J Jastrzebski M Oron A Wenger E Famulare M Klein DJ Covasim: an agent-based model of COVID-19 dynamics and interventions PLoS Comput Biol 2021 17 7 e1009149 10.1371/journal.pcbi.1009149 34310589
12. Wang Q Spall JC Discrete simultaneous perturbation stochastic approximation for resource allocation in public health Am Control Conf 2014 2014 3639 3644
13. Bureau of Labor Statistics (2021) Consumer price index - all urban consumers, 2000–2020. United States Department of Labor. http://data.bls.gov. Accessed 21 Jan 2021
14. Wang Q (2013) Optimization with discrete simultaneous perturbation stochastic approximation using noisy loss function measurements. Dissertation, Johns Hopkins University
15. Wang Q, Spall JC (2011) Discrete simultaneous perturbation stochastic approximation on loss function with noisy measurements. Proc 2011 Am Control Conf: 4520–4525
16. U.S. Census Bureau (2001) Census 2000 Summary File 1. United States Department of Commerce. https://www.census.gov/data/datasets/2000/dec/summary-file-1.html. Accessed 9 July 2019
17. U.S. Census Bureau (2011) Census 2010 Summary File 1. United States Department of Commerce. https://www.census.gov/data/datasets/2010/dec/summary-file-1.html. Accessed 9 July 2019
18. Chao DL Matrajt L Basta NE Sugimoto JD Dean B Bagwell DA Oiulfstad B Halloran ME Longini IM Jr Planning for the control of pandemic influenza A (H1N1) in Los Angeles County and the United States Am J Epidemiol 2011 173 10 1121 1130 10.1093/aje/kwq497 21427173
19. Halder N Kelso JK Milne GJ Cost-effective strategies for mitigating a future influenza pandemic with H1N1 2009 characteristics PloS One 2011 6 7 e22087 10.1371/journal.pone.0022087 21760957
20. Araz OM Damien P Paltiel DA Burke S Van De Geijn B Galvani A Meyers LA Simulating school closure policies for cost effective pandemic decision making BMC Public Health 2012 12 1 449 460 10.1186/1471-2458-12-449 22713694
21. Molinari NA Ortega-Sanchez IR Messonnier ML Thompson WW Wortley PM Weintraub E Bridges CB The annual impact of seasonal influenza in the US: measuring disease burden and costs Vaccine 2007 25 27 5086 5096 10.1016/j.vaccine.2007.03.046 17544181
22. Spall JC Introduction to stochastic search and optimization: estimation, simulation, and control 2003 Wiley-Interscience
23. Basta NE Chao DL Halloran ME Matrajt L Longini IM Jr Strategies for pandemic and seasonal influenza vaccination of schoolchildren in the United States Am J Epidemiol 2009 170 6 679 686 10.1093/aje/kwp237 19679750
24. Matsuoka T Sato T Akita T Yanagida J Ohge H Kuwabara M Tanaka J High vaccination coverage among children during influenza A(H1N1)pdm09 as a potential factor of herd immunity Int J Environ Res Public Health 2016 13 10 1017 1034 10.3390/ijerph13101017 27763532
25. Pasquini-Descomps H Brender N Maradan D Value for money in H1N1 influenza: a systematic review of the cost-effectiveness of pandemic interventions Value Health 2017 20 6 819 827 10.1016/j.jval.2016.05.005 28577700
26. Strong A, Welburn JC (2020) An estimation of the economic costs of social-distancing policies. RAND Corporation: RR-A173-1
27. Thunstrom L Newbold S Finnoff D Ashworth M Shogren J The benefits and costs of using social distancing to flatten the curve for COVID-19 J Benefit-Cost Anal 2020 11 2 179 195 10.1017/bca.2020.12
28. U.S. Census Bureau (2020) Census Bureau QuickFacts. United States Department of Commerce. https://www.census.gov/quickfacts/MD. Accessed 23 June 2020
29. National Center for Education Statistics (2014) Table 2 number of operating public schools and districts, state enrollment, teacher and pupil/teacher ratio by state: school year 2012–13. United States Department of Education. https://nces.ed.gov/pubs2014/2014098/tables/table_02.asp. Accessed 5 July 2020
30. U.S. Center for Medicare and Medicaid Services (2021) Medicare Administrative Contractor (MAC) COVID-19 Test Pricing. United States Department of Health and Human Services. https://www.cms.gov/files/document/mac-covid-19-test-pricing.pdf. Accessed 18 June 2021
31. Watson C, Cicero A, Blumenstock J, Fraser M (2020) A national plan to enable comprehensive COVID-19 case finding and contact tracing in the U.S. Association of State and Territorial Health Officials. https://www.centerforhealthsecurity.org/our-work/pubs_archive/pubs-pdfs/2020/200410-national-plan-to-contact-tracing.pdf. Accessed 17 Mar 2021
32. Bartsch SM Ferguson MC McKinnell JA O’Shea KJ Wedlock PT Siegmund SS Lee BY The potential health care costs and resource use associated with COVID-19 in the United States Health Aff 2020 39 6 927 935 10.1377/hlthaff.2020.00426
33. Cohen M, Whittal K, Murray T (2020) COVID-19 cost scenario modeling. Wakely consulting group LLC. https://www.ahip.org/documents/AHIP-COVID-19-Modeling.pdf. Accessed 17 Mar 2021
34. Eichenbaum MS Rebelo S Trabandt M The macroeconomics of epidemics Rev Financ Stud 2021 34 11 5149 5187 10.1093/rfs/hhab040
35. U.S. Centers for Disease Control and Prevention (2020) Options to reduce quarantine for contacts of persons with SARS-CoV-2. United States Department of Health and Human Services. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/scientific-brief-options-to-reduce-quarantine.html. Accessed 10 Aug 2021
36. Zhang J Litvinova M Liang Y Wang Y Wang W Zhao S Wu Q Merler S Viboud C Vespignani A Ajelli M Yu H Changes in contact patterns shape the dynamics of the COVID-19 outbreak in China Science 2020 368 6498 1481 1486 10.1126/science.abb8001 32350060
37. Chen S Yang J Yang W Wang C Bärnighausen T COVID-19 control in China during mass population movements at New Year Lancet 2020 395 10226 764 766 10.1016/S0140-6736(20)30421-9 32105609
38. Wang L Zhu J Spall JC Mixed simultaneous perturbation stochastic approximation for gradient-free optimization with noisy measurements Am Control Conf 2018 2018 3774 3779
| 0 | PMC9734801 | NO-CC CODE | 2022-12-14 23:28:30 | no | Oper. Res. Forum. 2022 Dec 9; 3(4):68 | utf-8 | null | null | null | oa_other |
==== Front
Educ Inf Technol (Dordr)
Educ Inf Technol (Dordr)
Education and Information Technologies
1360-2357
1573-7608
Springer US New York
11486
10.1007/s10639-022-11486-7
Article
A review of eye tracking research on video-based learning
http://orcid.org/0000-0002-6914-7233
Deng Ruiqi [email protected]
1
http://orcid.org/0000-0003-2781-6862
Gao Yifan [email protected]
2
1 grid.410595.c 0000 0001 2230 9154 Jing Hengyi School of Education, Hangzhou Normal University, Hangzhou, China
2 grid.13402.34 0000 0004 1759 700X College of Civil Engineering and Architecture, Zhejiang University, Hangzhou, China
7 12 2022
132
20 7 2022
24 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Eye tracking technology is increasingly used to understand individuals’ non-conscious, moment-to-moment processes during video-based learning. This review evaluated 44 eye tracking studies on video-based learning conducted between 2010 and 2021. Specifically, the review sought to uncover how the utilisation of eye tracking technology has advanced understandings of the mechanisms underlying effective video-based learning and what type of caution should be exercised when interpreting the findings of these studies. Four important findings emerged from the analysis: (1) not all the studies explained the mechanisms underlying effective video-based learning through employing eye tracking technology, and few studies disentangled the complex relationship between eye tracking metrics and cognitive activities these metrics represent; (2) emotional factors potentially serve to explain the processes that facilitate video-based learning, but few studies captured learners’ emotional processes or evaluated their affective gains; (3) ecological validity should be improved for eye tracking research on video-based learning through methods such as using eye tracking systems that have high tolerance for head movements, allowing learners to take control of the pacing of the video, and communicating the learning objectives of the video to participants; and (4) boundary conditions, including personal (e.g. age, prior knowledge) and environmental factors (e.g. the topic of videos, type of knowledge), must be considered when interpreting research findings. The findings of this review inspire a number of propositions for designing and interpreting eye tracking research on video-based learning.
Keywords
Instructional video
Video-based learning
Eye tracking
Multimedia learning
Review
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 72204072 Deng Ruiqi
==== Body
pmcIntroduction
Videos are becoming an increasingly important medium of instruction in educational contexts such as MOOCs, flipped classrooms, blended learning, and online training, particularly when teaching and learning are severely interrupted by COVID-19 (Cojean & Jamet, 2022; Deng & Benckendorff, 2021). Research supports that videos offer an advantage to student learning over textbook-style readings when used for pre-class content learning in flipped classrooms at universities (Jensen et al., 2018). In blended learning, university students who watched online instructional videos and participated in classroom teaching achieved better performances than those who only received traditional face-to-face instruction (Expósito et al., 2020). Videos were also found to foster better learning performance than static text and image-based materials in school settings (Chen & Wang, 2011). Researchers have undertaken a series of empirical studies to investigate how learning performance can be strengthened and optimised by designing effective videos (e.g. Arslan-Ari, 2018; Beege et al., 2017; Tarchi et al., 2021). However, these studies have inclined to focus on the impact of design on learning outcomes while lacking attention to individuals’ learning processes. This in turn results in an insufficient understanding of the mechanisms underlying effective video-based learning (Mayer, 2021).
To explain these underlying mechanisms, research has been conducted on the impact of the design of instructional videos on individuals’ learning processes. Self-reporting assessments such as surveys are adopted to make inferences about processes during video-based learning (Boucheix et al., 2018; Fiorella et al., 2017; Hoogerheide et al., 2015; Pan et al., 2020; van Gog et al., 2009). While these measures offer possible explanations for learning activities, they are less successful in documenting temporal fluctuations, non-conscious responses, and latent changes. Consequently, there is a need for measurements that directly capture individuals’ moment-to-moment learning processes. The eye tracking method, which has been extensively used by psychologists to investigate information processing during reading (Gordon et al., 2006), has emerged as a promising tool for investigating processes in video-based learning. However, evaluating eye movements is particularly complex for dynamic stimuli such as videos (Madsen et al., 2021). Research has shown that design principles that apply to other formats of learning materials may not work for instructional videos (Pi, Chen, et al., 2020).
Eye tracking data are sometimes used as a proxy for learners’ cognitive activities such as paying attention to key elements in a video for further processing and incorporating new information into a coherent cognitive structure (Fiorella et al., 2019). It is argued that ‘eye tracking…provides insight into processes underlying learning’ (Kok & Jarodzka, 2017, p. 119). In other words, eye tracking technology has the potential to offer effective explanations for how instructional videos facilitate or hamper learning outcomes. Although a growing number of scholars are deploying eye tracking technology in empirical studies (Colliot & Jamet, 2018; van Wermeskerken et al., 2018), no studies have yet addressed the following research question: How has the utilisation of eye tracking technology and the interpretation of eye tracking metrics advanced our understanding of the mechanisms underlying effective video-based learning? This question is important: if eye tracking research does not provide robust explanations for how instructional videos facilitate or impede learning, then supplemental or alternative measurement strategies must be utilised to scrutinise learning processes. A relevant and equally important research question is: What caution needs to be exercised when interpreting findings of eye tracking research on video-based learning?
This review interrogated the literature to identify key variables (including eye tracking metrics) explored in eye tracking research on video-based learning, and critiqued the evidence for relationships between these variables using Biggs’ (1993a) presage-process-product (3P) model as an organisational framework. This work enables researchers and practitioners to better appreciate the pros and cons of utilising eye tracking technology for investigating video-based learning and the intricate relationships among eye tracking metrics, learning processes, and personal and environmental factors. Moreover, the review evaluated where eye tracking research on video-based learning has been concentrated in the global context and where research opportunities for future studies lie.
Video-based learning is defined as a form of learning that enables individuals to acquire knowledge and skills through videos. The term ‘video’ conveys the same meaning as terms such as ‘instructional video’, ‘educational video’, ‘video lecture’, ‘video tutorial’, ‘video education’, and ‘video modelling example’ used in multimedia learning research. This review defines eye tracking research as evidence-based studies that employ research-grade eye tracking systems and specialised data analysis programmes to examine the positions and movements of an individual’s eyes.
Method
Narrative synthesis approach
This review adopted a narrative synthesis approach to summarise, analyse, and explain the data. Narrative synthesis is qualitative and relies primarily on using words and texts to synthesise the findings of multiple studies (Cook et al., 1997). Although narrative synthesis often presents results in a non-numeric manner, the results may take numerical forms. As eye tracking research on video-based learning was heterogeneous for the key variables explored, statistical meta-analysis was not appropriate at this stage. Narrative synthesis produces new insights that reflect the plurality of educational topics (Arai et al., 2007). It was deemed that a narrative synthesis approach would provide a richer and more fine-grained analysis of this topic.
Researchers began narrative synthesis by defining topics and target audiences. The broad topic (i.e. eye tracking research on video-based learning) is of interest to education researchers, academics, teachers, and practitioners such as video producers. This review employed a three-step article research process to identify the most relevant literature through database and manual journal searches. After identifying the relevant literature, the study followed the narrative synthesis practices adopted in internationally recognised academic work (Boyle et al., 2014; Popay et al., 2005). This entailed utilising a conceptual framework, reading and rereading materials, identifying key variables and patterns across studies, and investigating the relationships within and among studies. The present study adopted several tools and techniques to categorise and evaluate articles, including textual descriptions, frequency distributions, tabulations, and groupings. The paper concludes with a discussion of and reflection on these articles.
Conceptual framework
The 3P model was utilised as an organisational framework to facilitate the evaluation of eye tracking research on video-based learning, to group key variables that are conceptually and empirically similar, and to identify important relationships. Biggs (1993b) elaborates Dunkin and Biddle’s (1974) presage-process-product model and conceptualises relationships involving the student, teaching context, student learning processes, and learning outcomes. The model proposes that learning experience comprises three stages: presage, process, and product (Fig. 1). Presage factors exist prior to students’ engagement in learning. The two types of presage factors were student and teaching context factors. Student factors are relatively stable and learning-related characteristics of the student, such as intellectual abilities, preferred ways of learning, and prior knowledge. Teaching context factors are contextual and teaching-related factors, such as course structure, assessment methods, and institutional climate. These two sets of presage factors interact at the process level and produce a particular teaching and learning mix that determines learning-focused activities (Biggs, 1993b). The interaction of these factors determines the product of learning, which can be described and evaluated quantitatively, qualitatively, and affectively. The heavy arrows in Fig. 1 indicate the main directional flow, and the flow between key factors is regarded as bidirectional (Biggs, 1993a).
Fig. 1 3P model of teaching and learning. (adapted from Biggs, 1993b)
The 3P model was adopted for this review because it heuristically outlines important learning-related variables and their relationships from presage to process to product and provides scope for adaption to the context of video-based learning. Biggs (2003) indicated that the 3P model could be adapted to different learning environments, and any identifiable factors that affect learning can be accommodated in this model. In this review, student factors describe student characteristics that may affect video-based learning, such as social demographics, prior knowledge of video content, and prior interest in video content. The teaching context factors describe the characteristics of videos, such as video topic and length. Student and teaching context factors interact and codetermine learning-related activities at the process level, such as attention and engagement. The interaction among these factors determines the outcomes of video-based learning, such as academic performance and satisfaction.
Article search strategy
The researchers used two sets of search terms in six electronic academic databases: ScienceDirect, Springer, Taylor and Francis, Web of Science, Wiley, and Google Scholar. The first set narrowed the scope to studies that focused on video-based learning, and the second set narrowed the scope to studies that adopted eye tracking technology. For the first set, the researchers used search terms such as video lecture, instructional video, and educational video. For the second set, the researchers adopted both general terms (e.g. eye tracking, eye tracking, eye movement) and specific brands representing the application of eye tracking technology (e.g. Eyelink, FaceLab, Tobii). The search terms were identified through exploratory search results; consultation with experts in the field of educational technology; and a review of titles, abstracts, and keywords of the identified articles. Examples of search terms are shown in Fig. 2. The operator ‘OR’ was used to separate the search terms within each set, and the operator ‘AND’ was used to combine the search terms in the two sets.
Fig. 2 Article search strategy
The article search process followed procedures implemented in previous review studies (Deng et al., 2019, 2022) and contained three steps. In the first phase, the researchers examined the titles, abstracts, keywords, and research methods to determine whether an article should be included. Articles meeting the predetermined selection criteria were identified (Table 1). Articles which did not employ eye tracking technology to investigate video-based learning were not eligible for review (e.g. Fiorella et al., 2017). Nevertheless, these articles were used as background literature to help interpret the findings. Research-grade eye tracking systems often guarantee a sampling rate higher than 50 Hz and support specialised data analysis programmes. Articles which adopted off-the-shelf webcams to record learners’ eye movements and employed humans to assess and code gaze from video recordings were also excluded due to low sampling rates (e.g. Phillips et al., 2016). In the second phase, references from articles identified through the initial literature search were inspected to identify potentially relevant papers that had been overlooked during the database search. Duplicated articles and those not meeting the selection criteria were eliminated from the pool. In the third phase, the researchers read and evaluated the full texts of the articles identified in the first and second phases to ensure that they addressed the research question and met the selection criteria. At the end of the selection process, the combined results from the database and manual journal search yielded 37 articles. As some articles contained more than one study, 44 studies were included in the analysis.
Table 1 Selection criteria for articles
Selection criteria Rationale
Topic of interest Video-based learning The paper is set to review eye tracking research on video-based learning.
Research method Eye tracking technology
Type of scientific research Empirical studies This review is based on knowledge derived from experiences and observations, rather than personal opinions or assumptions. Conceptual work, editorials, and critiques of the literature are not included.
Type of publications Peer-reviewed academic journal articles Non-academic sources (e.g. news, webpages) may not be scientific. Non-peer-reviewed academic sources (e.g. technical reports) may not be rigorous. Conference papers sometimes use a very small sample size (e.g. Altan & Cagiltay 2015) and lack adequate details required to complete this review.
Quality of publications Transparent data collection procedures and analysis methods Sources that are not methodologically sound yield untenable conclusions and would affect the quality of this review. It was expected that procedural details such as participant recruitment, materials, apparatus, and measurements are clearly explained in the sources. Restrictions were not placed on the participants’ educational stages.
Date of publications Between 2010 and 2021 Both older and newer eye tracking technology provides insight into video-based learning. As few academic sources employed eye tracking technology to investigate video-based learning before 2010, this review set the date range for publications to 2010–2021.
Language English It can be difficult to access and evaluate the quality of sources published in languages other than English.
Analysis
Each article was treated as a basic unit of analysis. An overall synthesis table was produced after reading all the articles. The table contains descriptive information such as authors, year of publication, journal name, title, location of the study, research objectives, and major findings. Drawing on the 3P model, the key variables investigated and reported were extracted from all the articles and recorded in the table. These variables were classified into one or more of four categories: student factors, teaching context factors, learning-focused activities, and learning outcomes. Each category comprised multiple subcategories. For example, the learning outcomes category contained subcategories such as knowledge retention, knowledge comprehension, knowledge transfer, satisfaction, and perceived learning. Wang et al. (2020d) examined the impact of cues on learning processes and outcomes, and the outcomes were measured using retention and transfer tests. Key information about retention and transfer tests (e.g. question types and materials) were documented in the learning outcomes category and the knowledge retention and transfer subcategories of the table. This categorisation facilitated the identification of similarities and differences between articles. The labels of the subcategories were constantly refined and merged to better capture similarities and differences.
Patterns and themes were identified across the selected articles using an iterative rereading process. This process ensured that all important information was identified and analysed. The following section summarises and compares evidence related to the four categories in the adapted 3P model. To ensure an informative and concise review, examples of reviewed articles were selected and displayed in tables to complement the textual descriptions. Journal information regarding the reviewed studies is presented in Table 2.
Table 2 Journal information about the reviewed studies
Journal Frequency Percentage
Computers in Human Behaviour 7 15.91
Learning and Instruction 6 13.64
Computers & Education 5 11.36
Journal of Educational Psychology 3 6.82
The Proceedings of the National Academy of Sciences 3 6.82
Others 20 45.45
Results
Student factors
All the reviewed studies reported the number, sex, age, and occupation of the participants. The number of participants varied from 21 (Jarodzka et al., 2010) to 174 (Pi et al., 2020b). The mean number of participants in the study was 68. The highest male-to-female ratio was 3:1 (Pi et al., 2017), and the highest female-to-male ratio was 8:1 (Pi et al., 2020a). The average age of the participants ranged from 12.1 (van Marlen et al., 2018) to 30.7 (Gegenfurtner et al., 2017). Age or occupation was not controlled for in eye tracking research on video-based learning because most of the studies were conducted with university students (n = 42). Only two studies recruited secondary school students (van Marlen et al., 2018) and high school students (Wang et al., 2016) as participants. No reviewed studies recruited participants from primary schools.
Thirty-two studies considered prior knowledge to be an important student factor. A variety of assessment methods, such as true or false (Pi et al., 2020a), multiple choice (Montero Perez et al., 2015), fill-in-the-blank (Pi et al., 2022), open questions (van Marlen et al., 2018), and Likert scales (Wang et al., 2020b), were used to measure participants’ prior knowledge of the video content. All 32 studies employed objective tests to assess the participants’ prior knowledge, with two exceptions. Gegenfurtner et al. (2017) accepted participants’ own account of prior knowledge levels, and Wang et al. (2020b) used a subjective test by asking participants to self-report their prior knowledge of video content. Such efforts served to increase the likelihood that different groups had a similar level of prior knowledge but could not guarantee equality. To ensure that prior knowledge did not exert undue influence on learning outcomes, the reviewed studies either operationalised prior knowledge as covariates (Wang et al., 2020a) or established that different groups did not differ in prior knowledge scores (Wang et al., 2020d). Video design interventions that work for people with higher domain knowledge may be ineffective for individuals who have lower levels of prior knowledge (Gegenfurtner et al., 2017), and vice versa (Krebs et al., 2019; van Marlen et al., 2018). Experimental research that does not assess or control for prior knowledge (e.g. Ouwehand et al., 2015) may potentially bias or attenuate the effect of the design intervention on learning outcomes.
Teaching context
The topic and length of videos have been descriptively reported in all the reviewed studies. The topic of videos differs widely among the reviewed studies and demonstrate no distinct patterns, ranging from education (Pi et al., 2019), psychology (Kruger & Steyn, 2014), and management (Wang et al., 2016), to programming (Kokoç et al., 2020), statistics (Wang et al., 2020), and mathematics (van Marlen et al., 2018). Of the 44 studies, 35 retained the length of the video for < 10 min. The length of the videos was up to 44 min (Kruger & Steyn, 2014). One study did not disclose the length of the videos used in their study (Wang et al., 2019b). To ensure the accuracy of the eye tracking data, eight studies clearly indicated that a chinrest was used to minimise head movement, and twelve studies acknowledged that participants were not allowed to pause or rewind while watching an instructional video.
The teaching context can also be interpreted from the perspective of being manipulated and operationalised as independent variables in a controlled experiment (Table 3). This review classified these studies into three categories. The first research category explores the effects of an instructor’s presence in videos and accompanying social cues on student learning. Research supports that videos featuring both the instructor and content enhance learning performance (Colliot & Jamet, 2018; Pi & Hong, 2016; van Gog et al., 2014) for both easy (Wang & Antonenko, 2017) and difficult topics (Wang et al., 2020b). This design principle was tested with videos on the topics such as attachment, Ebola, sleep, and mathematics, with a length of between 3 and 10 min. Eye tracking data indicate that the instructor-present videos resulted in more fixation counts, longer dwell time (Pi & Hong, 2016) and a higher percentage of fixation on the instructor (Wang & Antonenko, 2017), which suggests that the processing of the instructor’s image may have provided social cues to facilitate the processing of cognitively relevant information and elicit beneficial social-emotional responses from learners (Wang et al., 2020b). That is, eye tracking metrics may have served as process factors, providing a way to explain the mechanism by which instructor presence affects learning performance.
Table 3 Factors tested in controlled experiments
Author Tested factor Experimental conditions Key finding
de Koning et al. (2010) Non-social cue Single cue, multiple cues, or no cue Watching a video with a single spotlight cue or with multiple spotlight cues did not lead to better learning performance than viewing the video without cues
Jarodzka et al. (2012) Non-social cue Circle, spotlight, or no cue Spotlight cues enhanced interpretation performance
Jarodzka et al. (2013) Non-social cue Dot, spotlight, or no cue Cues enhanced the perceptual task performance
Jamet (2014) Non-social cue Colour change, no colour change Colour change enhanced the retention of signalled information
van Gog et al. (2014) Instructor’s presence Instructor-present or instructor-absent Instructor presence enhanced learners’ performance
Montero Perez et al. (2015) Non-social cue Full or keyword captioning Keyword captioning promoted learners’ performance in form recognition tests
Motivational strategy Informed or not informed of a pending test Informing learners about an upcoming vocabulary test promoted learners’ performance in meaning recall tests
Ouwehand et al. (2015) Social cue Gaze cue, gesture and gaze cue, or no cue The instructors’ gaze or gesture had no effects on transfer performance
van Marlen et al. (2016) Non-social cue Meaningful cues, meaningless cues, or no cue Visual cues had no effects on learning performance
Non-social cue Cues or no cue
Pi and Hong (2016) Instructor’s presence Slides, instructor, or slides and instructor Videos showing both slides and the instructor enhanced learners’ performance
van Wermeskerken and van Gog (2017) Instructor’s presence, social cue No face visible, face visible with gaze guidance, or face visible without gaze guidance Instructor presence neither facilitated nor hampered retention and transfer performance
Wang and Antonenko (2017) Instructor’s presence Instructor-present or instructor-absent Instructor presence improved retention performance for the easy topic, reduced cognitive load for the difficult topic, and enhanced perceived learning and satisfaction for both easy and difficult topics
Colliot and Jamet (2018) Instructor’s presence Instructor-present or instructor-absent Instructor presence enhanced retention performance
Stull et al. (2018) Social cue Conventional or transparent whiteboard There was no difference in learning performance between individuals who watched a transparent whiteboard video and those who viewed a conventional whiteboard video
Wang et al. (2018) Instructor’s presence Embodied pedagogical agent (PA) or no PA A highly embodied PA enhanced learners’ performance.
Social cue High or low embodiment
Krebs et al. (2019) Motivational strategy No guidance, guidance of a successful learner, or guidance of a peer The framing of the instructor as a peer learner enhanced the comprehension of learners with lower domain knowledge.
Pi et al. (2019) Social cue Pointing, depictive, or no gesture The instructor’s gestures had a more positive effect for learners with low prior knowledge
Wang et al. (2019a) Social cue With or without gaze guidance The instructor’s gaze guidance improved learners’ performance
Chisari et al. (2020) Non-social cue Translucent blue dots or no cue Cues did not lead to higher learning outcomes
Pi et al. (2022) Motivational strategy Happy or neutral face The instructor’s happy facial expression enhanced learners’ performance
Motivational strategy Direct or averted gaze There was no significant effect of gaze on learners’ performance
Wang et al. (2020b) Social cue Instructor-present or instructor-absent Instructor presence improved transfer performance and reduced cognitive load for a difficult topic, and enhanced satisfaction for both easy and difficult topics
Pi et al. (2020b) Social cue Direct, guided, or averted The instructor’s guided gaze improved retention and transfer performance
Motivational strategy Frontal or lateral There was no significant effect of body orientation on learners’ performance
Wang et al. (2020d) Non-social cue Textual, visual, textual and visual, or no cue The visual cues and combined textual and visual cues improved both retention and transfer performance
Pi et al. (2021) Social cue Direct or guided gaze Videos showing an instructor’s guided gaze and surprised face resulted in lower learning performance
Motivational strategy Surprised or neutral face
Zhang et al. (2022) Instructor’s presence, social cue Instructor on the left, instructor in the middle, instructor on the right, or no instructor Videos presenting the instructor on the right side of the screen improved learners’ performance and satisfaction
However, the effects of instructor presence on learning remain inconclusive. van Wermeskerken and van Gog (2017) and van Wermeskerken et al. (2018), for instance, found that the presence of an instructor had neither beneficial nor detrimental effects on learning performance. Even though instructor presence did not affect learning performance, it still increased the percentage of dwell time on the instructor (van Wermeskerken & van Gog, 2017). This observation suggests that while eye tracking metrics can reveal learners’ allocation of visual attention, these metrics cannot always explain why learning is facilitated or not. This is likely because learners’ allocation of visual attention conveys multiple cognitive meanings that can be difficult to interpret solely relying on the analysis of global eye movement measures such as dwell time.
When the instructor’s image is presented in videos, the influence of accompanying social cues on student learning, such as the instructor’s eye gaze and gestures, was further investigated. It is contended that the activation of social schemata trigged by social cues leads to (para-)social processes influencing all cognitive processes in multimedia learning environments (Schneider et al., 2022). Research indicates that instructors’ guided gaze promotes learners’ performance (Pi et al., 2020b). Similarly, a pedagogical agent using a handheld pointer that signals where to look on the screen also enhances learning performance (Wang et al., 2018). Eye tracking data show that guided gaze (Pi et al., 2020b) and using a pointer (Wang et al., 2018) contribute to a longer fixation time on the learning content. A plausible explanation is that social cues effectively draw learners’ attention to important, relevant materials for cognitive processing, thereby improving students’ learning performance. However, the effect of social cues on student learning is not always positive. Although the main effect of guided gaze on learning was reported to be significant (Pi et al., 2020b), a combination of guided gaze and a surprised face was found to decrease learners’ dwell time on the learning content and subsequently their performance (Pi et al., 2021). These findings highlight the importance of considering the possible interaction effects between embedding social cues and applying motivational strategies in instructional videos, which instead of benefitting, may hamper learning processes and outcomes.
Eye tracking metrics shed light on visual attention distribution that explains why learning performance was facilitated or hindered. However, eye tracking metrics alone may not show whether individuals who spent more time looking at task-relevant areas successfully processed this information and that this would facilitate learning. The combination of two or more social cues, such as the instructor’s guided gaze and pointing gestures, was found to effectively direct learners’ visual attention to task-relevant areas but had no effect on learning performance (Ouwehand et al., 2015), highlighting the necessity to perform a more nuanced analysis of eye movement indicators and/or using additional measures to comprehend the meaning behind visual attention distribution.
The second category of research explores the effects of non-social cues, such as video captions, textual cues, and visual cues, on learning performance. For instance, Montero Perez et al. (2015) found that learners who watched videos showing keyword captions outperformed their counterparts who watched videos with full captions in a retention test. Eye tracking data demonstrated that the former group had a longer total fixation duration for target words. These findings signal that the relationship between captioning and retention performance is mediated by the allocation of visual attention. However, it is worth noting that Montero Perez et al.’s (2015) study was undertaken in the context of second language acquisition, where learning novel words was given a high priority, and when learners were informed of an upcoming test. The design principle may not be generally applicable. A longer total fixation duration contains multiple layers of cognitive significance, such as increased intention to acquire knowledge and processing problems. To accurately interpret allocation of visual attention, additional eye movement indicators (e.g. second pass time) and complementary measures (e.g. think-aloud protocols) (Gegenfurtner et al., 2017) are worth consideration.
Eye movement indicators revealed visual attention processes that helped to explain why learning performance was impacted. For example, Wang et al. (2020d) found that visual cues were more effective in prompting learners’ performance than no cues, whereas de Koning et al. (2010) did not observe such a difference. A possible explanation is that Wang et al. (2020d) designed dynamic lines, highlighted colouring, and moving dots to serve as visual cues, which helped learners pinpoint the exact location of key information. In comparison, de Koning et al. (2010) used spotlight cues, which may have limited the size of the content area learners focused on, but failed to guide processing cognitively relevant information within this area. This conjecture is substantiated by eye tracking data: visual cues comprising lines, colouring, and dots reduced the time of the first fixation to the cued areas (Wang et al., 2020d), whereas in de Koning et al.’s (2010) study spotlight cues increased attention but not necessarily to cued areas. Jarodzka et al. (2012), by contrast, found that spotlight cues enhanced learning performance. The varying effectiveness of spotlight cues can be explained by eye tracking metrics showing that spotlight cues in Jarodzka et al.’s (2012) research prompted students to look significantly earlier, not longer, at all relevant cued parts. This result is in line with Chisari et al.’s (2020) finding that translucent blue dots helped learners to look faster at referenced information, thereby improving learning outcomes. Despite the inconsistency in study results and the type of visual cues employed, eye tracking metrics provided a way to explain how timely selection of the right information mediates the effect of non-social cues on learning performance.
The last research category explores the effects of motivational strategies on student learning. Montero Perez et al. (2015), for example, revealed a significant positive effect on retention performance by announcing an upcoming test to students. Specifically, eye tracking data showed that individuals who received a test announcement showed longer second pass reading times, indicative of the reanalysis of target words, outperformed those who were not informed. This is aligned with Madsen et al.’s (2021) finding that individuals in the incidental learning condition had lower attentional levels than those in the intentional learning condition, resulting in less correlated eye movements across learners. These results indicate that motivational factors may play a prominent role in video-based learning.
However, eye tracking metrics alone may not always explain how motivational strategies mediate learning. For instance, research shows that instructors with happy faces1 improved learning performance (Pi et al., 2022). Despite the improvement, eye tracking data revealed that a happy face did not lead to a longer dwell time on the content or the instructor area (Pi et al., 2022). This observation suggests that factors beyond the allocation of visual attention may have mediated the learning process. In other words, researchers may need to consider factors beyond the allocation of visual attention when identifying the principles of effective video design and use alternative measures to capture individuals’ emotional and motivational processes during video-based learning.
Learning-focused activities
Eye tracking data were used in all the reviewed studies to investigate the learning processes. Prior to analysing the eye tracking data, one or more areas of interest (AOIs) were predetermined by researchers to select specific regions of the video material and extract metrics specifically for those regions. The selected AOIs differed among the reviewed studies, but common AOIs were the instructor area, social cues, content area, non-social cues, progress bar, caption area, blank area of the screen, and entire screen.
Table 4 illustrates eight eye tracking metrics used more than once in the reviewed studies to capture the learning processes and the definition of each metric. The most frequently used metric is dwell time, which depicts the total amount of time spent looking at an AOI. This metric is strongly correlated with the fixation count (Tullis & Albert, 2013), which is measured by counting the number of fixations on an AOI. This correlation explains why many scholars report either dwell time or fixation count, but not both (e.g. Stull et al., 2018). The reviewed studies used dwell time more frequently than the fixation count. This is likely because instructional videos contain dynamic content, and eye movements such as ‘smooth pursuit’ cannot be appropriately captured by using the number of fixations. An increased dwell time and fixation count can imply complexity, engagement, or interest (Geisen & Romano Bergstrom, 2017). Percentage of dwell time and percentage of fixations serve similar purposes, except that they capture relative rather than absolute attention allocation.
Table 4 Repeatedly used eye tracking metrics and their definitions
Metric name Definition Number of the reviewed studies using this metric Example study
Dwell time The total amount of time that an individual spent looking within an AOI. 27 Kokoç et al. (2020)
Fixation count The frequency of fixations on an AOI in a period of time. 11 Wang and Antonenko (2017)
Percentage of fixations The number of fixations on a given AOI divided by the number of fixations on all AOIs, or the number of total fixations on the video. 8 van Gog et al. (2014)
Percentage of dwell time The total dwell time on a given AOI divided by the fixation duration on all AOIs, or the total fixation duration on the video. 7 Zhang et al. (2022)
Average fixation duration The average time for fixations on an AOI. 7 Colliot and Jamet (2018)
Time to first fixation The amount of time it takes for an individual to look at an AOI for the first time from stimulus onset. 7 Wang et al. (2020d)
Fixation transitions The number of fixation transitions an individual made between two or more AOIs. 7 Wang et al. (2020b)
Fixation dispersion Dispersion on the screen divided by the maximum dispersion. 3 Jang et al. (2020)
Fixation transitions, which describe the frequency of transitions between AOIs, were also repeatedly used in the reviewed studies. Fixation transitions can be used to infer learners’ attempts to establish connections between pieces of information or challenges encountered by learners when coordinating multimedia elements (Alemdag & Cagiltay, 2018). Additionally, average fixation duration indicates how long the average fixation lasted, and a longer duration often indicates that individuals spend more time analysing the content or expend more effort to solve the task (Sharafi et al., 2015). Time to first fixation represents the amount of time taken to first pay attention to specific AOIs in a video scene. It can provide information about learners’ visual search speed or how certain aspects of the scene are prioritised (Neta et al., 2017). Fixation dispersion represents how fixations are spread across a scene, and can be used to signify an internal deviation in the content of thoughts from ongoing tasks (Faber et al., 2020).
Most reviewed studies used eye tracking metrics as a proxy for the allocation of visual attention but under various terms, including but not limited to: ‘attentional resources’ (Montero Perez et al., 2015, p. 323) ‘attentional bias’ (Ouwehand et al., 2015, p. 85), ‘amount of attention’ (van Wermeskerken & van Gog, 2017, p. 100), ‘attentional dynamics’ (Wang & Antonenko, 2017, p. 87), ‘attention allocation’ (Pi, Xu, et al., 2020, p. 5), ‘visual attention distribution’ (Wang et al., 2020b, p. 2), and ‘attentional state’ (Madsen et al., 2021, p. 1). The reviewed studies provide evidence that eye tracking technology can identify what information is visually attended to by the learner and for how long, thereby detecting attention during video-based learning. However, many scholars have not only considered eye tracking metrics as an indication of the allocation of visual attention, but also learners’ cognitive processes (e.g. Pi & Hong, 2016; Wang et al., 2019b). This is based on the eye-mind assumption, which posits that there is no appreciable delay between what is being fixated on and what is being processed by the learner (Just & Carpenter, 1980).
Researchers commonly interpret the cognitive meaning of the same eye tracking metric differently. For instance, Krebs et al. (2019) and Wang et al. (2020) interpreted the number of fixation transitions between two AOIs as the cognitive process of organising and integrating information that would benefit learning, whereas Wang et al. (2020b) considered the same measure as the amount of split attention that could harm learning. While an increase in fixation count may imply that an AOI is prominent (Kokoç et al., 2020), the same metric can also represent a higher level of difficulty when processing an AOI (Wang et al., 2019b). A longer fixation duration on an AOI can evince the investment of more cognitive resources (Pi et al., 2020a), but it can also be used to approximate mind-wandering (Jang et al., 2020).
These discrepancies are not surprising, given that interpretation of eye tracking metrics often depends on the context of each study. However, researchers have sometimes failed to provide strong justifications as to why the eye tracking metrics they used can represent cognitive processes they assumed to reflect. For instance, Wang et al. (2020b, p. 6) utilised ‘the number of transitions between the two [AOIs] to understand the amount of split attention’ without explaining why this metric represented split attention, not information integration. Wang et al. (2020d, p. 6) considered ‘transitions between…AOIs as an indication that represented attempts at organising and integrating information’ because ‘in previous studies, transition measures were used to represent attempts at organising and integrating information’. Similarly, Krebs et al. (2019, p. 132) interpreted the same metric as an indicator of the learners’ attempts to integrate information, which was ‘based on previous research’. Deducing cognitive processes directly from eye movement indicators without elaborating on why the used indicators can represent the cognitive processes runs the risk of confabulating the cognitive meaning of eye tracking metrics and deriving erroneous working mechanisms. The actual cognitive meaning behind these eye tracking metrics awaits further clarification, empirical validation, and methodological triangulation.
This review shows that eye tracking metrics provide a way to explain the mechanisms underlying effective video-based learning that otherwise would be difficult to discover through traditional measurement approaches. For instance, Pi et al. (2020b) revealed that learners watching instructional videos with a guided gaze showed an improved learning performance against individuals viewing the video with a direct or averted gaze; here, the guided gaze encouraged learners to pay more attention to important, task-relevant areas. Despite its potential usefulness, not all the reviewed studies successfully explained the mechanisms underlying effective video-based learning through utilising eye tracking technology. Zhang et al. (2022), for example, found that learners achieved better performance when the instructor appeared on the right side of the instructional video compared to those without an instructor on screen; however, eye tracking metrics provided no evidence that having the instructor on the right side prompted learners to pay more attention to the learning content or make more meaningful transitions between the learning content and the instructor. Wang et al. (2020b) found that instructor presence positively influenced learning performance for the difficult topic video yet did not affect learning performance for the easy topic video; however, eye tracking metrics indicated that the instructor attracted more fixations and a longer dwell time in both difficult and easy topic videos. In other words, analysing eye tracking metrics alone cannot explicate the mechanism by which instructor presence enhances learning performance (or lack thereof) in videos with varying levels of difficulty.
In addition to the eye tracking approach, self-report measures were adopted to explore the learners’ experiences and complement eye movement measures. Table 5 displays the four psychological constructs used more than once in the reviewed studies and their definitions. The most frequently measured construct is cognitive load, which in this context evaluates the mental resources learners perceive to have used in working memory to comprehend the content of instructional videos. Wang and Antonenko (2017) and Wang et al. (2020b), for example, revealed that instructor presence reduced cognitive load when students were learning from instructional videos. That is, self-report measures explained how the effect of instructor presence in videos on learning performance was mediated by the reduction in cognitive load. Furthermore, the positive effect of the instructor appearing on the right side of the screen on learning performance was explained by students’ self-report motivation, not eye tracking metrics (Zhang et al., 2022). Although the discrete nature of self-report data implies that the temporality of learners’ non-conscious processes is ignored, they serve to capture individuals’ perceptions of the learning process and exist as an alternative avenue to explain why a video design intervention improved the learning outcome. Self-report measures also help rule out mechanisms that do not apply. For example, the effects of the instructor’s face (Colliot & Jamet, 2018) and facial expression (Pi et al., 2021) on learning performance cannot be explained by the medium of learners’ subjective ratings of social presence. As such, self-report measures should not be dismissed when investigating learning-focused activities during video-based learning.
Table 5 Constructs and their definitions
Construct Definition Number of the reviewed studies measuring this construct Example study
Cognitive load ‘the load that performing a particular task imposes on the cognitive system’ (Sweller et al., 1998, p. 266). 6 Wang and Antonenko (2017)
Social presence ‘the degree of salience of the other person in the interaction and the consequent salience of interpersonal relationships’ (Short et al., 1976, p. 65). 3 Colliot and Jamet (2018)
Engagement ‘a meta-construct that includes behavioural, emotional, and cognitive engagement’ (Fredricks & McColskey, 2012, p. 764). 2 Zhang et al. (2020)
Situational interest ‘temporary interest that arises spontaneously due to environmental factors such as task instructions or an engaging text’ (Schraw et al., 2001, p. 211). 2 Wang et al. (2020b)
The reviewed studies also assessed learners’ social presence, engagement, and situational interest using a self-reporting approach. Social presence, engagement, and situational interest are distinct sets of psychological constructs; however, they all touch the affective or emotional aspects of learning to varying degrees. For instance, Colliot and Jamet (2018, p. 1423) measured social presence based on a semantic differential scale ‘cold-warm’; Zhang et al. (2020, p. 452) assessed engagement on a Likert scale by asking learners to indicate the degree to which ‘the material covered…was interesting’; and Wang et al. (2020b, p. 146) evaluated situational interest on a Likert scale and asked respondents to rate the level of agreement with the statement ‘I am willing to watch more videos like this because it is exciting…’. This observation highlights that emotion could be a salient factor that mediates learning processes in video-based learning. Despite its potential usefulness, only seven studies attempted to capture learners’ self-reported emotional state. Measurement of other affective outcomes, such as change in affect (Wong & Adesope, 2021), was not observed in the reviewed studies. None applied physiopsychological measures to track changes in learners’ continuous emotion during video-based learning.
Learning outcomes
This review categorises learning outcomes based on knowledge tests and self-report measures. Knowledge tests are considered more objective than self-report measures and are used to determine whether participants have shown discipline-specific cognitive learning gains after viewing an instructional video. This review further divided knowledge tests into retention, comprehension, and transfer tests. Retention tests are a form of testing that estimates learners’ memory of the material and normally involves the task practiced during an acquisitional phase (Seel, 2012); comprehension tests assess learners’ ability to read and mentally grasp the meaning of information (Conradie & Frith, 2000); and transfer tests measure the transferability of what was learned in practice conditions to a novel situation (Seel, 2012). It is generally accepted that knowledge retention is less cognitively complex than knowledge comprehension, which in turn is less intricate than knowledge transfer (Krathwohl, 2002). This review showed that knowledge acquisition was assessed at all three levels of retention (n = 27), comprehension (n = 15), and transfer (n = 26).
Of the 44 studies, 41 used knowledge test scores as learning outcome indicators. Twelve studies adopted a single test type to assess knowledge retention, comprehension, or transfer. Twenty-nine studies combined two test types to measure knowledge retention and transfer (e.g. Wang et al., 2020b), knowledge retention and comprehension (e.g. Stull et al., 2018), and knowledge comprehension and transfer (e.g. Pi & Hong, 2016). However, these studies tended not to disclose the cognitive objective that the participants were expected to achieve after watching a video. Instructional videos are produced to help learners perform tasks at various levels of cognitive complexity, ranging from less cognitively complex tasks, such as recalling previously learned information to drawing out factual answers (Xiang & Miller, 2020), to more cognitively complex tasks, such as applying previously learned knowledge on new scenarios (Garrett, 2021). Transparent reporting of the educational objectives of a video and the rationale for adopting a certain type of knowledge test can contribute to clarity and validity and assist the reader in understanding the cognitive level at which video design principles may apply.
Compared to objective testing, fewer studies have adopted self-report measures for evaluating learning outcomes. Self-report measures were either used alone (J. Wang et al., 2019) or in conjunction with knowledge tests (Stull et al., 2018). This review divided self-report measures into learner satisfaction (n = 5), perceptions of the instructor (n = 2), and perceived learning (n = 2). Learner satisfaction is derived by asking individuals to rate the overall quality of their educational experience (Benton & Cashin, 2014); perceptions of the instructor provide information regarding learners’ subjective feelings towards the instructor (Harnish & Bridges, 2011); and perceived learning represents changes in people’s perceptions of knowledge and skills before and after the learning experience (Calvo-Ferrer, 2017). Perceived learning was operationalised as an outcome indicator to assess cognitive gain. Learner satisfaction and perceptions of the instructor, on the other hand, were operationalised as learning outcome indicators to assess participants’ affective gains, which are viewed by some educators as an equally important educational outcome (Rogaten et al., 2019). Evaluating affective outcomes could be particularly important in research exploring the effectiveness of design interventions orchestrated to arouse learners’ social-emotional responses (e.g. Wang et al., 2018), which are also likely to affect cognitive processes during video-based learning. This effort may help identify factors that facilitate or impede video-based learning from emotional and motivational perspectives.
Discussion
This review adopted a narrative synthesis approach to analyse and critique 44 eye tracking studies on video-based learning. The review moves the field forward by making four important contributions.
First, it shows that not all the studies managed to explain the mechanisms underlying effective video-based learning through employing eye tracking technology. The instructor’s image, for instance, attracted a substantial amount of visual attention from learners irrespective of whether their learning performance was improved (e.g. Colliot & Jamet, 2018) or not (e.g. van Wermeskerken & van Gog, 2017). Such ambiguity highlights the necessity of introducing additional measures to explain the underlying mechanisms. The review identified that self-report methods exist as an alternative avenue to explain why a video design intervention could enhance the learning outcome when eye tracking technology fails to fulfil the task (e.g. Zhang et al., 2022). Variables such as cognitive load (e.g. Wang & Antonenko, 2017) have been measured through self-report methods and used in association with eye tracking data to probe the learning process and explain the working mechanisms of instructional videos. However, adopting self-report measures to capture the learning process is subject to measurement problems such as social desirability bias (Pi et al., 2017) and floor effect (Wang et al., 2020b), which may attenuate the effect of interventions on learning outcomes. These potential weaknesses call for non-invasive physiopsychological measures to complement eye tracking and self-report data when investigating the mechanisms underlying effective video-based learning, such as utilising electroencephalography to continuously assess learners’ cognitive load (Wang et al., 2020c).
In addition, this review shows that few studies disentangled the complex relationship between eye tracking metrics and the cognitive activities these metrics represent. Researchers have challenged the eye-mind assumption through empirical investigations, maintaining that the interpretation of eye tracking parameters should depend on the context in which they are applied, and under certain circumstances, these parameters do not align with learners’ cognitive processes (Faber et al., 2020; Schindler & Lilienthal, 2019; Wu & Liu, 2022). Although several reviewed studies asserted that they were firmly based on the eye-mind assumption, few have disentangled the complex relationship between eye tracking metrics and cognitive activities these metrics truly represent; rather, they come up with ad hoc explanations for the observed set of eye movement indicators. Eye movement indicators reflect ‘ongoing processes to the extent that the processes depend on the encoding of information’ (Anderson et al., 2004, p. 230). Because these indicators can mirror the combined effects of several ongoing cognitive processes (Anmarkrud et al., 2019; Kok & Jarodzka, 2017), deciphering the cognitive meaning of learners’ visual attention distribution based solely on eye tracking technology can be difficult. Future research could triangulate eye tracking data with additional measurement approaches, such as cued retrospective reporting (Bender et al., 2021), to minimise ambiguity and avoid misinterpretation of eye movement indicators.
Second, this review found that emotional factors can potentially explain the processes that facilitate video-based learning, yet few studies captured learners’ emotional processes and evaluated their affective gains. Motivational strategies, such as instructors showing a happy face in videos (Pi, Chen, et al., 2020), did not influence learners’ allocation of visual attention but still improved learning performance. Informing students about upcoming tests (Montero Perez et al., 2015), for example, motivated learners to invest additional cognitive resources when watching instructional videos. This observation supports Moreno’s (2006) cognitive-affective theory of learning with media, which posits that motivational factors can mediate learning processes by increasing or decreasing cognitive engagement. The observation also reflects Plass and Kaplan’s (2016) integrated cognitive-affective model of learning with multimedia, maintaining that affective processes are inseparable from cognitive processes. Empirical research has also shown that individuals can recognise the emotions portrayed by an instructor in video lectures (Lawson et al., 2021b), and they perform better on learning outcome tests when the instructor in the video is more emotionally appealing (Lawson et al., 2021a).
Several reviewed studies attempted to identify the affective processes during video-based learning. Specifically, social presence (Colliot & Jamet, 2018), situational interest (Zhang et al., 2020), and emotional engagement data (Wang et al., 2020b) were assessed alongside eye tracking metrics to identify aspects of affective experiences that were not captured by eye tracking devices. Survey questionnaires and Likert scales were employed to ask respondents to self-report their affective state after watching a video. Although self-report measures have advantages such as low cost, accessibility, and ease of administration, they have limitations when evaluating affective processes in video-based learning. In a multimedia learning context, individuals’ affective experiences tend to be continuous and dynamic. The affective state captured by filling out the survey at a single point in time (see for example Deng et al., 2020) does not represent learners’ emotional experiences in the entire learning process, nor can it reflect the ups and downs of the affective process (Plass et al., 2014). A meta-analysis failed to identify the mechanism by which colours and anthropomorphisms affect learning outcomes, because most multimedia learning studies did not use continuous process measures or conduct mediation analyses (Brom et al., 2018).
Moreover, affective processes differ from cognitive ones. Learners are capable of reconstructing cognitive processes, whereas the temporality of emotions suggests that the reconstruction of affective processes is more difficult (Le et al., 2018). Furthermore, learners can be influenced by social desirability bias, speculate on research objectives, and hide their true feelings, further affecting the accuracy of self-reported ratings of experienced emotions. In view of these potential limitations, future research could employ physiological measurements, such as facial electromyography (Lackmann et al., 2021) and electrocardiography (Parong & Mayer, 2021), to detect individuals’ affective experiences and combine cognitive, emotional, and behavioural data to further identify factors that facilitate or impede video-based learning.
Third, this review highlights the necessity of improving ecological validity when conducting eye tracking research on video-based learning. The results showed that eight studies required learners to sit in front of an eye tracking device with their head positioned in a chin rest to minimise head movement (e.g. van Marlen et al., 2018), and eleven studies did not allow learners to pause, rewind, or take notes while viewing a video (e.g. Wang et al., 2020b). Such research settings are very different from authentic learning contexts. Students confront various distractors and engage with other tasks while watching instructional videos in authentic learning environments (Alemdag, 2022). In autonomous, self-directed, and independent learning environments, such as flipped classrooms and MOOCs, it is extremely rare for learners to keep their heads still and be prohibited from interacting with the video content in any form. Interactivity is a key factor in the management of cognitive resources in the context of video-based learning, and the absence of interactivity in experimental research implies that recommendations for the design of instructional videos may not be generalised (Bétrancourt & Benetos, 2018).
This review also showed that the outcomes of video-based learning were assessed at various cognitive levels, such as knowledge retention, comprehension, and transfer. However, the reviewed studies did not disclose the learning objectives that the participants were expected to achieve after watching a video. This can deviate from natural teaching environments, where the intended outcomes for a lesson or unit are often stated before learning takes place (Biggs, 2014). To enhance ecological validity, it is contended that activities, time, physical space, roles, and perceptions be considered when designing and conducting research (Frey, 2018). Future research should strive to strengthen the degree of correspondence between the research settings and the phenomenon being investigated, such as using eye tracking systems that have a high tolerance for head movements, allowing learners to take control of the pacing of the video, and communicating learning objectives to participants at the beginning of the video.
Finally, this review highlights that boundary conditions must be considered when interpreting research findings. A revised 3P model was developed to reflect the key variables and relationships extracted from 44 eye tracking studies on video-based learning (Fig. 3). While scholars frequently manipulated the instructor’s presence and social cues, non-social cues, and motivational strategies to predict learning-focused activities and learning outcomes, they tended to only provide descriptive reports of many student factors (e.g. age and occupation) and teaching context variables (e.g. topic and length of videos); to date, the correlations between these variables and other teaching and learning factors remain largely unknown. This is not consistent with the original 3P model and Biggs’ proposition that teaching and learning factors are not static but interact with each other at different stages of learning (Biggs et al., 2001). The exploration of boundary conditions is intertwined with the theory development process—boundary conditions should not only be perceived as an amendment to theory but also a means for theory development (Busse et al., 2017). Some of the descriptively reported variables may be important boundary conditions in determining how video design principles work across different types of learners and teaching contexts.
Fig. 3 Key variables and relationships extracted from the reviewed studies
The boundary conditions that require consideration include learner characteristics (Mayer, 2021), such as age and prior knowledge. This review provides unambiguous evidence that eye tracking research on video-based learning is primarily conducted with university students. This finding coincides with Alemdag and Cagiltay’s (2018) and Çeken and Taşkın’s (2022) observation that college students are the main participant group in broader multimedia learning research. Due to differences in age, literacy, and academic progress, video design principles that are effective for university students may not be equally efficacious for other learner categories. The literature has revealed that multimedia learning strategies that are effective for university students, such as providing graphical representations and cued texts (McTigue, 2009), incorporating motion and signalling in PowerPoint presentations (Schrader & Rapp, 2016), using peers for video explanation and demonstration (Hoogerheide et al., 2016), and training learners to actively link verbal and pictorial information (Hoch et al., 2021) have a limited effect on K-12 students. These differences highlight the importance of identifying boundary conditions and testing the video design principles that worked for university students in pre-college populations instead of indiscriminately applying pre-existing ones.
Other boundary conditions that require consideration are environmental factors, such as the topic of videos and type of knowledge. The topics of videos varied substantially across the reviewed studies, yet no studies have probed the interactive effects of design principles with the topic of videos on student learning. This raises concerns about the transferability of video design principles. The preferred way of disseminating knowledge and skills through instructional videos can vary significantly across academic disciplines: arts and humanities disciplines show a predilection for a person-centric video style, science and technology disciplines favour a media-centric video style, and social sciences disciplines display a preference for a balance between person-centric and media-centric video styles (Santos Espino et al., 2016). These preferences are likely to be rooted in the intrinsic properties of disciplinary content. Future research could explore whether a design principle proven robust in a discipline holds valid in an entirely different area. A shift in the type of knowledge transmitted through instructional videos can also render an established design principle obsolete. For example, empirical research has shown that the instructor’s image facilitates the learning of declarative knowledge but interferes with procedural knowledge (Hong et al., 2018). A recent meta-analysis has also shown that visual cues were most beneficial to learning performance when non-procedural tasks were taught in instructional videos (Xie et al., 2021). Practitioners need this contextual information to determine the boundary conditions for video design principles to be effective. Therefore, it is important for scholars to not only state for whom the video design principles are potentially effective but also explore the teaching circumstances and learning opportunities where these principles work the best.
Conclusion
Video-based learning is becoming increasingly prevalent in an era in which educational technology, multimedia learning, and the democratisation of education are valued in society (Madariaga et al., 2021; Sablić et al., 2021). To explain the underlying mechanisms that facilitate video-based learning, a growing number of empirical studies have used eye tracking technology to capture learners’ unconscious, moment-to-moment processes when watching instructional videos. This begs consideration of how the utilisation of eye tracking technology and the interpretation of eye movement indicators have improved our understanding of the mechanisms underlying effective video-based learning and what caution needs to be exercised when interpreting findings of eye tracking research on video-based learning. To address these research questions, this review evaluated 44 eye tracking studies on video-based learning conducted between 2010 and 2021. The findings of this review suggest that eye tracking metrics are not a panacea for analysing non-conscious processes during video-based learning. Not all the reviewed studies successfully explained the mechanisms underlying effective video-based learning through utilising eye tracking technology, and few reviewed studies disentangled the complex relationship between eye tracking metrics and cognitive activities these metrics represent. While emotion plays a critical role in multimedia learning environments, learners’ emotional processes and affective gains were often ignored. When interpreting findings of eye tracking research on video-based learning, it is imperative that researchers and practitioners pay close attention to the ecological validity and boundary conditions of video design interventions that have been proven effective in existing studies.
This review has important implications for researchers. Specifically, its key findings inspire a number of propositions for designing and interpreting eye tracking research on video-based learning. Firstly, researchers should use additional physiopsychological and/or self-report measures in conjunction with eye tracking devices to explain the mechanisms underlying effective video-based learning. Similarly, it is critical that researchers use triangulation to disentangle the relationship between eye tracking metrics and the cognitive activities these metrics represent, rather than coming up with ad hoc explanations for the observed set of eye movement indicators. Secondly, researchers should consider capturing learners’ continuous and dynamic affective processes while they watch instructional videos to investigate the emotional factors that may potentially mediate learning with instructional videos. Thirdly, it is important for researchers to strengthen the ecological validity of eye tracking research on video-based learning; for example, they may use eye tracking devices with a high tolerance for head movements, allow learners to take control of the pace of the video, and communicate the learning objectives of the video to participants. Finally, researchers should consider boundary conditions, including personal (e.g. learners’ prior knowledge of videos) and environmental factors (e.g. the type of knowledge transmitted through videos) when interpreting findings. Practitioners such as teachers and video production managers also need this contextual information to determine when to apply established principles to the design and production of instructional videos.
Limitations
This review highlighted a number of opportunities for advancing the field. However, several limitations should be kept in mind when considering the findings of this review. While the 3P model of teaching and learning has provided a useful heuristic tool for organising and interrogating literature, adopting a different research framework may provide additional insights. In addition, this review adopted a deductive approach and superimposed the key variables in the model. For instance, given that situational interest is a psychological state characterised by increased affect, attention, and concentration during learner engagement (Quinlan, 2019) and is often operationalised as a learning process variable (Linnenbrink-Garcia et al., 2013), this review categorised situational interest as a process factor. This categorisation process may introduce ontological constraints. Other strategies may be used to explore this topic: future research could apply alternative frameworks or adopt a more inductive approach towards organising and analysing the literature. In addition, the selection criteria used in this review allowed the researchers to capture a representative selection of scientific studies on the topic of interest. An analysis of conference papers, dissertations, and sources published in languages other than English may yield slightly different results. Future studies should adopt different selection criteria to evaluate eye tracking research on video-based learning.
Authors’ contributions
RD collected the data, performed the analysis, and wrote the paper. YG validated the findings and revised the paper. All authors read and approved the final manuscript.
Funding
This study is supported by the National Natural Science Foundation of China (Grant No. 72204072).
Data availability
The datasets analysed during the current study are available from the first author on reasonable request.
Declarations
Human and animal rights and informed consent
The study does not include any human participants or animals.
Conflict of interest
The authors declare that they have no competing interests.
1 The instructor having a happy face is considered a motivational strategy instead of a social cue. This is because happy faces do not have a directive function. That is, they do not direct learners’ visual attention to task-relevant areas at the right time.
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Alemdag, E., (2022). Effects of instructor-present videos on learning, cognitive load, motivation, and social presence: A meta-analysis. Education and Information Technologies, 27, 12713–12742.
Alemdag E Cagiltay K A systematic review of eye tracking research on multimedia learning Computers & Education 2018 125 413 428 10.1016/j.compedu.2018.06.023
Altan, T., & Cagiltay, K. (2015). An eye-tracking analysis of spatial contiguity effect in educational animations. International Conference on Learning and Collaboration Technologies, Los Angeles.
Anderson JR Bothell D Douglass S Eye movements do not reflect retrieval processes: limits of the eye-mind hypothesis Psychological Science 2004 15 4 225 231 10.1111/j.0956-7976.2004.00656.x 15043638
Anmarkrud Ø Andresen A Bråten I Cognitive load and working memory in multimedia learning: conceptual and measurement issues Educational Psychologist 2019 54 2 61 83 10.1080/00461520.2018.1554484
Arai L Britten N Popay J Roberts H Petticrew M Rodgers M Sowden A Testing methodological developments in the conduct of narrative synthesis: a demonstration review of research on the implementation of smoke alarm interventions Evidence & Policy 2007 3 3 361 383 10.1332/174426407781738029
Arslan-Ari I Learning from instructional animations: how does prior knowledge mediate the effect of visual cues? Journal of Computer Assisted Learning 2018 34 2 140 149 10.1111/jcal.12222
Beege M Schneider S Nebel S Rey GD Look into my eyes! Exploring the effect of addressing in educational videos Learning and Instruction 2017 49 113 120 10.1016/j.learninstruc.2017.01.004
Bender L Renkl A Eitel A When and how seductive details harm learning. A study using cued retrospective reporting Applied Cognitive Psychology 2021 35 4 948 959 10.1002/acp.3822
Benton, S. L., & Cashin, W. E. (2014). Student ratings of instruction in college and university courses. In M. B. Paulsen (Ed.), Higher education: handbook of theory and research (pp. 279–326). Springer.
Bétrancourt M Benetos K Why and when does instructional video facilitate learning? A commentary to the special issue “developments and trends in learning with instructional video” Computers in Human Behavior 2018 89 471 475 10.1016/j.chb.2018.08.035
Biggs JB From theory to practice: a cognitive systems approach Higher Education Research & Development 1993 12 1 73 85 10.1080/0729436930120107
Biggs JB What do inventories of students’ learning processes really measure? A theoretical review and clarification British Journal of Educational Psychology 1993 63 1 3 19 10.1111/j.2044-8279.1993.tb01038.x 8466833
Biggs, J. B. (2003). Teaching for quality learning at university (2nd ed.). Open University Press.
Biggs JB Constructive alignment in university teaching HERDSA Review of Higher Education 2014 1 5 22
Biggs JB Kember D Leung DYP The revised two-factor study process questionnaire: R-SPQ-2F British Journal of Educational Psychology 2001 71 1 133 149 10.1348/000709901158433 11307705
Boucheix JM Gauthier P Fontaine JB Jaffeux S Mixed camera viewpoints improve learning medical hand procedure from video in nurse training? Computers in Human Behavior 2018 89 418 429 10.1016/j.chb.2018.01.017
Boyle EA MacArthur EW Connolly TM Hainey T Manea M Kärki A van Rosmalen P A narrative literature review of games, animations and simulations to teach research methods and statistics Computers & Education 2014 74 1 14 10.1016/j.compedu.2014.01.004
Brom C Stárková T D’Mello SK How effective is emotional design? A meta-analysis on facial anthropomorphisms and pleasant colors during multimedia learning Educational Research Review 2018 25 100 119 10.1016/j.edurev.2018.09.004
Busse C Kach AP Wagner SM Boundary conditions: what they are, how to explore them, why we need them, and when to consider them Organizational Research Methods 2017 20 4 574 609 10.1177/1094428116641191
Calvo-Ferrer JR Educational games as stand-alone learning tools and their motivational effect on L2 vocabulary acquisition and perceived learning gains British Journal of Educational Technology 2017 48 2 264 278 10.1111/bjet.12387
Çeken B Taşkın N Multimedia learning principles in different learning environments: a systematic review Smart Learning Environments 2022 9 1 1 22 10.1186/s40561-022-00200-2
Chen CM Wang HP Using emotion recognition technology to assess the effects of different multimedia materials on learning emotion and performance Library & Information Science Research 2011 33 3 244 255 10.1016/j.lisr.2010.09.010
Chisari LB Mockevičiūtė A Ruitenburg SK Vemde L Kok EM Gog T Effects of prior knowledge and joint attention on learning from eye movement modelling examples Journal of Computer Assisted Learning 2020 36 4 569 579 10.1111/jcal.12428
Cojean, S., & Jamet, E. (2022). Does an interactive table of contents promote learning from videos? A study of consultation strategies and learning outcomes. British Journal of Educational Technology, 53, 269–285.
Colliot T Jamet É Understanding the effects of a teacher video on learning from a multimedia document: an eye-tracking study Educational Technology Research and Development 2018 66 6 1415 1433 10.1007/s11423-018-9594-x
Conradie J Frith J Comprehension tests in mathematics Educational Studies in Mathematics 2000 42 3 225 235 10.1023/A:1017502919000
Cook DJ Mulrow CD Haynes RB Systematic reviews: synthesis of best evidence for clinical decisions Annals of Internal Medicine 1997 126 5 376 380 10.7326/0003-4819-126-5-199703010-00006 9054282
de Koning BB Tabbers HK Rikers RMJP Paas F Attention guidance in learning from a complex animation: seeing is understanding? Learning and Instruction 2010 20 2 111 122 10.1016/j.learninstruc.2009.02.010
Deng R Benckendorff P What are the key themes associated with the positive learning experience in MOOCs? An empirical investigation of learners’ ratings and reviews International Journal of Educational Technology in Higher Education 2021 18 9 10.1186/s41239-021-00244-3
Deng R Benckendorff P Gannaway D Progress and new directions for teaching and learning in MOOCs Computers & Education 2019 129 48 60 10.1016/j.compedu.2018.10.019
Deng R Benckendorff P Gannaway D Learner engagement in MOOCs: scale development and validation British Journal of Educational Technology 2020 51 1 245 262 10.1111/bjet.12810
Deng R Benckendorff P Gao Y Limited usefulness of learning style instruments in advancing teaching and learning The International Journal of Management Education 2022 20 3 100686 10.1016/j.ijme.2022.100686
Dunkin, M. J., & Biddle, B. J. (1974). The study of teaching. Holt, Rinehart & Winston.
Expósito A Sánchez-Rivas J Gómez-Calero MP Pablo-Romero MP Examining the use of instructional video clips for teaching macroeconomics Computers & Education 2020 144 103709 10.1016/j.compedu.2019.103709
Faber M Krasich K Bixler RE Brockmole JR D’Mello SK The eye-mind wandering link: identifying gaze indices of mind wandering across tasks Journal of Experimental Psychology: Human Perception and Performance 2020 46 10 1201 1221 32730072
Fiorella L Stull AT Kuhlmann S Mayer RE Instructor presence in video lectures: the role of dynamic drawings, eye contact, and instructor visibility Journal of Educational Psychology 2019 111 7 1162 1171 10.1037/edu0000325
Fiorella L van Gog T Hoogerheide V Mayer RE It’s all a matter of perspective: viewing first-person video modeling examples promotes learning of an assembly task Journal of Educational Psychology 2017 109 5 653 665 10.1037/edu0000161
Fredricks, J. A., & McColskey, W. (2012). The measurement of student engagement: a comparative analysis of various methods and student self-report instruments. In S. L. Christenson, A. L. Reschly, & C. Wylie (Eds.), Handbook of research on student engagement (pp. 319–339). Springer.
Frey, B. (2018). The SAGE encyclopedia of educational research, measurement, and evaluation. SAGE.
Garrett N Segmentation’s failure to improve software video tutorials British Journal of Educational Technology 2021 52 1 318 336 10.1111/bjet.13000
Gegenfurtner A Lehtinen E Jarodzka H Säljö R Effects of eye movement modeling examples on adaptive expertise in medical image diagnosis Computers & Education 2017 113 212 225 10.1016/j.compedu.2017.06.001
Geisen, E., & Romano Bergstrom, J. (2017). Developing the usability testing protocol. In E. Geisen, & J. Romano Bergstrom (Eds.), Usability testing for survey research (pp. 111–129). Morgan Kaufmann.
Gordon PC Hendrick R Johnson M Lee Y Similarity-based interference during language comprehension: evidence from eye tracking during reading Journal of Experimental Psychology: Learning Memory and Cognition 2006 32 6 1304 1321 17087585
Harnish RJ Bridges KR Effect of syllabus tone: students’ perceptions of instructor and course Social Psychology of Education 2011 14 3 319 330 10.1007/s11218-011-9152-4
Hoch, E., Scheiter, K., Stalbovs, K., & Gerjets, P. (2021). The intention was good: How promoting strategy use does not improve multimedia learning for secondary students. British Journal of Educational Psychology, 91, 1291–1309.
Hong J Pi Z Yang J Learning declarative and procedural knowledge via video lectures: cognitive load and learning effectiveness Innovations in Education and Teaching International 2018 55 1 74 81 10.1080/14703297.2016.1237371
Hoogerheide V Loyens SMM van Gog T Learning from video modeling examples: does gender matter? Instructional Science 2015 44 1 69 86 10.1007/s11251-015-9360-y
Hoogerheide V van Wermeskerken M Loyens SMM van Gog T Learning from video modeling examples: Content kept equal, adults are more effective models than peers Learning and Instruction 2016 44 22 30 10.1016/j.learninstruc.2016.02.004
Jamet E An eye-tracking study of cueing effects in multimedia learning Computers in Human Behavior 2014 32 47 53 10.1016/j.chb.2013.11.013
Jang DM Yang IH Kim SU Detecting mind-wandering based on eye-tracking data during a physics video lecture Education Sciences 2020 10 1 13 10.3390/educsci10030051
Jarodzka H Balslev T Holmqvist K Nyström M Scheiter K Gerjets P Eika B Conveying clinical reasoning based on visual observation via eye-movement modelling examples Instructional Science 2012 40 5 813 827 10.1007/s11251-012-9218-5
Jarodzka H Scheiter K Gerjets P van Gog T In the eyes of the beholder: how experts and novices interpret dynamic stimuli Learning and Instruction 2010 20 2 146 154 10.1016/j.learninstruc.2009.02.019
Jarodzka H van Gog T Dorr M Scheiter K Gerjets P Learning to see: guiding students’ attention via a Model’s eye movements fosters learning Learning and Instruction 2013 25 62 70 10.1016/j.learninstruc.2012.11.004
Jensen JL Holt EA Sowards JB Ogden H West RE Investigating strategies for pre-class content learning in a flipped classroom Journal of Science Education and Technology 2018 27 6 523 535 10.1007/s10956-018-9740-6
Just MA Carpenter PA A theory of reading: from eye fixations to comprehension Psychological Review 1980 87 4 329 354 10.1037/0033-295X.87.4.329 7413885
Kok EM Jarodzka H Before your very eyes: the value and limitations of eye tracking in medical education Medical Education 2017 51 1 114 122 10.1111/medu.13066 27580633
Kokoç M Iigaz H Altun A Effects of sustained attention and video lecture types on learning performances Educational Technology Research and Development 2020 68 6 3015 3039 10.1007/s11423-020-09829-7
Krathwohl DR A revision of Bloom’s taxonomy: an overview Theory into Practice 2002 41 4 212 218 10.1207/s15430421tip4104_2
Krebs MC Schüler A Scheiter K Just follow my eyes: the influence of model-observer similarity on eye movement modeling examples Learning and Instruction 2019 61 126 137 10.1016/j.learninstruc.2018.10.005
Kruger JL Steyn F Subtitles and eye tracking: Reading and performance Reading Research Quarterly 2014 49 1 105 120 10.1002/rrq.59
Lackmann S Léger PM Charland P Aubé C Talbot J The influence of video format on engagement and performance in online learning Brain Sciences 2021 11 2 128 10.3390/brainsci11020128 33498205
Lawson AP Mayer RE Adamo-Villani N Benes B Lei X Cheng J The positivity principle: do positive instructors improve learning from video lectures? Educational Technology Research and Development 2021 69 6 3101 3129 10.1007/s11423-021-10057-w 34729003
Lawson AP Mayer RE Adamo-Villani N Benes B Lei X Cheng J Recognizing the emotional state of human and virtual instructors Computers in Human Behavior 2021 114 106554 10.1016/j.chb.2020.106554
Le Y Liu J Deng C Dai DY Heart rate variability reflects the effects of emotional design principle on mental effort in multimedia learning Computers in Human Behavior 2018 89 40 47 10.1016/j.chb.2018.07.037
Linnenbrink-Garcia L Patall EA Messersmith EE Antecedents and consequences of situational interest British Journal of Educational Psychology 2013 83 591 614 10.1111/j.2044-8279.2012.02080.x 24175684
Madariaga, L., Nussbaum, M., Gutiérrez, I., Barahona, C., & Meneses, A. (2021). Assessment of user experience in video-based learning environments: From design guidelines to final product. Computers & Education, 167, 104176.
Madsen, J., Júlio, S. U., Gucik, P. J., Steinberg, R., & Parra, L. C. (2021). Synchronized eye movements predict test scores in online video education. PNAS, 118(5), Article e2016980118.
Mayer RE Evidence-based principles for how to design effective instructional videos Journal of Applied Research in Memory and Cognition 2021 10 2 229 240 10.1016/j.jarmac.2021.03.007
McTigue EM Does multimedia learning theory extend to middle-school students? Contemporary Educational Psychology 2009 34 2 143 153 10.1016/j.cedpsych.2008.12.003
Montero Perez M Peters E Desmet P Enhancing vocabulary learning through captioned video: an eye-tracking study The Modern Language Journal 2015 99 2 308 328 10.1111/modl.12215
Moreno R Does the modality principle hold for different media? A test of the method-affects-learning hypothesis Journal of Computer Assisted Learning 2006 22 3 149 158 10.1111/j.1365-2729.2006.00170.x
Neta M Tong TT Rosen ML Enersen A Kim MJ Dodd MD All in the first glance: first fixation predicts individual differences in valence bias Cognition and Emotion 2017 31 4 772 780 10.1080/02699931.2016.1152231 26963703
Ouwehand K Gog T Paas F Designing effective video-based modeling examples using gaze and gesture cues Educational Technology & Society 2015 18 78 88
Pan SC Sana F Schmitt AG Bjork EL Pretesting reduces mind wandering and enhances learning during online lectures Journal of Applied Research in Memory and Cognition 2020 9 4 542 554 10.1016/j.jarmac.2020.07.004
Parong J Mayer RE Learning about history in immersive virtual reality: does immersion facilitate learning? Educational Technology Research and Development 2021 69 3 1433 1451 10.1007/s11423-021-09999-y
Phillips NE Ralph BCW Carriere JSA Smilek D Examining the influence of saliency of peer-induced distractions on direction of gaze and lecture recall Computers & Education 2016 99 81 93 10.1016/j.compedu.2016.04.006
Pi, Z., Chen, M., Zhu, F., Yang, J., & Hu, W. (2022). Modulation of instructor’s eye gaze by facial expression in video lectures. Innovations in Education and Teaching International, 59, 15–23.
Pi, Z., Tang, M., & Yang, J. (2020a). Seeing others’ messages on the screen during video lectures hinders transfer of learning. Interactive Learning Environments, 1–14.
Pi Z Xu K Liu C Yang J Instructor presence in video lectures: Eye gaze matters, but not body orientation Computers & Education 2020 144 103713 10.1016/j.compedu.2019.103713
Pi Z Hong J Learning process and learning outcomes of video podcasts including the instructor and PPT slides: a chinese case Innovations in Education and Teaching International 2016 53 2 135 144 10.1080/14703297.2015.1060133
Pi Z Hong J Yang J Effects of the instructor’s pointing gestures on learning performance in video lectures British Journal of Educational Technology 2017 48 4 1020 1029 10.1111/bjet.12471
Pi Z Zhang Y Yang J Hu W Yang HH All roads lead to Rome: instructors’ pointing and depictive gestures in video lectures promote learning through different patterns of attention allocation Journal of Nonverbal Behavior 2019 43 4 549 559 10.1007/s10919-019-00310-5
Pi, Z., Zhang, Y., Zhu, F., Chen, L., Guo, X., & Yang, J. (2021). The mutual influence of an instructor’s eye gaze and facial expression in video lectures. Interactive Learning Environments, 1–18.
Plass JL Heidig S Hayward EO Homer BD Um E Emotional design in multimedia learning: Effects of shape and color on affect and learning Learning and Instruction 2014 29 128 140 10.1016/j.learninstruc.2013.02.006
Plass, J. L., & Kaplan, U. (2016). Emotional design in digital media for learning. In S. Tettegah, & M. Gartmeier (Eds.), Emotions, Technology, Design, and Learning (pp. 131–162). Academic.
Popay J Roberts H Sowden A Petticrew M Britten N Arai L Roen K Rodgers M Developing guidance on the conduct of narrative synthesis in systematic reviews Journal of Epidemiology and Community Health 2005 59 A7
Quinlan KM What triggers students’ interest during higher education lectures? Personal and situational variables associated with situational interest Studies in Higher Education 2019 44 10 1781 1792 10.1080/03075079.2019.1665325
Rogaten J Rienties B Sharpe R Cross S Whitelock D Lygo-Baker S Littlejohn A Reviewing affective, behavioural and cognitive learning gains in higher education Assessment & Evaluation in Higher Education 2019 44 3 321 337 10.1080/02602938.2018.1504277
Sablić M Mirosavljević A Škugor A Video-based learning (VBL)—Past, present and future: an overview of the research published from 2008 to 2019 Technology Knowledge and Learning 2021 26 1061 1077 10.1007/s10758-020-09455-5
Santos Espino JM Suárez A Artal G Speakers and boards: a survey of instructional video styles in MOOCs Technical Communication 2016 63 2 101 115
Schindler M Lilienthal AJ Domain-specific interpretation of eye tracking data: towards a refined use of the eye-mind hypothesis for the field of geometry Educational Studies in Mathematics 2019 101 1 123 139 10.1007/s10649-019-9878-z
Schneider S Beege M Nebel S Schnaubert L Rey GD The cognitive-affective-social theory of learning in digital environments (CASTLE) Educational Psychology Review 2022 34 1 1 38 10.1007/s10648-021-09626-5 34226808
Schrader PG Rapp EE Does multimedia theory apply to all students? The impact of multimedia presentations on science learning Journal of Learning and Teaching in Digital Age 2016 1 1 32 46
Schraw G Flowerday T Lehman S Increasing situational interest in the classroom Educational Psychology Review 2001 13 3 211 224 10.1023/A:1016619705184
Seel, N. M. (2012). Retention test. In N. M. Seel (Ed.), Encyclopedia of the Sciences of Learning (pp. 2859–2859). Springer.
Sharafi Z Soh Z Guéhéneuc YG A systematic literature review on the usage of eye-tracking in software engineering Information and Software Technology 2015 67 79 107 10.1016/j.infsof.2015.06.008
Short, J., Williams, E., & Christie, B. (1976). The social psychology of telecommunications. Wiley.
Stull AT Fiorella L Mayer RE An eye-tracking analysis of instructor presence in video lectures Computers in Human Behavior 2018 88 263 272 10.1016/j.chb.2018.07.019
Sweller J van Merrienboer JJG Paas FGWC Cognitive architecture and instructional design Educational Psychology Review 1998 10 3 251 296 10.1023/A:1022193728205
Tarchi C Zaccoletti S Mason L Learning from text, video, or subtitles: a comparative analysis Computers & Education 2021 160 104034 10.1016/j.compedu.2020.104034
Tullis, T., & Albert, B. (2013). Measuring the user experience. Morgan Kaufmann.
van Gog T Jarodzka H Scheiter K Gerjets P Paas F Attention guidance during example study via the model’s eye movements Computers in Human Behavior 2009 25 3 785 791 10.1016/j.chb.2009.02.007
van Gog T Verveer I Verveer L Learning from video modeling examples: Effects of seeing the human model’s face Computers & Education 2014 72 323 327 10.1016/j.compedu.2013.12.004
van Marlen T van Wermeskerken M Jarodzka H van Gog T Showing a model’s eye movements in examples does not improve learning of problem-solving tasks Computers in Human Behavior 2016 65 448 459 10.1016/j.chb.2016.08.041
van Marlen T van Wermeskerken M Jarodzka H van Gog T Effectiveness of eye movement modeling examples in problem solving: the role of verbal ambiguity and prior knowledge Learning and Instruction 2018 58 274 283 10.1016/j.learninstruc.2018.07.005
van Wermeskerken M Ravensbergen S van Gog T Effects of instructor presence in video modeling examples on attention and learning Computers in Human Behavior 2018 89 430 438 10.1016/j.chb.2017.11.038
van Wermeskerken M van Gog T Seeing the instructor’s face and gaze in demonstration video examples affects attention allocation but not learning Computers & Education 2017 113 98 107 10.1016/j.compedu.2017.05.013
Wang CY Tsai MJ Tsai CC Multimedia recipe reading: Predicting learning outcomes and diagnosing cooking interest using eye-tracking measures Computers in Human Behavior 2016 62 9 18 10.1016/j.chb.2016.03.064
Wang F Li W Mayer RE Liu H Animated pedagogical agents as aids in multimedia learning: Effects on eye-fixations during learning and learning outcomes Journal of Educational Psychology 2018 110 2 250 268 10.1037/edu0000221
Wang F Zhao T Mayer RE Wang Y Guiding the learner’s cognitive processing of a narrated animation Learning and Instruction 2020 69 1 12 10.1016/j.learninstruc.2020.101357
Wang J Antonenko P Dawson K Does visual attention to the instructor in online video affect learning and learner perceptions? An eye-tracking analysis Computers & Education 2020 146 1 16 10.1016/j.compedu.2019.103779
Wang J Antonenko P Keil A Dawson K Converging subjective and psychophysiological measures of cognitive load to study the effects of instructor-present video Mind Brain and Education 2020 14 3 279 291 10.1111/mbe.12239
Wang X Lin L Han M Spector JM Impacts of cues on learning: using eye-tracking technologies to examine the functions and designs of added cues in short instructional videos Computers in Human Behavior 2020 107 106279 10.1016/j.chb.2020.106279
Wang H Pi Z Hu W The instructor’s gaze guidance in video lectures improves learning Journal of Computer Assisted Learning 2019 35 1 42 50 10.1111/jcal.12309
Wang J Antonenko P Celepkolu M Jimenez Y Fieldman E Fieldman A Exploring relationships between eye tracking and traditional usability testing data International Journal of Human–Computer Interaction 2019 35 6 483 494 10.1080/10447318.2018.1464776
Wang J Antonenko P Instructor presence in instructional video: Effects on visual attention, recall, and perceived learning Computers in Human Behavior 2017 71 79 89 10.1016/j.chb.2017.01.049
Wong RM Adesope OO Meta-analysis of emotional designs in multimedia learning: a replication and extension study Educational Psychology Review 2021 33 357 385 10.1007/s10648-020-09545-x
Wu, C. J., & Liu, C. Y. (2022). Refined use of the eye-mind hypothesis for scientific argumentation using multiple representations. Instructional Science, 50, 551–569.
Xiang XM Miller D Effects of simulation video on parental recall of seizure first aid: a quality improvement project Journal of Child Neurology 2020 35 13 908 911 10.1177/0883073820939390 32677499
Xie H Zhao T Deng S Peng J Wang F Zhou Z Using eye movement modelling examples to guide visual attention and foster cognitive performance: a meta-analysis Journal of Computer Assisted Learning 2021 37 4 1194 1206 10.1111/jcal.12568
Zhang H Miller KF Sun X Cortina KS Wandering eyes: Eye movements during mind wandering in video lectures Applied Cognitive Psychology 2020 34 2 449 464 10.1002/acp.3632
Zhang, Y., Xu, K., Pi, Z., & Yang, J. (2022). Instructor’s position affects learning from video lectures in Chinese context: An eye-tracking study. Behaviour & Information Technology, 41, 1988–1997.
| 0 | PMC9734802 | NO-CC CODE | 2022-12-14 23:28:30 | no | Educ Inf Technol (Dordr). 2022 Dec 7;:1-32 | utf-8 | Educ Inf Technol (Dordr) | 2,022 | 10.1007/s10639-022-11486-7 | oa_other |
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Environ Sci Pollut Res Int
Environ Sci Pollut Res Int
Environmental Science and Pollution Research International
0944-1344
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Springer Berlin Heidelberg Berlin/Heidelberg
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24067
10.1007/s11356-022-24067-5
Research Article
Numerical simulation of social distancing of preventing airborne transmission in open space with lateral wind direction, taking into account temperature of human body and floor surface
Issakhov Alibek [email protected]
123
Omarova Perizat [email protected]
1
Abylkassymova Aizhan [email protected]
2
1 grid.77184.3d 0000 0000 8887 5266 Al-Farabi Kazakh National University, Almaty, Republic of Kazakhstan
2 grid.443463.2 0000 0004 0387 9110 Present Address: Kazakh British Technical University, Almaty, Republic of Kazakhstan
3 grid.449060.f 0000 0004 1797 0898 International Information Technology University, Almaty, Republic of Kazakhstan
Responsible Editor: Marcus Schulz
7 12 2022
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3 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
This paper presents the numerical results of particle propagation in open space, taking into account the temperature of the human body and the surface of the ground. And also, the settling of particles or droplets under the action of gravitational force and transport in the open air is taken into account, taking into account the temperature during the process of breathing and sneezing or coughing. The temperature of the body and the surface of the ground, different rates of particle emission from the mouth, such as breathing and coughing or sneezing, are numerically investigated. The effect of temperature, cross-inlet wind, and the velocity of particle ejection from a person’s mouth on social distancing is being investigated using a numerical calculation. The variable temperature of the human body forms a thermal plume, which affects the increase in the trajectory of the particle propagation, taking into account the lateral air flow. The thermal plume affects the particles in the breathing zone and spreads the particles over long distances in the direction of the airflow. The result of this work shows that in open space, taking into account the temperature of the body and the surface of the ground, a 2-m social distance may be insufficient for the process of sneezing and social distance must be observed depending on the breathing mode.
Keywords
Airborne transmission
Thermal effects from body
Particle dispersion
Indoor
Breathe
COVID-19
Social distancing
SARS-CoV-2-laden droplets
Computational fluid dynamic (CFD)
==== Body
pmcIntroduction
Over the past two decades, the third highly pathogenic representative of the coronavirus family is MERS and SARS-CoV-2 (Issakhov et al. 2021a, b). At present, due to the rapid growth of infected people around the world, there is a sharp need to combat the spread of the virus. So far, certain and effective treatments have been developed to mitigate the effects of the disease (Smieszek et al. 2019). One of them is vaccination — which has greatly improved the general population confinement in some countries by relaxing strict quarantine measures (Grimalt et al. 2022). However, there are some risks of reinfection for the vaccinated population. For this, strict precautions must be taken in public places, as public places are hotspots for the spread of the virus (Birgand et al. 2020).
In addition, COVID-19 is transmitted from asymptomatic people through the airborne route, so it is necessary to understand the spread of the virus in the environment in order to prevent the accumulation of infection (Morawska et al. 2020, Bai et al. 2020, Feng et al. 2020, Gao et al. 2021). In connection with this, many research papers have been carried out, for example, on outbreaks of infectious diseases in various enclosed spaces, such as hospitals (Takanabe et al. 2021, Xian et al. 2020; Xu et al. 2021, Chia et al. 2020, Mizukoshi et al. 2021) public places (Rencken et al. 2021, Park et al. 2021), public transportation (Alexei Pichardo-Orta et al. 2022), air travel (Li et al. 2016, Zee et al. 2021) and open-space office (Weissberg et al. 2020). Everyone knows that most cases of respiratory diseases are transmitted by airborne droplets or through close contact. For example, such as tuberculosis, measles, chicken pox (Busco et al. 2020; Li et al. 2020) influenza, bronchitis, and pneumonic plague (Leclair et al. 1980, Escombe et al. 2007, Roy and Milton 2004, Sattar et al. 1987, Chan et al. 2020) are transmitted by airborne droplets.
The main mechanism for the spread of viral diseases is coughing and sneezing. When simply breathing, sneezing or coughing, small droplets are formed, consisting of water and air. Consequently, these small particles have different generation rates and durations, with different effects on the environment and the human body (Hinds 1982, Zhao et al. 2005). And also, the spread of the virus by airborne droplets indoors and outdoors depends on many factors, such as, humidity, pollution, particle size, temperature, population density, ventilation rate, particle settling rate, the presence of other aerosols or volatile organic compounds (VOC), and others (Cai et al. 2020, Memarzadeh 2012, Schaffer et al. 1976, Lowen et al. 2007). Moreover, all these factors affect different infectious organisms differently and to varying degrees, and in some cases it is difficult to draw a conclusion, since different experimental methods were used during the study (Tang 2009).
Coughing and sneezing is a major source of exhaled pollutants and is also a symptom of most respiratory infections (Duguid 1945, Gupta et al. 2009). There are many scientific papers on the size of the distribution of droplets during active breathing, sneezing, and coughing and have a wide range of diameters approximately dp < 10–6 m (Chao et al. 2009, Zhang et al. 2015, Morawska et al. 2009, Papineni and Rosenthal 1997). Therefore, the distance and settling of particles also depends on the size and speed of their propagation. And also, the number and size of the particles differ significantly, for example, when sneezing, about 40,000 drops are formed, and when coughing, about 3000 drops (Cole and Cook 1998, Wei and Li 2016). Moreover, the behavior of large and small particles in the air plays an important role in reducing the risk of SARS-CoV-2 infection. In addition, the particles spread differently from 0 to 7 m and beyond. This spread depends on the influence of various factors, such as settling, size, air flow and evaporation of droplets, etc. Another important point is that at high temperature and relative humidity, particles can evaporate and shrink, changing their propagation trajectory. The work (van Doremalen et al. 2020) showed that viable SARS-CoV-1 and SARS-CoV-2 influenza infectious particles remain in the air for about 1–3 h (Kampf et al. 2020, van Doremalen et al. 2020). Thus, droplets or particles are more likely to spread both indoors and outdoors, increasing the risk of infecting people in a certain period of time after exposure (Wang et al. 2020a, b, Zhang and Li, 2012). Xian et al. 2020; Li et al. 2020 consider the evaporation and propagation of particles in the open air. It should be noted that this kind of study is quite rare in studies, and most studies focus on ventilation assessment, vehicle pollution dispersion, various chemical reactions and particulate matter associated with outdoor ventilation (Chen et al. 2017; Zhang et al. 2020a, 2020b; He et al. 2017; Liu et al. 2015; Yang et al. 2020; Scungio et al. 2018; Tung et al. 2021; Yao et al. 2020; Bartzis et al. 2015). From those studies, it can be observed that the spread of COVID-19 in the open air is still to be studied, since the virus can be transmitted not only indoors, but also outdoors (Zhang et al. 2020c, Xu et al. 2021). There is a lot of work and WHO recommends a certain social distance, at least 1–2 m from each other in rooms, to reduce the risk of infection (WHO 2020). To determine the optimal distance to prevent the transmission of infectious diseases, there are still no solutions for physical distancing in the outdoors (Kissler et al. 2020; Gao et al. 2021). As the results of some simulation studies show, 2 m for social distancing may not be enough (Dbouk and Drikakis 2020; Feng et al. 2020, Pendar and Páscoa, 2020; Issakhov et al. 2021a, b).
Computational Fluid Dynamics (CFD) simulations are used to predict airborne spread of the virus (Holmes and Morawska 2006) because, CFD simulations are affordable and inexpensive compared to experiments. In order to get a more accurate forecast, setting the boundary conditions close to reality plays an important role, for example, flow velocity, flow direction, temperature, pollutant source area, etc. Therefore, numerical simulation makes it possible to obtain a more accurate prediction for particle propagation even taking into account particle evaporation (Li et al. 2018).
The purpose of this work is to determine the optimal distance to prevent the transmission of infectious diseases in the open air, which takes into account the distributed body temperature and ambient temperature during various breathing patterns, coughing, and sneezing. Accounting for these factors during simulation brings this calculation closer to a more realistic case. As it is knowing, the spread of infectious diseases depends on many factors, and determining a safe distance without taking into account these factors may lead to incorrect results, which may not lead to a very good result.
Mathematical model
For the correct construction of the mathematical model of the air flow, the system of Navier–Stokes equations is used, which is numerically implemented through the ANSYS Fluent. For modeling are used the incompressible Navier–Stokes equations. The continuity and momentum equations used in the model are defined as follows:1 ∂uj∂xj=0
2 ∂ui∂t+∂∂xjuiuj=fi-1ρ∂p∂xjμeff∂ui∂xj+∂xj∂ui
where μeff – the effective viscosity, p – the pressure, μeff=μ+μt, where μt – the turbulence viscosity. The external force of the body considered is gravity, so that f=ρg, where g is the acceleration due to gravity, ρ—the density.
The kinematic relationship between the position of particles and the speed of particles is3 dxpdt=up
4 mpdupdt=FD+FG
where xp, the particles location, FG is the gravity force, FD, the drag force, up, the velocity of particles, uf, the velocity of fluids, mp, the mass of particles and FD calculated as follows5 FD=12ρfπdp24CDuf-upuf-up
where the resistance coefficient6 CD=24Re;Re<124Re1+0.15Re0.687;1≤Re≤1000
where ρf is the density of the fluid, ρp is the particle density and dp is the particle diameter, Re=ρdpu→-u→pμ is the Reynolds number.
In order to close the system of equations was used SST k-ω turbulent model, which described in detail in (Spalart, 1997; Menter and Kuntz 2003; Menter 1994; Jones and Launder 1972; Issakhov and Mashenkova 2019; Issakhov and Omarova 2019; Issakhov et al. 2020a; Issakhov et al. 2020b; Issakhov, Alimbek, Zhandaulet, 2021).
These equations are approximated by using the finite volume method. The numerical model for this problem was presented using the widely used SIMPLE method (Semi-Implicit Method for Pressure-Linked Equations). This method is used in many works to solve various problems of hydrodynamics and heat transfer and served to create a whole class of numerical methods. All variables that were used in this method are completely physical. For discretization of the all equations of convective term was used Second Order Upwind scheme (Issakhov and Omarova 2021; Issakhov and Zhandaulet 2019; Issakhov and Borsikbayeva 2021; Issakhov et al. 2022a, b, c; Issakhov et al. 2022a, b, c; Issakhov, Alimbek, Abylkassymova, 2022).
Numerical simulations
Validation of the mathematical model and numerical algorithm was performed for the test problem and the obtained results were compared with experimental data, this procedure is described in more detail in the works papers (Issakhov et al. 2021a, b; Issakhov et al. 2022a, b, c). This work represents the propagation of a particle in open space, taking into account the temperature of the human body, the environment and the lateral inlet air flow, and also takes into account different speed regimes for breathing, coughing and sneezing. For implementations of numerical simulations, the problems were taken in an indoor room with a person. The size of the constructed room with a person is X × Y × Z = 8 × 3 × 3 m, and the total height of a European person is 1.8 m. To describe the process of breathing, coughing, and sneezing, the level of the mouth was used; in addition to this process, particles are ejected from the mouth. The height from the floor to the mouth inside the box is approximately 1.65 m. In the presented work, the distribution of concentration and particles was considered, taking into account the influence of the inlet wind, body temperature and the surface of the ground, provided that a person is talking, sneezing or coughing. The full size of the area under consideration is shown in Fig. 1.Fig. 1 Geometry of the study area
The studies show that the speeds for sneezing, coughing while talking are different from each other (Verma et al. 2017, Xu et al. 2018, Hasan 2020, Redrow et al. 2011). The variation in the speed of ejected particles from the human mouth was from 1 to 20 m/s. In this study, a simpler version of sneezing and coughing was investigated, but it should be taken into account that this process of sneezing and coughing occurs once. The main factor is that many people sneeze more than once per sneeze cycle. Thus, in the problem, the rate of simple breathing is periodic, and the rate of the process of coughing or sneezing is pulsed. In addition, repeated sneezing or coughing increases the distance of the ejected particles by an even greater propagation distance.
The particle diameter is set in the range of about 10–6–10–3 m depending on normal breathing, coughing or sneezing (Zhao et al. 2005).
The total duration of one sneeze was approximately 0.1925s (Busco et al. 2020). The following formulas were used to describe the rate of particle ejection from the mouthu=V,10.1≤t≤10.25u=Vsin2πt,10.25≤t≤10.5u=sin2πt,10.5≤t
Particles are droplets of a mixture consisting of water and air, based on some works for this problem, the particle density was set to 600 kg/m3 (Zhao et al. 2005). In this paper, it was considered several scenarios with variable body and ambient temperatures in open space: (a) breathing at a speed of V = 1 m/s; (b) coughing at a speed V = 6 m/s; and (c) sneezing at a speed of V = 20 m/s. For all cases, the initial 10 s is simulated taking into account the variable temperature of a person and the surface of the ground, taking into account the lateral inlet wind (inlet), and the particles are ejected from the mouth from 10.1 to 10.3 s, and then up to 20.5 s, the process of inhalation and exhalation of a person without ejection. This sets the particle ejection temperature to 309.75 K. The floor temperature is also set to a constant value of 305 K. This procedure is given by the connection in order to approximate a more real process. All scenarios take into account the influence of variable body and floor temperatures, taking into account the inlet wind on the movement and concentration of emitted particles before the process of breathing, coughing and sneezing.
In order to obtain a more accurate result in a short period, the computational grid was refined in certain areas. For the study area, it was used clumps around the mouth (face mouth = 0.001) and around the human body (face body = 0.005) to reduce the number of cells and computational costs, since this geometry is complex. The total number of elements of the study area is 7 731 570 and nodes (nodes = 1 366 119). The three-dimensional (3D) computational grid of this area is shown in Fig. 2. The following functions were taken as the distribution profile of the incoming flow and for body temperature:Fig. 2 Computational grid of the study area
Uinlet=0.71-exp-2z+3
In order to realize the initial distribution of body temperature, it was taken into account that body temperature is not evenly distributed throughout the body (Psikuta et al. 2017), since the maximum temperature is on the human head (310.75 K), and the minimum temperature is on the lower extremities (309.75 K). For this purpose, the initial approximation of body temperature is given by the following formulaTbody=309.75+z/1.8
where z varies according to the height of the person.
Numerical simulation results
Figures 3, 4 and 5 show the temperature distribution over time for various speed modes. To obtain these results, the first 10 s of the simulation was performed taking into account the variable temperature of the body and floor, but the emission of particles from the mouth is not carried out. This procedure is carried out in order to form temperature and velocity fields. After the formation of temperature and velocity fields, the particle is ejected. As it can be seen from the obtained numerical results, the influence of a variable body temperature and the presence of an air flow significantly affect the distribution of velocity and the distance of particle movement. It should be noted that, taking into account the force of friction and gravity, a thermal plume arises due to the variable body temperature and the presence of a lateral inlet air flow accelerates the transfer and diffusion of the particles. As a result, one can see a huge change in the thermal plume at different points in time for each scenario. Moreover, it should be noted that due to the thermal plume, an additional lift force is generated, which lifts up the lateral inlet air flow, which ultimately leads to the fact that the ejected particles rise up.Fig. 3 Contour temperature 10.5–20.5 s cough = 1 m/s
Fig. 4 Contour temperature 10.5–20.5 s cough = 6 m/s
Fig. 5 Contour temperature 10.5–20.5 s cough = 20 m/s
And it should also be noted that with different breathing patterns (coughing and sneezing), there is a change in the thermal plume around the body. As can be seen from Figs. 3, 4 and 5, at 12.5 s, one can notice changes in the thermal plume due to different breathing modes at the initial time, and then, due to the lateral inlet wind flow, the heat propagation characteristics are almost similar. Figures 6, 7 and 8 show the transfer of particles at different times. As can be seen from Fig. 6, the particle propagation distance, taking into account the temperature plume, in the time period from 10.2 to 10.5 s, reaches 0.12 m. From the obtained results, it can be seen that different breathing modes play an important role in particle propagation. However, it should be noted that after the process of coughing and sneezing from 12.5 s, the lifting force that is created due to the variable temperature emanating from the human body significantly affects the particle propagation behavior and, despite the force of gravity, the particle rises upwards. At 16.5 s, it can be seen that around the person, due to the lateral inlet air flow and the temperature plume, small vortices are formed with particles from both sides, which move downstream. However, some particles remain in the center. After the process of coughing or sneezing during breathing, due to the high velocity value, some part of the particle remains around the person, and part of the ejected particle due to the influence of the lateral inlet air flow and the temperature plume spreads downstream.Fig. 6 Particles, cough = 1 m/s open space with temperature 20.5 s. a Time step = 10.2 s, b Time step = 10.3 s, c Time step = 10.4 s, d Time step = 10.5 s, e Time step = 12.5 s, f Time step = 16.5 s, g Time step = 20.5 s
Figure 7 shows the spread of a particle during coughing, where the speed is V = 6 m/s. As the results show, due to the influence of the temperature plume, particles with small diameters are very strongly subject to lift and rise up, while slowing down and propagating the particles downstream. As a result, due to the influence of the lifting force, small particles rise up to 1.343 m.Fig. 7 Particles, cough = 6 m/s open space with temperature 20.5 s. a Time step = 10.2 s, b Time step = 10.3 s, c Time step = 10.4 s, d Time step = 10.5 s, e Time step = 12.5 s, f Time step = 16.5 s, g Time step = 20.5 s
At the same time, it should be noted that on the trajectory of the particle transfer, the lateral inlet air flow plays an important role. However, from the obtained results, it can be noted that at the initial moments of coughing and sneezing, the influence of the temperature plume and the lateral inlet air flow shows a minimal effect. However, if it compares the obtained results after the process of coughing and sneezing, one can observe changes in the distance of particle propagation. So in 10.5 s with simple breathing, the distance reaches 0.12 m, and with coughing up to 0.46 m, which is almost 4 times more.
Figure 8 presents the results of particle propagation for the sneezing process at a speed of 20 m/s. The distance from a person during the propagation of a particle at 10.5 s reaches 0.99 m. At the same time, at the last moment, due to the lateral inlet air flow, it transports the particles much further. As can be seen from the obtained data, in the initial process of breathing, coughing, and sneezing, the influence of the crosswind and temperature plume has a minimal effect, while after this process, the further distribution of particles is very much dependent on the crosswind and temperature plume. It is also possible to note the spread of particles along the width depending on the lateral velocity and the presence of a temperature plume.Fig. 8 Particles, cough = 20 m/s open space with temperature 20.5 s. a Time step = 10.2 s, b Time step = 10.3 s, c Time step = 10.4 s, d Time step = 10.5 s, e Time step = 12.5 s, f Time step = 16.5 s, g Time step = 20.5 s
In all calculation scenarios, it can be seen that a large number of small droplets disperse along the jet air flow, while some small droplets diffuse upward easily depending on the temperature plume. The difference is noticed only when the emission of particles occurs for the process of respiration and larger particles after the release largely settle to the ground due to gravity.
Thus, from the obtained data, it can be concluded that most of the larger particles begin to settle due to gravitational forces, while small particles are transported over a long distance, which, in terms of airborne disease transmission from a person, poses a greater danger or risk. As a result, in the presence of a lateral inlet wind, the risk of infection increases, since the particle transfer distance increases several times compared to without a wind event.
Figure 9 shows the range of particle propagation in open space, taking into account the temperature of the body and the floor surface. As the results show, under different modes of particle ejection, it significantly affects the transport of particles along the height. In the mode of particle ejection with a speed of 20 m/s and 1 m/s (case 1) in the last 20.5 s, the propagation trajectory is the same, the difference is only at the level h (height). It should be noted that due to the speed of breathing or coughing, the settling of particles, taking into account the temperature, is approximately the same, except for the sneezing option.Fig. 9 Particle propagation range (scenarios 1–3)
From the results, it can be seen that due to the lateral air flow, small vortices are formed behind the human body, which led the particles to a non-standard movement. These small vortices are formed due to the fact that the lateral air flows around the human body, while forming vortex movements behind the human body. It must be taken into account that a process of dissipation occurs, which leads to random motion. It can also be observed that due to the vortex motion in the central region behind the human body, reduced velocities are observed. In this case, the particles due to the vortex motion are brought into the external flow of motion. After these particles begin to move downstream, so that these particles are almost indicators of air flow. However, it should be noted that inertial particles are mainly collected in areas with low vorticity. At the same time, particles with greater inertia have relatively little effect on vortex movements and are mainly subject to mainly the direction of movement of the air side flow. It should also be noted that the particles move along a circular path with an almost equal radius. However, this process will not last for a long time, since an actively dissipative process takes place behind the human body. Due to this downstream phenomenon, vortex motions are generally not observed and particles move along the air flow.
According to the obtained data, it can be concluded that when taking into account the temperature of the human body and the temperature of the ground surface in the outdoor, by sneezing or coughing, particles can be transported to a much greater distance compared to not taking into account the temperature effect. To reduce the risk of infection, it is recommended not to stand or talk to people face to face in the direction of the wind, as particles spread much faster. Taking into account the temperature of the human body and the temperature of the ground surface in the outdoor, as well as taking into account the direction of the wind, which is directed along the distribution of particles, during the process of coughing or sneezing, particles can spread in 2 s in different ways, so for breathing 0.65 m, for coughing 1.63 m, for sneezing 2.86 m. It should be noted that in order to reduce the risk of infection, not only these factors play a much role, but also the time period of influence in which a person is located.
Conclusion
In this work, computational fluid dynamics was used to investigate the effect of body temperature and the heating of the earth's surface from sunlight on the transport and dispersion of particles produced by coughing or sneezing in open space. Computational calculations have been made of the emission of particles during normal human breathing, sneezing, and coughing. The verification of the model for test problem is in good agreement with the experimental data, which was described in details in the papers (Issakhov et al. 2021a, b; Issakhov et al. 2022a, b, c) and it can be said that the entire mechanism is effectively simulated.
Based on the results of a numerical calculation on the transfer and distribution of particles or droplets formed during normal breathing, sneezing, or coughing in open space, taking into account the temperature of the human body and the floor surface, the following conclusions were made: during a normal breathing process, particles or droplets can be transferred only for short distances, when sneezing or coughing, the particles are carried almost the same distance, the difference is only in the range. Also, the presence of body temperature and the floor surface strongly influences the propagation of the particles and the thermal plume is completely destroyed due to the speed of the incoming wind. However, the presence of temperature at high ejection velocities transport particles over a much greater distance.
It can be seen, even with simple breathing and taking into account the body temperature, there is a risk of infection. Thus, concluding it was vital to keep a distance between people in the open air in order to reduce the risk of infection. According to the results of the study, it is recommended not to stand or talk to people face to face in the area in the direction of the wind in order to reduce the risk of infection, to comply with quarantine measures and at the same time maintain social distance. At the initial time, the distance of particle propagation depends on the mode of breathing, since after the process of coughing or sneezing in 2 s, the particles can spread in different ways, so the distance for simple breathing can be noted 0.65 m, the distance for coughing is 1.63 m, the distance for sneezing is 2.86 m. As can be seen by taking into account the effect of temperature of human and the heating of the ground surface from the sun's rays in an open space for the process of sneezing, a 2-m social distance may not be sufficient. It should be added that the obtained results do not take into account some influencing factors, such as humidity, evaporation of droplets, etc. Despite this study considered complex phenomena, such as the transfer of a particle in open space, taking into account the temperature of the body and the surface of the ground prevent the transmission of infectious diseases more realistic conditions.
Author contribution
Alibek Issakhov has made the conception, designs of the study, writing the manuscript and interpretation of data. Perizat Omarova and Aizhan Abylkassyova have made simulation, visualization, analysis, and interpretation of data.
Funding
This work is supported by the grant from the Ministry of Education and Science of the Republic of Kazakhstan (AP09259783).
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Consent to participate
Not applicable.
Consent for publication
All authors agree to publish.
Conflict of interest
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Alexei Pichardo-Orta F, Patiño-Luna AO, Vélez-Cordero JR (2022) Natural ventilation in urban buses: from negative pressure to velocity-driven dispersion of aerosols.10.21203/rs.3.rs-1308008/v1
Birgand G Peiffer-Smadja N Fournier S Kerneis S Lescure F-X Lucet J-C Assessment of air contamination by SARS-CoV-1 in hospital settings J Am Med Assoc 2020 3 12 e20333232 10.1001/jamaetworkopen.2020.33232
Busco G Yang SR Seo J Hassan YA Sneezing and asymptomatic virus transmission Phys Fluids 2020 32 7 073309 10.1063/5.0019090
Bai Y Yao L Wei T Tian F Jin D-Y Chen L Presumed asymptomatic carrier transmission of COVID-19 J Am Med Assoc 2020 323 1406 1407 10.1001/jama.2020.2565
Bartzis J Efthimiou G Andronopoulos S Modelling short term individual exposure from airborne hazardous releases in urban environments J Hazard Mater 2015 300 182 188 10.1016/j.jhazmat.2015.06.057 26184800
Chan JFW Yuan S Kok KH To KK Chu H Yang J Xing F Liu J Yip CCY Poon RWS A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Lancet 2020 395 514 523 10.1016/S0140-6736(20)30154-9 31986261
Cai J, Sun W, Huang J, Gamber M, Wu J, He G (2020) Indirect virus transmission in cluster of COVID-19 cases, Wenzhou, China, 2020. Emerging Infect Dis 26(6). 10.3201/eid2606.200412
Chia PY Coleman KK Tan YK Ong SWX Gum M Lau SK Sutjipto S Lee PH Son TT Young BE Detection of air and surface contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hospital rooms of infected patients Nat Commun 2020 11 1 7 10.1038/s41467-020-16670-2 31911652
Chao CYH Wan MP Morawska L Johnson GR Ristovski ZD Hargreaves M Mengersen K Corbett S Li Y Xie X Katoshevski D Characterization of expiration air jets and droplet size distributions immediately at the mouth opening J Aerosol Sci 2009 40 122 133 10.1016/j.jaerosci.2008.10.003 32287373
Cole EC Cook CE Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies Am J Infect Control 1998 26 4 453 464 10.1016/s0196-6553(98)70046-x 9721404
Chen L Hang J Sandberg M Claesson L Di Sabatino S Wigo H The impacts of building height variations and building packing densities on flow adjustment and city breathability in idealized urban models Build Environ 2017 118 344 361 10.1016/j.buildenv.2017.03.042
Duguid JP The size and the duration of air-carriage of respiratory droplets and droplet-nuclei J Hyg 1945 54 471 479
Dbouk T, Drikakis D (2020) On coughing and airborne droplet transmission to humans. Phys Fluids 32:053310–1–053310–10. 10.1063/5.0011960
Escombe AR, Oeser C, Gilman RH, Navincopa M, Ticona E, Martinez C, …, Evans CA (2007) The detection of airborne transmission of tuberculosis from HIV-infected patients, using an in vivo air sampling model. Clin Infect Dis 44(10):1349–1357.10.1086/515397
Feng Y Marchal T Sperry T Yi H Influence of wind and relative humidity on the social distancing effectiveness to prevent COVID-19 airborne transmission: a numerical study J Aerosol Sci 2020 147 105585 10.1016/j.jaerosci.2020.105585 32427227
Grimalt JO Vílchez H Fraile-Ribotc PA Marco E Campins A Orfila J van Drooge BL Fanjul F Spread of SARS-CoV-2 in hospital areas Environ Res 2022 204 Part B, March 2022 112074 10.1016/j.envres.2021.112074 34547251
Gupta JK Lin C-H Chen Q Flow dynamics and characterization of a cough Indoor Air 2009 19 6 517 525 10.1111/j.1600-0668.2009.00619.x 19840145
Gao C Li Y Wei J Cotton S Hamilton M Wang L Cowling B Multi-route respiratory infection: when a transmission route may dominate Sci Total Environ 2021 752 141856 10.1016/j.scitotenv.2020.141856 32889280
Hinds WC (1982) Aerosol technology: properties, behavior, and measurement of airborne particles. Wiley, New York, p. 504.
Holmes NS Morawska L A review of dispersion modelling and its application to the dispersion of particles: an overview of different dispersion models available Atmos Environ 2006 40 30 5902 5928 10.1016/j.atmosenv.2006.06.00
Hasan A Tracking the flu virus in a room mechanical ventilation using CFD tools and effective disinfection of an HVAC system Int J Air-Cond Refrig 2020 10.1142/s2010132520500194
He L Hang J Wang X Lin B Li X Lan G Numerical investigations of flow and passive pollutant exposure in high-rise deep street canyons with various street aspect ratios and viaduct settings Sci Total Environ 2017 584–585 189 206 10.1016/j.scitotenv.2017.01.138
Issakhov A Mashenkova A Numerical study for the assessment of pollutant dispersion from a thermal power plant under the different temperature regimes Int J Environ Sci Technol 2019 10.1007/s13762-019-02211-y
Issakhov A Omarova P Numerical simulation of pollutant dispersion in the residential areas with continuous grass barriers Int J Environ Sci Technol 2019 10.1007/s13762-019-02517-x
Issakhov A Omarova P Issakhov As Numerical study of thermal influence to pollutant dispersion in the idealized urban street road Air Qual Atmos Health 2020 10.1007/s11869-020-00856-0
Issakhov A Alimbek A Issakhov As A numerical study for the assessment of air pollutant dispersion with chemical reactions from a thermal power plant Eng Appl Comput Fluid Mech 2020 10.1080/19942060.2020.1800515
Issakhov A Alimbek A Zhandaulet Y The assessment of water pollution by chemical reaction products from the activities of industrial facilities: Numerical study J Clean Prod 2021 282 125239 10.1016/j.jclepro.2020.125239
Issakhov A Zhandaulet Y Omarova P Alimbek A Borsikbayeva A Mustafayeva A A numerical assessment of social distancing of preventing airborne transmission of COVID-19 during different breathing and coughing processes Sci Rep 2021 11 9412 10.1038/s41598-021-88645-2 33941805
Issakhov A Omarova P Modelling and analysis of the effects of barrier height on automobiles emission dispersion J Clean Prod 2021 10.1016/j.jclepro.2021.126450
Issakhov A Zhandaulet Y Numerical simulation of thermal pollution zones’ formations in the water environment from the activities of the power plant Eng Appl Comput Fluid Mech 2019 10.1080/19942060.2019.1584126
Issakhov A Borsikbayeva A The impact of a multilevel protection column on the propagation of a water wave and pressure distribution during a dam break: numerical simulation J Hydrol 2021 10.1016/j.jhydrol.2021.126212
Issakhov A Abylkassymova A Issakhov A Assessment of the influence of the barriers height and trees with porosity properties on the dispersion of emissions from vehicles in a residential area with various types of building developments J Clean Prod 2022 366 132581 10.1016/j.jclepro.2022.132581
Issakhov A Tursynzhanova A Abylkassymova A Numerical study of air pollution exposure in idealized urban street canyons: porous and solid barriers Urban Climate 2022 43 101112 10.1016/j.uclim.2022.101112
Issakhov A Omarova P Borsikbayeva A Assessment of airborne transmission from coughing processes with thermal plume adjacent to body and radiators on effectiveness of social distancing Environ Sci Pollut Res 2022 10.1007/s11356-022-18713-1
Issakhov A, Alimbek A, Abylkassymova A(2022) Numerical modeling of water pollution by products of chemical reactions from the activities of industrial facilities at variable and constant temperatures of the environment. J Contamin Hydrol 104116–S0169772222001644 104116. 10.1016/j.jconhyd.2022.104116
Jones WP and Launder BE (1972) The prediction of laminarization with a two-equation model of turbulence. Int J Heat Mass Trans 15(2):301–314 0017931072900762. 10.1016/0017-9310(72)90076-2
Kissler S Tedijanto C Goldstein E Grad Y Lipsitch M Projecting the transmission dynamics of SARS-CoV-2 through the post pandemic period Science 2020 368 6493 860 868 10.1126/science.abb5793 32291278
Kampf G Todt D Pfaender S Steinmann E Persistence of coronaviruses on inanimate surfaces and its inactivation with biocidal agents J Hosp Infect 2020 10.1016/j.jhin.2020.01.022
Li H Leong FY Xu G Ge Z Kang CW Lim KH Dispersion of evaporating cough droplets in tropical outdoor environment Phys Fluids 2020 32 113301 10.1063/5.0026360
Li Y Wang J-X Chen X Can a toilet promote virus transmission? From a fluid dynamics perspective Phys Fluids 2020 32 6 065107 10.1063/5.0013318
Leclair JM Zaia JA Levin MJ Congdon RG Goldmann DA Airborne transmission of chickenpox in a hospital N Engl J Med 1980 302 8 450 453 10.1056/nejm198002213020807 7351951
Lowen AC Mubareka S Steel J Palese P Influenza virus transmission is dependent on relative humidity and temperature PLoS Pathog 2007 3 10 e151 10.1371/journal.ppat.0030151 17953482
Li F Liu J Ren J Cao X Zhu Y Numerical investigation of airborne contaminant transport under different vortex structures in the aircraft cabin Int J Heat Mass Transf 2016 96 287 295 10.1016/j.ijheatmasstransfer.2016.01.004 32226103
Liu C Ng C Wong C A theory of ventilation estimate over hypothetical urban areas J Hazard Mater 2015 296 9 16 10.1016/j.jhazmat.2015.04.018 25901939
Li X Shang Y Yan Y Yang L Tu J Modelling of evaporation of cough droplets in inhomogeneous humidity fields using the multi-component Eulerian-Lagrangian approach Build Environ 2018 128 68 76 10.1016/j.buildenv.2017.11.025 32287977
Memarzadeh F Literature review of the effect of temperature and humidity on viruses Ashrae Trans 2012 118 1049 1060
Menter FR (1994) Two-Equation Eddy-Viscosity Turbulence Models for Engineering Applications. AIAA J 32(8):1598–1605
Menter FR and Kuntz M (2003) Development and Application of a Zonal DES Turbulence Model for CFX-5, CFX-Validation Report, CFX-VAL17/0503
Morawska L Tang JW Bahnfleth W Bluyssend PM Boerstrae A Buonanno G How can airborne transmission of COVID-19 indoors be minimised? Environ Int 2020 142 105832 10.1016/j.envint.2020.105832 32521345
Mizukoshi A Nakama C Okumura J Azuma K Assessing the risk of COVID-19 from multiple pathways of exposure to SARS-CoV-2: Modeling in health-care settings and effectiveness of nonpharmaceutical interventions Environ Int 2021 147 106338 10.1016/j.envint.2020.106338 33401172
Morawska L Johnson GR Ristovski Z Hargreaves M Mengersen K Chao CYH Li Y Katoshevski D Size distribution and sites of origins of droplets expelled from the human respiratory tract during expiratory activities J Aerosol Sci 2009 40 256 269 10.1016/j.jaerosci.2008.11.002
Park S Choi Y Song D Kim EK Natural ventilation strategy and related issues to prevent coronavirus disease 2019 (COVID-19) airborne transmission in a school building Sci Total Environ 2021 789 147764 10.1016/j.scitotenv.2021.1477 34051507
Papineni RS Rosenthal FS The size distribution of droplets in the exhaled breath of healthy human subjects J Aerosol Med 1997 10 105 116 10.1089/jam.1997.10.105 10168531
Pendar M-R, Páscoa JC (2020) Numerical modeling of the distribution of virus carrying saliva droplets during sneeze and cough. Phys Fluids 32:083305–1–083305–18. 10.1063/5.0018432
Psikuta A, Allegrini J, Koelblen B, Bogdan A, Annaheim S, Martínez N, Derome D, Carmeliet J, Rossi RM (2017) Thermal manikins controlled by human thermoregulation models for energy efficiency and thermal comfort research – A review. Renew Sustain Energy Rev 78:1315–1330
Redrow J Mao S Celik I Posada JA Feng Z Modeling the evaporation and dispersion of airborne sputum droplets expelled from a human cough Build Environ 2011 46 10 2042 2051 10.1016/j.buildenv.2011.04.011
Rencken GK Rutherford EK Ghanta N Kongoletos J Glicksman L Patterns of SARS-CoV-2 aerosol spread in typical classrooms Build Environ 2021 204 108167 10.1016/j.buildenv.2021.10816 34305270
Roy CJ Milton DK Airborne transmission of communicable infection — the elusive pathway N Engl J Med 2004 350 17 1710 1712 10.1056/nejmp048051 15102996
Smieszek T Lazzari G Salathé M Assessing the dynamics and control of droplet and aerosol-transmitted influenza using an indoor positioning system Nat Sci Rep 2019 9 2185
Sattar SA Ijaz MK Gerba CP Spread of viral infections by aerosols Crit Rev Environ Control 1987 17 2 89 131 10.1080/10643388709388331
Schaffer FL Soergel ME Straube DC Survival of airborne influenza virus: Effects of propagating host, relative humidity, and composition of spray fluids Adv Virol 1976 51 4 263 273 10.1007/bf01317930
Scungio M Stabile L Rizza V Pacitto A Russi A Buonanno G Lung cancer risk assessment due to traffic-generated particles exposure in urban street canyons: a numerical modelling approach Sci Total Environ 2018 631–632 1109 1116 10.1016/j.scitotenv.2018.03.093
Spalart PR (1997) Comments on the feasibility of LES for wing and on a hybrid RANS/LES approach. 1st ASOSR CONFERENCE on DNS/LES. Arlington
Takanabe Y Maruoka Y Kondo J Yagi S Chikazu D Okamoto R Saitoh M Dispersion of aerosols generated during dental therapy Int J Environ Res Public Health 2021 18 21 11279 10.3390/ijerph182111279 34769795
Tang JW The effect of environmental parameters on the survival of airborne infectious agents J Royal Soc Interface 2009 6 Suppl_6 S737 S746 10.1098/rsif.2009.0227.focus
Tung N Cheng P Chi K Hsiao T Jones T BéruBé K Ho KF Chuang H Particulate matter and SARS-CoV-2: a possible model of COVID-19 transmission Sci Total Environ 2021 750 141532 10.1016/j.scitotenv.2020.141532 32858292
Verma TN Sahu AK Sinha SL Numerical simulation of air pollution control in hospital Air Pollut Control 2017 10.1007/978-981-10-7185-0_11
van Doremalen N Bushmaker T Morris DH Holbrook MG Gamble A Williamson BN Tamin A Harcourt JL Thornburg NJ Gerber SI Lloyd-Smith JO de Wit E Munster VJ Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1 N Engl J Med 2020 382 1564 1567 10.1056/nejmc2004973 32182409
Weissberg D, Böni J, Rampini SK, Kufner V, Zaheri M, Schreiber PW, …, Wolfensberger A (2020) Does respiratory co-infection facilitate dispersal of SARS-CoV-2? investigation of a super-spreading event in an open-space office. Antimicrob Resist Infect Control 9(1). 10.1186/s13756-020-00861-z
Wang J Yang W Pan L Ji J Shen J Zhao K Ying B Wang X Zhang L Wang L Shi X Prevention and control of COVID-19 in nursing homes, orphanages, and prisons Environ Pollut 2020 266 115161 10.1016/j.envpol.2020.115161 32645554
Wang W Yao X Shu J Air advection induced differences between canopy and surface heat islands Sci Total Environ 2020 725 138120 10.1016/j.scitotenv.2020.138120 32298885
Wei J Li Y Airborne spread of infectious agents in the indoor environment Am J Infect Control 2016 44 9 S102 S108 10.1016/j.ajic.2016.06.003 27590694
World Health Organization (2020) Coronavirus disease (COVID-19) advice for the public. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-forpublic. Accessed 15 Nov 2020
Xian P Xu X Li Y Cheng L Zhou X Ren B Transmission routes of 2019-nCoV and controls in dental practice Int J Oral Sci 2020 12 9 10.1038/s41368-020-0075-9 32127517
Xu X Shang Y Tian L Weng W Tu J A numerical study on firefighter nasal airway dosimetry of smoke particles from a realistic composite deck fire J Aerosol Sci 2018 123 91 104 10.1016/j.jaerosci.2018.06.006
Xu X Zhang J Zhu L Huang Q Settings open access review transmission of SARS-CoV-2 indoor and outdoor environments Atmosphere 2021 12 12 1640 10.3390/atmos12121640
Ye F Xu S Zhihua R Xu R Liu X Deng P Delivery of infection from asymptomatic carriers of COVID-19 in a familial cluster Int J Infect Dis 2020 94 133 138
Yang H Chen T Lin Y Buccolieri R Mattsson M Zhang M Hang J Wang Q Integrated impacts of tree planting and street aspect ratios on CO dispersion and personal exposure in full-scale street canyons Build Environ 2020 169 106529 10.1016/j.buildenv.2019.106529
Yao Y Pan J Wang W Liu Z Kan H Qiu Y Meng X Wang W Association of particulate matter pollution and case fatality rate of COVID-19 in 49 Chinese cities Sci Total Environ 2020 741 140396 10.1016/j.scitotenv.2020.140396 32592974
Zhao B Zhang Z Li X Numerical study of the transport of droplets or particles generated by respiratory system indoors Build Environ 2005 40 8 1032 1039 10.1016/j.buildenv.2004.09.01 32287997
Zee M et al (2021) Computational fluid dynamics modeling of cough transport in an aircraft cabin. Sci Rep 11:23329–10. 10.1038/s41598-021-02663-8
Zhang H Li D Xie L Xiao Y Documentary research of human respiratory droplet characteristics Procedia Eng 2015 121 1365 1374 10.1016/j.proeng.2015.09.023 32288921
Zhang L Li Y Dispersion of coughed droplets in a fully-occupied high-speed rail cabin Build Environ 2012 47 58 66 10.1016/j.buildenv.2011.03.015
Zhang X Weerasuriya A Tse K CFD simulation of natural ventilation of a generic building in various incident wind directions: comparison of turbulence modelling, evaluation methods, and ventilation mechanisms Energy Build 2020 229 110516 10.1016/j.enbuild.2020.110516
Zhang K Chen G Zhang Y Liu S Wang X Wang B Hang J Integrated impacts of turbulent mixing and NOx-O3 photochemistry on reactive pollutant dispersion and intake fraction in shallow and deep street canyons Sci Total Environ 2020 712 135553 10.1016/j.scitotenv.2019.135553 31787286
Zhang X, Ji Y, Yue Y, Liu H, Wang J (2020c) Infection risk assessment of COVID-19 through aerosol transmission: a case study of south China seafood market. Environ Sci Technol
| 36478554 | PMC9734804 | NO-CC CODE | 2022-12-14 23:28:30 | no | Environ Sci Pollut Res Int. 2022 Dec 7;:1-23 | utf-8 | Environ Sci Pollut Res Int | 2,022 | 10.1007/s11356-022-24067-5 | oa_other |
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Nat Rev Microbiol
Nat Rev Microbiol
Nature Reviews. Microbiology
1740-1526
1740-1534
Nature Publishing Group UK London
36474012
825
10.1038/s41579-022-00825-7
Review Article
A molecular understanding of alphavirus entry and antibody protection
http://orcid.org/0000-0003-4101-6642
Kim Arthur S. 12
http://orcid.org/0000-0002-8791-3165
Diamond Michael S. [email protected]
3456
1 grid.214007.0 0000000122199231 Department of Chemistry, The Scripps Research Institute, La Jolla, CA USA
2 grid.214007.0 0000000122199231 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA USA
3 grid.4367.6 0000 0001 2355 7002 Department of Medicine, Washington University School of Medicine, Saint Louis, MO USA
4 grid.4367.6 0000 0001 2355 7002 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO USA
5 grid.4367.6 0000 0001 2355 7002 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO USA
6 grid.4367.6 0000 0001 2355 7002 The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO USA
6 12 2022
112
1 11 2022
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Alphaviruses are arthropod-transmitted RNA viruses that cause epidemics of human infection and disease on a global scale. These viruses are classified as either arthritogenic or encephalitic based on their genetic relatedness and the clinical syndromes they cause. Although there are currently no approved therapeutics or vaccines against alphaviruses, passive transfer of monoclonal antibodies confers protection in animal models. This Review highlights recent advances in our understanding of the host factors required for alphavirus entry, the mechanisms of action by which protective antibodies inhibit different steps in the alphavirus infection cycle and candidate alphavirus vaccines currently under clinical evaluation that focus on humoral immunity. A comprehensive understanding of alphavirus entry and antibody-mediated protection may inform the development of new classes of countermeasures for these emerging viruses.
In this Review, Kim and Diamond highlight recent advances in our understanding of the host factors required for alphavirus entry, the mechanisms of action by which protective antibodies inhibit different steps in the alphavirus infection cycle and candidate alphavirus vaccines currently under clinical evaluation.
Subject terms
Alphaviruses
Viral infection
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pmcIntroduction
Alphaviruses are single-stranded, positive-sense RNA viruses of the Togaviridae family that cause worldwide outbreaks with substantial morbidity. These viruses are categorized into groups based on their genetic relatedness and clinical manifestations. Arthritogenic alphaviruses, including chikungunya virus (CHIKV), Ross River virus (RRV), O’nyong’nyong virus (ONNV), Barmah Forest virus (BFV), Mayaro virus (MAYV) and Sindbis virus (SINV), cause musculoskeletal disease that is characterized by fever, rash, arthralgia, myalgia, myositis and acute and chronic polyarthritis1. Encephalitic alphaviruses, including Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV) and Venezuelan equine encephalitis virus (VEEV), infect cells in the central nervous system and cause meningitis and encephalitis, often with long-term debilitating neurological sequelae2,3.
Socioeconomic and ecological factors, including urbanization and climate change, have affected the geographical distribution of mosquito-borne alphaviruses and enabled their emergence and spread (Box 1)4,5. Alphaviruses are principally transmitted by Aedes, Culiseta and Culex mosquito species, which facilitates infection of a range of mammalian and avian hosts5. As an example, over the past two decades, CHIKV has caused large-scale epidemics in Africa and Southeast Asia. In 2005–2006, an outbreak occurred on La Réunion island, where 266,000 cases of CHIKV infection were reported6. Subsequent epidemics occurred in Africa and Asia, and CHIKV emerged and spread in the Caribbean islands and the Americas in 2013–2014, with millions of infections documented7. RRV and BFV are endemic and enzootic in Australia8, and MAYV is emerging in Central and South America9. Encephalitic alphaviruses are a concern given their ability to cause severe neurological disease and their potential to be used in biological warfare10. A VEEV outbreak in South America in 1995 resulted in over 75,000 infected cases with 300 deaths11. Annual EEEV outbreaks occur in the United States, and the case-fatality rate is near 50%, although the number of human infections remains low. Despite their potential for epidemic spread and for causing severe disease, no specific countermeasures exist to combat or prevent alphavirus infections.
In this Review, we highlight recent advances in our understanding of alphavirus entry and antibody-mediated protection. As other reviews on these topics have been published, here we focus on new developments12–14. Technological advances, such as functional genomic screens and human monoclonal antibody isolation methods, have facilitated new mechanistic insights and development of strategies to combat emerging and re-emerging alphavirus infections.
Box 1 Social and clinical impact of alphavirus infections Owing to their epidemic outbreak potential, several alphaviruses including chikungunya virus (CHIKV), Eastern equine encephalitis virus, Venezuelan equine encephalitis virus and Western equine encephalitis virus are listed as Category B pathogens on the National Institute of Allergy and Infectious Diseases pathogen priority list. Alphaviruses are a global public health threat as reflected by the social and economic consequences that occur during outbreaks. The 2006 CHIKV epidemic on La Réunion island affected approximately one-third of the population and had an estimated economic burden of €43.9 million165. The economic burden from a subsequent CHIKV outbreak in the US Virgin Islands in 2014 ranged from US$14.8 million to $33.4 million, with a substantial fraction of individuals having long-term disability from CHIKV-induced chronic disease166. The emergence and re-emergence of alphavirus epidemics can be attributed in part to climate change, which enables increased vector-borne disease outbreaks and transmission167. Vector adaptation has also enhanced the spread and dissemination of alphaviruses as seen in the 2006 La Réunion island epidemic168.
Alphaviruses are clinically distinguished by their ability to cause either arthritogenic or encephalitic disease. Acute clinical symptoms from arthritogenic alphavirus infection include fever, malaise, polyarthritis, myositis, myalgia and maculopapular rash1,169. Chronic disease can lead to persistent joint pain and inflammation. Encephalitic alphavirus infections can cause fever, meningitis, encephalitis and long-term neurological sequelae or death3. To date, treatment for alphavirus infections consists only of supportive care. Because of the disease alphaviruses cause and the potential for epidemic transmission, further studies to identify treatment and vaccine strategies against alphaviruses are warranted.
Alphavirus infection cycle and structure
The alphavirus RNA genome (~12 kb) encodes four nonstructural proteins (nsP1, nsP2, nsP3 and nsP4) and five structural proteins (capsid, E3, E2, 6K/TF and E1)15–17. Together, these proteins mediate viral transcription, replication and host cell antagonism18. The surface of the 70-nm virion is composed of 80 trimeric E2–E1 heterodimer spikes arranged in T = 4 icosahedral symmetry15,19,20 (Fig. 1). Each trimeric subunit can mediate viral attachment and entry, and E2 and E1 are the principal targets for neutralizing antibodies15.Fig. 1 Alphavirus structure and entry mechanisms.
The alphavirus virion (Protein Data Bank (PDB) ID: 6NK6) is composed of 80 trimeric E2–E1 heterodimer spikes (blue) arranged in T = 4 icosahedral symmetry. The fivefold (i5, pentagon), threefold (q3 and i3, triangle) and twofold (i2, circle) axes of symmetry are indicated on one icosahedral asymmetric unit (white triangle outline). An E2–E1 heterotrimer is shown in the zoomed left inset with E2 proteins depicted in light cyan, medium cyan and dark cyan, and E1 proteins depicted in light grey, medium grey and dark grey. Alphavirus entry is mediated by the E2 and E1 structural proteins through several attachment factors — namely, heparan sulfate, C-type lectin receptors (DC-SIGN55 and L-SIGN) and phosphatidylserine receptors (TIM1 (ref.163), TIM4 and AXL164) — and receptors (NRAMP2 (ref.64), MXRA8 (refs.20,35), LDLRAD3 (refs.67,68), VLDLR70 and ApoER2 (ref.70)). Upon attachment, the alphavirus virion undergoes clathrin-mediated internalization (endocytosis) and subsequent membrane fusion in the endosome. The nucleocapsid is disassembled in the cytoplasm and releases viral RNA, which encodes four nonstructural proteins (nsP1, nsP2, nsP3 and nsP4) and five structural proteins (capsid, E3, E2, 6K/TF and E1). The viral nonstructural proteins are synthesized after translation of the input viral RNA to generate a replication complex for synthesis of additional genomic (blue) and subgenomic (green) viral RNA. The subgenomic viral RNA encodes the viral structural proteins, which are processed in the endoplasmic reticulum (ER) and Golgi complex and are subsequently transported to the plasma membrane for assembly and budding of virions. CHIKV, chikungunya virus; EEEV, Eastern equine encephalitis virus; MAYV, Mayaro virus; NA, not applicable; ONNV, O’nyong’nyong virus; RRV, Ross River virus; SFV, Semliki Forest virus; SINV, Sindbis virus; VEEV, Venezuelan equine encephalitis virus; WEEV, Western equine encephalitis virus. Virion diagram adapted with permission from ref.20, Elsevier.
The E3 and E2 glycoproteins are synthesized as the precursor p62 protein, which is subsequently cleaved by furin21,22. The E3 glycoprotein is a chaperone for the folding of the other structural proteins and prevents premature conformational changes of the E2–E1 heterodimer during transit through the acidic environment of the secretory pathway23–25. Although the E3 glycoprotein is cleaved during the maturation process, for some alphaviruses (for example, SINV and CHIKV) it can remain bound to the mature E2–E1 heterodimer15,20,26. E3 dissociation also depends on the pH of the culture medium and the confluency of infected cells24. The E2 protein comprises three domains (A, B and C), with domain A situated towards the centre of the trimeric spike, domain B on the outermost tip of the spike and domain C proximal to the viral membrane15. The E2 protein has key roles in attachment to cellular receptors and is a primary target of neutralizing antibodies20,27–35. Although implicated in glycoprotein processing and in virion assembly and release, the precise role of the 6K/TF membrane protein is less well understood17,36,37. In addition, these transmembrane proteins have been excluded from the recombinant protein preparations used for structural analysis owing to their hydrophobic nature15. The E1 protein is a class II fusion protein that comprises three domains (I, II and III) and mediates viral membrane fusion via a hydrophobic peptide15,38,39. Although the fusion peptide is normally hidden beneath E2 domain B, upon exposure to low pH in the early endosome, the E1 protein undergoes rearrangement, which enables fusion peptide insertion into the host lipid membrane38–41. Upon endosomal membrane fusion, the nucleocapsid penetrates into the cytoplasm, it disassembles, and genomic viral RNA is released and translated. The nonstructural proteins form a replication complex for subsequent synthesis of genomic and subgenomic viral RNA. The subgenomic RNA encodes viral structural proteins, which are translocated to the endoplasmic reticulum and transited to the Golgi complex where the glycoproteins undergo processing and maturation18. The newly synthesized genomic RNA is packaged with capsid proteins to form the nucleocapsid core18. The processed glycoproteins and the nucleocapsid are transported through either the secretory pathway or the cytopathic vacuole type II pathway to the plasma membrane, where virion assembly and budding occurs42–44.
Alphavirus entry
Alphavirus entry into cells requires the engagement of attachment factors, receptors and endocytosis. The broad cellular tropism of alphaviruses is due in part to the utilization of multiple host factors during the attachment and entry process. Recently performed functional genomics and biochemical screens have provided new details as to how arthritogenic and encephalitic alphaviruses enter cells.
Alphaviruses can utilize multiple molecules to attach to the surface of host cells (Fig. 1). Heparan sulfate, a negatively charged glycosaminoglycan, interacts with positively charged amino acids in the E2–E1 heterodimer as described for CHIKV (E2–R82)45,46, RRV (E2–R218)47, SINV (E2–K70 and E2–R114)48, EEEV (E2–K71, E2–K74 and E2–K74)19,49,50 and VEEV (E2–K76, E2–K120 and E2–K209)51. Alphavirus dependence on heparan sulfate for binding occurs naturally or as an adaptation to cell culture passage45,52. The acquisition of positively charged amino acids that enable heparan sulfate binding increases viral infection in vitro but generally reduces pathogenesis in vivo51,53 except for EEEV, for which heparan sulfate binding can increase neurovirulence in mice49. C-type lectins, including dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and liver/lymph node-specific intracellular adhesion molecules-3 grabbing non-integrin (L-SIGN), are other reported attachment factors for alphaviruses. SINV produced in mosquito cells, which skews glycosylation to high-mannose N-linked oligosaccharides, shows greater binding to cells expressing DC-SIGN and L-SIGN54, which is consistent with their preferential binding to proteins displaying high-mannose glycans55. Phosphatidylserine receptor proteins, such as TIM1, TIM4 and AXL, promote alphavirus attachment through interaction with phosphatidylserine on the viral membrane56,57. However, the extent to which these phosphatidylserine receptors enhance alphavirus attachment and infection is dependent on virus and cell type, as differences in utilization were observed in macrophages, keratinocytes and hepatocytes56,58. Further studies are warranted to elucidate the role of phosphatidylserine receptor proteins as alphavirus attachment factors and their contributions to pathogenesis.
The discovery of bona fide entry receptors for alphaviruses has historically been challenging. Although several putative receptors for alphaviruses have been identified using biochemical methods and genome-wide cDNA screens, direct physical binding to virions or effects of genetic ablation of the host factor on infection have not been demonstrated (Fig. 1). The laminin receptor was identified as an entry factor for SINV using a panel of antibodies reactive to host proteins59. Subsequent biochemical studies also implicated the laminin receptor as a receptor for VEEV60, and similar methods have been utilized to identify other possible host receptors for alphaviruses including prohibitin and CD147 for CHIKV61,62 and MHC class I for Semliki Forest virus (SFV)63. Application of a genome-wide RNA interference screen in Drosophila cells identified the metal ion transporter NRAMP and, subsequently, the mammalian orthologue NRAMP2 as receptors for SINV64. NRAMP2 was required for binding and infection by SINV but not for RRV. Gene editing of NRAMP2 in vitro and dNRAMP in Drosophila reduced SINV infection, establishing the role of these proteins in SINV infection in vitro and in vivo.
Recent advances with CRISPR–Cas9-based genome-wide screening have enabled the identification of several host receptors that facilitate alphavirus infection and pathogenesis (Fig. 1). Mouse MXRA8, a dual-immunoglobulin-like domain molecule, was identified as a receptor for multiple arthritogenic alphaviruses including CHIKV, MAYV, ONNV, RRV and SFV, but not for encephalitic alphaviruses or SINV35. Deletion of MXRA8 or its human orthologue reduced infection by arthritogenic alphaviruses. Direct binding was observed between MXRA8 and CHIKV, which was abrogated by anti-MXRA8 monoclonal antibodies (mAbs), anti-CHIKV mAbs or soluble MXRA8-Fc decoy molecules. X-ray crystallography and cryo-electron microscopy (cryo-EM) studies confirmed the MXRA8–CHIKV interaction and revealed a unique binding mode with both domains of MXRA8 engaging the E2 and E1 proteins on the alphavirus virion20,34. Through use of MXRA8-Fc decoy molecules and gene-edited mice, MXRA8 was shown to have a key role in arthritogenic alphavirus infection and disease pathogenesis in vivo35,65,66.
A separate CRISPR–Cas9 screen identified the low-density lipoprotein (LDL) family scavenger receptor LDLRAD3 as a receptor for VEEV67. Gene editing of LDLRAD3 abrogated infection of VEEV but not of EEEV or WEEV. Biophysical experiments demonstrated direct binding between domain 1 of LDLRAD3 and the VEEV p62–E1 structural protein. Administration of a LDLRAD3-domain 1-Fc decoy molecule or gene editing of LDLRAD3 in mice abolished VEEV infection and pathogenesis. Cryo-EM studies revealed that LDLRAD3 engages VEEV E2–E1 in a mechanism analogous to that by which CHIKV engages MXRA8, albeit with a smaller footprint on the virion68,69. Both MXRA8 and LDLRAD3 recognize similar sites on the virion that encompass residues in both E2 (domains A and B) and E1 (domain II) proteins. Most recently, another CRISPR–Cas9 screen identified two additional LDL-scavenger receptors, VLDLR and ApoER2, that promote infection by SFV, EEEV and SINV70. Administration of a VLDLR-Fc decoy molecule prolonged survival in SFV-infected mice.
The identification of NRAMP2, MXRA8, LDLRAD3, VLDLR and ApoER2 as alphavirus host receptors may explain the broad and differential host tropism of alphaviruses. Structural studies are needed to determine whether NRAMP2, VLDLR and ApoER2 engage the E2–E1 proteins of SINV, SFV and EEEV in a manner similar to the engagement of MXRA8 and LDLRAD3 with other alphaviruses. Understanding the molecular and structural basis of the interaction between alphaviruses and host receptors could facilitate the identification of mAbs, receptor decoys or small-molecule inhibitors that prevent alphavirus entry, infection and pathogenesis.
Protective monoclonal antibodies
The use of mAb therapy to combat emerging viruses has recently been shown as a promising and feasible strategy against SARS-CoV-2 as both prophylaxis and therapy71,72. Modifications to the Fc region can extend the half-life of mAbs up to approximately 90 days71,73. Over the past five decades, antibody-mediated protection against alphavirus infection has been studied intensively. Passive transfer of purified polyclonal antibodies or mAbs with neutralizing activity confers protection against alphavirus challenge in animals. Non-neutralizing alphavirus mAbs can also confer protection in animals via Fc effector functions and engagement of cell-mediated immune mechanisms. In all cases, protective antibodies target the E3, E2 and E1 proteins on the alphavirus heterodimer.
In early studies, researchers infected mice with different alphaviruses and used B cell–myeloma fusion and hybridoma technology to generate mAbs against the structural proteins of SFV74,75, SINV76,77, RRV78 and the encephalitic alphaviruses79–81. The most protective mAbs in vivo recognized different epitopes on the alphavirus E2 or E1 protein. These seminal studies used competition binding assays to classify and identify mAbs as specific to alphavirus E2 or E1 proteins. Although these experiments provided valuable insight as to how antibody-mediated protection occurred, this Review highlights more recently described mouse and human mAbs (Table 1) against the alphavirus structural proteins, including many mAbs with comprehensive epitope mapping or structural characterization, extensive in vivo protection data, mechanism-of-action data and cross-reactivity among alphaviruses.Table 1 Summary of alphavirus monoclonal antibodies described in this Review
Domain Alphavirus class Antibody Species Key binding residues within specified domaina Alphavirus reactivity Protective efficacy (prophylactic) Protective efficacy (therapeutic)
E2 domain A Arthritogenic CHK-152 Mouse D59 CHIKV >70% survival 30–70% survival
IM-CKV063 Human E24, G55, W64, K66, R80, I121 CHIKV >70% survival 30–70% survival
MAY-X Absb Mouse S27-H29, T57-T61, G72-E77, S81-H86 MAYV >70% survival 30–70% survival
RRV-92 Human K66, V75 RRV 30–70% survival ND
RRV-196 Human G60, K66, Y69 RRV ND ND
Encephalitic EEEV-18 Mouse M68 EEEV >70% survival 30–70% survival
EEEV-82 Mouse M68, L81 EEEV >70% survival 30–70% survival
EEEV-102 Mouse M68, L81 EEEV ND ND
hEEEV-33 Human E34, K74, G116, N118, H120 EEEV >70% survival <30% survival
mVEEV-36 Mouse D56, K62 VEEV >70% survival >70% survival
mVEEV-68 Mouse D56, K62, G63, R64, D94 VEEV >70% survival >70% survival
mVEEV-43 Mouse T49, I110 VEEV >70% survival 30–70% survival
E2 domain B Arthritogenic CHK-265 Mouse Q184, S185, I190, V197, Y199, G209, L210, T212, I217 CHIKV, ONNV, MAYV, RRV, BEBV, UNAV, SFV, GETV >70% survival ND
DC2.M16 Human G209, K215 CHIKV, MAYV >1 log10-fold reduction in viral titres ND
DC2.M108 Human G209, K215 CHIKV, MAYV, ONNV ND ND
DC2.M357 Human K189, N218 CHIKV, ONNV, MAYV, RRV, SFV >1 log10-fold reduction in viral titres ND
MAY-117 Mouse L181, S182, Q183, Q184, S185, G186, I190 MAYV, CHIKV, RRV, UNAV 30–70% survival ND
RRV-12 Human Q183-N187, N218-K221, D223 CHIKV, ONNV, MAYV, RRV, GETV, SAGV ND 30–70% survival
E2 domain C Arthritogenic RRV-210 Human T283, D289 RRV ND ND
RRV-221 Human T283 RRV ND ND
mVEEV-19 Mouse N332 VEEV ND ND
mVEEV-68 Mouse N332 VEEV >70% survival 30–70% survival
E1 domain II Arthritogenic CHK-166 Mouse K61, G64 CHIKV >70% survival 30–70% survival
DC2.112 Human W89, G91, N100 CHIKV, ONNV, MAYV, RRV, BEBV, UNAV, SINV, BBKV, OCKV, BCRV, EEEV, VEEV, WEEV >70% survival >70% survival
DC2.315 Human K52, V54, I55, K61, G83, V84, Y85, M88, Y93, F95, N100 CHIKV, MAYV, RRV, BEBV, UNAV, BCRV, EEEV, VEEV, WEEV >70% survival >70% survival
IM-CKV057 Human W89, N100 CHIKV, EEEV ND ND
IM-CKV061 Human W89, N100 CHIKV, EEEV ND ND
IM-CKV062 Human W89, N100 CHIKV, EEEV ND ND
IM-CKV066 Human G83, Y85, F87, D97 CHIKV ND ND
IM-CKV067 Human W89, N100 CHIKV, EEEV ND ND
Encephalitic EEEV-138 Human F95, N100 CHIKV, EEEV, MADV, VEEV, WEEV ND 30–70% survival
EEEV-179 Human Y93 CHIKV, EEEV, MADV, VEEV, WEEV ND >70% survival
EEEV-346 Human N100 CHIKV, EEEV, VEEV, WEEV 30–70% survival 30–70% survival
1A4B-6 Mouse C94, C96, N100 CHIKV, RRV, SFV, SINV, EEEV, VEEV, WEEV >70% survival ND
Abs, antibodies; BBKV, Babanki virus; BCRV, Buggy Creek virus; BEBV, Bebaru virus; CHIKV, chikungunya virus; EEEV, Eastern equine encephalitis virus; GETV, Getah virus; MADV, Madariaga virus; MAYV, Mayaro virus; ND, not determined; OCKV, Ockelbo virus; ONNV, O’nyong’nyong virus; RRV, Ross River virus; SAGV, Sagiyama virus; SFV, Semliki Forest virus; SINV, Sindbis virus; UNAV, Una virus; VEEV, Venezuelan equine encephalitis virus; WEEV, Western equine encephalitis virus. aResidue numbering is based on the autologous virus from which the monoclonal antibody was generated. bMultiple non-neutralizing anti-MAYV monoclonal antibodies92.
E3 antibodies
The E3 protein participates in transport, stabilization and maturation of the E2–E1 protein, and its dissociation from the virion upon release into the extracellular space enables priming of the E2–E1 spike protein for membrane fusion upon exposure to the acidic environment of the endosome23,24,82. Nonetheless, a cleaved form of E3 can remain bound to the virion of some alphaviruses and under specific culture conditions15,24,25. A panel of mAbs against the E3 protein were isolated from mice inoculated with a recombinant VEEV strain containing a mutation in the furin cleavage site that prevents furin processing and subsequent release of the E3 glycoprotein83. These mAbs neutralized infection by the mutant but not by the parental VEEV strain. Interestingly, among the six anti-E3 neutralizing mAbs, mAb 13D4 protected mice from a lethal challenge with the parental VEEV strain. The mechanism of neutralization and protection by anti-E3 mAbs warrants further study. Moreover, protective or neutralizing mAbs against the E3 protein of arthritogenic alphaviruses have not yet been reported.
E2 antibodies
Epitopes recognized by neutralizing human and mouse antibodies have been identified in all three domains of the E2 protein (Fig. 2a–c). Neutralizing mAbs against the E2 glycoprotein of arthritogenic alphaviruses (CHIKV84–91, RRV86,90,92,93, ONNV86,90, BFV86,87, MAYV86,90,94, SINV and SFV86,90) and encephalitic alphaviruses (EEEV95,96, WEEV97 and VEEV79,81,98,99) have been isolated using classic hybridoma fusions, single-antigen-specific B cell sorting or phage display.Fig. 2 Neutralizing and non-neutralizing monoclonal antibody epitopes on the alphavirus p62–E1 heterotrimer.
The key amino acids of alphavirus monoclonal antibodies (mAbs) described in this Review are highlighted on the chikungunya virus (CHIKV) E2–E1 heterodimer (Protein Data Bank ID: 6NK5). Each E2–E1 panel highlights the amino acids of protective epitopes (magenta spheres) from each mAb class (E2 domain A (part a), E2 domain B (part b), E2 domain C (part c) and E1 domain II (part d)) that are shared by two or more mAbs. CHIKV amino acid numbering is used. EEEV, Eastern equine encephalitis virus; hEEEV, human EEEV; MAYV, Mayaro virus; mVEEV, mouse VEEV; RRV, Ross River virus; VEEV, Venezuelan equine encephalitis virus.
Domain A mAbs
The finding that some mAbs targeting alphavirus E2 domain A could neutralize infection was anticipated based on the hypothesis that this region engaged host cell receptors27,100–103. Although the amino acid sequence of domain A varies among alphaviruses (34–93% sequence identity), several studies have identified mAbs against different alphaviruses that bind in similar regions of domain A and share functional properties. Nonetheless, most neutralizing and protective domain A mAbs are type-specific and do not cross-react or cross-protect against heterologous alphaviruses.
Within domain A, both neutralizing and protective mAbs have been localized predominantly to residues 56–81 and, to a lesser extent, residues 99–121, indicating an exposed protective epitope (Fig. 2a). Here we highlight selected mAbs for which the binding epitopes and protective activity have been extensively evaluated. The mAb CHK-152 was isolated from CHIKV-infected mice after viral clearance and potently neutralized laboratory-adapted and clinical strains by inhibiting viral fusion85. Through neutralization escape selection85, residue 59 in domain A was identified as a critical interaction residue, which was corroborated by cryo-EM studies100. Passive transfer of CHK-152 protected against CHIKV challenge in immunocompetent and immunocompromised mice85 and reduced virus dissemination and tissue injury in rhesus macaques104. Human mAbs targeting similar epitopes in domain A of E2 have been identified from individuals with a previous history of arthritogenic alphavirus infection. Potently neutralizing mAbs isolated from individuals infected with CHIKV through either hybridoma fusion87 or phage display (mAb IM-CKV063)88 were mapped to domain A residues 55–81 and 99–121 through alanine-scanning mutagenesis and shown to protect mice against CHIKV pathogenesis88. In addition, functionally important human mAbs against RRV (mAbs RRV-92 and RRV-196) that engage residues 60–75 within domain A were isolated from individuals with a previous history of RRV infection92. Two RRV mAbs (RRV-92 and RRV-196) and IM-CKV063 protected mice against RRV and CHIKV infection, respectively.
Despite the sequence variation in domain A between arthritogenic and encephalitic alphaviruses, protective mAbs that target similar residues in encephalitic alphaviruses have been identified. Panels of mouse and human mAbs against domain A of the EEEV E2 glycoprotein have been isolated95,96,105. Through neutralization escape, mutagenesis and cryo-EM studies, three protective mouse mAbs (EEEV-18, EEEV-82 and EEEV-102) were mapped to residue 68 in domain A in addition to amino acids in domain B19,95. The human mAb EEEV-33 protected mice from lethal EEEV aerosol challenge and engaged domain A residues 34, 74 and 116–120 along with some contacts in domain B (residues 195–197)96. These mAbs inhibited early entry stages of EEEV infection. Neutralizing and protective VEEV mAbs have been mapped to similar residues in domain A by escape selection, alanine-scanning mutagenesis and structural analysis98,106. Protective mouse anti-VEEV mAbs (mVEEV-36 and mVEEV-68) bound an epitope in domain A spanning residues 56–64 (ref.98). These mAbs inhibited most stages of VEEV infection, including viral attachment to the LDLRAD3 receptor, fusion and egress, and protected mice against VEEV infection98. Collectively, the identification of mouse and human mAbs against domain A residues 56–81 establishes a protective epitope shared by both arthritogenic and encephalitic alphaviruses.
Domain A mAbs with poor neutralizing activity can also confer protection. The most protective non-neutralizing anti-MAYV mAbs recognized two linear epitopes in domain A (residues 57–61 and 159–163) (Fig. 2a), demonstrated high affinity to MAYV virions and prevented MAYV-induced musculoskeletal disease107. Protective activity against MAYV was mediated through monocyte-dependent Fc effector functions, as loss of protection occurred with monocyte depletion or introduction of mutations that abrogated engagement of Fc-γ receptors108,109. Similar findings were reported for a poorly neutralizing mAb, mVEEV-43, which protected mice against VEEV challenge, although the mechanism of action was not investigated98. Protection may be mediated by elimination of infected cells by antibody-dependent cellular phagocytosis or cytolysis, as alphavirus-infected cells display high levels of E2–E1 proteins on the cell surface42,108. An alternative protective mechanism, as demonstrated for SINV, may be non-cytolytic clearance of virus in which neutralizing domain A mAbs signal to decrease viral RNA synthesis and budding110–112. Interestingly, both non-neutralizing and neutralizing domain A mAbs against MAYV, CHIKV, RRV, EEEV and VEEV recognize proximal epitopes (for example, targeting residues 57–61). Although further analysis is required, differences in epitope recognition including the angle of mAb approach or tertiary and quaternary interactions could determine the neutralizing activity of mAbs that ostensibly bind to similar epitopes.
Domain B mAbs
Domain B is the most membrane-distal region of the alphavirus E2–E1 heterodimer15,16,30 and another target of neutralizing and protective mAbs (Fig. 2b). Domain B is positioned above the fusion loop and prevents premature fusion loop exposure. As with domain A, several studies have described mouse and human mAbs to domain B that protect against arthritogenic or encephalitic alphavirus infection. The relatively conserved sequence of domain B among arthritogenic alphaviruses (CHIKV versus ONNV: 86%)86 correlates with the identification of cross-reactive and cross-protective mAbs that target two epitopes spanning residues 180–199 in the A–B strands and 209–223 in the C–C′ strands, respectively (Fig. 2b). Studies on mechanism of action revealed that these domain B mAbs inhibit multiple stages of viral infection, including virus attachment, fusion and egress.
The mouse mAb CHK-265, which was isolated from mice infected with CHIKV85, neutralized multiple arthritogenic alphaviruses including CHIKV, MAYV, RRV, ONNV and SFV86,113. Mutagenesis and cryo-EM experiments revealed that CHK-265 recognizes residues in both the A–B strands (residues 184, 185, 190, 197 and 199) and the C–C′ strands (residues 209, 210, 211 and 217). RRV-12, which was isolated from an RRV-immune individual, potently neutralized multiple arthritogenic alphaviruses and bound to RRV domain B residues 183–187, 218–221 and 223, analogous to CHK-265 (ref.93). Both CHK-265 and RRV-12 inhibited multiple steps of the viral replication cycle and protected mice against infection and disease caused by CHIKV, MAYV and RRV. DC2.M357, which was isolated by single-B cell sorting from an individual with a history of CHIKV infection, neutralized infection by CHIKV, MAYV, ONNV, RRV and SFV90. Neutralization escape selection studies with DC2.M357 showed that binding of this mAb depends on residues 189 and 218 in domain B, which are proximal to the CHK-265 and RRV-12 epitopes. Cross-reactive neutralizing mAbs have also been isolated from mice inoculated with MAYV94. The protective mAb MAY-117 shares a virtually identical epitope with CHK-265 and RRV-12, as mutagenesis studies identified domain B residues 184, 185, 190 and 210 as critical for binding. Collectively, the overlapping binding epitopes, cross-reactivity and therapeutic studies indicate that some domain B-binding mAbs (for example, CHK-265, RRV-12, DC2.M357 and MAY-117) share a conserved, broadly neutralizing and protective epitope.
Cross-reactive mAbs with more limited breadth against arthritogenic alphaviruses that map to a second epitope in domain B have been identified through single-B cell sorting89,90. Virus neutralization escape studies identified domain B residues 209 and 215 as critical for neutralization by mAbs DC2.M16 and DC2.M108. These residues are separate from the binding epitope of CHK-265, RRV-12 and DC2.M357. Although many arthritogenic or encephalitic type-specific domain B mAbs have been isolated85–87,92,95,96,98,99,114,115, certain molecular determinants, such as recognition of residues 184 and 185, seem to be required for cross-reactivity. Although mAbs that are broadly reactive to this epitope have been elicited to arthritogenic alphaviruses in both mice and humans, such mAbs have not been described for encephalitic alphaviruses, possibly owing to the greater sequence divergence in domain B between EEEV, VEEV and WEEV (31–46%)15.
Domain C mAbs
Domain C is located proximal to the virus membrane and is much less accessible for mAbs to bind on the prefusion alphavirus trimer15,16. However, mAbs to RRV92 and VEEV98 domain C have been identified that block alphavirus engagement with host receptors, although these mAbs have additional contacts in domains A and/or B (Fig. 2c). In this section, we briefly highlight neutralizing domain C mAbs.
From individuals with previous RRV infection, two neutralizing mAbs, RRV-210 and RRV-221, were shown through alanine-scanning mutagenesis to recognize residue 283 in domain C along with residues in domains A and B92. These mAbs blocked MXRA8 receptor binding to RRV, thereby demonstrating a possible neutralization mechanism. Two neutralizing mAbs from mice inoculated with VEEV, mVEEV-19 and mVEEV-68, which also blocked LDLRAD3 receptor binding, bound residue 332 in domain C98. Analogous to the RRV mAbs, the VEEV mAbs also engaged residues in domain A. mVEEV-68 conferred protection against VEEV in mice, suggesting that domain C might be a protective mAb epitope. However, as these mAbs recognize residues in multiple domains, how much of this protection originates from domain C remains to be determined.
E1 antibodies
Although the E1 protein is not exposed to the same extent as the E2 protein, alphavirus-specific and cross-reactive E1 mAbs to SINV and encephalitic alphaviruses have been reported80,116–120. The E1 protein comprises three domains (I, II and II) and is situated beneath the E2 protein (Fig. 1). Domain I is located centrally in the E1 protein between domains II and III and is relatively inaccessible on the mature virion15. Domain III is located proximal to the viral membrane. To date, no neutralizing or protective mAbs to domains I or III have been identified. Within domain II is the hydrophobic fusion loop responsible for membrane fusion, and mAbs to this domain have been described. Although a majority of E1 mAbs have poor neutralizing activity in vitro, some protect in vivo85,119. In contrast to E2 mAbs, which protect primarily through neutralization, mAbs binding to epitopes proximal and within the fusion loop in domain II of E1 (Fig. 2d) protect by inhibiting viral morphogenesis and egress or through Fc-mediated effector mechanisms121–123.
The mAb CHK-166 was isolated from mice infected with CHIKV and mapped through neutralization escape to residue 61 in domain II of E1, which is proximal to the fusion loop85. Although CHK-166 exhibited moderate neutralizing activity in vitro, monovalent or combination therapy with CHK-152 protected mice against CHIKV-induced mortality principally through a mechanism dependent on monocyte-mediated Fc effector functions85,124. Other studies identified poorly neutralizing mAbs against residues in the E1 fusion loop (for example, F95 and N100) that were broadly cross-reactive to both arthritogenic and encephalitic alphaviruses and protective against multiple alphaviruses in mice121,122. These epitopes were not accessible on the intact virion, which explains the poor neutralizing activity of these mAbs. The EEEV mouse mAb 1A4B-6, which cross-reacts with multiple alphaviruses including CHIKV, RRV, SINV, SFV, EEEV, VEEV and WEEV, was shown to protect mice against a lethal VEEV challenge116,123. As with previously reported protective E1 mAbs121,122, subsequent alanine-scanning mutagenesis experiments identified N100 as a critical E1 residue for 1A4B-6 binding123.
Other studies have identified mAbs to similar residues in domain II, although the in vivo efficacy or protective mechanisms were not determined. From a phage display library constructed from the peripheral blood of individuals immune to CHIKV, five E1 mAbs were found to recognize similar key residues (for example, residue N100) in the fusion loop through alanine-scanning mutagenesis88. From mice immunized with CHIKV 6K–E1 protein, a subset of mAbs with poor neutralizing activity were established as cross-reactive against both arthritogenic and encephalitic alphaviruses, although protection and key binding residues were not evaluated125.
The isolation of human and mouse mAbs to the E1 fusion loop from both natural infection and immunization suggests that the alphavirus fusion loop is an immunodominant epitope. The E1 residue N100, at the distal end of the fusion loop, is highly conserved among all alphaviruses15,121 and is a critical binding residue for all broadly protective E1 mAbs (Fig. 2d). This class of E1 mAbs holds potential as a pan-alphavirus immunotherapy and presents a new target towards the development of a pan-alphavirus immunogen.
Development of antibody-based therapies
To date, no alphavirus mAb has been licensed for use in humans. However, mAb therapy has been shown to have promise in the prevention of virus infection126 as demonstrated with respiratory syncytial virus127 and more recently with SARS-CoV-2 (refs.128,129). Passive immunization of mice and nonhuman primates (NHPs)130 with neutralizing mAbs has been demonstrated to confer protection against alphavirus infection. In this section, we highlight the preclinical studies demonstrating protective efficacy of alphavirus mAbs beyond mouse models and one that utilized a novel delivery platform to control alphavirus infection.
Both mAb monotherapy and combination therapy have been shown to have therapeutic efficacy against alphavirus infection in NHP models. Administration of the E2 mAb 4N12 (ref.87) to rhesus macaques reduced CHIKV-induced disease and acute inflammation130. In an NHP study with VEEV, two anti-E2 mAbs, 1A3B-7 and 1A4A-1, protected animals against severe VEEV disease and reduced viraemia as monotherapy131. Despite the protective efficacy of these mAbs, viral sequencing of serum from NHPs revealed escape mutations in their domain B epitope within 4 days of infection. To overcome rapid viral escape from mAb therapy, combination therapies have been evaluated. Therapeutic administration of mAbs CHK-152 and CHK-166 protected rhesus macaques from CHIKV infection and dissemination104. Although previous studies identified virus escape mutants against CHK-152 or CHK-166 in cell culture or in mice when used as monotherapy, escape mutations were not identified in the rhesus macaques given combination therapy85,104. Thus, combination therapy against two separate mAb epitopes may limit the emergence of viral escape mutations and resistance.
Although the studies described above have utilized passive transfer of mAbs in animals, limitations exist including the medical complexity of delivery and high cost of treatment. To overcome these limitations, a recent study evaluated whether lipid nanoparticles (LNPs) containing mRNA encoding a potently neutralizing CHIKV mAb could protect against infection and disease132. Administration of mAb CHKV-24 protected mice from CHIKV-induced disease and abrogated viraemia. When evaluated in an NHP model, protective levels of mAb CHKV-24 were achieved upon LNP administration. In addition, CHKV-24 mRNA-LNPs have been evaluated in clinical trials and produced no serious adverse effects (NCT03829384)133. Given the safety and recent success with mRNA-based vaccines against SARS-CoV-2 (ref.134), the development of mRNA-encoded mAbs may hold promise for limiting alphavirus infection and disease.
Alphavirus vaccine approaches
Although alphavirus vaccines are not currently approved for humans, many candidates have been evaluated in animals and advanced to clinical-phase testing. Various approaches have been used to generate live-attenuated viral vaccines, including the introduction of attenuating mutations or deletions in structural and nonstructural proteins or the ablation of the p62 furin cleavage site135–145. Inactivated virus vaccines have been generated by chemical treatment of infectious virions, for example, with formalin137,146,147. Virus-like particle (VLP) vaccines, which are composed of only the structural proteins, recapitulate the structural features of the virion but are not infectious148–150. Adenoviral and measles-based vectors have been used as a delivery platform for alphavirus protein immunogens145,151–154. These viral vectors often induce more potent CD8 T cell responses155. Several alphavirus candidates prevent alphavirus infection and disease in animals and have been advanced into clinical trials, which we review here (Table 2).Table 2 Alphavirus vaccine candidates in advanced clinical development
Type of vaccine Vaccine candidate Clinical trial sponsor Clinical trial identifier
Live-attenuated VLA1553 (CHIKV)
VEE 3526 (VEEV)
VEE TC-83 (VEEV)
Valneva
DynPort Vaccine
USAMRIID
NCT04546724
NCT00109304
NCT00582504
Inactivated BBV87 (CHIKV)
TSI-GSD 104 (EEEV)
VEE C-84 (VEEV)
TSI-GSD 210 (WEEV)
Bharat Biotech
USAMRIID
USAMRIID
USAMRIID
NCT04566484
NCT00584805
NCT00582088
NCT02466750, NCT01159561
Virus-like particle VRC-CHKVLP059 (CHIKV)
PXVX0317 (CHIKV)
VRC-WEVVLP073 (EEEV/VEEV/WEEV)
NIH/NIAID
Emergent BioSolutions
NIH/NIAID
NCT01489358, NCT02562482
NCT03483961, NCT05072080
NCT03879603
Viral vector MV-CHIK (CHIKV)
ChAdOx1 Chik (CHIKV)
Themis Bioscience
University of Oxford
NCT03101111, NCT02861586, NCT03807843
NCT03590392
mRNA-based mRNA-1944 (CHIKV) Moderna NCT03829384
CHIKV, chikungunya virus; EEEV, Eastern equine encephalitis virus; NIAID, National Institute of Allergy and Infectious Diseases; USAMRIID, United States Army Medical Research Institute of Infectious Diseases; VEEV, Venezuelan equine encephalitis virus; WEEV, Western equine encephalitis virus.
Given the epidemic potential of CHIKV, most clinical trials have focused on vaccines against this emerging alphavirus. Current vaccines against CHIKV that are under evaluation include recombinant VLPs composed of the structural proteins C–E3–E2–6K–E1 (NCT03483961, NCT05072080, NCT02562482 and NCT01489358)156,157, measles (NCT03101111, NCT02861586 and NCT03807843)158 and adenoviral (NCT03590392)159 vectors that express the C–E3–E2–6K–E1 structural proteins, and live-attenuated viruses (NCT04546724 and NCT04566484). Generally, these vaccines have been shown as safe and immunogenic in early clinical trials. One of the most advanced candidates is the live-attenuated VLA1553 CHIKV vaccine, which has a large deletion in the nsP3 replicase region145. In a recently completed phase III trial, VLA1553 was shown to have good safety and tolerability profiles and to elicit high levels of neutralizing antibody in serum (NCT04546724). Because encephalitic alphaviruses pose a substantial threat due to high mortality, neurological sequelae and possible weaponization, clinical trials to evaluate encephalitic alphavirus vaccines have begun. Live-attenuated vaccine trials against EEEV (NCT02654509 and NCT00584805), VEEV (NCT00109304, NCT00582504 and NCT00582088) and WEEV (NCT02466750 and NCT01159561) have been initiated, although there are concerns of reactogenicity and limited immunogenicity160,161. To address these limitations, replication-incompetent trivalent VLPs composed of the EEEV, VEEV and WEEV structural proteins were generated based on a strategy utilized for the CHIKV VLP-based vaccine148,150. Administration of the trivalent vaccine to NHPs conferred complete protection against all three encephalitic alphaviruses, and this vaccine is currently under evaluation in a phase I clinical trial (NCT03879603).
Concluding remarks
The identification of mAbs that engage protective epitopes on arthritogenic and encephalitic alphaviruses provides an opportunity to understand humoral immune responses during infection or immunization, develop mAb therapeutic strategies and, more importantly, guide iterative vaccine design. There are numerous challenges with vaccine development, but the understanding of immunodominant and protective B cell epitopes during alphavirus infection is a major component of advancing vaccine development. In theory, such information can be used to focus the induction of neutralizing mAbs on protective alphavirus epitopes through reverse vaccinology162. Although this Review has focused on mAb neutralization as a primary protective mechanism, other immune correlates should be considered during alphavirus vaccine design including T cell responses and cell-mediated immunity. The most advanced alphavirus vaccine clinical trials to date (NCT04546724 and NCT03483961) have focused on analysing neutralizing antibody responses, although going forward it will be important to profile other responses when evaluating immune correlates of protection. The intensive study of antibody protection, receptor biology, antigenicity and vaccine development has enabled the development and new strategies to counteract alphavirus infection. Such approaches may provide a pathway for the rapid development of countermeasures against alphavirus infection that limit future morbidity, mortality and epidemic transmission.
Acknowledgements
The authors thank J. Fox for insightful discussions and comments. Research in the authors’ laboratories was supported by US NIH grants R01 AI143673, U19 AI142790, R01 AI164653, R01 AI141436 and R01 AI127513 (to M.S.D.), and T32 AI172293 (to A.S.K.). A.S.K. acknowledges support from Open Philanthropy and the Life Sciences Research Foundation.
Author contributions
A.S.K. and M.S.D. contributed equally to all aspects of the article.
Peer review
Peer review information
Nature Reviews Microbiology thanks the anonymous reviewers for their contribution to the peer review of this work.
Competing interests
M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, Immunome and Emergent BioSolutions. A.S.K. declares no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Suhrbier A Jaffar-Bandjee MC Gasque P Arthritogenic alphaviruses — an overview Nat. Rev. Rheumatol. 2012 8 420 429 10.1038/nrrheum.2012.64 22565316
2. Carrera JP Eastern equine encephalitis in Latin America N. Engl. J. Med. 2013 369 732 744 10.1056/NEJMoa1212628 23964935
3. Morens DM Folkers GK Fauci AS Eastern equine encephalitis virus — another emergent arbovirus in the United States N. Engl. J. Med. 2019 381 1989 1992 10.1056/NEJMp1914328 31747726
4. Baker RE Infectious disease in an era of global change Nat. Rev. Microbiol. 2022 20 193 205 10.1038/s41579-021-00639-z 34646006
5. Weaver SC Reisen WK Present and future arboviral threats Antivir. Res. 2010 85 328 345 10.1016/j.antiviral.2009.10.008 19857523
6. Schuffenecker I Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak PLoS Med. 2006 3 e263 10.1371/journal.pmed.0030263 16700631
7. Rezza G Dengue and chikungunya: long-distance spread and outbreaks in naive areas Pathog. Glob. Health 2014 108 349 355 10.1179/2047773214Y.0000000163 25491436
8. Harley D Sleigh A Ritchie S Ross River virus transmission, infection, and disease: a cross-disciplinary review Clin. Microbiol. Rev. 2001 14 909 932 10.1128/CMR.14.4.909-932.2001 11585790
9. Aguilar-Luis MA An emerging public health threat: Mayaro virus increases its distribution in Peru Int. J. Infect. Dis. 2020 92 253 258 10.1016/j.ijid.2020.01.024 31978575
10. Sidwell RW Smee DF Viruses of the Bunya- and Togaviridae families: potential as bioterrorism agents and means of control Antivir. Res. 2003 57 101 111 10.1016/S0166-3542(02)00203-6 12615306
11. Weaver SC Re-emergence of epidemic Venezuelan equine encephalomyelitis in South America. VEE Study Group Lancet 1996 348 436 440 10.1016/S0140-6736(96)02275-1 8709783
12. Torres-Ruesta A Chee RS Ng LFP Insights into antibody-mediated alphavirus immunity and vaccine development landscape Microorganisms 2021 10.3390/microorganisms9050899
13. Kafai NM Diamond MS Fox JM Distinct cellular tropism and immune responses to alphavirus infection Annu. Rev. Immunol. 2022 40 615 649 10.1146/annurev-immunol-101220-014952 35134315
14. Holmes AC Basore K Fremont DH Diamond MS A molecular understanding of alphavirus entry PLoS Pathog. 2020 16 e1008876 10.1371/journal.ppat.1008876 33091085
15. Voss JE Glycoprotein organization of chikungunya virus particles revealed by X-ray crystallography Nature 2010 468 709 712 10.1038/nature09555 21124458
16. Li L Jose J Xiang Y Kuhn RJ Rossmann MG Structural changes of envelope proteins during alphavirus fusion Nature 2010 468 705 708 10.1038/nature09546 21124457
17. Snyder JE Functional characterization of the alphavirus TF protein J. Virol. 2013 87 8511 8523 10.1128/JVI.00449-13 23720714
18. Jose J Snyder JE Kuhn RJ A structural and functional perspective of alphavirus replication and assembly Fut. Microbiol. 2009 4 837 856 10.2217/fmb.09.59
19. Hasan SS Cryo-EM structures of Eastern equine encephalitis virus reveal mechanisms of virus disassembly and antibody neutralization Cell Rep. 2018 25 3136 3147.e5 10.1016/j.celrep.2018.11.067 30540945
20. Basore K Cryo-EM structure of chikungunya virus in complex with the Mxra8 receptor Cell 2019 177 1725 1737.e16 10.1016/j.cell.2019.04.006 31080061
21. Zhang X Fugere M Day R Kielian M Furin processing and proteolytic activation of Semliki Forest virus J. Virol. 2003 77 2981 2989 10.1128/JVI.77.5.2981-2989.2003 12584323
22. de Curtis I Simons K Dissection of Semliki Forest virus glycoprotein delivery from the trans-Golgi network to the cell surface in permeabilized BHK cells Proc. Natl Acad. Sci. USA 1988 85 8052 8056 10.1073/pnas.85.21.8052 3186706
23. Uchime O Fields W Kielian M The role of E3 in pH protection during alphavirus assembly and exit J. Virol. 2013 87 10255 10262 10.1128/JVI.01507-13 23864626
24. Sjöberg M Lindqvist B Garoff H Activation of the alphavirus spike protein is suppressed by bound E3 J. Virol. 2011 85 5644 5650 10.1128/JVI.00130-11 21430054
25. Snyder AJ Mukhopadhyay S The alphavirus E3 glycoprotein functions in a clade-specific manner J. Virol. 2012 86 13609 13620 10.1128/JVI.01805-12 23035234
26. Chen L Implication for alphavirus host-cell entry and assembly indicated by a 3.5A resolution cryo-EM structure Nat. Commun. 2018 9 5326 10.1038/s41467-018-07704-x 30552337
27. Davis NL Pence DF Meyer WJ Schmaljohn AL Johnston RE Alternative forms of a strain-specific neutralizing antigenic site on the Sindbis virus E2 glycoprotein Virology 1987 161 101 108 10.1016/0042-6822(87)90175-9 2445100
28. Flynn DC Olmsted RA Mackenzie JM Jr Johnston RE Antibody-mediated activation of Sindbis virus Virology 1988 166 82 90 10.1016/0042-6822(88)90149-3 3413988
29. Meyer WJ Johnston RE Structural rearrangement of infecting Sindbis virions at the cell surface: mapping of newly accessible epitopes J. Virol. 1993 67 5117 5125 10.1128/jvi.67.9.5117-5125.1993 7688818
30. Smith TJ Putative receptor binding sites on alphaviruses as visualized by cryoelectron microscopy Proc. Natl Acad. Sci. USA 1995 92 10648 10652 10.1073/pnas.92.23.10648 7479858
31. Mukhopadhyay S Mapping the structure and function of the E1 and E2 glycoproteins in alphaviruses Structure 2006 14 63 73 10.1016/j.str.2005.07.025 16407066
32. Ubol S Griffin DE Identification of a putative alphavirus receptor on mouse neural cells J. Virol. 1991 65 6913 6921 10.1128/jvi.65.12.6913-6921.1991 1658382
33. Vrati S Kerr PJ Weir RC Dalgarno L Entry kinetics and mouse virulence of Ross River virus mutants altered in neutralization epitopes J. Virol. 1996 70 1745 1750 10.1128/jvi.70.3.1745-1750.1996 8627696
34. Song H Molecular basis of arthritogenic alphavirus receptor MXRA8 binding to chikungunya virus envelope protein Cell 2019 177 1714 1724.e12 10.1016/j.cell.2019.04.008 31080063
35. Zhang R Mxra8 is a receptor for multiple arthritogenic alphaviruses Nature 2018 557 570 574 10.1038/s41586-018-0121-3 29769725
36. Ramsey J Mukhopadhyay S Disentangling the frames, the state of research on the alphavirus 6K and TF proteins Viruses 2017 10.3390/v9080228
37. Loewy A Smyth J von Bonsdorff CH Liljestrom P Schlesinger MJ The 6-kilodalton membrane protein of Semliki Forest virus is involved in the budding process J. Virol. 1995 69 469 475 10.1128/jvi.69.1.469-475.1995 7983743
38. Lescar J The fusion glycoprotein shell of Semliki Forest virus: an icosahedral assembly primed for fusogenic activation at endosomal pH Cell 2001 105 137 148 10.1016/S0092-8674(01)00303-8 11301009
39. Roussel A Structure and interactions at the viral surface of the envelope protein E1 of Semliki Forest virus Structure 2006 14 75 86 10.1016/j.str.2005.09.014 16407067
40. Gibbons DL Visualization of the target-membrane-inserted fusion protein of Semliki Forest virus by combined electron microscopy and crystallography Cell 2003 114 573 583 10.1016/S0092-8674(03)00683-4 13678581
41. Gibbons DL Conformational change and protein-protein interactions of the fusion protein of Semliki Forest virus Nature 2004 427 320 325 10.1038/nature02239 14737160
42. Jin J Neutralizing antibodies inhibit chikungunya virus budding at the plasma membrane Cell Host Microbe 2018 24 417 428.e5 10.1016/j.chom.2018.07.018 30146390
43. Soonsawad P Structural evidence of glycoprotein assembly in cellular membrane compartments prior to alphavirus budding J. Virol. 2010 84 11145 11151 10.1128/JVI.00036-10 20739526
44. Jose J Taylor AB Kuhn RJ Spatial and temporal analysis of alphavirus replication and assembly in mammalian and mosquito cells mBio 2017 10.1128/mBio.02294-16
45. Silva LA A single-amino-acid polymorphism in chikungunya virus e2 glycoprotein influences glycosaminoglycan utilization J. Virol. 2014 88 2385 2397 10.1128/JVI.03116-13 24371059
46. Tanaka A Genome-wide screening uncovers the significance of N-sulfation of heparan sulfate as a host cell factor for chikungunya virus infection J. Virol. 2017 10.1128/jvi.00432-17
47. Zhang W Heil M Kuhn RJ Baker TS Heparin binding sites on Ross River virus revealed by electron cryo-microscopy Virology 2005 332 511 518 10.1016/j.virol.2004.11.043 15680416
48. Byrnes AP Griffin DE Binding of Sindbis virus to cell surface heparan sulfate J. Virol. 1998 72 7349 7356 10.1128/JVI.72.9.7349-7356.1998 9696831
49. Gardner CL Ebel GD Ryman KD Klimstra WB Heparan sulfate binding by natural Eastern equine encephalitis viruses promotes neurovirulence Proc. Natl Acad. Sci. USA 2011 108 16026 16031 10.1073/pnas.1110617108 21896745
50. Gardner CL Natural variation in the heparan sulfate binding domain of the Eastern equine encephalitis virus E2 glycoprotein alters interactions with cell surfaces and virulence in mice J. Virol. 2013 87 8582 8590 10.1128/JVI.00937-13 23720725
51. Bernard KA Klimstra WB Johnston RE Mutations in the E2 glycoprotein of Venezuelan equine encephalitis virus confer heparan sulfate interaction, low morbidity, and rapid clearance from blood of mice Virology 2000 276 93 103 10.1006/viro.2000.0546 11021998
52. Klimstra WB Ryman KD Johnston RE Adaptation of Sindbis virus to BHK cells selects for use of heparan sulfate as an attachment receptor J. Virol. 1998 72 7357 7366 10.1128/JVI.72.9.7357-7366.1998 9696832
53. Ashbrook AW Residue 82 of the chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice J. Virol. 2014 88 12180 12192 10.1128/JVI.01672-14 25142598
54. Klimstra WB Nangle EM Smith MS Yurochko AD Ryman KD DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses J. Virol. 2003 77 12022 12032 10.1128/JVI.77.22.12022-12032.2003 14581539
55. Feinberg H Mitchell DA Drickamer K Weis WI Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR Science 2001 294 2163 2166 10.1126/science.1066371 11739956
56. Jemielity S TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine PLoS Pathog. 2013 9 e1003232 10.1371/journal.ppat.1003232 23555248
57. Moller-Tank S Kondratowicz AS Davey RA Rennert PD Maury W Role of the phosphatidylserine receptor TIM-1 in enveloped-virus entry J. Virol. 2013 87 8327 8341 10.1128/JVI.01025-13 23698310
58. Kirui J The phosphatidylserine receptor TIM-1 enhances authentic chikungunya virus cell entry Cells 2021 10.3390/cells10071828
59. Wang KS Kuhn RJ Strauss EG Ou S Strauss JH High-affinity laminin receptor is a receptor for Sindbis virus in mammalian cells J. Virol. 1992 66 4992 5001 10.1128/jvi.66.8.4992-5001.1992 1385835
60. Ludwig GV Kondig JP Smith JF A putative receptor for Venezuelan equine encephalitis virus from mosquito cells J. Virol. 1996 70 5592 5599 10.1128/jvi.70.8.5592-5599.1996 8764073
61. Wintachai P Identification of prohibitin as a chikungunya virus receptor protein J. Med. Virol. 2012 84 1757 1770 10.1002/jmv.23403 22997079
62. De Caluwé L The CD147 protein complex is involved in entry of chikungunya virus and related alphaviruses in human cells Front. Microbiol. 2021 12 615165 10.3389/fmicb.2021.615165 33717005
63. Helenius A Human (HLA-A and HLA-B) and murine (H-2K and H-2D) histocompatibility antigens are cell surface receptors for Semliki Forest virus Proc. Natl Acad. Sci. USA 1978 75 3846 3850 10.1073/pnas.75.8.3846 278998
64. Rose PP Natural resistance-associated macrophage protein is a cellular receptor for Sindbis virus in both insect and mammalian hosts Cell Host Microbe 2011 10 97 104 10.1016/j.chom.2011.06.009 21843867
65. Kim AS An evolutionary insertion in the Mxra8 receptor-binding site confers resistance to alphavirus infection and pathogenesis Cell Host Microbe 2020 27 428 440.e9 10.1016/j.chom.2020.01.008 32075743
66. Zhang R Expression of the Mxra8 receptor promotes alphavirus infection and pathogenesis in mice and Drosophila Cell Rep. 2019 28 2647 2658.e5 10.1016/j.celrep.2019.07.105 31484075
67. Ma H LDLRAD3 is a receptor for Venezuelan equine encephalitis virus Nature 2020 588 308 314 10.1038/s41586-020-2915-3 33208938
68. Basore K Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor Nature 2021 598 672 676 10.1038/s41586-021-03963-9 34646020
69. Ma B Huang C Ma J Xiang Y Zhang X Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3 Nature 2021 598 677 681 10.1038/s41586-021-03909-1 34646021
70. Clark LE VLDLR and ApoER2 are receptors for multiple alphaviruses Nature 2022 602 475 480 10.1038/s41586-021-04326-0 34929721
71. Levin MJ Intramuscular AZD7442 (tixagevimab–cilgavimab) for prevention of Covid-19 N. Engl. J. Med. 2022 386 2188 2200 10.1056/NEJMoa2116620 35443106
72. Gupta A Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab N. Engl. J. Med. 2021 385 1941 1950 10.1056/NEJMoa2107934 34706189
73. Robbie GJ A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults Antimicrob. Agents Chemother. 2013 57 6147 6153 10.1128/AAC.01285-13 24080653
74. Boere WA Benaissa-Trouw BJ Harmsen M Kraaijeveld CA Snippe H Neutralizing and non-neutralizing monoclonal antibodies to the E2 glycoprotein of Semliki Forest virus can protect mice from lethal encephalitis J. Gen. Virol. 1983 64 1405 1408 10.1099/0022-1317-64-6-1405 6854274
75. Boere WA Identification of distinct antigenic determinants on Semliki Forest virus by using monoclonal antibodies with different antiviral activities J. Virol. 1984 52 575 582 10.1128/jvi.52.2.575-582.1984 6208379
76. Stanley J Cooper SJ Griffin DE Alphavirus neurovirulence: monoclonal antibodies discriminating wild-type from neuroadapted Sindbis virus J. Virol. 1985 56 110 119 10.1128/jvi.56.1.110-119.1985 2411947
77. Stec DS Waddell A Schmaljohn CS Cole GA Schmaljohn AL Antibody-selected variation and reversion in Sindbis virus neutralization epitopes J. Virol. 1986 57 715 720 10.1128/jvi.57.3.715-720.1986 2419586
78. Vrati S Fernon CA Dalgarno L Weir RC Location of a major antigenic site involved in Ross River virus neutralization Virology 1988 162 346 353 10.1016/0042-6822(88)90474-6 2448952
79. Roehrig JT Day JW Kinney RM Antigenic analysis of the surface glycoproteins of a Venezuelan equine encephalomyelitis virus (TC-83) using monoclonal antibodies Virology 1982 118 269 278 10.1016/0042-6822(82)90346-4 6178209
80. Roehrig JT Gorski D Schlesinger MJ Properties of monoclonal antibodies directed against the glycoproteins of Sindbis virus J. Gen. Virol. 1982 59 421 425 10.1099/0022-1317-59-2-421 6281377
81. Roehrig JT Mathews JH The neutralization site on the E2 glycoprotein of Venezuelan equine encephalomyelitis (TC-83) virus is composed of multiple conformationally stable epitopes Virology 1985 142 347 356 10.1016/0042-6822(85)90343-5 2414905
82. Mayne JT Rice CM Strauss EG Hunkapiller MW Strauss JH Biochemical studies of the maturation of the small Sindbis virus glycoprotein E3 Virology 1984 134 338 357 10.1016/0042-6822(84)90302-7 6443592
83. Parker MD Antibody to the E3 glycoprotein protects mice against lethal Venezuelan equine encephalitis virus infection J. Virol. 2010 84 12683 12690 10.1128/JVI.01345-10 20926570
84. Warter L Chikungunya virus envelope-specific human monoclonal antibodies with broad neutralization potency J. Immunol. 2011 186 3258 3264 10.4049/jimmunol.1003139 21278338
85. Pal P Development of a highly protective combination monoclonal antibody therapy against chikungunya virus PLoS Pathog. 2013 9 e1003312 10.1371/journal.ppat.1003312 23637602
86. Fox JM Broadly neutralizing alphavirus antibodies bind an epitope on E2 and inhibit entry and egress Cell 2015 163 1095 1107 10.1016/j.cell.2015.10.050 26553503
87. Smith SA Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus Cell Host Microbe 2015 18 86 95 10.1016/j.chom.2015.06.009 26159721
88. Fong RH Exposure of epitope residues on the outer face of the chikungunya virus envelope trimer determines antibody neutralizing efficacy J. Virol. 2014 88 14364 14379 10.1128/JVI.01943-14 25275138
89. Quiroz JA Human monoclonal antibodies against chikungunya virus target multiple distinct epitopes in the E1 and E2 glycoproteins PLoS Pathog. 2019 15 e1008061 10.1371/journal.ppat.1008061 31697791
90. Malonis RJ Near-germline human monoclonal antibodies neutralize and protect against multiple arthritogenic alphaviruses Proc. Natl Acad. Sci. USA 2021 10.1073/pnas.2100104118
91. Goh LY Neutralizing monoclonal antibodies to the E2 protein of chikungunya virus protects against disease in a mouse model Clin. Immunol. 2013 149 487 497 10.1016/j.clim.2013.10.004 24239837
92. Powell LA Human monoclonal antibodies against Ross River virus target epitopes within the E2 protein and protect against disease PLoS Pathog. 2020 16 e1008517 10.1371/journal.ppat.1008517 32365139
93. Powell LA Human mAbs broadly protect against arthritogenic alphaviruses by recognizing conserved elements of the Mxra8 receptor-binding site Cell Host Microbe 2020 28 699 711.e7 10.1016/j.chom.2020.07.008 32783883
94. Earnest JT Neutralizing antibodies against Mayaro virus require Fc effector functions for protective activity J. Exp. Med. 2019 216 2282 2301 10.1084/jem.20190736 31337735
95. Kim AS Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein Nat. Microbiol. 2019 4 187 197 10.1038/s41564-018-0286-4 30455470
96. Williamson LE Human antibodies protect against aerosolized Eastern equine encephalitis virus infection Cell 2020 183 1884 1900.e23 10.1016/j.cell.2020.11.011 33301709
97. Liu JL Shriver-Lake LC Zabetakis D Goldman ER Anderson GP Selection of single-domain antibodies towards Western equine encephalitis virus Antibodies 2018 10.3390/antib7040044
98. Kafai NM Neutralizing antibodies protect mice against Venezuelan equine encephalitis virus aerosol challenge J. Exp. Med. 2022 10.1084/jem.20212532
99. Porta J Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies J. Virol. 2014 88 9616 9623 10.1128/JVI.01286-14 24920796
100. Sun S Structural analyses at pseudo atomic resolution of chikungunya virus and antibodies show mechanisms of neutralization eLife 2013 2 e00435 10.7554/eLife.00435 23577234
101. Johnston RE Smith JF Selection for accelerated penetration in cell culture coselects for attenuated mutants of Venezuelan equine encephalitis virus Virology 1988 162 437 443 10.1016/0042-6822(88)90484-9 3341117
102. Russell DL Dalrymple JM Johnston RE Sindbis virus mutations which coordinately affect glycoprotein processing, penetration, and virulence in mice J. Virol. 1989 63 1619 1629 10.1128/jvi.63.4.1619-1629.1989 2926866
103. Pence DF Davis NL Johnston RE Antigenic and genetic characterization of Sindbis virus monoclonal antibody escape mutants which define a pathogenesis domain on glycoprotein E2 Virology 1990 175 41 49 10.1016/0042-6822(90)90184-S 2309450
104. Pal P Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes J. Virol. 2014 88 8213 8226 10.1128/JVI.01032-14 24829346
105. EnCheng S Analysis of murine B-cell epitopes on Eastern equine encephalitis virus glycoprotein E2 Appl. Microbiol. Biotechnol. 2013 97 6359 6372 10.1007/s00253-013-4819-8 23512478
106. Agapov EV Localization of four antigenic sites involved in Venezuelan equine encephalomyelitis virus protection Arch. Virol. 1994 139 173 181 10.1007/BF01309462 7529989
107. Earnest JT The mechanistic basis of protection by non-neutralizing anti-alphavirus antibodies Cell Rep. 2021 35 108962 10.1016/j.celrep.2021.108962 33826892
108. Lu LL Suscovich TJ Fortune SM Alter G Beyond binding: antibody effector functions in infectious diseases Nat. Rev. Immunol. 2018 18 46 61 10.1038/nri.2017.106 29063907
109. Tao MH Morrison SL Studies of aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and effector functions mediated by the human IgG constant region J. Immunol. 1989 143 2595 2601 2507634
110. Després P Griffin JW Griffin DE Effects of anti-E2 monoclonal antibody on Sindbis virus replication in AT3 cells expressing bcl-2 J. Virol. 1995 69 7006 7014 10.1128/jvi.69.11.7006-7014.1995 7474120
111. Levine B Antibody-mediated clearance of alphavirus infection from neurons Science 1991 254 856 860 10.1126/science.1658936 1658936
112. Navaratnarajah CK Kuhn RJ Functional characterization of the Sindbis virus E2 glycoprotein by transposon linker-insertion mutagenesis Virology 2007 363 134 147 10.1016/j.virol.2007.01.006 17306321
113. Fox JM A cross-reactive antibody protects against Ross River virus musculoskeletal disease despite rapid neutralization escape in mice PLoS Pathog. 2020 16 e1008743 10.1371/journal.ppat.1008743 32760128
114. Lee CY Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants PLoS Pathog. 2011 7 e1002390 10.1371/journal.ppat.1002390 22144891
115. Strauss EG Stec DS Schmaljohn AL Strauss JH Identification of antigenically important domains in the glycoproteins of Sindbis virus by analysis of antibody escape variants J. Virol. 1991 65 4654 4664 10.1128/jvi.65.9.4654-4664.1991 1714515
116. Roehrig JT Identification of monoclonal antibodies capable of differentiating antigenic varieties of Eastern equine encephalitis viruses Am. J. Trop. Med. Hyg. 1990 42 394 398 10.4269/ajtmh.1990.42.394 2158755
117. Mendoza QP Stanley J Griffin DE Monoclonal antibodies to the E1 and E2 glycoproteins of Sindbis virus: definition of epitopes and efficiency of protection from fatal encephalitis J. Gen. Virol. 1988 69 3015 3022 10.1099/0022-1317-69-12-3015 2462014
118. Schmaljohn AL Johnson ED Dalrymple JM Cole GA Non-neutralizing monoclonal antibodies can prevent lethal alphavirus encephalitis Nature 1982 297 70 72 10.1038/297070a0 6280072
119. Schmaljohn AL Kokubun KM Cole GA Protective monoclonal antibodies define maturational and pH-dependent antigenic changes in Sindbis virus E1 glycoprotein Virology 1983 130 144 154 10.1016/0042-6822(83)90124-1 6195815
120. Stanley J Cooper SJ Griffin DE Monoclonal antibody cure and prophylaxis of lethal Sindbis virus encephalitis in mice J. Virol. 1986 58 107 115 10.1128/jvi.58.1.107-115.1986 2419592
121. Kim AS Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope Cell 2021 184 4414 4429.e19 10.1016/j.cell.2021.07.006 34416146
122. Williamson LE Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress Cell 2021 184 4430 4446.e22 10.1016/j.cell.2021.07.033 34416147
123. Calvert AE Exposing cryptic epitopes on the Venezuelan equine encephalitis virus E1 glycoprotein prior to treatment with alphavirus cross-reactive monoclonal antibody allows blockage of replication early in infection Virology 2022 565 13 21 10.1016/j.virol.2021.09.007 34626907
124. Fox JM Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcγR interaction on monocytes Sci. Immunol. 2019 10.1126/sciimmunol.aav5062
125. Tuekprakhon A Broad-spectrum monoclonal antibodies against chikungunya virus structural proteins: promising candidates for antibody-based rapid diagnostic test development PLoS ONE 2018 13 e0208851 10.1371/journal.pone.0208851 30557365
126. Marston HD Paules CI Fauci AS Monoclonal antibodies for emerging infectious diseases — borrowing from history N. Engl. J. Med. 2018 378 1469 1472 10.1056/NEJMp1802256 29513615
127. Simoes EA Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing J. Pediatr. 2007 151 34 42 10.1016/j.jpeds.2007.02.032 17586188
128. Zost SJ Potently neutralizing and protective human antibodies against SARS-CoV-2 Nature 2020 584 443 449 10.1038/s41586-020-2548-6 32668443
129. Pinto D Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody Nature 2020 583 290 295 10.1038/s41586-020-2349-y 32422645
130. Broeckel R Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques PLoS Negl. Trop. Dis. 2017 11 e0005637 10.1371/journal.pntd.0005637 28628616
131. Burke CW Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure PLoS Pathog. 2019 15 e1008157 10.1371/journal.ppat.1008157 31790515
132. Kose N A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection Sci. Immunol. 2019 10.1126/sciimmunol.aaw6647
133. August A A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against chikungunya virus Nat. Med. 2021 27 2224 2233 10.1038/s41591-021-01573-6 34887572
134. Corbett KS Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates N. Engl. J. Med. 2020 383 1544 1555 10.1056/NEJMoa2024671 32722908
135. Gorchakov R Attenuation of chikungunya virus vaccine strain 181/clone 25 is determined by two amino acid substitutions in the E2 envelope glycoprotein J. Virol. 2012 86 6084 6096 10.1128/JVI.06449-11 22457519
136. Edelman R Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218 Am. J. Trop. Med. Hyg. 2000 62 681 685 10.4269/ajtmh.2000.62.681 11304054
137. Pittman PR Long-term duration of detectable neutralizing antibodies after administration of live-attenuated VEE vaccine and following booster vaccination with inactivated VEE vaccine Vaccine 1996 14 337 343 10.1016/0264-410X(95)00168-Z 8744562
138. Paessler S Recombinant Sindbis/Venezuelan equine encephalitis virus is highly attenuated and immunogenic J. Virol. 2003 77 9278 9286 10.1128/JVI.77.17.9278-9286.2003 12915543
139. Paessler S Replication and clearance of Venezuelan equine encephalitis virus from the brains of animals vaccinated with chimeric SIN/VEE viruses J. Virol. 2006 80 2784 2796 10.1128/JVI.80.6.2784-2796.2006 16501087
140. Rossi SL IRES-containing VEEV vaccine protects cynomolgus macaques from IE Venezuelan equine encephalitis virus aerosol challenge PLoS Negl. Trop. Dis. 2015 9 e0003797 10.1371/journal.pntd.0003797 26020513
141. Trobaugh DW Sun C Dunn MD Reed DS Klimstra WB Rational design of a live-attenuated Eastern equine encephalitis virus vaccine through informed mutation of virulence determinants PLoS Pathog. 2019 15 e1007584 10.1371/journal.ppat.1007584 30742691
142. Tucker PC Griffin DE Mechanism of altered Sindbis virus neurovirulence associated with a single-amino-acid change in the E2 glycoprotein J. Virol. 1991 65 1551 1557 10.1128/jvi.65.3.1551-1557.1991 1995953
143. Wang E Chimeric Sindbis/Eastern equine encephalitis vaccine candidates are highly attenuated and immunogenic in mice Vaccine 2007 25 7573 7581 10.1016/j.vaccine.2007.07.061 17904699
144. Plante K Novel chikungunya vaccine candidate with an IRES-based attenuation and host range alteration mechanism PLoS Pathog. 2011 7 e1002142 10.1371/journal.ppat.1002142 21829348
145. Roques P Attenuated and vectored vaccines protect nonhuman primates against chikungunya virus JCI Insight 2017 2 e83527 10.1172/jci.insight.83527 28352649
146. Robinson DM Cole FE Jr McManus AT Pedersen CE Jr. Inactivated Mayaro vaccine produced in human diploid cell cultures Mil. Med. 1976 141 163 166 10.1093/milmed/141.3.163 815839
147. Tiwari M Assessment of immunogenic potential of Vero adapted formalin inactivated vaccine derived from novel ECSA genotype of chikungunya virus Vaccine 2009 27 2513 2522 10.1016/j.vaccine.2009.02.062 19368794
148. Akahata W A virus-like particle vaccine for epidemic chikungunya virus protects nonhuman primates against infection Nat. Med. 2010 16 334 338 10.1038/nm.2105 20111039
149. Goo L A virus-like particle vaccine elicits broad neutralizing antibody responses in humans to all chikungunya virus genotypes J. Infect. Dis. 2016 214 1487 1491 10.1093/infdis/jiw431 27655868
150. Ko SY A virus-like particle vaccine prevents equine encephalitis virus infection in nonhuman primates Sci. Transl. Med. 2019 10.1126/scitranslmed.aav3113
151. Brandler S A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus Vaccine 2013 31 3718 3725 10.1016/j.vaccine.2013.05.086 23742993
152. Ramsauer K Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial Lancet Infect. Dis. 2015 15 519 527 10.1016/S1473-3099(15)70043-5 25739878
153. Wang D A complex adenovirus vaccine against chikungunya virus provides complete protection against viraemia and arthritis Vaccine 2011 29 2803 2809 10.1016/j.vaccine.2011.01.108 21320541
154. Henning L Endt K Steigerwald R Anderson M Volkmann A A monovalent and trivalent MVA-based vaccine completely protects mice against lethal Venezuelan, Western, and Eastern equine encephalitis virus aerosol challenge Front. Immunol. 2020 11 598847 10.3389/fimmu.2020.598847 33542715
155. Tatsis N Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines Blood 2007 110 1916 1923 10.1182/blood-2007-02-062117 17510320
156. Chang LJ Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial Lancet 2014 384 2046 2052 10.1016/S0140-6736(14)61185-5 25132507
157. Chen GL Effect of a chikungunya virus-like particle vaccine on safety and tolerability outcomes: a randomized clinical trial JAMA 2020 323 1369 1377 10.1001/jama.2020.2477 32286643
158. Reisinger EC Immunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active-controlled phase 2 trial Lancet 2019 392 2718 2727 10.1016/S0140-6736(18)32488-7 30409443
159. Folegatti PM A single dose of ChAdOx1 Chik vaccine induces neutralizing antibodies against four chikungunya virus lineages in a phase 1 clinical trial Nat. Commun. 2021 12 4636 10.1038/s41467-021-24906-y 34330906
160. Paessler S Weaver SC Vaccines for Venezuelan equine encephalitis Vaccine 2009 27 D80 D85 10.1016/j.vaccine.2009.07.095 19837294
161. Pierson BC Safety and immunogenicity of an inactivated Eastern equine encephalitis virus vaccine Vaccine 2021 39 2780 2790 10.1016/j.vaccine.2021.03.030 33888325
162. Rappuoli R Reverse vaccinology Curr. Opin. Microbiol. 2000 3 445 450 10.1016/S1369-5274(00)00119-3 11050440
163. Santiago C Structures of T cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family Immunity 2007 26 299 310 10.1016/j.immuni.2007.01.014 17363299
164. Sasaki T Structural basis for Gas6-Axl signalling EMBO J. 2006 25 80 87 10.1038/sj.emboj.7600912 16362042
165. Soumahoro MK The chikungunya epidemic on La Réunion Island in 2005–2006: a cost-of-illness study PLoS Negl. Trop. Dis. 2011 5 e1197 10.1371/journal.pntd.0001197 21695162
166. Feldstein LR Estimating the cost of illness and burden of disease associated with the 2014-2015 chikungunya outbreak in the U.S. Virgin Islands PLoS Negl. Trop. Dis. 2019 13 e0007563 10.1371/journal.pntd.0007563 31323020
167. Semenza JC Menne B Climate change and infectious diseases in Europe Lancet Infect. Dis. 2009 9 365 375 10.1016/S1473-3099(09)70104-5 19467476
168. Tsetsarkin KA Vanlandingham DL McGee CE Higgs S A single mutation in chikungunya virus affects vector specificity and epidemic potential PLoS Pathog. 2007 3 e201 10.1371/journal.ppat.0030201 18069894
169. Suhrbier A Rheumatic manifestations of chikungunya: emerging concepts and interventions Nat. Rev. Rheumatol. 2019 15 597 611 10.1038/s41584-019-0276-9 31481759
| 36474012 | PMC9734810 | NO-CC CODE | 2022-12-14 23:28:30 | no | Nat Rev Microbiol. 2022 Dec 6;:1-12 | utf-8 | Nat Rev Microbiol | 2,022 | 10.1038/s41579-022-00825-7 | oa_other |
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Mol Biotechnol
Mol Biotechnol
Molecular Biotechnology
1073-6085
1559-0305
Springer US New York
36462102
624
10.1007/s12033-022-00624-8
Review Paper
Lipid-Based Delivery Systems in Development of Genetic and Subunit Vaccines
http://orcid.org/0000-0001-7363-7406
Bolhassani Azam [email protected]
[email protected]
grid.420169.8 0000 0000 9562 2611 Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
3 12 2022
130
20 9 2022
26 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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Lipidic carriers are composed of natural, synthetic, or physiological lipid/phospholipid materials. The flexibility of lipid-based delivery systems for transferring a variety of molecules such as immunomodulators, antigens, and drugs play a key role in design of effective vaccination and therapeutic strategies against infectious and non-infectious diseases. Genetic and subunit vaccines are two major groups of promising vaccines that have the potential for improving the protective potency against different diseases. These vaccine strategies rely greatly on delivery systems with various functions, including cargo protection, targeted delivery, high bioavailability, controlled release of antigens, selective induction of antigen-specific humoral or cellular immune responses, and low side effects. Lipidic carriers play a key role in local tissue distribution, retention, trafficking, uptake and processing by antigen-presenting cells. Moreover, lipid nanoparticles have successfully achieved to the clinic for the delivery of mRNA. Their broad potential was shown by the recent approval of COVID-19 mRNA vaccines. However, size, charge, architecture, and composition need to be characterized to develop a standard lipidic carrier. Regarding the major roles of lipid-based delivery systems in increasing the efficiency and safety of vaccine strategies against different diseases, this review concentrates on their recent advancements in preclinical and clinical trials.
Graphical Abstract
Keywords
Lipid-based delivery systems
Genetic vaccine
Subunit vaccine
Infectious and non-infectious diseases
Preclinical and clinical trials
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pmcIntroduction
Nanomaterial-based delivery systems (e.g., lipid-based, polymer-based, inorganic nanomaterials-based vehicles) show desirable efficiency in the development of prophylactic and therapeutic vaccines such as lipid nanoparticles (LNPs) in the context of coronavirus disease 2019 (COVID-19) [1, 2]. These nanoplatforms have been tested for delivery of vaccines in the form of protein subunits and DNA/mRNA sequences encoding the antigens [3–6]. The designed nanomaterial-based therapeutic vaccines showed outstanding properties, such as encapsulation efficiency, enhancement of immunogenicity, biocompatibility, stability, and induction of specific CD8+ T-cell responses [1].
One of the potential ways for delivery of plasmid-based vaccines, protein-based vaccines, and conventional vaccines is the use of lipid-based vehicles [7]. Lipidic delivery systems include bilayer lipid vesicles, such as liposomes, nanoliposomes, archaeosomes, vesicular lipid gels, immunovesicles, lipospheres, solid lipid nanoparticles (SLN), tocosomes, and some other micro- and nanocarrier systems [8]. The use of lipidic structures (e.g., liposomes, virosomes, immune-stimulating complexes, gas-filled microbubbles, and emulsions) was efficient for the mucosal delivery of antigens, and the induction of local and systemic immune responses in preclinical and clinical trials [9]. Moreover, lipid-based bioactive delivery systems were employed for the encapsulation and targeted release of vaccine components [1].
The lipid-based nano-delivery of drug/vaccine is a therapeutic option for the treatment of infectious diseases (e.g., COVID-19, MERS, SARS, and Ebola) due to some advantages, such as low cost, easy preparation, increased bioavailability, cellular permeability, and uptake and stability of drug/vaccine [10]. Indeed, lipidation was known as a convenient and useful approach to improve the stability and transport across biological membranes. The lipid core peptide (LCP) system has appeared as a promising lipidation tool due to its flexible features and an effective approach for delivery of DNA/oligonucleotides and peptide drugs by improving their uptake, targeting, and enzymatic stability [11]. On the other hand, lipid-based DNA therapeutics could deliver an encoding gene sequence specifically to the target tissue expressing therapeutic protein of interest in unhealthy cells [12]. For example, lipid carrier systems including liposomes were proven to be the most suitable vehicles for delivery of nucleic acid-based drugs into the target tissues and reduction of their toxicity [13]. Ideal nanocarriers for delivery of DNA and in vitro-transcribed mRNA (IVT-mRNA) to the nasal and pulmonary mucosa in an effective vaccination against infectious diseases (e.g., COVID-19) should be able to protect genetic materials, overcome physical and biological barriers at the airway mucosal site, facilitate transfection in targeted epithelial or antigen-presenting cells, and incorporate adjuvants [14]. Recently, two mRNA-based vaccines encapsulated in lipidic delivery system created by BioNTech/Pfizer and Moderna/National Institute of Allergy and Infectious Diseases (NIAID) have become the first approved mRNA vaccines for human use against COVID-19 [15]. On the other hand, the effects of protein therapeutics are increasing in healthcare. Their safety and efficacy are often limited by instability, short half-life, and immunogenicity. Nanodelivery systems could overcome these limitations, such as covalent attachment of biocompatible polymers (e.g., polyethylene glycol (PEG) and other synthetic or naturally derived macromolecules) and protein nanoencapsulation in colloidal systems (e.g., liposomes and other lipid or polymeric nanocarriers) [16].
Generally, lipid-based delivery systems could act as an effective vector for enhancing the potency of vaccines and inducing effective immune protection against severe infectious and non-infectious diseases. However, the physical and chemical properties of lipidic carriers can influence their efficiency and safety in vaccine development. Characterization of these systems is a complex process. Indeed, size, charge, architecture, and composition need to be characterized to develop a standard lipid nanoparticle. Moreover, the safety and toxicity profiles of each novel nanoparticle should be determined to avoid unpredictable adverse effects. The design of lipidic delivery system is more complex with adding surface modification and with coatings and/or ligands. Thus, it is required to optimize a suitable and potent vaccine/lipid formulation for in vivo studies. This review represents the efficiency of lipid-based delivery systems for development of nucleic acid- and protein-based vaccines in preclinical and clinical trials (Graphical Abstract).
Classification of Lipidic Vaccine Carriers
Generally, lipidic vaccine carriers include bilayer lipid vesicles, solid lipid nanoparticles, tocosomes, and some other micro- and nanocarrier systems as follows. Figure 1 shows some properties of major lipidic delivery systems. Lipidic nanocarriers are composed of natural, synthetic, or physiological lipid/phospholipid materials [8].Fig. 1 Several properties of major lipidic delivery systems
Liposomes
Liposomes known as bilayer lipid or phospholipid vesicles are mainly composed of amphiphilic lipid and phospholipid molecules (i.e., natural components in different scales). However, other ingredients (e.g., sterols, polypeptides, antioxidants, and polymers) may be added in their structures for modulation of the bilayer structure, enhancement of their half-life in blood circulation, improvement of their tolerance against reactive oxygen species, and development of a targeting strategy for the lipid vesicles [8]. Liposomes improve the stability and efficacy of bioactive compounds by entrapment, release, and delivery to target cells/tissues [8]. Two-layered liposomes are preferred for the formulations due to ease of cellular endocytosis. Cholesterol and polyethylene glycol are used to stabilize liposomes and to avoid immune cell attack, respectively [17]. The first use of liposomes in mRNA vaccines was demonstrated in 1978 by delivery of rabbit globin mRNA sequences to mouse lymphocyte cells [17]. Liposomes and lipid nanoparticles have been developed to improve subunit vaccines against infectious diseases for several decades, such as tuberculosis (TB) subunit vaccines [18, 19]. However, several factors should be optimized to increase the efficacy of liposomes, such as the liposome size, surface charge, and composition of the lipid bilayers [19]. Depending on the preferred effect, ligands such as drug, peptide, cytokine, RNA or nucleotide, and antibody were conjugated onto or loaded within liposomes in different ways [20].
Liposomal vaccines were developed to target specific immune cell types for the induction of certain immune responses [21]. Cationic liposomes as an adjuvant or a delivery system could increase the potential of different subunit vaccines (e.g., TB) due to their enhanced interaction with the negatively charged immune cells [21, 22]. Cationic liposomes combined with other immunostimulatory factors such as TDB (trehalose 6, 60-dibehenate), MPL (monophosphoryl lipid A), TDM (trehalose dimycolate), and Poly I:C showed strong electrostatic interactions with antigen-presenting cells (APCs) and thus induced both humoral and cellular immune responses as well as a strong memory response [22]. Two approved liposomal vaccine formulations for antigen delivery are available, including Inflexal® V (influenza vaccine) and Epaxal® (hepatitis A vaccine). Both of these formulations used virosome-based technology in which viral proteins were bonded to the surface of a liposome carrier [14]. Up to now, various methods have been used to improve the stability of liposome formulations during storage including freeze-drying, spray-drying, supercritical fluid technology, and lyophilization [14].
Nanoliposomes
Nanoliposomes or lipidic nanovesicles known as colloidal nanostructures are composed of lipid or phospholipid molecules and possess the physicochemical properties similar to liposomes. However, nanoliposomes and liposomes are different in their size and surface area. Nanoliposomes have higher potency than liposomes in enhancing solubility and bioavailability, improving the controlled release of cargo, and accurate targeting of the encapsulated vaccine compounds [8].
Solid Lipid Nanoparticles (SLNs)
Solid lipid nanoparticles known as nano-sized colloidal carriers are composed of accurate ratios of lipid, surfactants, and bioactive compounds. They are efficient drug carriers due to their small size and lipid core (i.e., the solid lipids including triglycerides, acetyl alcohol, emulsifying wax, beeswax, carnauba wax, cholesterol, and cholesterol butyrate) [8].
Immunostimulatory Complexes (ISCOMs)
The immunostimulatory complexes known as ISCOMs (size: 40–60 nm) are vaccine carriers (e.g., hydrophobic antigens) with potent adjuvant properties as used in clinical trials. These cage-like particles with a hollow center are composed of saponin adjuvant Quil A, a protein antigen, cholesterol, and phospholipid in certain ratios that are self-assembled in solution. ISCOM-based vaccines significantly increase both humoral and cellular immune responses [8]. ISCOMATRIX is a vaccine carrier and adjuvant which is more applicable than ISCOMs due to its potency to remove the limitation of hydrophobic antigens. Several research groups published the use of different antigens, such as antigens derived from human immunodeficiency virus (HIV), human papilloma virus (HPV), Newcastle disease, and influenza for forming ISCOMs and ISCOMATRIX vaccines [8].
Tocosome
Tocosome is a vesicular and colloidal bioactive carrier that is mainly composed of the phosphorylated form of alpha-tocopherol (Alpha-tocopherol phosphate: TP). This component is available naturally in human tissues, some animal tissues, and certain food compounds. Also, tocosomes can possess proteins, polymers, and sterols in their structures. TP molecule has an inhibitory effect against tumors. Formulations of tocosomes containing various phospholipid molecules and different combinations of cholesterol were successfully used for the entrapment and controlled release of the anticancer drugs [8].
Vaccine Formulation Based on Lipidic Carrier
Lipids and their derivatives (especially the cationic/ionizable lipid materials with one or more amino groups) have been widely applied for in vivo delivery of vaccines due to encapsulation of vaccine compounds (e.g., mRNA vaccines) for their protection from enzymatic degradation and effective delivery of vaccine molecules into the cell cytosol through endocytosis processes [8]. However, the efficacy of vaccine delivery could be affected by modification of fatty acids in the hydrophobic tails. Moreover, the helper lipids could stabilize the structures of lipidic nanocarriers and facilitate endosomal escape. On the other hand, the PEG-lipid conjugates with a hydrophilic outer layer could stabilize the nanocarriers and extend the circulation time after in vivo administration [8]. As reported, lipid nanoparticles (LNPs) could protect the mRNA against degradation, help in endocytosis and endosomal escape, and incorporate adjuvants to activate immune system. Moreover, LNPs were targeted to specific cell types by decorating their surfaces with specific ligands. However, it should be noted that some cationic lipids (containing three domains: the polar headgroup, hydrophobic moiety, and linker) showed toxicity, and the repeated use of PEG-lipid induced an immune response against PEG [23]. Adjuvant activity was shown for the engineered ionizable lipids containing cyclic amino head groups, isocyanide linker, and two unsaturated alkyl tails. Covering the surface of lipidic nanocarriers with immune cell receptors could facilitate their uptake by the desired type of immune cells. For instance, the nanocarriers were designed to target the lymph node (with high concentration of APCs) based on their size and surface composition. Indeed, the nanoparticles with diameters less than about 150 nm could enter the lymphatic capillaries, and were subsequently drained to the peripheral lymphatics [8]. Moreover, inclusion of certain polymers to the lipid vesicles prevented opsonization by the cells of the immune system mainly in the liver and spleen leading to the stable vesicles in intravenous injection. On the other hand, the lipidic nanoparticles were not actively targeted toward dendritic cells (DCs). Thus, DC uptake was enhanced by modification of the surfaces of vesicles with suitable molecules, such as antibodies or peptides targeting integrins or the c-type lectin receptor [8]. It was reported that while adjuvant-free antigens tend to induce humoral response, delivery complexes (delivery with immune stimulatory complexes) form depot effect for efficient antigen uptake, and presentation by professional APCs. The physicochemical properties of the delivery systems determine both the efficiency and the mechanism of antigen uptake which in turn play critical roles in antigen-specific immune activation. On the other hand, immune stimulatory complexes lead to activation and maturation of innate immune cells for generation of targeted acquired immunity [24].
Generally, surface engineering of nanocarriers with different lipids increases the target specificity, reduces cytotoxicity, extends circulation half-life in vivo, and improves transfection efficiency of the nanocarriers. However, the concentration and composition of different lipids should be exactly controlled especially in gene delivery, because these factors directly influence the efficiency of nanocarriers [25].
Different genetic and subunit vaccines such as mRNA-based vaccines, DNA-based vaccines, and protein-based vaccines could be formulated with lipidic carriers as follows. Subunit vaccines designed as nanoparticle formulations could improve antigen uptake by APCs and enhance immunogenicity against nanoparticles or adjuvant molecules co-delivered by the nanoparticles. These vaccine platforms are biodegradable and biocompatible with minimal toxicity as compared to traditional microorganism-based vaccines. Moreover, nanoparticle vaccines showed higher ability to increase cross-presentation of subunit antigens and induce strong cellular immunity than traditional vaccines. The nanoparticle vaccines can be considered as a promising approach in clinical trials against cancer and intracellular infections [e.g., HIV, TB and Hepatitis C (HCV)] [26]. Figure 2 shows vaccine delivery using lipidic carriers.Fig. 2 Vaccine delivery using lipidic carriers: Different vaccine constructs (e.g., DNA, RNA, peptide, and protein) can be loaded in lipidic carriers and enter the target cells. The exogenous (i.e., protein or peptide) or endogenous (i.e., the expressed DNA or RNA) antigens undergo the endosomal or proteasomal pathways in antigen-presenting cells, present on the MHC I or MHC II molecules, activate the CD8+ or CD4+ T cells, and stimulate humoral or cellular immune responses
Lipid-Based Delivery Systems (Lipid Nanoparticles) and mRNA-Based Vaccine
The mRNA vaccines possess many advantages as compared to other subunit vaccines. For instance, they are relatively safe and also induce different types of immune responses leading to the activation of CD4+ and CD8+ T cells [17]. However, the mRNA vaccines have some disadvantages such as degradation by nucleases in vivo. For this purpose, different mRNA delivery systems were designed to protect the mRNA molecules from degradation and to promote their cellular uptake into the targeted cells [27]. Nanoparticles (NPs) based delivery systems such as polymers and liposomes are effective tools to target the mRNA molecules safely to the APCs. Hybrid NP delivery platforms with the adjuvant potency were also used to enhance various immune responses and subsequently the efficiency of vaccines [17]. Monslow et al. reported that mRNA encoding gE antigen of Varicella-zoster virus (VZV) formulated with lipid-based nanoparticles induced higher immune responses than live attenuated VZV in preclinical trials [28]. In addition, lipidic nanoparticles-formulated mRNA vaccine encoding multiple conserved antigens of Influenza virus showed protection against challenge with a panel of Group 1 Influenza A viruses in mice [29]. Lo et al. also reported that a lipid-based mRNA vaccine encoding the soluble glycoprotein of Hendra virus provided protection against Nipah virus challenge in Syrian hamsters [30]. Moreover, lipidic carriers were effective in cancer vaccine development. For example, Arya et al. indicated that the ovalbumin (OVA) mRNA-liposome nanocomplex significantly inhibited B16-OVA tumor progression and increased mouse survival without clear toxicity [31]. Also, Zhang et al. showed that a minimalist nanovaccine with C1 lipid nanoparticle (LNP) effectively increased mRNA delivery and antigen presentation with a self-adjuvant feature through activating TLR4 signaling. The C1 LNP mRNA nanovaccines showed significant in vivo efficacy in both tumor prevention and therapeutic vaccine trials [32].
For COVID-19 mRNA vaccines, the mRNA coding for spike protein was encapsulated in a solid lipid structure composed of ionizable lipids (i.e., Ionizable lipid-based nanoparticles (iLNPs) [17]. This lipid structure is neutral (or slightly charged) at physiological pH and positive at acidic pH (e.g., in endosomes) and contains cholesterol (for complexation), helper lipids (for stabilization of nanoparticles), and PEGylated lipids (for reduction of non-specific interactions) [27]. In addition, Moyo et al. developed a tetravalent iLNP-mRNA vaccine “HIVconsvM” against HIV, which induced strong T-cell responses in mice [33]. On the other hand, the use of cationic lipid-based nanoparticles for mRNA vaccine delivery induced strong immune responses in mice similar to iLNPs [34]. For instance, the mRNA encoding cytokeratin 19 delivered by cationic liposome/protamine complex increased cellular immune responses and anti-tumor activity in a Lewis lung cancer model [35]. The researchers showed that lipid-based nanoparticles containing cholesterol analogs have higher potency of gene transfection [36]. For example, the mRNA vaccine formulation containing DOTAP/cholesterol nanoparticles reduced Influenza A viral titers and morbidity in mice [37]. However, different approaches were used to enhance the immunologic activity of lipid-based nanoparticles such as the use of lipid and polylactic acid (PLA) nanoparticles in mRNA vaccine for increasing Th1 response [38; and/or the use of hybrid PLGA-core/lipid-shell nanoparticles in mRNA vaccine along with a TLR7 agonist for stimulating immune responses in mice [39].
Lipid-Based Delivery Systems (Lipid Nanoparticles) and DNA-Based Vaccine
Several lipidic vectors were utilized for gene delivery including cationic lipids, ionizable lipids, lipidoids (lipid-like compounds containing tertiary amines), gene-lipid conjugates, and functional LNPs. Cationic lipids were used to deliver nucleic acids in gene therapy more than two decades ago. The size of the lipoplex (cationic lipid: nucleic acid complex) is a major factor for lipofection efficiency in vitro. It was reported that larger liposomes are eliminated from the blood circulation more rapidly than smaller liposomes. Moreover, positively charged liposomes have a shorter half-life than neutral or negative liposomes [40]. Ionizable lipids can self-assemble into nanoparticles after mixing with polyanionic nucleic acids. Indeed, ionizable cationic lipids (e.g., DLin-KC2-DMA or DLin-MC3-DMA) enhance nucleic acid delivery and subsequently the therapeutic efficacy of gene therapy. Moreover, nucleic acid conjugation with lipids (i.e., gene-lipid conjugates) could improve gene therapy in vivo [40]. Several functional LNPs have been developed to enhance targeted gene delivery using different strategies such as modification of the nanoparticles with tumor-specific ligands (e.g., iron-saturated transferrin, folic acid, RGD and anisamide) to enhance intracellular uptake and escape from endosomal/lysosomal vesicles using pH-sensitive functional groups applied to the LNPs (e.g., pH-sensitive linkers including diorthoester, orthoester, vinyl ether, phosphoramidate, hydrazine, and beta-thiopropionate) [40].
Liposomes and some other vesicular systems were used as delivery systems for DNA vaccines [14]. The preventive and therapeutic potential of DNA vaccines delivered by lipids (lipofection) was investigated in treatment of infectious diseases, cancers, or autoimmune disorders. Cationic and neutral lipids may play the role of adjuvants, as well. Cationic polyprenyl derivatives along with helper lipids were effective for cell transfection and for immunization of animals [41]. Mucker et al. showed that Andes virus or Zika virus DNA vaccines formulated with lipid nanoparticle (LNP) could significantly increase neutralizing antibodies in rabbits and non-human primates as compared to unformulated DNA vaccine [42]. The plasmid DNA could be either electrostatically complexed on the surface of cationic liposomes or encapsulated in the aqueous core by a dehydration–rehydration procedure. Cationic liposomes could increase transfection efficiency in vitro, while non-ionic or anionic liposomes could enhance antibody responses in animal models [14].
On the other hand, surface modifications with antigenic components or targeting ligands could significantly augment immune responses of liposome-based vaccines (e.g., liposomes coated with glycol chitosan) [14]. For instance, surface-modified cationic liposomes such as phosphatidylcholine, dioleoyl phosphatidylethanolamine, and cholesterol induced stronger humoral, cellular, and mucosal immune responses after intranasal administration in mice against hepatitis than unmodified liposomes [43]. Several studies indicated the use of liposomes as DNA vaccine carriers to induce efficient immune responses against respiratory pathogens. For instance, Rosada et al. demonstrated a single intranasal immunization with liposome-based formulations of plasmid DNA encoding heat shock protein 65 (HSP65) against M. tuberculosis led to a significant reduction of bacterial load in lungs of mice [44]. Furthermore, intranasal immunization with liposome-based DNA vaccine induced complete protection against challenge with influenza virus [45]. On the other hand, liposomes conjugated to cell penetrating peptides (CPPs) and transferrin (Tf) ligand were developed to deliver plasmid DNA in brain cells based on targeting molecular recognition of transferrin receptor overexpressed on the blood–brain barrier (BBB) with enhanced internalization ability of CPPs. CPP-Tf-conjugated liposomes demonstrated high potency to overcome the BBB and penetrate the brain of mice [46]. Vaxfectin®-adjuvanted plasmids were used to enhance humoral responses of DNA vaccines, as well. Vaxfectin is a combination of cationic lipid with neutral lipid. A tetravalent DNA vaccine with and without Vaxfectin adjuvant compound was studied in a Phase I clinical trial in Dengue virus-seronegative healthy volunteers. The tetravalent dengue DNA vaccine (TVDV) was safe and well tolerated and induced significantly anti-dengue IFN-gamma responses in a dose-dependent approach [47].
Niosomes known as non-ionic surfactant-based vesicles possess some advantages, such as cost-effective manufacturing, large-scale production, and stability. Niosomes were applied as carriers for delivery of plasmid DNA, small interference RNAs (siRNAs), and aptamers into target cells due to their structural similarities to liposomes [14]. Cationic niosomes showed ~ 95% DNA transfection efficiency in vitro [48]. Furthermore, successful transfection of human tyrosinase gene was reported by cationic niosomes in vivo [49]. Mannolysated niosomes encapsulated with plasmid DNA encoding HBsAg (Hepatitis B surface antigen) were reported to induce protective immunity against hepatitis B as both DNA vaccine carrier and adjuvant for oral immunization [50].
Lipid-Based Delivery Systems (Lipid Nanoparticles) and Protein/Peptide-Based Vaccine
Proteins and peptides are more desirable therapeutic molecules than small molecular drugs because of their high selectivity and efficacy and low side effects. Due to their poor stability and limited permeability through gastrointestinal tract and epithelia, they are usually injected through parenteral route. However, the development of oral formulations for therapeutic peptides and proteins is necessary. Recently, researches focused on developing novel strategies to overcome these barriers, including enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, and intestinal microdevices. Some of them were achieved to clinical trials and even marketing [51]. In general, lipid-based nanocarriers (e.g., oil-in-water nanoemulsions, self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes and micelles) were known as the most promising formulation approaches [52]. Lipid-based delivery systems have been used to deliver active compounds through overcoming issues of pure active compounds, such as rapid release and metabolism, poor solubility, low stability, poor bioavailability, poor bioaccessibility, and toxicity [53]. For example, to increase the immunogenicity of the model subunit vaccine, ovalbumin (OVA) was combined with platycodin (PD), a saponin adjuvant and both of them were loaded into liposomes. Mice treated with the non-toxic OVA- and PD-loaded liposomes (OVA-PD-Lipos) showed a significantly enhanced immune response [54]. Lipid nanoparticles especially nanostructured lipid carriers (NLC) are a promising approach for the formulation of peptides and proteins with poor aqueous solubility [55]. The importance of lipid-based colloidal carriers and their pharmaceutical implications in the delivery of peptides and proteins was evaluated for oral and parenteral administration. However, the nanoencapsulation of biomacromolecules in colloidal particles protects them against the gastrointestinal environment, and increases their transmucosal transport. This ability is related to various mechanisms depending on the nanocarrier composition, such as mucoadhesion, particle internalization phenomenon, and permeation enhancing effect [55]. For example, the size of particles smaller than 1 μm may pass across the intestinal mucosa and thus facilitate the absorption of the bioactive drugs from the gut lumen. Moreover, hydrophobic nanoparticles are usually transported through the gut-associated lymphoid tissue, whereas particles with a more hydrophilic nature are transported across the regular enterocytes [55]. Nanocarriers with a size < 200 nm and a mucoinert surface (e.g., PEG or zwitterionic surfaces) show high mucus permeating properties [52]. Lipid-based nanocarriers facilitate paracellular and lymphatic drug uptake, induce endocytosis and transcytosis, or simply fuse with the cell membrane releasing their cargo into the systemic circulation. Different studies indicated the potential of these delivery systems in vivo [52]. On the other hand, lipid-protein conjugation is a novel strategy due to having both lipids and proteins in one delivery system and subsequently causing better synergistic effects in the body. Its major results are higher stability, better mechanical strength, controlled release, higher circulation time, targeted delivery, less cytotoxicity, higher loading capacity, co-encapsulation, and better bioavailability [53].
Lipid-Based Delivery of Genetic and Subunit Vaccines in Preclinical and Clinical Trials
Lipid-based nanoparticles are efficient candidates for vaccine delivery which were achieved to clinical trials especially for design of therapeutic cancer vaccines [1]. LNPs consist of four components, such as ionizable cationic lipids, PEGylated lipids, cholesterol, and helper lipids [56]. Ionizable lipids function as binding reagents for nucleic acids and help mRNA escape from the endosome/lysosome into the cytoplasm (e.g., Dlin-MC3-DMA from Alnylam Pharmaceuticals, SM-102 from Moderna, and ALC-0159 from Pfizer/BioNTech are all under patent protection). PEGylated lipids and cholesterol maintain LNP stability and influence the biodistribution of LNPs [39, 57]. Helper lipids [e.g., 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC) used in the mRNA-1273 and BNT162b2 COVID-19 vaccines and dioleoyl phosphatidylethanolamine (DOPE)] were reported to assist endosome escape [39]. Liposomal RNA vaccines also mediated durable objective responses in immune checkpoint blockade-experienced patients with advanced melanoma when optimized to target immature DCs in lymphoid tissues and to drive tumor-associated antigen presentation on both major histocompatibility complex I or II (MHC I or II) [39]. Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Indeed, as compared to the naked mRNAs, their formulations with chemical carriers led to more internalization of mRNA in dendritic cells for better immune responses and dose reduction [58].
Liposomes and liposome-derived nanovesicles (e.g., archaeosomes and virosomes) are known as major carrier systems in vaccine development [59]. For example, liposomes can encapsulate antigens, protect the antigen from degradation, fuse with cell membranes, present antigens to APCs, and induce adaptive immunity. For the first time, in 1974, liposomes were applied as a safe and effective adjuvant in human vaccination protocols. After that, various liposome-based vaccine systems were achieved to clinical trials [1]. The use of cationic lipids, neutral lipids, anionic lipids, and PEG-lipids in liposomes showed specific structure–functional properties. For example, the ionizable cationic lipid components and neutral lipids (as helper lipids) were used to improve the transfection efficiency of DNA or mRNA vaccines [60–62]. Moreover, anionic lipids are less toxic compared to cationic lipids in vivo inducing a continuous and potent immune response [63].
On the other hand, different modified cationic lipids could induce high CD8+ and CD4+ T-cell responses [64]. For instance, PEG-modified nanoparticles provided a biocompatible platform for gene transfer enhancing the circulation time and the stability of vaccines in vivo [65]. Recently, the use of liposome-targeted delivery with specific ligands or by targeting molecules to the relevant receptors on APCs is of interest. For example, lymph node-targeted delivery of vaccines (e.g., melittin-lipid nanoparticles) led to higher humoral and cellular immune responses especially for cancer immunotherapy [66]. Different LNP-complexed mRNA vaccines were designed to deliver mRNA, and activate a systemic immune response including a) heterocyclic LNPs to activate immunity through the mRNA-mediated STING pathway, b) mRNA loaded into cationic lipid-based nanoparticles to enhance transfection efficiency, and c) a nucleoside-modified mRNA-LNP vaccine to induce potent immune responses [67–69].
Preclinical and clinical studies demonstrated that mRNA delivered intramuscularly with LNPs produces the increased immune responses [57]. Most of mRNA-based vaccine candidates are currently being tested in clinical trials [1]. For instance, lipid NP-formulated mRNA vaccines against influenza achieved to clinical trials (NCT03076385, NCT03345043) after preclinical studies in primates and mice. These vaccines were shown to induce humoral immune response against H10N8 and H7N9 influenza viruses in humans [17]. As known, the mRNA vaccines against COVID-19 infection were approved by the U.S. Food and Drug Administration [1].
In general, depending on the chemical properties, water-soluble antigens (proteins, peptides, nucleic acids, carbohydrates, haptens) are entrapped within the aqueous inner space of liposomes, whereas lipophilic compounds (lipopeptides, antigens, adjuvants, linker molecules) are intercalated into the lipid bilayer, and antigens or adjuvants can be attached to the liposome surface either by adsorption or stable chemical linking [59]. Effective mRNA vaccines require both mRNA delivery and antigen expression to enable antigen-specific immunity [70]. Efforts to generate lipids with adjuvant effect have also provided promising results. It was known that cyclic dinucleotides may activate the stimulator of the interferon genes (STING) pathway, which activates IFN secretion and may enhance immune responses [67, 71].
Various functions can be achieved using strategies, such as molecule modification, cargo selection, and nanoparticle design [56]. The adjuvant and delivery property are influenced by formulation parameters, including size, surface charge, stability, lamellarity, composition and method of preparation [24]. The size of the particle plays a crucial role in determining the distribution and antigen uptake of the vaccine formulation following immunization. Some studies explained the role of particle size on immune stimulation [24]. LNP particle size without altering lipid composition showed that while small diameter LNPs were significantly less immunogenic in mice, all the tested particle sizes induced an increased immune response in non-human primates [70]. For mRNA vaccines, LNP uptake by APCs is necessary for generating antigen-specific immunity. The mRNA particles with the size of 500–5000 nm are significantly taken up by macrophages, whereas particles with the size of 20–200 nm are importantly taken up by DCs. The mRNA particles with the size of 80–100 nm elicit APC uptake and antigen expression. Subcutaneous administration (of mRNA vaccine) shows that smaller lipid particles leave the injection site more readily than larger particles, allowing them to drain more efficiently to lymph nodes [70]. However, an optimum size is important to facilitate both efficient lymph node drainage and cellular interactions in subcutaneous administration (e.g., too small particles are not efficient). It is required modulating particle size of lipid-based systems in intramuscular injection. Particle size was shown to affect cell recruitment of nanoparticles. For example, emulsion droplets with diameter 160 nm can recruit a greater number of immune cells to the injection site (or the highest number of antigen-positive immune cells within the draining lymph node) compared to smaller particles of identical composition (20 and 90 nm) for mRNA vaccines [70]. However, the kinetics of LNP entry into the cell may change within the size range. Moreover, it should be considered that the smaller-scale murine lymphatics are more sensitive to particle size within the range than the larger primate lymphatics. Thus, optimal mRNA vaccine particle size determined in rodents may not translate to primates [70]. However, the route of immunization, nature of antigens, and the composition of particles can influence the strength and type of immune responses, as well. Lipid composition determines the stability and immunomodulatory properties of lipid vesicles. Unsaturated lipids with a low transient point are used to release vesicles easily, while saturated lipids are generally used for stable formulations. Use of helper lipids further adds to the stability of lipid particle [24]. On the other hand, LNP therapeutic agents for gene therapy are currently used in clinical trials, such as ALN-TTRsc (targeting TTR for treatment of transthyretin-mediated amyloidosis) and ALN-PCS02 (targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to lower cholesterol for treatment of hypercholesterolemia). SNALP technology is one of the most widely used lipid-based nucleic acid delivery approaches (i.e., lipid vesicles encapsulating nucleic acids) for systemic administration in clinical trials [40]. Table 1 shows preclinical and clinical studies of genetic and subunit vaccines delivered by lipid-based vehicles.Table 1 Development of lipid-based vaccines in preclinical and clinical trials
Lipidic carrier Vaccination type Preclinical trials Clinical trials Descriptions References
Genetic and protein subunit vaccines
Lipid nanoparticles (LNPs) DNA vaccine Mice – Type of administration: Intranasal
Disease: Hepatitis
Composition:
L-a-phosphatidylcholine (PC)/1,2-dioleoyl-snglycero-3-phosphoethanolamine/cholesterol (Chol)
Antigen: S protein
Function: Induction of humoral, mucosal, and cellular immune responses
[43]
DNA vaccine Mice – Type of administration: Intranasal
Disease: Tuberculosis
Composition:
(±)-N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(dodecyloxy)-1-propanaminium bromide (GAP-DLRIE)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)
Antigen: 85A
Function: Induction of Th1 cellular immune response
[72]
DNA vaccine Mice – Type of administration: Intranasal
Disease: Tuberculosis
Composition:
Egg phosphatidylcholine (EPC)/DOPE/1,2-dioleoyl-3-trimethyl-ammonium-propane (DOTAP)
Antigen: Heat shock protein (HSP65)
Function: Induction of Th1 cellular immune response
[44]
DNA vaccine Mice – Type of administration: Intranasal
Disease: Influenza
Composition:
Dioleyldimethylammonium chloride (DODAC)/DOPE/polyethylene glycol (PEG)
Antigen: Hemagglutinin (HA)
Function: Induction of humoral and mucosal
Immune responses
[45, 73]
CpG-based adjuvant vaccine Mice – Type of administration: Subcutaneous
Disease: Influenza (H1N1; H3N2)
Composition:
1,2-dioleoyl-3-trimethylammoniumpropane/
1,2-dipalmitoyl-sn-glycero-3-phosphocholine/
Cholesterol/N-(carbonyl-methoxypolyethyleneglycol
2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine
Antigen/adjuvant: Hemagglutinin/CpG-ODN (LNP-CpGs) Function: Improved T-cell responses; protection against strains; improved adjuvant effects with higher production of cytokines and co-stimulatory molecules
[74]
Liposome DNA vaccine Mice – Type of administration: Intramuscular
Disease: HIV infection
Composition:
Mannosylated zwitterionic-based cationic liposome
Antigen: Envelope (Env)
Function: Non-inflammasome-mediated immune responses
[75]
CpG-based adjuvant vaccine Mice – Type of administration: Intravenous
Disease: Neuroblastoma (NB)
Composition: Anti-GD2-targeted CpG encapsulated in stealth liposomes (TL-CpG)
Antigen/adjuvant: Neuroblastoma growth inhibiting CpGs/TLR9-dependent growth inhibition of NB induced by TL-CpG adjuvant
Tumor model: HTLA-230 neuroblastoma expressing high levels of GD2 and TLR9
Function:
Inhibition of TLR9-expressing NB cells proliferation, induction of apoptosis, and prolonged survival
[76]
CpG-based endogenous vaccine Mice – Type of administration: subcutaneous/intratumoral
Disease: CT26 tumor models (murine colorectal carcinoma)
Composition:
1,2-distearoyl-sn-glycero-3-phosphacholine (DSPC)/DOTAP/cholesterol
Antigen/adjuvant: Fluorophore-loaded liposomes (IR-7-lipo) coated with a multivalent immunoadjuvant (HA-CpG))
Function: Strong photothermal therapy
and immunotherapy effects
[77]
Liposome Protein vaccine – Phase III clinical trial Type of administration: Intramuscular
Disease: Malaria; varicella-zoster virus infection
Composition:
Cationic lipid adjuvanted with saponin and monophosphoryl lipid A/Cationic lipid adjuvanted with trehalose dibehenate
Antigen: RTS,S; glycoprotein E
Function: Safe and well tolerated;
Robust immune response in the elderly
[9, 78, 79]
Protein vaccine Chickens – Type of administration: oral
Disease: Newcastle disease
Composition:
PC/cholesterol-adjuvanted with Gypenoside-saponin encapsulated in liposomes
Antigen: Viral protein
Function: Enhanced immune response; T- and B-cell proliferation
[80]
Protein vaccine Chickens – Type of administration: Intramuscular
Disease: Newcastle disease
Composition:
PC/cholesterol/sonicated small unilamellar vesicles (SUV)-adjuvanted with Glycyrrhetinic acid
Antigen: Viral protein
Function: Enhanced immune response; higher IgG, IgM antibody titers; T- and B-cell proliferation
[81]
Protein vaccine Chickens – Type of administration: Intranasal
Disease: Newcastle disease
Composition:
1-palmitoyl-2-palmitoyl-sn-glycero-phosphocholine (DPPC)/cholesterol/multilamellar vesicles (MLV)
Antigen: Viral protein
Function: High mucosal IgA; high serum IgG; macrophage activation; high survival rate
[82]
Protein vaccine Chickens – Type of administration: oral
Disease: Newcastle disease
Composition:
DOTAP/cholesterol/cationic MLV
Antigen: Viral protein
Function: Higher antibody titers; complete survival
[83]
Protein vaccine Chickens – Type of administration: Intranasal
Disease: Newcastle disease
Composition:
DPPC/cholesterol, humane erythrocytes membrane (DPPS)/cholesterol, stearylamine (SA)/cholesterol/MLV
Antigen: Viral protein
Function: 90% survival
[84]
Protein vaccine Chickens – Type of administration: Intramuscular
Disease: Newcastle disease
Composition:
PC/cholesterol/α-tocopherol SUV adjuvanted with Epimedium polysaccharide propolis flavones, epimedium-propolis (EP)
Antigen: Viral protein
Function: High protection; high T-cell, B-cell proliferation; low mortality
[85]
Protein vaccine Chickens – Type of administration: Oral
Disease: Salmonella enteritidis infection
Composition:
Liposome-associated fimbriae antigen
Antigen/adjuvant: Salmonella enteritidis fimbrial protein (SEF14)/live Salmonella enteritidis
Function: High IgG, IgA in intestinal mucus and serum; Low bacterial and low excretion of Salmonella enteritidis in feces
[86]
Protein vaccine Swine – Type of administration: Intramuscular
Disease: Foot and mouth disease
Composition:
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/DOPE/DOTAP cationic SUV
Antigen: Recombinant foot and mouth protein/Porcine IFN-alpha DNA adsorbed to SUV
Function: Strong inflammatory cytokine production and Th 1 response; high IFN-alpha; No viremia or lesions
[87]
Protein vaccine Cattle – Type of administration: Subcutaneous
Disease: Neospora caninum infection
Composition:
Dipalmitoylphosphatidylcholine (DPPC)/cholesterol/Mannotriose dipalmitoylphosphatidylcholine (DPPE)
Antigen/adjuvant: Mannotriose/Dense granule protein 7 of Neospora caninum (M3-NcGRA7)
Function: Decreased parasite load
[88]
Protein vaccine Calves of different age – Type of administration: Subcutaneous
Disease: Mycobacterium avium paratuberculosis
Composition:
Dimethyldioctadecylammonium bromide/
trehalose dibehenate (DDA/TDB)
Antigen/adjuvant: Mycobacterium avium paratuberculosis proteins/CAF01
Function: Age-dependent IFN-gamma response; Age-independent humoral response
[89]
Protein vaccine Mice – Type of administration: Subcutaneous
Disease: HPV-related cancer
Composition:
Cationic TDB/DDA
Antigen/adjuvant: Ovalbumin and HPV16 E7 protein/CAF01 + poly I:C (= CAF05)
Tumor model: Lung B16-OVA TC-1 expressing HPV16 E7 protein
Function: Significant reduction of tumor growth; CD8+ T cell-induced target cell lysis
[90]
Protein therapeutics and vaccines Rat/mice – Type of administration: Subcutaneous
Diseases: Different diseases
Composition:
1,2-dimyristoyl sn-glycero-3-phosphocholine (DMPG): 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC): cholesterol (Chol); Chol: Palmitoyl-2-oleoyl-sn-glycero-
3-phosphocholine (POPC): 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEPEG2k); L-a-phosphatidylcholine (PC)/Chol; PC/Chol; 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethyleneglycol)]-hydroxy succinamide (DSPEPEG2k-RMP-7/DSPE-PEG2k); PC/Chol/DSPEPEG2k/stearoyl-poly(ethylene glycol)-poly(methacryloyl sulfadimethoxine)
copolymer (S-PEGpolySDM)/
N-(Lissamine Rhodamine B sulfonyl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt (Rh-DHPE); PC:Chol:DSPEPEG; PC/Chol; hexadecylcarbamoylmethylhexadecanoate (HDAS):Chol: hexadecylcarbamoylmethylhexadecanoate-PEG2000 conjugated (HDASPEG2k), respectively
Antigens/compounds: Recombinant human granulocyte colony-stimulating factor (rhG-CSF); ovalbumin (OVA) and tetanus toxoid (TT); basic fibroblast growth factor (bFGF); nerve growth factor (NGF); (FTIC-) BSA; bovine serum albumin (BSA); human gamma-globulin (hIgG);
hemoglobin (Hb), respectively
Functions: Protein-loaded liposomes for in vivo applications including Immunization; Immunization; Wound healing; Transport across BBB; Bladder epithelium targeting; Safety and pharmacokinetic studies; Biodistribution; Hemorrhagic shock, respectively
[16]
Seven protein vaccines – Commercial
names in clinical trials: Epaxal; Inflexal-V; Curosurf; T4N5 liposome
Lotion; Hepatic-directed
vesicles-insulin
(HDV-I); Biphasix;
IL-2- liposome
Type of administration: Different injections, such as intranasal
Diseases: Hepatitis A; Trivalent influenza
Vaccine; Lung activator for stress disorder; Skin cancer; Diabetes; Genital warts and cervical dysplasia;
Pulmonary metastases, respectively
Composition:
Liposome
Antigens: Hepatitis A virus Proteins; Influenza virus
Proteins; SP-B and SP-C Proteins; T4 endonuclease V
(T4N5) enzyme; Insulin; Interferon-alpha (INF-a); Interleukin-2 (IL-2), respectively
Functions: safe and immunogenic
Companies: Crucell (former Berna Biotech Ltd.) on market 1994; Crucell (former Berna Biotech Ltd.) on market 1997; Chiesi Farmaceutici on market 1999; AGI Dermatics Inc. (Phase III 2007); Diasome Pharmaceuticals (Phase II 2019); Altum Pharmaceuticals (Phase I/II 2011); Biomira United States (Phase I 2000), respectively
[16]
Lipid nanoparticles (LNPs) Protein vaccine Mice – Type of administration: Subcutaneous
Disease: Ebola virus infection
Composition:
Lipid nanoparticle
Antigen: Ebola virus spike protein
Function: Induction of potent antibody and polyfunctional T-cell responses; protection of mice against Ebola virus infection
[91, 92]
Virosomes Protein vaccine – Licensed Type of administration: Intramuscular
Disease: Influenza
Composition:
Virosomes
Antigen: Envelope proteins
Function: Good immunogenicity in both healthy and immunocompromised elderly, adults, and children
[93]
Virosomes Protein vaccine – Licensed Type of administration: Intramuscular
Disease: Influenza
Composition:
Virosomes
Antigen: Hemagglutinin
Function: Safe and well tolerated; Robust and long-lasting immune responses against subunit antigens
[94]
Immune-stimulating complexes (ISCOMATRIX) Protein vaccine – Phase I clinical trial Type of administration: Intramuscular
Disease: HCV infection
Composition:
Immune-stimulating complexes
Antigen: Core protein
Function: Safe and low reactogenicity in healthy adults and elderly
[95]
Emulsions Protein vaccine – Phase I clinical trial Type of administration: Intranasal
Disease: Seasonal influenza
Composition: Nanoemulsion
Antigen/adjuvant: Influenza antigens/mucosal adjuvant W805EC
Function: Well tolerated; no significant adverse events
[96]
Cationic lipids Protein vaccine Lymph node cells/mice – Type of administration: Subcutaneous
Disease: Hepatitis B
Composition:
3beta-[N-(N′,N′-dimethylaminoethane)carbamoyl]-Cholesterol (DC-Chol)
Antigen: Hepatitis B virus surface antigen (HBsAg)
Function: Induction of more consistent IgG1 and IgG2a antibody responses in mice; Controlled Th1 and Th2 immune responses
[97]
Cationic lipids Protein vaccine Mice – Type of administration: Intranasal
Disease: Influenza H3N2
Composition:
1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), DMPC/1,2-dimyristoyl-sn-glycero-3-phospho-(1ʹ-racglycerol (DMPG), DC-Chol/DOPE, 1,2-stearoyl-
3-trimethylammonium-propane (DSTAP)/Chol, dimethyldioctadecylammonium (DDA)/Chol, DOTAP/Chol, 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP)/Chol and the polycationic
sphingolipid ceramide carbamoyl-spermine (CCS)/Chol
Antigen: The influenza A antigens (hemagglutinin and neuraminidase (HN))
Function: Strong systemic (serum) and local (lung) Th1 and Th2 responses
[98]
Lipophilic quaternary ammonium salt (DDA) Protein vaccine Mice – Type of administration: Intranasal
Disease: Respiratory Syncytial Virus
Composition:
A new potent nasal adjuvant named as dimethyldioctadecylammonium bromide (DDA)
Antigen: Recombinant fragment (BBG2Na) of the G protein
Function: Induction of both local and systemic anti-RSV immune responses; Protection against viral challenge
[99]
Liposome mRNA vaccine Mice – Type of administration: Intravenously
Disease: Melanoma
Composition:
Mannosylated and histidylated lipopolyplexes with MART-1 mRNA [Man (11)-LPR100]
Antigen: MART-1 (MelanA mRNA)
Tumor model: Mice challenge with B16F10 tumor cells
Function: Better transfection of DCs and increased survival
[100]
RNA vaccine
(liposomal RNA (RNA-LPX) vaccine)
– Phase I clinical trial in patients with advanced melanoma (NCT02410733) Type of administration: Intravenous
Disease: Melanoma
Composition:
1,2-di-O-octa decenyl-3-trimethyl-ammonium-propane (R-DOTMA), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)
Antigen: Tumor-associated antigen-encoded RNA
Function: Induction of effector T-cell responses against tumor-associated antigens; Manageable adverse clinical events
[101, 102]
mRNA vaccine:
Conventional,
unmodified
Mice – Type of administration: Subcutaneous
Disease: Influenza
Composition:
Lipids such as cholesterol/dipalmitoyl
phosphatidylcholine/phosphatidylserine
Antigen: Nucleoprotein
Function: Induction of cellular immune response
[103]
mRNA vaccine Mice – Type of administration: Intranasal
Disease: Aggressive Lewis lung cancer model
Composition:
Cationic liposome/protamine
Antigen: Cytokeratin 19
Function: Induction of cellular immune response
[104]
Lipid nanoparticles (LNP) mRNA vaccines: mRNA-1440; mRNA-1851; mRNA-1893; mRNA-1345; mRNA-1653; mRNA-1647; mRNA-1388; CV7202; mRNA-5671/V941; mRNA-4157; mRNA-4650; FixVac; TNBC- MERIT;
HARE-40; RO7198457; W_ova1, respectively
– Clinical trials such as:
Phase I: NCT03076385; Phase I: NCT03345043; Phase I: NCT04064905; Phase I: NCT04528719; Phase I: NCT03392389; Phase II: NCT04232280; Phase I: NCT03325075; Phase I: NCT03713086; Phase I: NCT03948763; Phase I: NCT03897881; Phase I/II: NCT03480152; Phase I: NCT02410733; Phase I: NCT02316457; Phase I: NCT03418480; Phase II: NCT03815058; Phase I: NCT04163094, respectively
Type of administration: Intramuscular (IM); IM; IM; IM; IM; IM; IM; IM; IM; IM; IM; intravenous (IV); IV; intradermal (ID); IV; IV, respectively
Diseases: Influenza H10N8; Influenza H7N9; Zika virus; Respiratory syncytial virus; Metapneumovirus
and parainfluenza virus type 3 (MPV/PIV3); Cytomegalovirus; Chikungunya virus; Rabies virus; Non- small- cell lung cancer/colorectal cancer/pancreatic adenocarcinoma; Melanoma; Gastrointestinal cancer; Melanoma; Triple- negative breast cancer; HPV- positive cancers; Melanoma; Ovarian cancer, respectively
Composition:
Lipid nanoparticles
Antigens: Hemagglutinin; Hemagglutinin; Pre-membrane and envelope glycoproteins; F glycoprotein; MPV and PIV3 F glycoproteins; Pentameric complex and B glycoprotein; Chikungunya virus antigens; G glycoprotein; KRAS antigens; Personalized neoantigens; Personalized
neoantigens; NY- ESO-1/tyrosinase/MAGE- A3/TPTE antigen; Personalized neoantigens; HPV oncoproteins E6
and E7; Personalized neoantigens; Ovarian cancer
antigens, respectively
Function: Great therapeutic potential in clinical applications
[105]
mRNA vaccine Mice – Type of administration: Subcutaneous
Disease: Melanoma; Human papillomavirus
Composition:
Ionizable lipidoid, DOPE, C14-PEG2000 and cholesterol (the stimulator of the interferon genes (STING) stimulation LNPs)
Antigen: Luc-, OVA-, and E7-encoded mRNA
Function: Optimized lipids with strong STING stimulation capability using 3D multicomponent reaction system
[67, 106]
mRNA vaccine – Phase III clinical trial; approved by FDA Type of administration: Intramuscular
Disease: COVID-19
Composition:
SM-102, cholesterol, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG), DSPC
Antigen: mRNA encoding the prefusion-stabilized spike protein of SARS-CoV-2
Function: Moderna Company, Approved by FDA (mRNA-1273), Easier to transport and store; less temperature sensitive; Safety and efficiency
[2, 15, 39]
mRNA vaccine Mice – Type of administration: Intranasal
Disease: Influenza (H1N1)
Composition: LNP
Antigen: Hemagglutinin
Function: Induction of humoral and cellular
immune responses
[107]
mRNA vaccine – Phase III clinical trial; approved by FDA Type of administration: Intramuscular
Disease: COVID-19
Composition:
ALC-0159 (PEGylated lipid), ALC-0315 (Synthetic lipid), cholesterol, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG), DSPC
Antigen: mRNA encoding the full-length spike protein of SARS-CoV-2
Function: BioNTech/Pfizer Company, Approved by FDA (BNT162b2), Less frequency of adverse effects; Safety and efficiency
[2, 15, 39]
RNA vaccine Mice/non-human primates
(NHPs)
– Type of administration: Intramuscular
Disease: COVID-19
Composition:
Iron oxide-contained LNPs (DOTAP, Span 80, Tween 60, super-paramagnetic iron oxide nanoparticles)
Antigen: Alphavirus-derived replicon RNA encoding the SARS-CoV-2 S protein
Function: Enhanced stability and delivery efficiency; Rapid immune protection
[108, 109]
Self-Amplifying mRNA vaccine Mice – Type of administration: Intramuscular, intradermal
Disease: Influenza
Composition:
Mannosylated lipid nanoparticles
Antigen: H1N1 hemagglutinin encoding RNA
Function: Development of novel skin delivery systems; induction of enhanced antigen-specific CD4+ T and CD8+ T cells, Higher IgG2a antibody responses
[110]
RNA vaccine Mice – Type of administration: Intradermal
Disease: Influenza
Composition:
Lipid nanoparticles
Antigen: H1N1 hemagglutinin encoding RNA
Function: Induction of influenza virus hemagglutinin stalk-specific antibodies
[111]
RNA vaccine Humanized mice – Type of administration: Intravenous
Disease: HIV infection
Composition:
Lipid nanoparticles
Antigen: Anti-HIV-1 antibody encoding RNA
Function: Protection of humanized mice from HIV-1 challenge
[112]
mRNA vaccine Mice/cynomolgus monkeys – Type of administration: Intramuscular
Disease:COVID-19
Composition:
Lipid nanoparticles
Antigen: mRNA encoding the SARS-CoV-2 RBD
Function: Protection of humanized mice from HIV-1 challenge
[113]
mRNA vaccine Mice – Type of administration: Intramuscular
Disease: COVID-19
Composition:
Lipid nanoparticles
Antigen: Self-amplifying RNA encoding the SARS-CoV-2 spike protein
Function: High neutralizing antibody titers in mice
[114]
mRNA vaccine Mice/Rhesus macaques – Type of administration: Intradermal
Disease: ZIKA virus
Composition:
Lipid nanoparticles
Antigen: mRNA encoding pre-membrane and envelope glycoproteins
Function: Virus protection by a single low-dose nucleoside-modified mRNA vaccination
[115]
mRNA vaccine Mice – Type of administration: Intramuscular
Disease: ZIKA virus
Composition:
Lipid nanoparticles
Antigen: mRNA encoding pre-membrane and envelope glycoproteins
Function: Protection against ZIKA virus
[116]
mRNA vaccine:
Conventional,
Sequence-optimized mRNA
Mice/NHPs – Type of administration: Intramuscular
Disease: Influenza
Composition: Ionizable amino lipid, phospholipid, cholesterol, and a PEGylated lipid
Antigen: HA
Function: Induction of humoral, cellular, and innate immune responses
[117, 118]
mRNA vaccine:
Conventional,
Nucleoside modified
Mice/ferre/NHPs – Type of administration: Intramuscular; intradermal
Disease: Influenza
Composition:
Ionizable lipid: DSPC:cholesterol: PEG-lipid
Antigen: HA
Function: Induction of humoral, cellular, and innate immune responses; Protection against virus
[69, 111, 119]
mRNA vaccine:
Conventional,
Nucleoside modified
Mice/NHPs – Type of administration: Intramuscular; intradermal
Disease: Zika virus
Composition:
Ionizable lipid: DSPC:cholesterol: PEG-lipid
Antigen: prM-E
Function: Induction of humoral immune response; Protection against virus
[120, 121]
mRNA vaccine:
Conventional,
Nucleoside modified
Guinea pigs – Type of administration: Intramuscular
Disease: Ebola virus infection
Composition:
Ionizable lipid: DSPC:cholesterol: PEG-lipid
Antigent: gp
Function: Induction of humoral immune response; protection against virus
[122]
mRNA vaccine:
Conventional,
Nucleoside modified
Mice/NHPs – Type of administration: Intramuscular
Disease: Human cytomegalovirus (HCMV) infection
Composition:
Ionizable lipid: DSPC: cholesterol: PEG-lipid
Antigen: PC, gB, pp65
Function: Induction of humoral immune response; protection against virus
[123]
mRNA vaccine:
Conventional,
Nucleoside modified
Mice/NHPs – Type of administration: Intradermal
Disease: HIV infection
Composition:
Ionizable cationic lipid (Acuitas Therapeutics)/phosphatidylcholine/cholesterol/polyethylene glycol/lipid
Antigen: Env
Function: Induction of humoral and cellular immune responses
[69]
mRNA vaccine:
Self-amplifying
Mice – Type of administration: Intramuscular
Disease: Influenza
Composition:
DLinDMA: DSPC: DMG: PEG 2000: cholesterol
Antigen: NP, M1
Function: Induction of humoral and cellular immune responses; protection against virus
[124]
mRNA vaccine:
In vitro
transcribed
Mice – Type of administration: Intramuscular
Disease: Ovalbumin-expressing mouse lymphoma cells
Composition:
Ionizable lipid, cholesterol, DOPE, C16-polyethylene glycol-2000 (PEG-lipid)
Antigen: Ovalbumin (OVA)
Function: Induction of cellular and innate immune responses
[125]
mRNA vaccine BALB/c mice; AG129 mice; BALB/c mice; CD-1 mice, respectively – Type of administration: Intracereboventicular; intramuscular; intravenous; and intravenous, respectively
Diseases: Friedreich’s ataxia; Zika; Elevated
(low-density lipoprotein) LDL-Cholesterol; Elevated
LDL-Cholesterol and amyloidosis, respectively
Composition:
Lipid nanoparticles
Antigens: frataxin (FXN) gene; pre-membrane protein (pRM0 and envelope protein (E) gene; proprotein convertase subtilisin/kexin type 9 (PCSK9); transthyretin (TTR) and PCSK9, respectively
Function: Improvement of nucleic acid delivery; Therapeutic purposes
[126]
mRNA vaccine – NCT03739931 (Active); NCT03323398 (Active); NCT04283461 (Active); NCT03767270 (Withdrawn); NCT04064905 (Active); NCT03382405(Active), respectively Type of administration: Intratumoral (IT); IT; IM’ IV; IM; and IM, respectively
Diseases: Solid tumors and Lymphomas; Solid tumors,
lymphomas and ovarian cancer; COVID-19; Ornithine Transcarbamylase (OTC) deficiency; Zika; and CMV infection, respectively
Composition:
Lipid nanoparticles
Antigens: Ligand for OX40 receptor associated with tumor necrosis factor receptor superfamily (OX40L); OX40L; S protein; ornithine transcarbamylase (OTC); pre-membrane protein (prM) and envelope protein (E); Pentamer and T-cell antigen, respectively
Function: Nucleic acid therapy
[126]
unmodified mRNA vaccine: CV7202
(Sequence optimized)
– NCT03713086 (Phase I)
(Sponsoring
Manufacturer: CureVac)
Type of administration: Intramuscular
Disease: Rabies
Composition:
Lipid nanoparticles
Antigen: Rabies virus glycoprotein (RABV-G)-mRNA vaccine
Function: Neutralizing antibody responses; well tolerated (Active, not recruiting (PCD: January 2022))
[117, 127]
mRNA vaccine (nucleoside modified): mRNA-1440; mRNA-1851; mRNA-1653;
mRNA-1325;
mRNA-1893; mRNA-1647;
mRNA-1443;
mRNA-1388, respectively
– Phase I clinical trials:
NCT03076385, NCT03345043, NCT03392389, NCT03014089, NCT04064905, NCT03382405, NCT03325075, respectively
Type of administration: Intramuscular
Diseases: Influenza H10N8; Influenza H7N9; HMPV/HPIV3; Zika; Zika; HCMV; and Chikungunya, respectively
Composition:
Lipid nanoparticles
Antigen: Viral antigens (e.g., HA antigen of influenza)
Function: Safety and reactogenicity profiles; Completed PCD: October 2018; Active, not recruiting, PCD: February 2020;
Completed, PCD: July 2019;
Completed, PCD: July 2019;
Active, not recruiting, PCD: February 2021;
Active, not recruiting, PCD: July 2020;
Completed, PCD: November 2019, respectively
[117]
Emulsion mRNA vaccine Mice/non-human primates – Type of administration: Intramuscular
Disease:COVID-19
Composition:
Lipid nanoparticles
Antigen: Self-amplifying RNA encoding the SARS-CoV-2 spike protein
Function: Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T-cell responses
[110]
Cationic nanoemulsion (CNE)/LNP/
Multistage delivery nanoparticle (MDNP)
mRNA vaccine:
Self-amplifying
Mice/ferrets – Type of administration: Intramuscular
Disease: Influenza
Composition:
Squalene, DOTAP, Sorbitan trioleate, and polysorbate 80
Antigen: HA
Function: Induction of humoral and cellular immune responses; protection against virus
[128]
Cationic Nanoemulsion (CNE) mRNA vaccine:
Self-amplifying
Mice/rabbit,
NHPs
– Type of administration: Intramuscular
Disease: HIV infection
Composition:
Squalene, Span 85, DOTAP
Antigen: gp140
Function: Induction of humoral and cellular immune responses
[129]
Cationic Nanoemulsion (CNE) mRNA vaccine:
Self-amplifying
Mice – Type of administration: Intramuscular
Disease: Streptococci
Composition:
Squalene, DOTAP, sorbitan trioleate, and polysorbate 80
Antigen: SLOdm, BP-2a
Function: Induction of humoral immune response; protection against virus
[130]
Cationic Nanoemulsion (CNE) mRNA vaccine:
Self-amplifying
NHPs – Type of administration: Intramuscular
Disease: HCMV infection
Composition:
Squalene, Span 85, DOTAP
Antigen: gB, pp65-IE1
Function: Induction of humoral and cellular immune responses
[131]
Cationic Nanoemulsion (CNE) mRNA vaccine:
Self-amplifying
Mice – Type of administration: Intramuscular
Disease: Malaria
Composition:
Squalene, DOTAP, sorbitan trioleate and polysorbate 80
Antigen: PMIF
Function: Induction of humoral and cellular immune responses
[132]
CNE/LNP mRNA vaccine:
Self-amplifying
Mice/cotton/rats – Type of administration: Intramuscular
Disease: Respiratory Syncytial Virus (RSV)
Composition:
DSPC, cholesterol, DMG-PEG 2000, DLinDMA
Antigen: F
Function: Induction of humoral and cellular immune responses; protection against virus
[133]
MDNP/NLC mRNA vaccine:
Self-amplifying
Mice/Guinea
pigs
– Type of administration: Intramuscular
Disease: Zika virus
Composition:
Modified dendrimer and DMG-PEG 2000
Antigen: prM-E
Function: Induction of humoral immune response
[134, 135]
Other vaccines
Liposome Bacterial vector-based vaccine: Cell wall skeleton extracts of M. bovis Bacillus Calmette-Guerin (BCG) Rat – Type of administration: Intravesical
Disease: Bladder cancer
Composition:
PC/cholesterol/octaarginine SUV liposomes with cell wall skeleton extracts of BCG (R8-liposome-BCG-CWS)
Antigen: BCG liposome-incorporating cell wall skeleton (BCG-CWS)
Tumor model: Fisher-344 rats with nitrosamine-induced bladder cancer
Function: R8-liposome-BCG-CWS-treated rats had significantly lower numbers of tumors
[136]
Liposome Inactivated bacterial vaccine Chickens – Type of administration: Eye drops/Coarse spraying
Disease: E. coli infection
Composition:
PC/cholesterol/Dimethyldioctadecylammonium (DDA) cationic SUV
Antigen: Inactivated avian pathogenic E.coli
Function: Higher mucosal and serum antibodies; reduced bacteria in blood
[137]
Liposome Cell-based vaccine: Tumor cell lysate Mice - Type of administration: Subcutaneous; Intraperitoneal
Disease: Mouse hepatocellular carcinoma
Composition:
DOTAP-PIC-liposome complex
Antigen/adjuvant: Hepa 1–6 cell lysates/Polyriboinosinic: polyribocytidylic acid (poly I:C)
Tumor model: Hepa 1–6
Function: High tumor-specific CTL response and IFN-gamma levels; Significant tumor growth inhibition
[138]
Liposome Peptide-based vaccine Mice – Type of administration: Subcutaneous
Disease: HPV-related cancer (ErbB2 protein-expressing tumor cells)
Composition:
PC/PG/cholesterol + DOG (Man)2 liposomes + mannosylated ligands
Antigen/adjuvant: ErbB2 CTL and influenza virus HA Th-peptide epitopes/TLR2/1 (Pam3CAG), TLR2/6 (Pam2CAG, Pam2CGD) agonists
Tumor model: Mice-bearing RenCa-lacZ/ErbB2 tumors
Function: 100% cures after vaccination with mannosylated liposomes + TLR2 ligand Pam3CAG
[139]
Dilauroylphosphatidylcholine (DLPC) liposomes Peptide-based vaccine Mice – Type of administration: Intranasal
Disease: Influenza (H1N1)
Composition:
DLPC liposomes
Antigen/adjuvant: M2, HA, NP highly conserved peptides/Monophosphoryl lipid A (MPL) and trehalose 6, 6′-dimycolate
Function: Protection against different strains;
Highly specific T-cell response leading to the limitation of viral replication
[140]
Emulsion Immunologic adjuvant-based vaccine – Licensed Type of administration: Intramuscular
Disease: Influenza
Composition:
Emulsion (oil-in-water influenza vaccine adjuvant)
Adjuvant: MF59
Function: Some levels of reactogenicity depending on formulation
[9, 141]
Conclusion
This study shows the importance of Lipid-based delivery systems especially LNPs for protection of vaccine constructs against nucleases and proteases, continuous release of antigens, and enhancement of immunogenicity. These systems need to be optimized for increasing the potency of cargo delivery, cell targeting, safety, and immune stimulation. At present, the success of LNPs in development of COVID-19 mRNA vaccines has attracted a special interest for researchers working on other infectious or non-infectious diseases. Also, lipidic carriers are effectively used to deliver drugs as well as vaccines with high bioavailability and low side effects in clinical studies. Thus, lipidic delivery systems possess suitable and vital properties for the development of novel drug and vaccine formulations.
Future Perspective
Recently, a large range of compounds and technologies are available to design and develop formulations that can induce potent immune responses against different pathogens. Lipid-based nanoparticles (LNPs) play an important role due to natural adjuvant properties. LNPs can be easily decorated with small molecules or glycans targeting the vaccine to specific type of immune cells and finally enhancing the potency of the immune response. In addition, adjuvants or antigens can be encapsulated into lipid nanoparticles. Some processes were developed to control the size of LNPs independent of lipid composition. It is interesting that mice require an average particles size (~ 100 nm) for generating high antibody levels. In contrast, all particle sizes (~ 60–150 nm) generate strong immune responses in non-human primates. The impact of LNP biophysical parameters on immunogenicity is an important step for enabling rapid development of potent vaccines against novel growing diseases. Recent advances in lipid gene delivery systems have significantly improved the efficacy and the level of expression of targeted genes. The improved structure–activity design has increased the potential of LNPs in gene therapy in tumors, and other disorders.
Although, effective vaccine encapsulation and delivery systems with simple formulations play an important role in vaccine development; but however, optimization of the safety profile and enhancement of the vaccination efficacy are still required for various preclinical and clinical trials. Some studies demonstrate that hybrid delivery platforms increase the efficiency of vaccines for boosting a variety of immune responses. Among the all-available delivery systems, lipidic carriers show one of the most advanced platforms for vaccine delivery and targeting in vivo. Lipidic delivery systems include bilayer lipid vesicles such as liposomes, nanoliposomes, archaeosomes, vesicular lipid gels, immunovesicles, lipospheres, solid lipid nanoparticles (SLN), tocosomes, and some other micro- and nanocarrier systems. The lipid-based nano-delivery of drug/vaccine is a therapeutic option for the treatment of infectious diseases (e.g., COVID-19, MERS, SARS, and Ebola) due to some advantages, such as low cost, easy preparation, increased bioavailability, cellular permeability, and uptake and stability of drug/vaccine. Moreover, lipid-based nanoparticles are a major platform for the design of multicomponent adjuvant systems. Immunotherapy with lipid adjuvants can add to the effective disease management strategies alone and in combination. Although, the loaded antigen or adjuvant with the nanoparticle and other adjuvants could be more useful than a simple mixture, but its manufacturing is commonly complex and difficult. The design of lipidic delivery system is more complex with adding surface modification and with coatings and/or ligands. The use of synthetic coatings and ligands can influence the biocompatibility, biodistribution, and toxicity of lipid-based formulations and thus it needs an exact assay of the interaction of nanoparticles with tissues or cells.
A balance between efficiency, production cost, and simple manufacturing is required to use lipidic delivery systems for development of effective multicomponent subunit vaccines. Furthermore, for using LNPs in a clinical trial, a better understanding of certain mechanisms and techniques is required including the interaction of lipid vectors and gene expression and the safety and immunogenicity profile of vectors. By overcoming these barriers, efficient delivery of genes will be performed by LNPs for clinical use. For instance, lipid-based delivery systems are potent vehicles to target the mRNA molecules safely to the antigen-presenting cells (APCs). Based on the studies, incorporation of the plasmids into the lipid carriers leads to their delivery through the mucosal surfaces or the transdermal route. The efficiency of the transdermal route as an effective administration is dependent on the composition of the lipid vehicles. However, characterization of these systems is a complex process. Size, charge, architecture, and composition need to be characterized to develop a standard lipid nanoparticle. In addition, the safety and toxicity profiles of each novel nanoparticle should be determined to avoid unpredictable adverse effects. Generally, the lipid carriers possess the ability to improve antigen stability and presentation to immunocompetent cells (depending on their specific properties, such as composition, size, and surface properties), to overcome biological barriers (e.g., skin or mucosa), to provide controlled and slow release of antigens, and finally to induce strong immune responses provided by coformulated adjuvants.
Author Contributions
AB performed literature search, draft writing, and manuscript revisions.
Funding
None.
Declarations
Conflict of interest
The authors have no conflicts of interest to disclose.
Research Involving Human and Animal Rights
This article does not contain any studies with human participants or animals performed by author.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Liang J Zhao X Nanomaterial-based delivery vehicles for therapeutic cancer vaccine development Cancer Biology & Medicine 2021 18 2 352 371 10.20892/j.issn.2095-3941.2021.0004 33979069
2. Ftouh M Kalboussi N Abid N Sfar S Mignet N Bahloul B Contribution of nanotechnologies to vaccine development and drug delivery against respiratory viruses Hindawi PPAR Research 2021 2021 1 28 10.1155/2021/6741290
3. Bolhassani A Improvements in chemical carriers of proteins and peptides Cell Biology International 2019 43 4 437 452 10.1002/cbin.11108 30672055
4. Hosseinzadeh S Bolhassani A Immunostimulant properties of chemical delivery systems in vaccine development Current Drug Delivery 2015 12 4 360 368 10.2174/1567201812666150309150755 25751632
5. Bolhassani A Safaiyan S Rafati S Improvement of different vaccine delivery systems for cancer therapy Molecular Cancer 2011 10 3 10.1186/1476-4598-10-3 21211062
6. Kim D Wu Y Kim YB Oh YK Advances in vaccine delivery systems against viral infectious diseases Drug Delivery and Translational Research 2021 11 1401 1419 10.1007/s13346-021-00945-2 33694083
7. Baca-Estrada ME Foldvari M Babiuk SL Babiuk LA Vaccine delivery: Lipid-based delivery systems Journal of Biotechnology 2000 83 91 104 10.1016/S0168-1656(00)00313-8 11000465
8. Raoufi E Bahramimeimandi B Salehi-Shadkami M Chaosri P Mozafari MR Methodical design of viral vaccines based on avant-garde nanocarriers: A multi-domain narrative review Biomedicines 2021 9 520 10.3390/biomedicines9050520 34066608
9. Corthésy B Bioley G Lipid-based particles: Versatile delivery systems for mucosal vaccination against infection Frontiers in Immunology 2018 9 431 10.3389/fimmu.2018.00431 29563912
10. Ansari MA Almatroudi A Alzohairy MA AlYahya S Alomary MN Al-Dossary HA Alghamdi S Lipid-based nano delivery of Tat-peptide conjugated drug or vaccine-promising therapeutic strategy for SARS-CoV-2 treatment Expert Opinion on Drug Delivery 2020 17 12 1671 1674 10.1080/17425247.2020.1813712 32820694
11. Zhong W Skwarczynski M Toth I Lipid core peptide system for gene, drug, and vaccine delivery Australian Journal of Chemistry 2009 62 956 967 10.1071/CH09149
12. Buck J Grossen P Cullis PR Huwyler J Witzigmann D Lipid-based DNA therapeutics: Hallmarks of non-viral gene delivery ACS Nano 2019 13 3754 3782 10.1021/acsnano.8b07858 30908008
13. Barba AA Bochicchio S Dalmoro A Lamberti G Lipid delivery systems for nucleic-acid-based-drugs: From production to clinical applications Pharmaceutics 2019 11 360 10.3390/pharmaceutics11080360 31344836
14. Tang J Cai L Xu C Sun S Liu Y Rosenecker J Guan S Nanotechnologies in delivery of DNA and mRNA vaccines to the nasal and pulmonary mucosa Nanomaterials 2022 12 226 10.3390/nano12020226 35055244
15. Chatzikleanthous D O’Hagan DT Adamo R Lipid-based nanoparticles for delivery of vaccine adjuvants and antigens: Toward multicomponent vaccines Molecular Pharmaceutics 2021 18 2867 2888 10.1021/acs.molpharmaceut.1c00447 34264684
16. Moncalvo F Martinez Espinoza MI Cellesi F Nanosized delivery systems for therapeutic proteins: Clinically validated technologies and advanced development strategies Frontiers in Bioengineering and Biotechnology 2020 8 89 10.3389/fbioe.2020.00089 32117952
17. Okay S Özcan OO Karahan M Nanoparticle-based delivery platforms for mRNA vaccine development AIMS Biophysics 2020 7 4 323 338 10.3934/biophy.2020023
18. Tretiakova DS Vodovozova EL Liposomes as adjuvants and vaccine delivery systems Biochemistry 2022 16 1 1 20
19. Luwi NEM Ahmad S Azlyna ASN Nordin A Sarmiento ME Acosta A Nor Norazmi M Uskoković V Mohamud R Kadir R Liposomes as immunological adjuvants and delivery systems in the development of tuberculosis vaccine: A review Asian Pacific Journal of Tropical Medicine 2022 15 1 7 16 10.4103/1995-7645.332806
20. Fobian SF Cheng Z ten Hagen TLM Smart lipid-based nanosystems for therapeutic immune induction against cancers: Perspectives and outlooks Pharmaceutics 2022 14 26 10.3390/pharmaceutics14010026
21. De Serrano LO Burkhart DJ Liposomal vaccine formulations as prophylactic agents: Design considerations for modern vaccines Journal of Nanobiotechnology 2017 15 83 10.1186/s12951-017-0319-9 29149896
22. Khademi F Taheri RA Momtazi-Borojeni AA Farnoosh G Johnston TP Sahebkar A Potential of cationic liposomes as adjuvants/delivery systems for tuberculosis subunit vaccines Reviews of Physiology, Biochemistry and Pharmacology 2018 175 47 69 10.1007/112_2018_9 29700609
23. Reichmuth AM Oberli MA Jaklenec A Langer R Blankschtein D mRNA vaccine delivery using lipid nanoparticles Therapeutic Delivery 2016 7 5 319 334 10.4155/tde-2016-0006 27075952
24. Sabur A Asad M Ali N Lipid based delivery and immuno-stimulatory systems: Master tools to combat leishmaniasis Cellular Immunology 2016 309 55 60 10.1016/j.cellimm.2016.07.011 27470274
25. Bose RJC Lee SH Park H Lipid-based surface engineering of PLGA nanoparticles for drug and gene delivery applications Biomaterials Research 2016 20 34 10.1186/s40824-016-0081-3 27807476
26. Sahdev P Ochyl LJ Moon JJ Biomaterials for nanoparticle vaccine delivery systems Pharmaceutical Research 2014 31 2563 2582 10.1007/s11095-014-1419-y 24848341
27. Pichon C Perche F Design and delivery of messenger RNA-based vaccines Biochemistry 2021 43 4 4 7 10.1042/bio_2021_151
28. Monslow MA Elbashir S Sullivan NL Thiriot DS Ahl P Smith J Miller E Cook J Cosmi S Thoryk E Citron M Thambi N Shaw C Hazuda D Vora KA Immunogenicity generated by mRNA vaccine encoding VZV gE antigen is comparable to adjuvanted subunit vaccine and better than live attenuated vaccine in nonhuman primates Vaccine 2020 38 5793 5802 10.1016/j.vaccine.2020.06.062 32703745
29. Freyn AW da Silva JR Rosado VC Bliss CM Pine M Mui BL Tam YK Madden TD de Souza Ferreira LC Weissman D Krammer F Coughlan L Palese P Pardi N Nachbagauer R A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice Molecular Therapy 2020 28 1569 1584 10.1016/j.ymthe.2020.04.018 32359470
30. Lo MK Spengler JR Welch SR Harmon JR Coleman-McCray JD Scholte FEM Shrivastava-Ranjan P Montgomery JM Nichol ST Weissman D Spiropoulou CF Evaluation of a single-dose nucleoside-modified messenger RNA vaccine encoding Hendra virus-soluble glycoprotein against lethal Nipah virus challenge in Syrian hamsters Journal of Infectious Diseases 2020 221 4 S493 S498 10.1093/infdis/jiz553 31751453
31. Arya S Lin Q Zhou N Gao X Huang JD Strong immune responses induced by direct local injections of modified mRNA-lipid nanocomplexes Molecular Therapy: Nucleic Acids 2020 19 1098 1109 32059336
32. Zhang H You X Wang X Cui L Wang Z Xu F Li M Yang Z Liu J Huang P Kang Y Wu J Xia X Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through toll-like receptor 4 signaling Proceedings of the National Academy of Sciences 2021 118 6 e2005191118 10.1073/pnas.2005191118
33. Moyo N Wee EG Korber B Bahl K Falcone S Himansu S Wong AL Dey AK Feinberg M Hanke T Tetravalent immunogen assembled from conserved regions of HIV-1 and delivered as mRNA demonstrates potent preclinical T-cell immunogenicity and breadth Vaccines 2020 8 360 10.3390/vaccines8030360 32640600
34. Lou G Anderluzzi G Schmidt ST Woods S Gallorini S Brazzoli M Giusti F Ferlenghi I Johnson R Roberts CW O’Hagan DT Baudner BC Perrie Y Delivery of self-amplifying mRNA vaccines by cationic lipid nanoparticles: The impact of cationic lipid selection Journal of Controlled Release 2020 325 370 379 10.1016/j.jconrel.2020.06.027 32619745
35. Mai Y Guo J Zhao Y Ma S Hou Y Yang J Intranasal delivery of cationic liposome-protamine complex mRNA vaccine elicits effective anti-tumor immunity Cellular Immunology 2020 354 104143 10.1016/j.cellimm.2020.104143 32563850
36. Eygeris Y Patel S Jozic A Sahay G Deconvoluting lipid nanoparticle structure for messenger RNA delivery Nano Letters 2020 20 4543 4549 10.1021/acs.nanolett.0c01386 32375002
37. Van Hoecke L Verbeke R De Vlieger D Dewitte H Roose K Van Nevel S Krysko O Bachert C Schepens B Lentacker I Saelens X mRNA encoding a bispecific single domain antibody construct protects against influenza A virus infection in mice Molecular Therapy Nucleic Acids 2020 20 777 787 10.1016/j.omtn.2020.04.015 32438313
38. Coolen AL Lacroix C Mercier-Gouy P Delaune E Monge C Exposito JY Verrier B Poly (lactic acid) nanoparticles and cell-penetrating peptide potentiate mRNA-based vaccine expression in dendritic cells triggering their activation Biomaterials 2019 195 23 37 10.1016/j.biomaterials.2018.12.019 30610991
39. Yang J Arya S Lung P Lin Q Huang J Li Q Hybrid nanovaccine for the co-delivery of the mRNA antigen and adjuvant Nanoscale 2019 11 21782 21789 10.1039/C9NR05475H 31709434
40. Zhao Y Huang L Lipid nanoparticles for gene delivery Advances in Genetics 2014 88 13 36 10.1016/B978-0-12-800148-6.00002-X 25409602
41. Rak M Góra-Sochacka A Madeja Z Lipofection-based delivery of DNA vaccines Methods in Molecular Biology 2021 2183 391 404 10.1007/978-1-0716-0795-4_20 32959255
42. Mucker EM Karmali PP Vega J Kwilas SA Wu H Joselyn M Ballantyne J Sampey D Mukthavaram R Sullivan E Chivukula P Hooper JW Lipid nanoparticle formulation increases efficiency of DNA-vectored vaccines/immunoprophylaxis in animals including transchromosomic bovines Scientific Reports 2020 10 8764 10.1038/s41598-020-65059-0 32472093
43. Khatri K Goyal AK Gupta PN Mishra N Mehta A Vyas SP Surface modified liposomes for nasal delivery of DNA vaccine Vaccine 2008 26 2225 2233 10.1016/j.vaccine.2008.02.058 18396362
44. Rosada RS de la Torre LG Frantz FG Trombone APF Zárate-Bladés CR Fonseca DM Souza PRM Brandão IT Masson AP Soares EG Ramos SG Faccioli LH Silva CL Santana MHA Coelho-Castelo AAM Protection against tuberculosis by a single intranasal administration of DNA-hsp65 vaccine complexed with cationic liposomes BMC Immunology 2008 9 38 10.1186/1471-2172-9-38 18647414
45. Wong JP Zabielski MA Schmaltz FL Brownlee GG Bussey LA Marshall K Borralho T Nagata LP DNA vaccination against respiratory influenza virus infection Vaccine 2001 19 2461 2467 10.1016/S0264-410X(00)00474-6 11257378
46. dos Santos Rodrigues B Lakkadwala S Kanekiyo T Singh J Development and screening of brain-targeted lipid-based nanoparticles with enhanced cell penetration and gene delivery properties International Journal of Nanomedicine 2019 14 6497 6517 10.2147/IJN.S215941 31616141
47. Danko JR Kochel T Teneza-Mora N Luke TC Raviprakash K Sun P Simmons M Moon JE De La Barrera R Martinez LJ Thomas SJ Kenney RT Smith L Porter KR Safety and immunogenicity of a tetravalent Dengue DNA vaccine administered with a cationic lipid-based adjuvant in a phase I clinical trial American Journal of Tropical Medicine and Hygiene 2018 98 3 849 856 10.4269/ajtmh.17-0416 29363446
48. Rose JK Buonocore L Whitt MA A new cationic liposome reagent mediating nearly quantitative transfection of animal cells BioTechniques 1991 10 520 525 1867862
49. Manosroi J Khositsuntiwong N Manosroi W Götz F Werner RG Manosroi A Enhancement of transdermal absorption, gene expression and stability of tyrosinase plasmid (pMEL34)-loaded elastic cationic niosomes: Potential application in vitiligo treatment Journal of Pharmaceutical Sciences 2010 99 3533 3541 10.1002/jps.22104 20213835
50. Jain S Singh P Mishra V Vyas SP Mannosylated niosomes as adjuvant-carrier system for oral genetic immunization against hepatitis B Immunology Letters 2005 101 41 49 10.1016/j.imlet.2005.04.002 15869802
51. Zhu Q Chen Z Paul PK Lu Y Wu W Qi J Oral delivery of proteins and peptides: Challenges, status quo and future perspectives Acta Pharmaceutica Sinica B 2021 11 8 2416 2448 10.1016/j.apsb.2021.04.001 34522593
52. Haddadzadegan S Dorkoosh F Bernkop-Schnürch A Oral delivery of therapeutic peptides and proteins: Technology landscape of lipid-based nanocarriers Advanced Drug Delivery Reviews 2022 182 114097 10.1016/j.addr.2021.114097 34999121
53. Dissanayake T Sun X Abbey L Bandara N Recent advances in lipid-protein conjugate-based delivery systems in nutraceutical, drug, and gene delivery Food Hydrocolloids for Health 2022 2 100054 10.1016/j.fhfh.2022.100054
54. Zhao JH Zhang QB Liu B Piao XH Yan YL Hu XG Zhou K Zhang YT Feng NP Enhanced immunization via dissolving microneedle array-based delivery system incorporating subunit vaccine and saponin adjuvant International Journal of Nanomedicine 2017 12 4763 4772 10.2147/IJN.S132456 28740383
55. Martins S Sarmento B Ferreira DC Souto EB Lipid-based colloidal carriers for peptide and protein delivery-liposomes versus lipid nanoparticles International Journal of Nanomedicine 2007 2 4 595 607 18203427
56. Huang, S., Zhu, Y., Zhang, L., & Zhang, Z. (2022). Recent advances in delivery systems for genetic and other novel vaccines. Advanced Materials, 2107946
57. Hassett KJ Benenato KE Jacquinet E Lee A Woods A Yuzhakov O Himansu S Deterling J Geilich BM Ketova T Mihai C Lynn A McFadyen I Moore MJ Senn JJ Stanton MG Almarsson Ö Ciaramella G Brito LA Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines Molecular Therapy: Nucleic Acids 2019 15 1 18 30785039
58. Midoux P Pichon C Lipid-based mRNA vaccine delivery systems Expert Review of Vaccines 2015 14 2 221 234 10.1586/14760584.2015.986104 25540984
59. Schwendener RA Liposomes as vaccine delivery systems: A review of the recent advances Therapeutic Advance in Vaccines 2014 2 6 159 182 10.1177/2051013614541440
60. Jayaraman M Ansell SM Mui BL Tam YK Chen J Du X Butler D Eltepu L Matsuda S Narayanannair JK Rajeev KG Hafez IM Akinc A Maier MA Tracy MA Cullis PR Madden TD Manoharan M Hope MJ Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo Angewandte Chemie 2012 51 8529 8533 10.1002/anie.201203263 22782619
61. Cullis PR Hope MJ Lipid nanoparticle systems for enabling gene therapies Molecular Therapy 2017 25 1467 1475 10.1016/j.ymthe.2017.03.013 28412170
62. Marty R N’Soukpoe-Kossi CN Charbonneau D Weinert CM Kreplak L Tajmir-Riahi HA Structural analysis of DNA complexation with cationic lipids Nucleic Acids Research 2009 37 849 857 10.1093/nar/gkn1003 19103664
63. Courant T Bayon E Reynaud-Dougier HL Villiers C Menneteau M Marche PN Navarro FP Tailoring nanostructured lipid carriers for the delivery of protein antigens: Physicochemical properties versus immunogenicity studies Biomaterials 2017 136 29 42 10.1016/j.biomaterials.2017.05.001 28511142
64. Zhu D Hu C Fan F Qin Y Huang C Zhang Z Lu L Wang H Sun H Leng X Wang C Kong D Zhang L Co-delivery of antigen and dual agonists by programmed mannose-targeted cationic lipid-hybrid polymersomes for enhanced vaccination Biomaterials 2019 206 25 40 10.1016/j.biomaterials.2019.03.012 30925286
65. Sekiya T Yamagishi J Gray JHV Whitney PG Martinelli A Zeng W Wong CY Sugimoto C Jackson DC Chua BY PEGylation of a TLR2-agonist-based vaccine delivery system improves antigen trafficking and the magnitude of ensuing antibody and CD8(+) T cell responses Biomaterials 2017 137 61 72 10.1016/j.biomaterials.2017.05.018 28544973
66. Yu X Dai Y Zhao Y Qi S Liu L Lu L Luo Q Zhang Z Melittin-lipid nanoparticles target to lymph nodes and elicit a systemic antitumor immune response Nature Communications 2020 11 1110 10.1038/s41467-020-14906-9 32111828
67. Miao L Li L Huang Y Delcassian D Chahal J Han J Shi Y Sadtler K Gao W Lin J Doloff JC Langer R Anderson DG Delivery of mRNA vaccines with heterocyclic lipids increases antitumor efficacy by STING-mediated immune cell activation Nature Biotechnology 2019 37 1174 1185 10.1038/s41587-019-0247-3 31570898
68. Sayour EJ Grippin A De Leon G Stover B Rahman M Karachi A Wummer B Moore G Castillo-Caro P Fredenburg K Sarkisian MR Huang J Deleyrolle LP Sahay B Carrera-Justiz S Mendez-Gomez HR Mitchell DA Personalized tumor RNA loaded lipid-nanoparticles prime the systemic and intratumoral milieu for response to cancer immunotherapy Nano Letters 2018 18 6195 6206 10.1021/acs.nanolett.8b02179 30259750
69. Pardi N Hogan MJ Naradikian MS Parkhouse K Cain DW Jones L Moody MA Verkerke HP Myles A Willis E LaBranche CC Montefiori DC Lobby JL Saunders KO Liao HX Korber BT Sutherland LL Scearce RM Hraber PT Tombácz I Muramatsu H Ni H Balikov DA Li C Mui BL Tam YK Krammer F Karikó K Polacino P Eisenlohr LC Madden TD Hope MJ Lewis MG Lee KK Hu SL Hensley SE Cancro MP Haynes BF Weissman D Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses Journal of Experimental Medicine 2018 215 1571 1588 10.1084/jem.20171450 29739835
70. Hassett KJ Higgins J Woods A Levy B Xia Y Hsiao CJ Acosta E Almarsson O Moore MJ Brito LA Impact of lipid nanoparticle size on mRNA vaccine immunogenicity Journal of Controlled Release 2021 335 237 246 10.1016/j.jconrel.2021.05.021 34019945
71. Li K Qu S Chen X Wu Q Shi M Promising targets for cancer immunotherapy: TLRs, RLRs, and STING-mediated innate immune pathways International Journal of Molecular Sciences 2017 18 2 404 10.3390/ijms18020404 28216575
72. D’Souza S Rosseels V Denis O Tanghe A De Smet N Jurion F Palfliet K Castiglioni N Vanonckelen A Wheeler C Huygen K Improved tuberculosis DNA vaccines by formulation in cationic lipids Infection and Immunity 2002 70 3681 3688 10.1128/IAI.70.7.3681-3688.2002 12065510
73. Wang D Christopher ME Nagata LP Zabielski MA Li H Wong JP Samuel J Intranasal immunization with liposome-encapsulated plasmid DNA encoding influenza virus hemagglutinin elicits mucosal, cellular and humoral immune responses Journal of Clinical Virology: Official Publication of the Pan America Society of the Clinical Virology 2004 31 1 99 106 10.1016/j.jcv.2004.09.013
74. Shirai S Shibuya M Kawai A Tamiya S Munakata L Omata D Suzuki R Aoshi T Yoshioka Y Lipid nanoparticles potentiate CpG-oligodeoxynucleotide-based vaccine for influenza virus Frontiers in Immunology 2020 10 3018 10.3389/fimmu.2019.03018 31998305
75. Qiao C Liu J Yang J Li Y Weng J Shao Y Zhang X Enhanced non-inflammasome mediated immune responses by mannosylated zwitterionic-based cationic liposomes for HIV DNA vaccines Biomaterials 2016 85 1 17 10.1016/j.biomaterials.2016.01.054 26851653
76. Brignole C Marimpietri D Di Paolo D Perri P Morandi F Pastorino F Zorzoli A Pagnan G Loi M Caffa I Erminio G Haupt R Gambini C Pistoia V Ponzoni M Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma Cancer Research 2010 70 9816 9826 10.1158/0008-5472.CAN-10-1251 20935225
77. Li L Yang S Song L Zeng Y He T Wang N Yu C Yin T Liu L Wei X Wu Q Wei Y Yang L Gong C An endogenous vaccine based on fluorophores and multivalent immunoadjuvants regulates tumor micro-environment for synergistic photothermal and immunotherapy Theranostics 2018 8 860 10.7150/thno.19826 29344312
78. Casares S Brumeanu TD Richie TL The RTS, S malaria vaccine Vaccine 2010 28 31 4880 4894 10.1016/j.vaccine.2010.05.033 20553771
79. Lal H Cunningham AL Heineman TC Adjuvanted herpes zoster subunit vaccine in older adults New England Journal of Medicine 2015 373 16 1576 1577 26465999
80. Yu Y Wang D Abula S Hu Y Zhao X Huang Y Liu J Wu Y Wang D Tao Y Pan H The immunological adjuvant activity of gypenosides liposome against Newcastle disease vaccine International Journal of Biological Macromolecules 2013 60 116 121 10.1016/j.ijbiomac.2013.05.024 23732326
81. Zhao X Fan Y Wang D Hu Y Guo L Ruan S Zhang J Yuan J Immunological adjuvant efficacy of glycyrrhetinic acid liposome against Newcastle disease vaccine Vaccine 2011 29 9611 9617 10.1016/j.vaccine.2011.10.053 22044741
82. Lin Y Deng M Tseng L Jiang PR Jan TR Hsieh FI Liu DZ Adjuvant effect of liposome in chicken result from induction of nitric oxide Biomedical Materials 2011 6 015011 10.1088/1748-6041/6/1/015011 21239850
83. Onuigbo E Okore V Ofokansi K Okoye JOA Nworu CS Esimone CO Attama AA Preliminary evaluation of the immunoenhancement potential of Newcastle disease vaccine formulated as a cationic liposome Avian Pathology 2012 41 355 360 10.1080/03079457.2012.691154 22834549
84. Tseng L Liang H Deng M Lee KM Pan RN Yang JC Huang YY Liu DZ The influence of liposomal adjuvant on intranasal vaccination of chickens against Newcastle disease The Veterinary Journal 2010 185 204 210 10.1016/j.tvjl.2009.05.019 19570697
85. Fan Y Wang D Hu Y Liu J Han G Zhao X Yuan J Liu C Liu X Ni X Liposome and epimedium polysaccharide-propolis flavone can synergistically enhance immune effect of vaccine International Journal of Biological Macromolecules 2012 50 125 130 10.1016/j.ijbiomac.2011.10.008 22020157
86. Pang Y Zhang Y Wang H Jin J Piao J Piao J Liu Q Li W Reduction of Salmonella enteritidis number after infections by immunization of liposome-associated recombinant SEFA Avian Diseases 2013 57 627 633 10.1637/10427-101812-Reg.1 24283128
87. Cheng G Zhao X Yan W Wang W Zuo X Huang K Liu Y Chen J Wang J Cong W Liu M Gao H Chen J Lu Y Zheng Z Alpha interferon is a powerful adjuvant for a recombinant protein vaccine against foot-and-mouth disease virus in swine, and an effective stimulus of in vivo immune response Vaccine 2007 25 5199 5208 10.1016/j.vaccine.2007.04.089 17555848
88. Nishimura M Kohara J Kuroda Y Hiasa J Tanaka S Muroi Y Kojima N Furuoka H Nishikawa Y Oligomannose-coated liposome-entrapped dense granule protein 7 induces protective immune response to Neospora caninum in cattle Vaccine 2013 31 3528 3535 10.1016/j.vaccine.2013.05.083 23742998
89. Thakur A Aagaard C Stockmarr A Andersen P Jungersen G Cell-mediated and humoral immune responses after immunization of calves with a recombinant multiantigenic Mycobacterium avium subsp. paratuberculosis subunit vaccine at different ages Clinical and Vaccine Immunology 2013 20 551 558 10.1128/CVI.05574-11 23389934
90. Hansen J Lindenstrom T Lindberg-Levin J Aagaard C Andersen P Agger E CAF05: Cationic liposomes that incorporate synthetic cord factor and poly(I:C) induce CTL immunity and reduce tumor burden in mice Cancer Immunology, Immunotherapy 2012 61 893 903 10.1007/s00262-011-1156-6 22095092
91. Fan Y Stronsky SM Xu Y Steffens JT van Tongeren SA Erwin A Cooper CL Moon JJ Multilamellar vaccine particle elicits potent immune activation with protein antigens and protects mice against Ebola virus infection ACS Nano 2019 13 11087 11096 10.1021/acsnano.9b03660 31497947
92. Bazzill JD Stronsky SM Kalinyak LC Ochyl LJ Steffens JT van Tongeren SA Cooper CL Moon JJ Vaccine nanoparticles displaying recombinant Ebola virus glycoprotein for induction of potent antibody and polyfunctional T cell responses Nanomedicine 2019 18 414 425 10.1016/j.nano.2018.11.005 30471480
93. Herzog C Hartmann K Künzi V Kürsteiner O Mischler R Lazar H Glück R Eleven years Inflexal V-a virosomal adjuvanted influenza vaccine Vaccine 2009 27 33 4381 4387 10.1016/j.vaccine.2009.05.029 19450630
94. Moser C Muller M Kaeser MD Weydemann U Amacker M Influenza virosomes as vaccine adjuvant and carrier system Expert Review of Vaccines 2013 12 7 779 791 10.1586/14760584.2013.811195 23885823
95. Drane D Maraskovsky E Gibson R Mitchell S Barnden M Moskwa A Shaw D Gervase B Coates S Houghton M Basser R Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX vaccine: A phase I study in healthy volunteers Human Vaccines 2009 5 3 151 157 10.4161/hv.5.3.6614 19246990
96. Stanberry LR Simon JK Johnson C Robinson PL Morry J Flack MR Gracon S Myc A Hamouda T Baker JR Safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W805EC combined with approved seasonal influenza antigens Vaccine 2012 30 2 307 316 10.1016/j.vaccine.2011.10.094 22079079
97. Brunel F Darbouret A Ronco J Cationic lipid DC-Chol induces an improved and balanced immunity able to overcome the unresponsiveness to the hepatitis B vaccine Vaccine 1999 17 2192 2203 10.1016/S0264-410X(98)00492-7 10367954
98. Joseph A Itskovitz-Cooper N Samira S Flasterstein O Eliyahu H Simberg D Goldwaser I Barenholz Y Kedar E A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoylspermine (CCS)-I. Immunogenicity and efficacy studies in mice Vaccine 2006 24 3990 4006 10.1016/j.vaccine.2005.12.017 16516356
99. Klinguer C Beck A De-Lys P Bussat MC Blaecke A Derouet F Bonnefoy JY Nguyen TN Corvaïa N Velin D Lipophilic quaternary ammonium salt acts as a mucosal adjuvant when co-administered by the nasal route with vaccine antigens Vaccine 2001 19 4236 4244 10.1016/S0264-410X(01)00156-6 11457550
100. Perche F Benvegnu T Berchel M Lebegue L Pichon C Jaffrès PA Midoux P Enhancement of dendritic cells transfection in vivo and of vaccination against B16F10 melanoma with mannosylated histidylated lipopolyplexes loaded with tumor antigen messenger RNA Nanomedicine 2011 7 445 453 10.1016/j.nano.2010.12.010 21220051
101. Bordon Y An RNA vaccine for advanced melanoma Nature Reviews Immunology 2020 20 517 10.1038/s41577-020-00417-7 32753762
102. Sahin U Oehm P Derhovanessian E Jabulowsky RA Vormehr M Gold M Maurus D Schwarck-Kokarakis D Kuhn AN Omokoko T Kranz LM Diken M Kreiter S Haas H Attig S Rae R Cuk K Kemmer-Brück A Breitkreuz A Tolliver C Caspar J Quinkhardt J Hebich L Stein M Hohberger A Vogler I Liebig I Renken S Sikorski J Leierer M Müller V Mitzel-Rink H Miederer M Huber C Grabbe S Utikal J Pinter A Kaufmann R Hassel JC Loquai C Türeci O An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma Nature 2020 585 107 10.1038/s41586-020-2537-9 32728218
103. Martinon F Krishnan S Lenzen G Magné R Gomard E Guillet JG Lévy JP Meulien P Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA European Journal of Immunology 1993 23 1719 1722 10.1002/eji.1830230749 8325342
104. Mai Y Guo J Zhao Y Yang J Intranasal delivery of cationic liposome-protamine complex mRNA vaccine elicits effective anti-tumor immunity Cellular Immunology 2020 354 104143 10.1016/j.cellimm.2020.104143 32563850
105. Hou X Zaks T Langer R Dong Y Lipid nanoparticles for mRNA delivery Nature Reviews: Materials 2021 6 1078 1094 34394960
106. Li K Qu S Chen X Wu Q Shi M Promising targets for cancer immunotherapy: TLRs, RLRs, and STING-mediated innate immune pathways International Journal of Molecular Sciences 2017 18 404 10.3390/ijms18020404 28216575
107. Zhuang X Qi Y Wang M Yu N Nan F Zhang H Tian M Li C Lu H Jin N mRNA vaccines encoding the HA protein of influenza a H1N1 virus delivered by cationic lipid nanoparticles induce protective immune responses in mice Vaccines 2020 8 123 10.3390/vaccines8010123 32164372
108. Erasmus JH Khandhar AP O’Connor MA Walls AC Hemann EA Murapa P Archer J Leventhal S Fuller JT Lewis TB Draves KE Randall S Guerriero KA Duthie MS Carter D Reed SG Hawman DW Feldmann H Gale M Veesler D Berglund P Fuller DH An Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates Science Translational Medicine 2020 12 eabc9396 10.1126/scitranslmed.abc9396 32690628
109. Laczkó D Hogan MJ Toulmin SA Hicks P Lederer K Gaudette BT Castaño D Amanat F Muramatsu H Oguin TH Ojha A Zhang L Mu Z Parks R Manzoni TB Roper B Strohmeier S Tombácz I Arwood L Nachbagauer R Karikó K Greenhouse J Pessaint L Porto M Putman-Taylor T Strasbaugh A Campbell TA Lin PJC Tam YK Sempowski GD Farzan M Choe H Saunders KO Haynes BF Andersen H Eisenlohr LC Weissman D Krammer F Bates P Allman D Locci M Pardi N A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in Mice Immunity 2020 53 724 10.1016/j.immuni.2020.07.019 32783919
110. Goswami R Chatzikleanthous D Lou G Giusti F Bonci A Taccone M Brazzoli M Gallorini S Ferlenghi I Berti F O'Hagan DT Pergola C Baudner BC Adamo R Mannosylation of LNP results in improved potency for self-amplifying RNA (SAM) vaccines ACS Infectious Disease 2019 5 1546 1558 10.1021/acsinfecdis.9b00084
111. Pardi N Parkhouse K Kirkpatrick E McMahon M Zost SJ Mui BL Tam YK Karikó K Barbosa CJ Madden TD Hope MJ Krammer F Hensley SE Weissman D Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies Nature Communications 2018 9 3361 10.1038/s41467-018-05482-0 30135514
112. Pardi N Secreto AJ Shan X Debonera F Glover J Yi Y Muramatsu H Ni H Mui BL Tam YK Shaheen F Collman RG Karikó K Danet-Desnoyers GA Madden TD Hope MJ Weissman D Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge Nature Communications 2017 8 14630 10.1038/ncomms14630 28251988
113. Zhang NN Li XF Deng YQ Zhao H Huang YJ Yang G Huang WJ Gao P Zhou C Zhang RR Guo Y Sun SH Fan H Zu SL Chen Q He Q Cao TS Huang XY Qiu HY Nie JH Jiang Y Yan HY Ye Q Zhong X Xue XL Zha ZY Zhou D Yang X Wang YC Ying B Qin CF A thermostable mRNA vaccine against COVID-19 Cell 2020 182 1271 1283 10.1016/j.cell.2020.07.024 32795413
114. McKay PF Hu K Blakney AK Samnuan K Brown JC Penn R Zhou J Bouton CR Rogers P Polra K Lin PJC Barbosa C Tam YK Barclay WS Shattock RJ Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice Nature Communications 2020 11 3523 10.1038/s41467-020-17409-9 32647131
115. Pardi N Hogan MJ Pelc RS Muramatsu H Andersen H DeMaso CR Dowd KA Sutherland LL Scearce RM Parks R Wagner W Granados A Greenhouse J Walker M Willis E Yu JS McGee CE Sempowski GD Mui BL Tam YK Huang YJ Vanlandingham D Holmes VM Balachandran H Sahu S Lifton M Higgs S Hensley SE Madden TD Hope MJ Karikó K Santra S Graham BS Lewis MG Pierson TC Haynes BF Weissman D Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination Nature 2017 543 248 251 10.1038/nature21428 28151488
116. Richner JM Himansu S Dowd KA Butler SL Salazar V Fox JM Julander JG Tang WW Shresta S Pierson TC Ciaramella G Diamond MS Modified mRNA vaccines protect against Zika virus infection Cell 2017 169 176 10.1016/j.cell.2017.03.016 28340344
117. Aldosari BN Alfagih IM Almurshedi AS Lipid nanoparticles as delivery systems for RNA-based vaccines Pharmaceutics 2021 13 206 10.3390/pharmaceutics13020206 33540942
118. Lutz J Lazzaro S Habbeddine M Schmidt KE Baumhof P Mui BL Tam YK Madden TD Hope MJ Heidenreich R Fotin-Mleczek M Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines NPJ Vaccines 2017 2 29 10.1038/s41541-017-0032-6 29263884
119. Liang F Lindgren G Lin A Thompson EA Ols S Röhss J John S Hassett K Yuzhakov O Bahl K Brito LA Salter H Ciaramella G Loré K Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques Molecular Therapy 2017 25 2635 2647 10.1016/j.ymthe.2017.08.006 28958578
120. Pardi N Hogan MJ Pelc RS Muramatsu H Andersen H DeMaso CR Dowd KA Sutherland LL Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination Nature 2017 543 248 251 10.1038/nature21428 28151488
121. Richner JM Jagger BW Shan C Fontes CR Dowd KA Cao B Himansu S Caine EA Nunes BTD Medeiros DBA Muruato AE Foreman BM Luo H Wang T Barrett AD Weaver SC Vasconcelos PFC Rossi SL Ciaramella G Mysorekar IU Pierson TC Shi PY Diamond MS Vaccine mediated protection against Zika virus-induced congenital disease Cell 2017 170 273 283 10.1016/j.cell.2017.06.040 28708997
122. Meyer M Huang E Yuzhakov O Ramanathan P Ciaramella G Bukreyev A Modified mRNA-based vaccines elicit robust immune responses and protect Guinea pigs from Ebola virus disease Journal of Infectious Diseases 2018 217 451 455 10.1093/infdis/jix592 29281112
123. John S Yuzhakov O Woods A Deterling J Hassett K Shaw CA Ciaramella G Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity Vaccine 2018 36 1689 1699 10.1016/j.vaccine.2018.01.029 29456015
124. Magini D Giovani C Mangiavacchi S Maccari S Cecchi R Ulmer JB De Gregorio E Geall AJ Brazzoli M Bertholet S Self-amplifying mRNA vaccines expressing multiple conserved influenza antigens confer protection against homologous and heterosubtypic viral challenge PLoS ONE 2016 11 e0161193 10.1371/journal.pone.0161193 27525409
125. Lee K Kim SY Seo Y Kim MH Chang J Lee H Adjuvant incorporated lipid nanoparticles for enhanced mRNA-mediated cancer immunotherapy Biomaterials Science 2020 8 1101 1105 10.1039/C9BM01564G 31793928
126. Wahane A Waghmode A Kapphahn A Dhuri K Gupta A Bahal R Role of lipid-based and polymer-based non-viral vectors in nucleic acid delivery for next-generation gene therapy Molecules 2020 25 2866 10.3390/molecules25122866 32580326
127. Aldrich C Leroux-Roels I Huang KB Bica MA Loeliger E Schoenborn-Kellenberger O Walz L Leroux-Roels G von Sonnenburg F Oostvogels L Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase I trial Vaccine 2021 39 8 1310 1318 10.1016/j.vaccine.2020.12.070 33487468
128. Brazzoli M Magini D Bonci A Buccato S Giovani C Kratzer R Zurli V Mangiavacchi S Casini D Brito LM De Gregorio E Mason PW Ulmer JB Geall AJ Bertholet S Induction of broad-based immunity and protective efficacy by self-amplifying mRNA vaccines encoding influenza virus hemagglutinin Journal of Virology 2016 90 332 344 10.1128/JVI.01786-15 26468547
129. Bogers WM Oostermeijer H Mooij P Koopman G Verschoor EJ Davis D Ulmer JB Brito LA Cu Y Banerjee K Otten GR Burke B Dey A Heeney JL Shen X Tomaras GD Labranche C Montefiori DC Liao HX Haynes B Geall AJ Barnett SW Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion Journal of Infectious Diseases 2015 211 947 955 10.1093/infdis/jiu522 25234719
130. Brito LA Chan M Shaw CA Hekele A Carsillo T Schaefer M Archer J Seubert A Otten GR Beard CW Dey AK Lilja A Valiante NM Mason PW Mandl CW Barnett SW Dormitzer PR Ulmer JB Singh M O'Hagan DT Geall AJ A cationic nanoemulsion for the delivery of next-generation RNA vaccines Molecular Therapy 2014 22 2118 2129 10.1038/mt.2014.133 25027661
131. Maruggi G Chiarot E Giovani C Buccato S Bonacci S Frigimelica E Margarit I Geall A Bensi G Maione D Immunogenicity and protective efficacy induced by self-amplifying mRNA vaccines encoding bacterial antigens Vaccine 2017 35 361 368 10.1016/j.vaccine.2016.11.040 27939014
132. Garcia AB Siu E Sun T Exler V Brito L Hekele A Otten G Augustijn K Janse CJ Ulmer JB Bernhagen J Fikrig E Geall A Bucala R Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection Nature Communication 2018 9 1 2714 10.1038/s41467-018-05041-7
133. Geall AJ Verma A Otten GR Shaw CA Hekele A Banerjee K Cu Y Beard CW Brito LA Krucker T O'Hagan DT Singh M Mason PW Valiante NM Dormitzer PR Barnett SW Rappuoli R Ulmer JB Mandl CW Non-viral delivery of self-amplifying RNA vaccines Proceedings of the National Academy of Science 2012 109 14604 14609 10.1073/pnas.1209367109
134. Chahal JS Fang T Woodham AW Khan OF Ling J Anderson DG Ploegh HL An RNA nanoparticle vaccine against Zika virus elicits antibody and CD8+ T cell responses in a mouse model Science and Reports 2017 7 1 252 10.1038/s41598-017-00193-w
135. Erasmus JH Khandhar AP Guderian J Granger B Archer J Archer M Gage E Fuerte-Stone J Larson E Lin S Kramer R Coler RN Fox CB Stinchcomb DT Reed SG Van Hoeven N A nanostructured lipid carrier for delivery of a replicating viral RNA provides single, low-dose protection against Zika Molecular Therapy 2018 26 2507 2522 10.1016/j.ymthe.2018.07.010 30078765
136. Miyazaki J Nishiyama H Yano I Nakaya A Kohama H Kawai K Joraku A Nakamura T Harashima H Akaza H The therapeutic effects of R8-liposome-BCG-CWS on BBN-induced rat urinary bladder carcinoma Anticancer Research 2011 31 2065 2071 21737624
137. Yaguchi K Ohgitani T Noro T Kaneshige T Shimizu Y Vaccination of chickens with liposomal inactivated avian pathogenic Escherichia coli (APEC) vaccine by eye drop or coarse spray administration Avian Diseases 2009 53 245 249 10.1637/8475-092908-Reg.1 19630231
138. Wang C Zhuang Y Zhang Y Luo Z Gao N Li P Pan H Cai L Ma Y Toll-like receptor 3 agonist complexed with cationic liposome augments vaccine elicited antitumor immunity by enhancing TLR3-IRF3 signaling and type I interferons in dendritic cells Vaccine 2012 30 4790 4799 10.1016/j.vaccine.2012.05.027 22634298
139. Thomann J Heurtault B Weidner S Brayé M Beyrath J Fournel S Schuber F Frisch B Antitumor activity of liposomal ERBB2/HER2 epitope peptide-based vaccine constructs incorporating TLR agonists and mannose receptor targeting Biomaterials 2011 32 4574 4583 10.1016/j.biomaterials.2011.03.015 21474175
140. Tai W Roberts L Seryshev A Gubatan JM Bland CS Zabriskie R Kulkarni S Soong L Mbawuike I Gilbert B Kheradmand F Corry DB Multistrain influenza protection induced by a nanoparticulate mucosal immunotherapeutic Mucosal Immunology 2011 4 197 207 10.1038/mi.2010.50 20736998
141. O’Hagan DT Ott GS De Gregorio E Seubert A The mechanism of action of MF59: An innately attractive adjuvant formulation Vaccine 2012 30 29 4341 4348 10.1016/j.vaccine.2011.09.061 22682289
| 36462102 | PMC9734811 | NO-CC CODE | 2022-12-14 23:28:30 | no | Mol Biotechnol. 2022 Dec 3;:1-30 | utf-8 | Mol Biotechnol | 2,022 | 10.1007/s12033-022-00624-8 | oa_other |
==== Front
Anal Bioanal Chem
Anal Bioanal Chem
Analytical and Bioanalytical Chemistry
1618-2642
1618-2650
Springer Berlin Heidelberg Berlin/Heidelberg
36469053
4461
10.1007/s00216-022-04461-1
Research Paper
Label-free ultra-sensitive colorimetric detection of hepatitis E virus based on oxidase-like activity of MnO2 nanosheets
Alam Naveed 1
Ravikumar Chandan Hunsur 2
Sreeramareddygari Muralikrishna 3
Somasundrum Mithran 4
Surareungchai Werasak [email protected]
156
1 grid.412151.2 0000 0000 8921 9789 School of Bioresources and Technology, King Mongkut’s University of Technology Thonburi, Bangkok, 10150 Thailand
2 grid.449351.e 0000 0004 1769 1282 Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Jakkasandra Post, Ramangaram Dist, Karnataka 562112 India
3 grid.412151.2 0000 0000 8921 9789 Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bangkok10150, Thailand
4 grid.425537.2 0000 0001 2191 4408 Biosciences and System Biology Team, Biochemical Engineering and System Biology Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at KMUTT (Bangkhuntien Campus), Bangkok, 10150 Thailand
5 grid.412151.2 0000 0000 8921 9789 Nanoscience & Nanotechnology Graduate Programme, Faculty of Science, King Mongkut’s University of Technology Thonburi, Bangkok, 10140 Thailand
6 grid.10223.32 0000 0004 1937 0490 Analytical Sciences and National Doping Test Institute, Mahidol University, Bangkok, 10400 Thailand
5 12 2022
111
3 9 2022
18 11 2022
22 11 2022
© Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Hepatitis E virus (HEV) is an evolving infectious entity that causes viral hepatitis infections worldwide. Current routine methods of identifying and diagnosing HEV are someway laborious and costly. Based on the biomimicking oxidase-like activity of MnO2 nanosheets, we designed a label-free, highly sensitive colorimetric sensing technique for HEV detection. The prepared MnO2 catalyst displays intrinsic biomimicking oxidase-like catalytic activity and efficiently oxidizes the 3,3′,5,5′-tetramethylbenzidine (TMB) substrate from colorless to blue colored oxidized TMB (oxTMB) product which can be measured at 652 nm by UV–visible spectrum. When the HEV-DNA was added, DNA adsorbed easily on MnO2 surface through physical adsorption and electrostatic interaction which hinders the oxidase-like catalytic activity of MnO2. Upon the introduction of target, the HEV target DNA binds with its complementary ssDNA on the surface of MnO2, the hybridized DNA releases from the surface of MnO2, which leads to recovery of oxidase-like catalytic activity of MnO2. This strategy was applied to construct a colorimetric technique for HEV detection. The approach works in the linear range of 1 fM–100 nM DNA concentration with the limit of detection (LOD) of 3.26 fM (S/N = 3) and quantitative limit (LOQ) of 36.08 fM. The TMB-MnO2 platform was highly selective for HEV target DNA detection when compared with potential interferences. Result of serum sample analysis demonstrates that this sensing system can be used for clinical diagnostic applications.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s00216-022-04461-1.
Keywords
Hepatitis E virus
MnO2
Nanozymes
DNA
Oxidase-mimicking
Biosensors
==== Body
pmcIntroduction
Hepatitis E virus (HEV) is an empirically transmitted RNA virus that causes outbreaks or various sporadic diseases [1]. The HEV major genotypes (G1 to G4) are well-recognized for infection around the world. However, the zoonotic nature of G3 and G4 genotypes can infect animals. HEV was first reported in Asia and Africa for causing acute hepatitis by fecal–oral transmission, while later on it has been found endemic in Japan and Europe [2]. HEV infects annually more than 20 million people worldwide, and for more than 3 million people it leads to hepatitis E [3]. According to WHO, about 44,000 people died from HEV infection in 2015 [4]. Several clinical diagnoses of HEV disease rely on antibody-based detection procedures and techniques involving RNAs such as reverse transcription-polymerase chain reaction (RT-PCR) and enzyme immunoassay, respectively [5]. Despite the sensitivity and specificity of RT-PCR techniques, there are still limitations due to their high cost and rate of false-positive detection. A fast and early detection is required to prevent and monitor the outbreak. This demands to develop a biosensor that could ideally quantify an individual viral particle [6]. Therefore, in order to ensure public health safety, it is vital to develop sensitive and reliable techniques for HEV detection. In the pandemic era, there is a great need for high-accuracy biosensors, which depends on the design of promising biosensing materials using composite sensing techniques.
Recently, the use of nanomaterials (NPs) as nanoenzymes that can mimic the intrinsic catalytic functional property similar to natural enzyme gains a widespread attention. Due to their unique structures, high stabilities and simple facile synthesis, as well as remarkable catalytic activities of NPs, gained more interest [7]. A high efficiency for the adsorption of numerous small molecules and biomolecules, such as amino acids, proteins, DNA, and ions present in biological media, can be attained by NPs with high specific surface area [8]. Additionally, nanozymes have been combined with biomolecules and biopolymers for a variety of clinical and sensing applications [9]. These widespread features make the nanozymes as the physicochemical entity alternative to some of natural enzyme with more or else similar properties [10, 11].
In addition, notably, some two-dimensional (2D) materials/nanosheets, such as graphene oxides [12], metal disulfides [13], metal oxides [14, 15], and carbon nitride [16], mimic the action of natural enzymes in widespread applications for biosensing [17, 18] and chemosensing [19, 20]. Furthermore, 2D nanosheets can create layered nanostructures that are more chemically and thermally stable than natural enzymes, which may open up new opportunities for new industrial and clinical applications [21]. As a result, 2D nanomaterials can be used to create artificial enzymes with target analyte selectivity and many catalytic active sites, which will boost the catalytic activity. This is made possible by the unique properties of having an ultra-large surface area and flexibility. MnO2 nanosheet (NS), is widely reported as a novel two-dimensional (2D) single-layer inorganic nanomaterial. With the precise material tailoring, an enzyme mimic can be produced that has great oxidase-like properties, low toxicity, high stability, and good water dispersion [22, 23]. MnO2 nanoparticles have been widely used in biosensing, bioimaging, delivery of single stranded DNA (ssDNA), and drugs [7, 24]. MnO2 nanosheets, in contrast to other biomimetic oxidases, have a unique capacity for decomposition, providing a substitute for the detection of glutathione [25], oxalate, DNA [26], ascorbic acid, and alkaline phosphatase [27]. In this case, the catalytic substrates 2,2′-azino-bis (3- ethylbenzthiazoline-6-sulfonate) diammonium salt (ABTS), 3,3′,5,5′-tetramethylbenzidine (TMB), and o-toluidine (OT) are oxidized to produce distinctive color change during reaction with MnO2 nanosheets [28]. MnO2 nanosheets could therefore be employed for colorimetric sensing and have higher compatibility with a number of biosensing pathways.
Here, based on the oxidase-like activity of MnO2 nanosheets, we designed for the first time a simple, label-free, cost-effective, and rapid colorimetric technique for the extremely sensitive detection of HEV. To achieve a more rapid and facile sensing platform, the DNA oligonucleotides were directly adsorbed on the surface of MnO2 to simplify our assay design. The multi-step sensor fabrication processes avoided that are usually associated with DNA hybridization-based assays. With a characteristic absorption peak at 652 nm, the MnO2 nanosheets in this sensing platform may directly catalyze the oxidation of TMB, turning it from colorless to blue oxTMB and exhibiting excellent biomimetic oxidase-like activity. The facile synthesized MnO2 nanosheet was characterized using structural and crystalline details to confirm the formation of sheet like structure using X-ray diffraction (XRD) and transmission electron microscopy (TEM). Further, the atomic force microscopy was carried out to confirm the adsorption of ssDNA on to the MnO2 sheets. This colorimetric approach has great sensing performance with lower limit of detection and high sensitivity and selectivity. Low-toxic, well-biocompatible, and readily synthesized biosensors are very promising for using in clinical samples to diagnose diseases.
Materials and methods
Materials
The chemicals used in this investigation were of the analytical grade and were utilized directly without any further purification. Potassium permanganate was acquired from Sinopharm Chemical Reagent Co., Ltd, China. Potassium dihydrogen phosphate (≥ 98%), di-potassium hydrogen phosphate anhydrous (≥ 98%), acetic acid (99.8%), and ethanol (99.9%) were obtained from Merck, USA. Sodium acetate (99–101%) was purchased from Ajax Fine Chem. 3,3′,5,5′-tetramethylbenzidine (> 98%) was procured from Tokyo Chemical Industry, Japan, and human serum from Sigma-Aldrich, USA. All the oligonucleotides were acquired from Integrated DNA Technologies Ltd., Singapore, and were used without additional purification. For all the experiments, Milli-Q water was used. The sequences of oligonucleotide [29] used in this study are as follows:o HEV capture probe sequences (18 bases)
p 5′-GGTGGTTTCTGGGGTGAC-3′
q HEV target probe sequences (51 bases)
r 5′-GGATTGCGAAGGGCTGAGAATCAACCCGGTCACCCCAGAAACCA CCGCCGG-3′
Synthesis of MnO2 nanosheets
Potassium permanganate (KMnO4) was used for the synthesis of MnO2 nanosheets through a thermal decomposition method with slight modification from literature [30]. Briefly, 2 g of KMnO4 was transferred into a porcelain crucible and was heated for 4 h at 500 °C in air and then cooled at room temperature. The product was harvested by centrifugation at 10,000 rpm for 8 min, and the soluble byproducts (K3MnO4 or K2MnO4) were removed by washing the product three times with distilled water. The MnO2 was dried for 12 h in an electric oven at 60 °C. For further experiments, the final product was stored at room temperature.
Preparation of HEV-DNA@MnO2
For the adsorption of DNA on the surface of MnO2, 5 μL of 1 mg/mL MnO2 (final concentration 20 μg/mL) was added to different concentrations (0, 0.5, 1.5, and 2.5 μM) of HEV capture probe. At room temperature, the mixture was vortexed for 2 h. The excess DNA was removed from the mixtures after incubation by centrifuging at 8000 rpm for 10 min. The pellet was kept at 0 °C for further use, while the supernatant was discarded.
Assay procedures
For detection of HEV, 2.5 μL of 1 mg/mL CP-modified MnO2 (10 μg/mL final concentration) was added to 10 μL of different concentrations (0, 1 fM, 100 fM, 1 pM, 100 pM, 1 nM, and 100 nM) of HEV target probes. The mixtures were incubated for 30 min at 37 °C for binding of HEV capture probe and target probe. After 30 min of incubation, 235 μL of Na-Ac buffer (pH 3.5, 0.1 M) was added to the above mixtures. Finally, 2.5 μL of TMB (final concentration 1 mM) was added to a total of 250 μL reaction system to initiate the reaction. The absorption spectra were recorded from 350 to 800 nm using the excitation wavelength of 652 nm using a microplate reader. All the experiments were recorded in 3 replicates.
Characterizations
Powder X-ray diffraction (P-XRD) patterns were recorded using Bruker D8 Diffraction system with a Cu Kα source (λ = 0.1541 nm). The surface morphology of the prepared materials was investigated using TEM JEM-2100Plus transmission electron microscopy. Through N2 adsorption desorption analysis utilizing a BET analyser, the surface area of the MnO2 was measured. The DNA adsorption on MnO2 was confirmed by atomic force microscopy (AFM) from Park NX10 SICM. A microplate reader (Cytation 5 Biotek) was used to examine the oxidase-like catalytic activities of the prepared material and TMB substrate. Zeta potentials of MnO2 nanosheets, DNA, MnO2-CP, and MnO2-CP-TP were recorded using Zetasizer [Malvern Panalytical-UK, Nano ZS].
Results and discussion
Characterizations of MnO2 nanosheets
MnO2 nanosheets were synthesized through a facile one step thermal decomposition route. As displayed in Fig. 1, the transmission electron microscopy images of MnO2 nanosheets exhibited a typical two-dimensional layer structure and displayed multiple folds and wrinkled like sheet structure. The high surface-to-volume ratios of ultra-thin sheets could provide large specific surface area and allowing easy contact between reactant molecules and the active sites of nanosheets, thus providing enhanced catalytic activities as well as unique optical properties. High-resolution TEM images (Fig. 1C), shows that obtained nanosheets are free of any particle on surface. The TEM of MnO2 nanosheets at 1 µm scale showing overall view is demonstrated in ESI (Fig. S1) and the size distribution at 200 nm scale in ESI (Fig. S2). From the HRTEM image, the d-spacing was analyzed and found to be around ~ 0.38 nm, which corresponds to the (002) plane displayed in Fig. 1D.Fig. 1 TEM image of the MnO2 nanosheets at different scales (A) 1 μm, (B) 200 nm, (C) 100 nm. (D) shows the d-spacing from the HRTEM image of MnO2 nanosheets
The energy-dispersive X-ray (EDS) spectra obtained using TEM microscope shows that Mn and O elements are present in MnO2 nanosheets. The atomic percentage of Mn and O was approximately 25.40% and 74.60%, respectively, as shown in ESI, Fig. S3 and Fig. S4. This confirms successful formation of MnO2 nanosheets.
The crystal structures and phase information of MnO2 nanosheets are acquired from powder X-ray diffraction (PXRD) pattern in Fig. 2A. The diffraction peaks are considerably broadened due to noncrystalline nature of as-synthesized materials. The diffraction pattern observed at 2Ɵ of 11.8°, 24.9°, 36.4°, 41.4°, and 66.6° are corresponding to (211), (301), (600), and (002) crystal planes, respectively, which corresponds to tetragonal MnO2 (JCPDS 44–0141). The minor variations in the distances between nanosheets in various restacked 2D structures can be used to explain the small variations in the (002) diffraction peak angles. By measuring the surface area by N2 adsorption–desorption analysis using a BET analyzer, the results of the surface characteristics studies are shown in Fig. 2B, C, and D. The curves shows the type IV isotherm profiles [31]. Such profiles reveal two types of characteristics of the surface: (1) mesoporous structure and (2) unrestricted multilayer adsorption of the materials. It was found that the surface area of the material was 12.939 m2 g−1. But it was interesting to know that the pore volume was more prominent with an average pore diameter of 19.895 nm. Such a large pore diameter is more suitable for catalytic processes, while the surface area of MnO2 with capture probe and target probe were 19.71 m2 g−1 and 14.76 m2 g−1, respectively, which also confirms the adsorption and desorption of capture and target probes.Fig. 2 A X-ray diffraction patterns of the synthesized MnO2 nanosheets. B Nitrogen adsorption and desorption isotherms of the MnO2 nanosheets, C MnO2 with capture probe, and D MnO2 with capture and target probes
To further understand the morphology and adsorption of HEV-DNA on the surface of MnO2 nanosheets, the atomic force microscopy (AFM) was used. From the AFM micrographs (Fig. 3A–C), the MnO2 produced from thermal decomposition method shows the root mean square (RMS) surface roughness around 0.0043 µm (Fig. 3A), whereas ssDNA modified MnO2 nanosheets attained a surface roughness 0.1916 µm (Fig. 3B). The change in morphology and surface roughness of MnO2 nanosheets and ssDNA modified MnO2 nanosheets clearly indicates that ssDNA adsorbed on the surface of MnO2 nanosheets. The wavey kind structure was produced on the surface of MnO2 representing the adherence of ssDNA and almost covered the area of the scan (Fig. 3B). Upon the addition of target DNA, it’s interacted with ssDNA on the surface of MnO2 nanosheets. The resulting hybridized DNA released from the surface of MnO2 nanosheets. However, some unhybridized DNA is still adhered on the surface of MnO2 nanosheets which can be seen as wavy kind of appearance on surface of the MnO2 nanosheet as shown in Fig. 3C. The RMS roughness of HEV CP-modified MnO2 + HEV TP is 0.0155 µm which confirm the adsorption and desorption of DNA on MnO2 nanosheets.Fig. 3 A AFM images of the MnO2 nanosheets, B MnO2 + HEV CP, and C HEV CP-modified MnO2 + HEV TP
This was further confirmed by zeta potential analysis of all the three materials along with the ssDNA. Unmodified MnO2 nanosheets shows a zeta potential of − 39.6 mV, and ssDNA was − 17.4 mV. After modification with ssDNA, it was found that the zeta potential was increased to − 55.3 mV. Upon adding the target DNA to the system, the hybridized DNA was released from the surface, and the zeta potential was decreased again to − 44.8 mV which is almost closer to the value of unmodified MnO2 zeta potential. This demonstrates that the majority of the ssDNA has been released while a small portion of unhybridized DNA is still remaining on the surface of MnO2 nanosheets Fig. 4A. Furthermore, the HEV capture probe was labeled with Cy3 dye. A 2.5 μM of Cy3-labeled HEV CP was mixed with 10 μg/mL MnO2 catalyst in Na-Ac buffer (pH 3.5, 0.1 M). The fluorescence was recorded in the absence and presence of HEV target probe as shown in Fig. 4B. The bare MnO2 did not show fluorescence, while a high fluorescence was observed for MnO2-CP demonstrating that MnO2 is successfully modified with HEV DNA. But when HEV target was added into the system, the target probe hybridized with capture probe and released from the surface; hence, a decrease in the fluorescence was observed.Fig. 4 Zeta-potential analysis of A MnO2 nanosheets, ssDNA, MnO2-CP and in the presence (MnO2-CP-TP) of the HEV target probe. B Fluorescence spectra of MnO2 nanosheets, MnO2-CP and presence of the HEV target probe (MnO2-CP-TP)
Proof of concept and verifications
In the presence of DNA, the surface of MnO2 nanosheets can be masked that inhibits the biomimetic oxidase-like activity of MnO2 nanosheets. DNA affects the catalytic activity of the MnO2 nanosheets; it adsorbs on the surface of MnO2 nanosheets via the negatively charged phosphate backbone [32] and by van der Waals force of interaction between the surface of MnO2 material and nucleobases of DNA [33] and, thus, reasonably inhibits the oxidase-like activity of MnO2 [34]. Encountering the HEV target DNA, the complementary target ssDNA is hybridized with the capture ssDNA probe, between the densely negatively charged phosphate backbones, the nucleobases are buried, and double-strand DNA (dsDNA) conformation is produced. By employing conserved sequences, no cross-reactivity existed because of specific complementarity. The dsDNA conformation can reduce the intensity of the Van der Waals interaction between dsDNA and the MnO2 surface and inhibit interactions between nucleobases and material surfaces [35]. As a result of the electrostatic repulsion between dsDNA and MnO2, the system’s oxidase activity will recover as dsDNA is released from the surface of MnO2 (Scheme 1). The basic principle behind the colorimetric sensing of HEV is based on the biomimetic oxidase-like activity of MnO2 nanosheets. As shown in Fig. 5A, the TMB was colorless with no characteristic absorbance from 350 to 800 nm. After adding the as-prepared MnO2 nanosheets, the oxidation of the colorless TMB produced a blue-colored product (oxTMB) as can be seen in the inset of Fig. 5A and giving a high absorbance peak. However, after the addition of the HEV capture probe into the MnO2-TMB system, the absorbance at 652 nm was decreased by hindering the oxidation of TMB to oxTMB shown in Fig. 5B. This can be attributed to the adsorption of the HEV capture probe on the basal plane of MnO2 through the negatively charged phosphate backbone [34]. The oxidation of TMB to oxTMB would be reduced as a result of covering the surface area of MnO2 nanosheets, leading to the inhibition of biomimetic activity. Consequently, the intensity of the 652 nm absorbance reduced. However, there is some incomplete surface coverage of captured ssDNA on MnO2 nanosheets for catalytic reaction which gives absorbance peak at 652 nm. But, upon the addition of target DNA to the MnO2-TMB-HEV-CP system, the target probe binds to the capture probe on the surface of MnO2 because of DNA hybridization. Hence, the hybridized DNA from the surface of MnO2 is released, and the oxidase-like activity of the MnO2 is recovered. Confirmation of the feasibility of the target sensing approach through visual observations can be seen in ESI, Fig. S5. Without the use of H2O2, this efficient reaction between the TMB substrate and MnO2 nanosheets offers tremendous stability and reproducibility. These results established the practicality of this colorimetric sensing mechanism and applied it to the detection of HEV target probe. Scheme 1 Schematic diagram of MnO2-TMB system for the colorimetric sensing of HEV
Fig. 5 UV–visible absorption spectra of (A) only TMB, only MnO2 and TMB + MnO2. Inset of A is the visual observations. (B) The mixtures (TMB, MnO2, TMB + MnO2, TMB + MnO2 + HEV CP and TMB + HEV CP-modified MnO2 + HEV TP) in the presence of TMB (1 mM) and MnO2 (20 μg/mL)
Optimization of assay conditions
For the highly throughput results of the HEV detection sensor, the critical parameters such as pH, MnO2, and HEV capture probe were studied systematically to establish the optimal conditions. The concentration of MnO2 was investigated to determine the optimum concentration for high oxidase-like activity. Different MnO2 concentrations (0, 10, 20, 40, and 60 μg/mL) were added to MnO2-TMB reaction system. In ESI, Fig. S6A depicts that the UV–visible absorbance peak intensity centered at 652 nm increases with increasing concentrations of MnO2. There was a linear relationship between MnO2 concentration and absorption spectra at 652 nm with the regression coefficient (R2 = 0.999) as shown in ESI, Fig. S6B. For high accuracy, we employed 10 μg of MnO2 for further experiments of HEV detection.
As the pH value is critical for the high oxidase-like activity of MnO2, Na-Ac buffer of pH range from 3 to 6 was studied. As presented in ESI, Fig. S7, the absorbance spectra of the reaction system decreased steadily with increasing pH value. MnO2 exhibits high enzymatic activity in mildly acidic conditions, and MnO2 nanosheets have a high oxidation capability [36]. So, Na-Ac buffer of pH 3.5 was selected for further experiments.
Adsorption of HEV-DNA on MnO2 nanosheets
To investigate the application of MnO2-TMB sensing platform for the detection of HEV, the system was first applied to investigate the adsorption of HEV capture probe on MnO2 surface. Under the optimum experimental conditions, different concentrations of HEV capture probe in the range of 0–2.5 μM were applied to adsorb on the surface of MnO2. The concentrations of HEV capture probe have a huge effect on the catalytic activity of MnO2. As the concentration of HEV capture probe increased from 0 to 2.5 μM, the absorbance spectra at 652 nm decreased as illustrated in Fig. 6A. The color of the reaction was considerably changed from dark blue to light blue which was also confirmed by visual observations shown in Fig. 6B. The HEV capture probe was physically adsorbed successfully by MnO2 via phosphate backbone of DNA which is often bound by some nanoparticles [37]. In literature, it is reported that due to large number of terminal phosphate groups, its binding affinity to nanoparticles is higher [38]. DNA affects the catalytic activity of the nanomaterial; it adsorbs on the surface of the nanomaterial via the negatively charged phosphate backbone [32]. This indicates that the adsorption of HEV capture probe masked the surface of MnO2, so less MnO2 surface is available for the catalytic oxidation of TMB and hence decreases the absorbance spectra at 652 nm. When the concentration of HEV capture probe increased, the absorbance spectra at 652 nm decreased. Figure 6C shows that there is an indirect relationship between the change in absorbance and the HEV capture probe concentration from 0 to 2.5 μM with a correlation coefficient of 0.984. Figure 6D shows a clear difference in the absorbance spectra of TMB + MnO2 and TMB + MnO2 + HEV CP.Fig. 6 UV–visible absorption spectra of A varied concentrations (0, 0.5, 1.5, and 2.5 μM) of DNA adsorption on MnO2 in presence of TMB (1 mM) and MnO2 (20 μg/mL). B shows the visual representations of adsorption of different concentrations of DNA on MnO2 resulting in decrease oxidation of TMB. C The liner calibration between the different concentrations of DNA adsorption on MnO2 and the decrease in TMB oxidation. D UV–visible absorption spectra of TMB + MnO2 sensing system in the absence (black) and presence (red) of adsorbed DNA on MnO2
Analytical performance of the sensor for HEV detection
The proposed colorimetric sensor was also employed to detect HEV under the ideal experimental conditions. With increasing the concentration of HEV target probe ranging from 1 fM to 100 nM, the absorbance spectra at 652 nm of the sensing platform was gradually increased as displayed in Fig. 7A. As the concentration of HEV target probe increases, more number of target probes bind with capture probe, and the surface of MnO2 is unmasked. Hence, the oxidase-like activity of the MnO2 is recovered by the oxidation of TMB to oxTMB. The absorbance spectra at 652 nm are intensified. Figure 7B shows the visual confirmation of the increased oxidation of TMB by MnO2. With the increasing concentration of target probes in the sensing system, more capture probes are released from the surface of MnO2. This confirms more availability of MnO2 for the oxidation of TMB and the color of the sensing system changes from light blue to dark blue. Figure 7C illustrates a linear relation of change in absorbance spectra and the target probe concentration from 1 fM to 100 nM with the regression coefficient of 0.998. The absorbance spectra at 652 nm were directly related to the sensing of HEV; this correlates linearly with the concentration of HEV target probe. The LOD was calculated to be 3.26 fM based on the standard deviation of the response (Sy) of the curve and the slope of the calibration curve (S) at levels approximating the LOD according to the formula: LOD = 3.3(Sy/S). The LOQ was calculated to be 36.08 fM on the basis of standard deviation of the response (SD) and the slope of the calibration curve (S) according to the formula: LOQ = 10(Sy/S). The standard deviation of the response was determined based on the standard deviation of y-intercepts of the regression lines. The results are comparatively better than those of earlier reports tabulated in Table S1 in ESI. There is an obvious change in the absorbance spectra of TMB + MnO2 + HEV CP and TMB + HEV CP-modified MnO2 + HEV TP. In TMB + MnO2 + HEV CP sensing system, most of the MnO2 surface is hindered by the adsorbed capture probe, so fewer MnO2 active sites are available to catalyze the TMB present in the reaction system. This can also be attributed to the presence of bigger pore size and volume. These can also provide necessitated active sites possible to even load the ssDNA to MnO2, and this is evident from BET analysis. As the target probe is added into the system, the capture probe binds with the target probe because of their complementarity with each other. Hence, the oxidase activity of MnO2 is recovered for the oxidation of TMB as shown in Fig. 7D.Fig. 7 A UV–visible absorption spectra for detection of different concentrations (0, 1 fM, 100 fM, 1 pM, 100 pM 1 nM, and 100 nM) of HEV target in presence of TMB (1 mM) and MnO2 (10 μg/mL). B Visual illustrations of detection of different concentrations of HEV target probes leading to recovery of oxidase-like catalytic activity of MnO2. C Displays the linear calibration of detection of HEV target probes and recovery of oxidase-like activity of MnO2. D UV–visible absorption spectra of TMB-MnO2 sensing system in the absence (red) and presence (black) of HEV target probe and 20 μg/mL of MnO2 catalyst
Stability and selectivity of the biosensor
In order to assess the reliability of the developed sensor, the cyclic stability tests of MnO2 and MnO2 + HEV-CP were performed at a 1-week interval for a period of 1 month as displayed in Fig. 8A. It indicates that our prepared material exhibits good catalytic activity and stability over a month without affecting its primary performance. The selectivity of this sensing system was subsequently studied by monitoring the change in absorbance activity with other interfering molecules. To assess the specificity of the suggested sensor, we selected other mismatched DNA sequences such as IBV, HBV, HCV, IAV, HAV, HEV-3, and HEV-4 as shown in Table S2. The concentrations of these interferents were set as 1 pM, while 100 fM concentration was set for HEV target (equivalent to 0.1 pM). As shown in Fig. 8B, due of the non-specific interaction with the HEV capture probe, the biosensor responses to the other virus sequences are much lower, even though they were in higher concentration than HEV. This makes our developed sensor unique to the target analyte. This confirms that our developed colorimetric sensor possesses excellent specificity and selectivity for HEV detection.Fig. 8 Stability and selectivity of the developed sensor. A Stability of oxidase activity of MnO2 nanosheets and hindering oxidase activity of MnO2 nanosheets by HEV-CP in the presence of TMB (1 mM), MnO2 (20 μg/mL), and HEV-CP (2.5 μM). B Selectivity of HEV target (100 fM) over potential interferences. IBV, HBV, HCV, IAV, HAV, HEV-3, HEV-4 (1 pM). The incubation time selected was 5 min. Error bar represents the standard deviation for three determinations
Analytical performance in spiked serum samples
To further explore the analytical performance of our colorimetric sensor in complex biological samples, the human serum obtained from Sigma-Aldrich was diluted tenfold after centrifugation. Then, the diluted serum sample was combined with 10 μL of various HEV DNA concentrations (100 fM, 1 pM, 100 pM, 1 nM, and 100 nM) and incubated for 30 min at 37 °C. To examine whether the developed sensor could be applied for the sensing of HEV in a real sample, the absorbance responses are tested in spiked serum samples. As depicted in Fig. 9A, the biosensor responses display a similar tendency of increasing absorbance with increasing concentrations (100 fM–100 nM) of HEV targets as in the buffer. The LOD and LOQ were calculated to be 9.32 fM and 28.24 fM, respectively. Figure 9B shows a linear relation of change in absorbance spectra vs different concentrations of target HEV (100 fM, 1 pM, 100 pM, 1 nM, and 100 nM) with the regression coefficient value of 0.99 (n = 3). The absorbance spectra of target detection in Na-Ac buffer and human serum are shown in ESI, Fig. S8. The recoveries of HEV target DNA ranged from 97.5 to 101.5% tabulated in Table 1, proving that the suggested method may be used to diagnose HEV in patients without the need for complex pretreatments.Fig. 9 Sensor performances for different concentrations of HEV analytes in serum. A UV–visible absorption spectra of detection of different concentrations (100 fM, 1 pM, 100 pM, 1 nM, and 100 nM) of HEV target in serum in presence of TMB (1 mM) and MnO2 (10 μg/mL). B depicts the linear calibration of detection of HEV target in human serum samples
Table 1 Detection of HEV target in serum sample with this sensor
Sample Added Detected Recovery (%) RSD (%, n = 3)
HEV 100 fM 99 fM 99.0 4.93
HEV 1 pM 0.98 pM 98.0 3.57
HEV 100 pM 97.5 pM 97.5 5.01
HEV 1 nM 0.99 nM 99.0 6.36
HEV 100 nM 101.5 nM 101.5 4.30
Conclusion
In conclusion, a label-free, highly sensitive colorimetric sensing system was developed to identify the Hepatitis E virus. The strategy has relied on effective biomimicking oxidase activity of MnO2 nanosheets. This approach can catalyze the oxidation of TMB into oxTMB that can be visualize by the naked eye as a clear absorption peak at 652 nm with a colorimetric change from colorless to blue product. The addition of HEV DNA capture probe to the system leads to the inhibition of biomimetic oxidase activity due to adsorption of the DNA on the surface of MnO2 nanosheets. The oxidase activity was regained by the introduction of HEV target probe. HEV target probe binds to the HEV capture probe, thus hindering the interaction between the MnO2 surface and DNA. This releases the DNA from the surface exposing them to more catalytic surface sites, recovering the oxidase-like activity. The assay was also used to quantify HEV target DNA in spiked serum samples with high accuracy showing its feasibility and reliability. Therefore, this simple approach could offer an easy, robust, and label-free sensing platform for biological and clinical diagnostic applications.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 1980 KB)
Acknowledgements
Naveed Alam gratefully acknowledges Petchra Pra Jom Klao PhD Research scholarship, King Mongkut’s University of Technology Thonburi (KMUTT). All the authors acknowledge the efforts of Dr. Asma Gul during the proofreading of the revised manuscript.
Declarations
Conflict of interest
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Emerson SU Purcell RH Hepatitis E virus 2003 13 3 145 154
2. Kaba M Moal V Gérolami R Colson P Epidemiology of Mammalian Hepatitis E Virus Infection Intervirology 2013 56 2 67 83 10.1159/000342301 23343760
3. Rein DB, Stevens GA, Theaker J, Wittenborn JS, Wiersma ST. The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology. 2012;55(4):988–97.
4. World Health Organisation Hepatitis E. (2018) Available at: https://www.who.int/news-room/fact-sheets/detail/hepatitis-e. Accessed 1 February 2019
5. Martin-Latil S Hennechart-Collette C Guillier L Perelle S Method for HEV detection in raw pig liver products and its implementation for naturally contaminated food Int J Food Microbiol 2014 176 1 8 10.1016/j.ijfoodmicro.2014.01.016 24553051
6. Khoris IM Takemura K Lee J Hara T Abe F Suzuki T Enhanced colorimetric detection of norovirus using in-situ growth of Ag shell on Au NPs Biosens Bioelectron 2019 126 425 432 10.1016/j.bios.2018.10.067 30471568
7. Chen W Li S Wang J Sun K Si Y Metal and metal-oxide nanozymes: bioenzymatic characteristics, catalytic mechanism, and eco-environmental applications Nanoscale 2019 11 34 15783 15793 10.1039/C9NR04771A 31432841
8. Singh S Dosani T Karakoti AS Kumar A Seal S Self WT A phosphate-dependent shift in redox state of cerium oxide nanoparticles and its effects on catalytic properties Biomaterials 2011 32 28 6745 6753 10.1016/j.biomaterials.2011.05.073 21704369
9. Liu B Liu J Surface modification of nanozymes Nano Res 2017 10 4 1125 1148 10.1007/s12274-017-1426-5
10. Lin Y Ren J Qu X Catalytically active nanomaterials: a promising candidate for artificial enzymes Acc Chem Res 2014 47 4 1097 1105 10.1021/ar400250z 24437921
11. Hassan SSM Sayour HEM Kamel AH A simple-potentiometric method for determination of acid and alkaline phosphatase enzymes in biological fluids and dairy products using a nitrophenylphosphate plastic membrane sensor Anal Chim Acta 2009 640 1 75 81 10.1016/j.aca.2009.03.019 19362623
12. Shi J Guo J Bai G Chan C Liu X Ye W A graphene oxide based fluorescence resonance energy transfer (FRET) biosensor for ultrasensitive detection of botulinum neurotoxin A (BoNT/A) enzymatic activity Biosens Bioelectron 2015 65 238 244 10.1016/j.bios.2014.10.050 25461164
13. Xi Q Zhou D-M Kan Y-Y Ge J Wu Z-K Yu R-Q Highly sensitive and selective strategy for microRNA detection based on WS2 nanosheet mediated fluorescence quenching and duplex-specific nuclease signal amplification Anal Chem 2014 86 3 1361 1365 10.1021/ac403944c 24446758
14. Liu J Tang D Chen Z Yan X Zhong Z Kang L Chemical redox modulated fluorescence of nitrogen-doped graphene quantum dots for probing the activity of alkaline phosphatase Biosens Bioelectron 2017 94 271 277 10.1016/j.bios.2017.03.017 28288447
15. Gopi PK Ngo DB Chen S-M Ravikumar CH Surareungchai W High-performance electrochemical sensing of hazardous pesticide Paraoxon using BiVO4 nano dendrites equipped catalytic strips Chemosphere 2022 288 132511 10.1016/j.chemosphere.2021.132511 34688713
16. Zhang X-L Zheng C Guo S-S Li J Yang H-H Chen G Turn-on fluorescence sensor for intracellular imaging of glutathione using g-C3N4 nanosheet–MnO2 sandwich nanocomposite Anal Chem 2014 86 7 3426 3434 10.1021/ac500336f 24655132
17. Lin T Zhong L Guo L Fu F Chen G Seeing diabetes: visual detection of glucose based on the intrinsic peroxidase-like activity of MoS2 nanosheets Nanoscale 2014 6 20 11856 11862 10.1039/C4NR03393K 25171261
18. Zhu C Zeng Z Li H Li F Fan C Zhang H Single-Layer MoS2-based nanoprobes for homogeneous detection of biomolecules J Am Chem Soc 2013 135 16 5998 6001 10.1021/ja4019572 23570230
19. Dong Y-l Zhang H-g Rahman ZU Su L Chen X-j Hu J Graphene oxide–Fe3O4 magnetic nanocomposites with peroxidase-like activity for colorimetric detection of glucose Nanoscale. 2012 4 13 3969 76 10.1039/c2nr12109c 22627993
20. Yuan Y Wu S Shu F Liu Z An MnO2 nanosheet as a label-free nanoplatform for homogeneous biosensing Chem Commun 2014 50 9 1095 1097 10.1039/C3CC47755J
21. Xie J Cao H Jiang H Chen Y Shi W Zheng H Co3O4-reduced graphene oxide nanocomposite as an effective peroxidase mimetic and its application in visual biosensing of glucose Anal Chim Acta 2013 796 92 100 10.1016/j.aca.2013.08.008 24016588
22. Tan Q Zhang R Kong R Kong W Zhao W Qu F Detection of glutathione based on MnO2 nanosheet-gated mesoporous silica nanoparticles and target induced release of glucose measured with a portable glucose meter Microchim Acta 2017 185 1 44 10.1007/s00604-017-2603-7
23. Huang W Deng Y He Y Visual colorimetric sensor array for discrimination of antioxidants in serum using MnO2 nanosheets triggered multicolor chromogenic system Biosens Bioelectron 2017 91 89 94 10.1016/j.bios.2016.12.028 27992804
24. HunsurRavikumar C Nair GV M. P R, Surareungchai W, Thakur A, Balakrishna RG Biomass derived carbon dot decorated ssDNA for a ‘turn-on’ fluorescent assay for detection of Staphylococcus aureus MNase New J Chem. 2021 45 13 5890 6 10.1039/D1NJ00199J
25. Ma Z Wu T Li P Liu M Huang S Li H A dual (colorimetric and fluorometric) detection scheme for glutathione and silver (I) based on the oxidase mimicking activity of MnO2 nanosheets Microchim Acta 2019 186 8 498 10.1007/s00604-019-3613-4
26. Chen J Wang Y Wei X Ni R Meng J Xu F A composite prepared from MnO2 nanosheets and a deep eutectic solvent as an oxidase mimic for the colorimetric determination of DNA Microchim Acta 2019 187 1 7 10.1007/s00604-019-4021-5
27. Yang Q Wang X Peng H Arabi M Li J Xiong H Ratiometric fluorescence and colorimetry dual-mode assay based on manganese dioxide nanosheets for visual detection of alkaline phosphatase activity Sens Actuators, B Chem 2020 302 127176 10.1016/j.snb.2019.127176
28. Liu J Meng L Fei Z Dyson PJ Zhang L On the origin of the synergy between the Pt nanoparticles and MnO2 nanosheets in Wonton-like 3D nanozyme oxidase mimics Biosens Bioelectron 2018 121 159 165 10.1016/j.bios.2018.08.004 30218923
29. Ngo DB Chaibun T Yin LS Lertanantawong B Surareungchai W Electrochemical DNA detection of hepatitis E virus genotype 3 using PbS quantum dot labelling Anal Bioanal Chem 2021 413 4 1027 1037 10.1007/s00216-020-03061-1 33236225
30. Komaba S Kumagai N Chiba S Synthesis of layered MnO2 by calcination of KMnO4 for rechargeable lithium battery cathode Electrochim Acta 2000 46 1 31 37 10.1016/S0013-4686(00)00535-1
31. Ravikumar CH M S, Mahto A, Nanjundaiah RT, Thippeswamy R, Teixeira SR Observation of oxo-bridged yttrium in TiO2 nanostructures and their enhanced photocatalytic hydrogen generation under UV/visible light irradiations Mater Res Bull. 2018 104 212 9 10.1016/j.materresbull.2018.04.014
32. Kim HY Ahn JK Kim MI Park KS Park HG Rapid and label-free, electrochemical DNA detection utilizing the oxidase-mimicking activity of cerium oxide nanoparticles Electrochem Commun 2019 99 5 10 10.1016/j.elecom.2018.12.008
33. He D He X Wang K Yang X Yang X Li X Nanometer-sized manganese oxide-quenched fluorescent oligonucleotides: an effective sensing platform for probing biomolecular interactions Chem Commun 2014 50 75 11049 11052 10.1039/C4CC04573D
34 Pautler R Kelly EY Huang P-JJ Cao J Liu B Liu J Attaching DNA to nanoceria: regulating oxidase activity and fluorescence quenching ACS Appl Mater Interface. 2013 5 15 6820 5 10.1021/am4018863
35. Ge J Ou E-C Yu R-Q Chu X A novel aptameric nanobiosensor based on the self-assembled DNA–MoS2 nanosheet architecture for biomolecule detection Journal of Materials Chemistry B 2014 2 6 625 628 10.1039/C3TB21570A 32261279
36. He L, Wang F, Chen Y, Liu Y. Rapid and sensitive colorimetric detection of ascorbic acid in food based on the intrinsic oxidase-like activity of MnO2 nanosheets. Luminescence. 2018;33(1):145–52.
37. Liu B Liu J DNA adsorption by magnetic iron oxide nanoparticles and its application for arsenate detection Chem Commun 2014 50 62 8568 8570 10.1039/C4CC03264K
38. Wang X Lopez A Liu J Adsorption of phosphate and polyphosphate on nanoceria probed by DNA oligonucleotides Langmuir 2018 34 26 7899 7905 10.1021/acs.langmuir.8b01482 29886738
| 36469053 | PMC9734815 | NO-CC CODE | 2022-12-14 23:28:30 | no | Anal Bioanal Chem. 2022 Dec 5;:1-11 | utf-8 | Anal Bioanal Chem | 2,022 | 10.1007/s00216-022-04461-1 | oa_other |
==== Front
Jpn J Radiol
Jpn J Radiol
Japanese Journal of Radiology
1867-1071
1867-108X
Springer Nature Singapore Singapore
36469224
1366
10.1007/s11604-022-01366-y
Original Article
Bayesian multidimensional nominal response model for observer study of radiologists
Nishio Mizuho [email protected]
Kobayashi Daigo
Matsuo Hidetoshi
Urase Yasuyo
Nishioka Eiko
Murakami Takamichi
grid.31432.37 0000 0001 1092 3077 Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017 Japan
5 12 2022
17
17 8 2022
23 11 2022
© The Author(s) under exclusive licence to Japan Radiological Society 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose
This study proposes a Bayesian multidimensional nominal response model (MD-NRM) to statistically analyze the nominal response of multiclass classifications.
Materials and methods
First, for MD-NRM, we extended the conventional nominal response model to achieve stable convergence of the Bayesian nominal response model and utilized multidimensional ability parameters. We then applied MD-NRM to a 3-class classification problem, where radiologists visually evaluated chest X-ray images and selected their diagnosis from one of the three classes. The classification problem consisted of 150 cases, and each of the six radiologists selected their diagnosis based on a visual evaluation of the images. Consequently, 900 (= 150 × 6) nominal responses were obtained. In MD-NRM, we assumed that the responses were determined by the softmax function, the ability of radiologists, and the difficulty of images. In addition, we assumed that the multidimensional ability of one radiologist were represented by a 3 × 3 matrix. The latent parameters of the MD-NRM (ability parameters of radiologists and difficulty parameters of images) were estimated from the 900 responses. To implement Bayesian MD-NRM and estimate the latent parameters, a probabilistic programming language (Stan, version 2.21.0) was used.
Results
For all parameters, the Rhat values were less than 1.10. This indicates that the latent parameters of the MD-NRM converged successfully.
Conclusion
The results show that it is possible to estimate the latent parameters (ability and difficulty parameters) of the MD-NRM using Stan. Our code for the implementation of the MD-NRM is available as open source.
Supplementary Information
The online version contains supplementary material available at 10.1007/s11604-022-01366-y.
Keywords
Item response theory
Nominal response model
Probabilistic programming language
Chest X-ray
http://dx.doi.org/10.13039/501100001691 Japan Society for the Promotion of Science JP19K17232 22K07665 Nishio Mizuho
==== Body
pmcIntroduction
Item response theory (IRT), also known as latent trait theory, is a statistical model/paradigm used for analyzing tests [1–3]. The IRT can be used to evaluate test items and test takers quantitatively and to perform quality assurance of tests. In addition, IRT can be used to equate the test results. Statistical analysis of the IRT is performed using the results of binary classifications (e.g., correct and incorrect answers to test items).
IRT can be implemented using probabilistic programming languages (e.g., WinBUGS, JAGS, and Stan) [4–6]. Extension of IRT is also possible using probabilistic programming languages. For example, the graded response model and nominal response model (NRM) as multiclass extensions of IRT were implemented in Stan [7]. In previous studies, the Bayesian IRT and NRM models were implemented in Stan, and statistical analyses were performed using them [7, 8].
In medical diagnosis, the results of various diagnostic procedures are frequently defined as binary classifications: the presence or absence of a disease, the presence or absence of distant metastasis of cancer, the prediction results of cancer death, etc. However, not all medical diagnoses can be expressed as binary classifications, and multiclass classifications are sometimes necessary. For example, the T, N, and M factors of the TNM classification system are expressed as multiclass classifications for many cancer types [9–11]. The statistical analysis of these multiclass classification results requires multiclass analysis (such as NRM).
IRT can be applied to medical diagnosis, by considering (i) the patient as the test item, (ii) the doctor as the test taker, and (iii) the results of the binary classification obtained through medical diagnosis as test results. For example, a previous study used Bayesian IRT to statistically evaluate improvements in radiologists’ diagnostic performance [8]. However, to the best of our knowledge, Bayesian NRM has not been applied to the medical diagnosis of multiclass classifications.
The purpose of this study was to use the Bayesian NRM for multiclass medical diagnosis. Although a Stan implementation of the Bayesian NRM has already been reported [7], it does not work stably [12]. Therefore, for the Bayesian NRM, we extended the conventional NRM in this study. There are two major differences between conventional and our extended NRM. First, while conventional NRM is frequently implemented by extending the 2PL-IRT, our NRM is implemented by extending the 1PL-IRT. We speculate that, because the existing Stan implementation of NRM extends the 2PL-IRT, the existing implementation produced unstable results. The second change in our NRM is to evaluate the ability of test takers using multidimensional parameters rather than a single parameter. Since this study used the results of multiclass classifications, it is natural for test-takers’ abilities to be evaluated based on multidimensional parameters rather than a single parameter. Our Stan implementation of the Bayesian NRM proposed in this study is disclosed as open source through GitHub (https://github.com/jurader/MDNRM).
Materials and methods
Binary and multiclass classification
Generally, the results of binary classification are summarized by a 2 × 2 confusion matrix between the ground truth and prediction. This 2 × 2 confusion matrix is composed of true positive, true negative, false positive, and false negative. Figure 1 shows the 2 × 2 confusion matrix. In a previous study [8], Bayesian IRT was applied by considering true positive and true negative as "correct" and false positive and false negative as "incorrect".Fig. 1 2 × 2 confusion matrix between ground truth and prediction. TP true positive, TN true negative, FP false positive, FN false negative
In general, the results of multiclass classification are summarized by an N × N confusion matrix. As an example, a 3 × 3 confusion matrix is shown in Fig. 2. Here, it is possible to define the diagonal values of the N × N confusion matrix as "correct" and the other values as "incorrect" and apply Bayesian IRT to these values. However, this method does not allow class-by-class evaluations. To solve this problem, conventional NRM was extended in this study.Fig. 2 3 × 3 confusion matrix between ground truth and prediction for 3-class classifications. (a–i) represent the frequencies of cells
IRT and NRM
IRT is a statistical model for analyzing the results of binary classifications. There are several types of IRT models. Here, 1PL-IRT and 2PL-IRT are shown [1]. In addition, conventional NRM, as a multiclass extension of 2PL-IRT, is also described [7]. Finally, an extended NRM is proposed. Hereafter, “case” and “radiologist” are used instead of “test item” and “test taker” of IRT, respectively.
1PL-IRT
In 1PL-IRT, one parameter (βi) is used to represent case i, and another parameter (θj) is used to represent radiologist j. The following equations represent the 1PL-IRT.Prrij=1=11+exp(-zij)
zij=θj-βi
Here,rij is the response (prediction) of radiologist j to case i,
rij=1 means that the response rij is correct,
Prrij=1 represents the probability that the response of radiologist j to case i is correct,
βi is the difficulty parameter of case i,
θj is the ability parameter of the radiologist j.
The equation of 1PL-IRT indicates that for converting logit (zij) to probability, 1PL-IRT uses the sigmoid function, which is used for logistic regression. In the 1PL-IRT, θjandβi are estimated based on the prediction results of the radiologists.
2PL-IRT
In the 2PL-IRT, two parameters (αi and βi) are used to represent case i. The following equations represent 2PL-IRT.Prrij=1=11+exp(-zij)
zij=αi(θj-βi)
Here,αi and βi are the discrimination and difficulty parameters of case i.
In 2PL-IRT, θj,αi, and βi are estimated based on the prediction results of radiologists as in 1PL-IRT.
Conventional NRM
Conventional NRM can be viewed as an extension of 2PL-IRT for multiclass classifications. The following equation represents the conventional NRM.Prrij=k=expαikθj+βik∑h=1cexpαihθj+βih
Here,Prrij=k represents the probability that the response of radiologist j to case i is class k,
The number of classes is c,
αik and βik are the two parameters of case i on class k,
θj is the ability parameter of radiologist j.
The equation of conventional NRM can be rewritten as follows:Prrij=k=expzijk∑h=1cexpzijh
zijk=αikθj+βik
This means that the NRM uses the softmax function to convert logit (zijk) to probability. Based on the results of the multiclass classification, αik,βik,andθj are estimated. Although a previous study provided the Stan code for conventional NRM (Bayesian NRM) [7], its calculation results were unstable [12].
Extended NRM (1PL-NRM and multidimensional NRM (MD-NRM))
To stabilize the results of the Bayesian NRM, we extended the conventional NRM. First, the discrimination parameter (α) is removed from conventional NRM. In other words, our extended NRM is based on 1PL-IRT. This deletion stabilizes the calculation results of our Bayesian NRM. Hereafter, this extension of NRM is referred to as 1PL-NRM. The following equations represent 1PL-NRM.Prrij=k=expzijk∑h=1cexpzijh
zijk=θj-βik
In this equation, θj-βik is used instead of θj+βik, to strengthen the meaning of the difficulty parameter of βik.
In both conventional NRM and 1PL-NRM, the probability of rij=k (the response of radiologist j to case i is class k) depends on only one parameter of the radiologist (θj). This assumption is unnatural, and the equations of both conventional NRM and 1PL-NRM indicate that the difficulty parameter of the case has a greater influence on which class a radiologist chooses for the diagnosis than their ability parameter. Because there are c classes in multiclass classification, the probability should be dependent on several parameters of the radiologists. To address this problem, we extended 1PL-NRM.
Herein, we propose a multidimensional NRM (MD-NRM) based on 1PL-NRM, which is represented by the following equations:Prrij=t|groundtruthofcasei=s=expzijst∑h=1cexpzijsh
zijst=θjst-βis
The number of classes is c,
s is the ground truth of case i,
rij=t means that the response of radiologist j to case i is t,
θjst is the ability parameter of radiologist j in class t when the ground truth of the case is s (θj.. can be represented by a matrix (c × c)),
βis is the difficulty parameter of case i on class s.
This extended NRM (MD-NRM) means that the multidimensional ability parameters of a radiologist are represented by a matrix, which corresponds to the confusion matrix of multiclass classification.
Relationship between IRT and NRM
The 2PL-IRT can be derived from the conventional NRM as a special case [13]. Here, we use only two classes (k or k′) for the NRM. Additionally, we consider the conditional probability for a response in class k given that the response is one of classes k or k′. Generally, the conditional probability is given by the following equation:Prr=kk,k′)=Pr(r=k)Prr=k+Prr=k′
Here, the conventional NRM is used for Pr(k) or Pr(k’). The conditional probability is represented by the following equation (case i and radiologist j are omitted for brevity):Prkk,k′)=11+exp(-αkcθ+β′kc)
β′kc=βk′-βk
αkc=αk-αk′
Further, this equation can be converted to the following equations.Prkk,k′)=11+exp(-αkc(θ-βkc))
βkc=β′kcαkc
These equations represent the 2PL-IRT. This derivation (conventional NRM to 2PL-IRT) can be applied to our 1PL-NRM; In our 1PL-NRM, the conditional probability is represented by the 1PL-IRT. This is one of the major reasons for using the extended NRM.
Experiments
Our institutional review board approved this retrospective study and waived the requirement for informed consent.
It is assumed that MD-NRM can be applied to data from medical diagnoses of multiclass classification. We applied MD-NRM to the classification results obtained by radiologists in a previous study [14]. In the previous study, there were three classes of medical diagnosis: novel coronavirus pneumonia (COVID), non-novel-coronavirus pneumonia (PNEUMONIA), and normal (NORMAL). Therefore, the classification results were summarized as a 3 × 3 confusion matrix. In total, 150 cases (50 COVID, 50 PNEUMONIA, and 50 NORMAL) were reported in the previous study. From the three classes, six radiologists determined their diagnoses based on visual evaluation of chest X-ray images. Therefore, 900 (150 × 6) nominal responses were obtained. The Supplementary material shows the ground truth of the case and the classification results of the six radiologists.
In this study, MD-NRM was applied to multiclass classification results to analyze the ability of six radiologists for the three classes. For all ability and difficulty parameters, a normal distribution with mean = 0 and standard deviation = 2 was used as the prior distribution. The following parameters were used for sampling in Stan: chains = 8, iter = 8000, warmup = 4000, thin = 1, adapt_delta = 0.9, and max_treedepth = 15. The convergence check of the MD-NRM was performed by evaluating the Rhat values of all parameters [7, 8, 15]. Since we focused on the ability parameters, the estimation results of the difficulty parameters were omitted in this study. We used the following software to implement MD-NRM: R, version 4.1.1; Stan, version 2.21.0; rstan, version 2.21.2; shinystan, version 2.5.0; and tidybayes, version 3.0.1.
Results
Figure 3 shows the convergence check of the Stan results for all the parameters. The Rhat values for all parameters (difficulty and ability parameters) were less than 1.10, which means that the MD-NRM converged successfully [7, 8, 15]. Thus, 1PL-NRM is useful for stabilizing Bayesian NRM.Fig. 3 Evaluation of convergence in MD-NRM. For all parameters, their Rhat values are less than 1.10
Table 1 shows the estimation results of the MD-NRM for the ability parameters of Radiologist 1. In the MD-NRM, radiologist ability is represented in a 3 × 3 matrix, so one radiologist has nine ability parameters. In Table 1, if θ 111, θ 122, and θ 133 are high, the diagnostic performance of radiologist 1 is high for NORMAL, PNEUMONIA, and COVID.Table 1 Result of MD-NRM for ability parameters of radiologist 1
Parameters 2.50% 25% 50% (median) 75% 97.50%
θ 111 − 0.137 1.46 2.288 3.117 4.665
θ 112 − 2.835 − 1.242 − 0.403 0.452 2.035
θ 113 − 4.44 − 2.763 − 1.896 − 1.009 0.655
θ 121 − 4.659 − 2.987 − 2.137 − 1.262 0.372
θ 122 − 0.796 0.762 1.589 2.418 3.969
θ 123 − 1.845 − 0.268 0.556 1.387 2.959
θ 131 − 3.652 − 2.077 − 1.249 − 0.422 1.155
θ 132 − 2.572 − 1.049 − 0.233 0.593 2.122
θ 133 − 0.831 0.682 1.491 2.297 3.824
2.50%, 25%, 50%, 75%, and 97.5% are percentile values of the estimated parameters. For example, the pair of − 0.137 at 2.50% and 4.665 at 97.5% represents a 95% credible interval of θ 111
Figure 4 shows a 3 × 3 ability matrix created from the median values of the ability parameters of radiologist 1 in Table 1. In Fig. 4, if the diagonal values of the ability matrix are high, the diagnostic ability of radiologist 1 is also high. In contrast, if the non-diagonal values of the ability matrix are low, the diagnostic ability is high.Fig. 4 Ability matrix of radiologist 1. This matrix was created from the median values of the ability parameters of radiologist 1 in Table 1
Figure 5 (A)–(C) show the summary of θ i11 (i = 1, 2, …, 6), θ i22 (i = 1, 2, …, 6), and θ i33 (i = 1, 2, …, 6) for radiologists 1–6 for NORMAL, PNEUMONIA, and COVID, respectively. The figures in the Supplementary Materials show all the ability parameters of radiologists 1–6.Fig. 5 Summary of ability parameters of six radiologist. (A) θ i11 (i = 1, 2, …, 6) for NORMAL, (B) θ i22 (i = 1, 2, …, 6) for PNEUMONIA, (C) θ i33 (i = 1, 2, …, 6) for COVID. Note: In (A–C), "theta[i,j,k]” represents θ ijk. For example, “theta [1,1,1]” represents θ 111. Circles, thick bars, and thin bars represent the median values, 50% credible interval (interquartile range), and 95% credible interval, respectively
Our Stan and R codes of the MD-NRM are shown in the Supplementary materials. In addition, these codes were disclosed as open source through GitHub (https://github.com/jurader/MDNRM).
Discussion
Using the MD-NRM, stable convergence in the Bayesian NRM calculation was achieved with our Stan code. This is a significant improvement because stable convergence cannot be obtained with the conventional NRM Stan code [7]. In addition, compared to the conventional NRM, MD-NRM makes it possible to determine the multidimensional ability parameters of a doctor. Furthermore, this extension of multidimensional parameters allows MD-NRM to provide a more detailed evaluation of a doctor's ability rather than a single parameter.
In IRT and NRM, parameters (ability and difficulty) are evaluated in the latent space [1, 8]. Because of this characteristic, IRT is known as the latent trait theory. Logistic regression is frequently used to analyze the results of medical diagnoses [16]. In logistic regression, the effect of covariates on the latent space is statistically evaluated. Therefore, IRT, NRM, and logistic regression share similar functionalities in the evaluation of the parameters.
In receiver operating characteristic (ROC) analysis, it is common to assign a multilevel score for each case to statistically analyze the results of binary classifications [17, 18]. For example, a radiologist’s ability to differentiate between benign and malignant tumors is frequently analyzed by assigning a score to each case on a 5-point scale [19]. However, there is no commonly used method of ROC analysis for multiclass classification results. Instead, for the analysis of multiclass classifications, it is relatively frequent to perform multiple ROC analyses of binary classifications in a one-vs-rest fashion [20]. On the other hand, MD-NRM can analyze the results of multiclass classifications by a single analysis, which is a major difference between MD-NRM and ROC analysis. In addition, MD-NRM does not require the multilevel scoring (please see the data of 150 cases in the Supplementary material), which is another major difference from ROC analysis.
As in a previous study [8], it is possible to introduce covariates into MD-NRM. This extension makes it possible to quantitatively evaluate the effect of covariates using MD-NRM; for example, the improvement in diagnostic performance with various experiences of doctors or with different diagnostic modalities/examinations.
This study had several limitations. First, the data from 150 patients were used. It has not been evaluated whether stable convergence will be obtained in MD-NRM with smaller data. Second, although an extension of the MD-NRM (MD-NRM with covariates) is proposed in this paper, no actual experiments have been conducted. We expect that the extension of MD-NRM will be investigated in the future based on our open-source code. Third, because MD-NRM has more latent parameters than 1PL-NRM, it will be difficult to obtain stable convergence in MD-NRM, compared with 1PL-NRM.
In conclusion, the MD-NRM was proposed as a statistical analysis method for multiclass classification. The MD-NRM achieved successful convergence of parameter estimation in the Bayesian NRM. In addition, using the MD-NRM, a more detailed evaluation of the doctor's ability was possible using multidimensional ability parameters.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 84 KB)
Supplementary file2 (PDF 149 KB)
Supplementary file3 (PDF 207 KB)
Supplementary file4 (PDF 35 KB)
Supplementary file5 (PDF 25 KB)
Supplementary file6 (PDF 146 KB)
Funding
This work was supported by JSPS KAKENHI (Grant Numbers: JP19K17232 and 22K07665).
Data availability
Data generated or analyzed during the study are available from the corresponding author by reasonable request.
Declarations
Conflict of interest
There are no conflicts of interest to declare.
Ethical statement
Our institutional review board (IRB of KOBE University Hospital) approved this retrospective study and waived the requirement for informed consent.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Cappelleri JC Jason Lundy J Hays RD Overview of classical test theory and item response theory for the quantitative assessment of items in developing patient-reported outcomes measures Clin Ther Clin Ther 2014 36 648 662 10.1016/j.clinthera.2014.04.006 24811753
2. Embretson SE Reise SP Item response theory for psychologists. Item response theory for psychologists 2000 New York Taylor and Francis
3. Hays RD Morales LS Reise SP Item response theory and health outcomes measurement in the 21st century Med Care 2000 38 28 42 10.1097/00005650-200009002-00007
4. Carpenter B Gelman A Hoffman MD Lee D Goodrich B Betancourt M Stan: a probabilistic programming language J Stat Softw 2017 76 1 32 10.18637/jss.v076.i01
5. Lunn DJ Thomas A Best N Spiegelhalter D WinBUGS—a Bayesian modelling framework: concepts, structure, and extensibility Stat Comput 2000 10 325 337 10.1023/A:1008929526011
6. Depaoli S Clifton JP Cobb PR Just another gibbs sampler (JAGS) J Educ Behav Stat 2016 41 628 649 10.3102/1076998616664876
7. Luo Y Jiao H Using the Stan program for bayesian item response theory: educational and psychological measurement 2017 Los Angeles SAGE Publications 384 408
8. Nishio M Akasaka T Sakamoto R Togashi K Bayesian statistical model of item response theory in observer studies of radiologists Acad Radiol Elsevier 2020 27 e45 54 10.1016/j.acra.2019.04.014
9. Lim W Ridge CA Nicholson AG Mirsadraee S The 8th lung cancer TNM classification and clinical staging system: review of the changes and clinical implications Quant Imaging Med Surg 2018 8 709 718 10.21037/qims.2018.08.02 30211037
10. Kalli S Semine A Cohen S Naber SP Makim SS Bahl M American joint committee on cancer’s staging system for breast cancer, eighth edition: What the radiologist needs to know Radiographics 2018 38 1921 1933 10.1148/rg.2018180056 30265613
11. Allen PJ Kuk D del Castillo CF Basturk O Wolfgang CL Cameron JL Multi-institutional validation study of the American joint commission on cancer (8th edition) changes for T and N staging in patients with pancreatic adenocarcinoma Ann Surg 2017 265 185 191 10.1097/SLA.0000000000001763 27163957
12. Non convergence issue on polytomous IRT model - Modeling - The Stan Forums [Internet]. [cited 2022 Jul 12]. Available from: https://discourse.mc-stan.org/t/non-convergence-issue-on-polytomous-irt-model/12576
13. Thissen D Cai L Bock RD The nominal categories item response model. Handbook of Polytomous Item Response Theory Models 2010 Routledge Handbooks Online
14. Nishio M Kobayashi D Nishioka E Matsuo H Urase Y Onoue K Deep learning model for the automatic classification of COVID-19 pneumonia, non-COVID-19 pneumonia, and the healthy: a multi-center retrospective study Sci Rep 2022 12 8214 10.1038/s41598-022-11990-3 35581272
15. Gelman A Carlin JB Stern HS Dunson DB Vehtari A Rubin DB Bayesian data analysis 2013 Bayesian Data Analysis Chapman and Hall/CRC
16. Kleinbaum DG Klein M Logistic regression 2010 New York Springer
17. Obuchowski NA Receiver operating characteristic curves and their use in radiology Radiology 2003 229 3 8 10.1148/radiol.2291010898 14519861
18. Zweig MH Campbell G Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine Clin Chem Oxford Acad 1993 39 561 577 10.1093/clinchem/39.4.561
19. Park SH Goo JM Jo CH Receiver operating characteristic (ROC) curve: practical review for radiologists Korean J Radiol 2004 5 18 10.3348/kjr.2004.5.1.11
20. Receiver Operating Characteristic (ROC)—scikit-learn 1.1.1 documentation [Internet]. [cited 2022 Jul 12]. Available from: https://scikit-learn.org/stable/auto_examples/model_selection/plot_roc.html#plot-roc-curves-for-the-multiclass-problem
| 36469224 | PMC9734816 | NO-CC CODE | 2022-12-14 23:28:30 | no | Jpn J Radiol. 2022 Dec 5;:1-7 | utf-8 | Jpn J Radiol | 2,022 | 10.1007/s11604-022-01366-y | oa_other |
==== Front
J Cancer Surviv
J Cancer Surviv
Journal of Cancer Survivorship
1932-2259
1932-2267
Springer US New York
36472761
1280
10.1007/s11764-022-01280-2
Article
The long-term financial experiences of adolescent and young adult cancer survivors
http://orcid.org/0000-0001-6239-1666
Thom Bridgette [email protected]
1
Friedman Danielle N. 2
Aviki Emeline M. 1
Benedict Catherine 3
Watson Samantha E. 4
Zeitler Michelle S. 4
Chino Fumiko 1
1 grid.51462.34 0000 0001 2171 9952 Affordability Working Group, Memorial Sloan Kettering Cancer Center, New York, NY USA
2 grid.51462.34 0000 0001 2171 9952 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY USA
3 grid.168010.e 0000000419368956 Stanford University School of Medicine, Stanford Cancer Institute, Palo Alto, CA USA
4 Expect Miracles Foundation, Boston, MA USA
6 12 2022
111
1 7 2022
17 10 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background
Cancer-related financial hardship can negatively impact financial well-being and may prevent adolescent and young adult (AYA) cancer survivors (ages 15–39) from gaining financial independence. This analysis explored the financial experiences following diagnosis with cancer among AYA survivors.
Methods
We conducted a cross-sectional, anonymous survey of a national sample of AYAs recruited online. The Comprehensive Score for Financial Toxicity (COST) and InCharge Financial Distress/Financial Well-Being Scale (IFDFW) assessed financial hardship (cancer-related and general, respectively), and respondents reported related financial consequences and financial coping behaviors (both medical and non-medical).
Results
Two hundred sixty-seven AYA survivors completed the survey (mean 8.3 years from diagnosis). Financial hardship was high: mean COST score was 13.7 (moderate-to-severe financial toxicity); mean IFDFW score was 4.3 (high financial stress). Financial consequences included post-cancer credit score decrease (44%), debt collection contact (39%), spending more than 10% of income on medical expenses (39%), and lacking money for basic necessities (23%). Financial coping behaviors included taking money from savings (55%), taking on credit card debt (45%), putting off major purchases (45%), and borrowing money (42%). In logistic regression models, general financial distress was associated with increased odds of experiencing financial consequences and engaging in both medical- and non-medical-related financial coping behaviors.
Discussion
AYA survivors face long-term financial hardship after cancer treatment, which impacts multiple domains, including their use of healthcare and their personal finances. Interventions are needed to provide AYAs with tools to navigate financial aspects of the healthcare system; connect them with resources; and create systems-level solutions to address healthcare affordability.
Implications for Cancer Survivors
Survivorship care providers, particularly those who interact with AYA survivors, must be attuned to the unique risk for financial hardships facing this population and make efforts to increase access available interventions.
Keywords
Financial toxicity
Young adult
Cancer survivorship
AYA
Chanel Endowment to fund Survivorship ResearchNIH/NCI Cancer Center Support Grant P30 CA008748
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pmcBackground
The high costs of cancer care, coupled with the disruptions to employment and earnings caused by cancer, its treatment, and the late effects of treatment, often result in financial hardship for cancer survivors [1, 2]. This hardship, which includes medical debt, difficulty paying out-of-pocket expenses, and associated psychosocial distress, can negatively impact financial well-being and may prevent adolescent and young adult (AYA) cancer survivors from gaining financial independence [3–6]. Survivors of AYA cancers are more likely to experience medical financial hardship than adults with no cancer history, and AYA survivors are more likely than older survivors to face financial hardship after treatment [4, 7–9].
An emergent body of evidence suggests financial hardship among AYA survivors is associated with inferior quality survivorship care, medication non-adherence, and diminished psychosocial well-being [9–13]. However, the longer term effects on personal finances, along with the impact on other components of healthcare use (e.g., vision, dental, mental health care), are not well-studied among AYAs. This analysis explored the financial experiences of a sample of AYA cancer survivors recruited online. Specifically, it sought to determine associations between financial hardship and material financial burden, including associated consequences and coping behaviors.
Methods
Design, subjects, and recruitment
This was a cross-sectional, anonymous online survey of a national sample of AYAs with a history of cancer, who were over 18 years of age or older and treated prior to age 40. The survey was conducted in English, and survivors of all disease types and treatment phases were eligible. The study was approved as exempt research by the Memorial Sloan Kettering Institutional Review Board. Data were collected from December 2020 to March 2021 using REDCap, a secure online platform [14]. Respondents were not paid for their participation. Given that data collection occurred during a peak of the COVID-19 pandemic, we sought to distinguish events specifically related to COVID-19 (e.g., job loss because of COVID-19, shift to remote work) from those that occurred prior to the pandemic. Questions relating to COVID-19 were analyzed separately, and these results are reported elsewhere [15].
Subjects were recruited online through multiple, concurrent methods, including (1) collaboration with AYA cancer advocacy organizations and programs (e.g., Expect Miracles Foundation, Stupid Cancer, Elephants and Tea, Teen Cancer America) to recruit through their social media channels (Facebook, Instagram, and Twitter, as applicable), email lists, and listservs; (2) tweets and Facebook posts by study investigators and the study account, which were then shared by their networks; (3) sharing of the study by program staff of hospital-based AYA programs throughout the USA; (4) purchase of Facebook and Instagram advertisements and use of paid promoted tweets on Twitter to promote the study.
Measurement
In this analysis, “financial experiences” were defined as respondents’ measured financial hardship and their self-reported material financial burden, both described below.
To gain a more complete understanding of financial hardship, and because of the lack of AYA-specific financial hardship measures, we assessed (1) overall financial distress and (2) financial toxicity related to cancer. Overall financial distress was measured using the InCharge Financial Distress/Financial Well-Being Scale (IFDFW), a validated 8-item scale. Respondents selected an answer choice from 1 to 10, and scores were averaged, with lower scores representing worse financial distress [16]. Severity thresholds were as follows: scores 1–4 indicated overwhelming to high distress; scores 5–7 indicated average to low distress; and scores 8–0 indicated very low to no distress. The financial toxicity of cancer was measured using the Comprehensive Score for Financial Toxicity (COST), an 11-question validated tool. Objective and subjective components of financial toxicity were rated on a 0–4 scale with a 0–44 composite score, with lower scores suggesting worse financial toxicity [17]. COST tool thresholds for severity of financial toxicity were based on thresholds previously published in the literature: scores 0–13 indicated severe financial toxicity; scores 14–25 indicated moderate financial toxicity; and scores over 25 indicated low to no financial toxicity [18, 19].
To understand material financial burden, we relied on a conceptualization proposed by Jones and colleagues, in which material financial burden is comprised of both financial consequences and financial coping behaviors [20]. Financial consequences refer to the difficulties associated with bill-paying, and financial coping behaviors are actions taken by the patient to ensure needs are met; both consequences and coping behaviors may be related to healthcare or non-healthcare expenses or circumstances. To assess financial consequences, respondents answered investigator-designed yes/no questions relating to methods of medical bill payment (or non-payment) and negative events associated with medical bills (e.g., bankruptcy thoughts/filing, using savings for bills); they also estimated their annual out-of-pocket expenses, student loan debt, and credit card debt. Financial coping behaviors were measured using questions relating to skipping or delaying components of healthcare derived from the Medical Expenditure Panel Survey and investigator-designed yes/no questions about general cost-coping (e.g., delaying purchases, borrowing money) [21].
Respondents self-reported relevant demographic (e.g., current age, race/ethnicity, employment status, income, education) and clinical (e.g., diagnosis, treatment status, recurrence status, age at diagnosis) information.
Analysis
Descriptive statistics (frequencies, central tendency) characterized the demographic and clinical characteristics of the sample. The IFDFW and COST tools were scored according to validated guidelines. Univariable testing (e.g., t-tests, Pearson correlation, ANOVA) assessed associations with IFDFW and COST scores among variables of interest (i.e., out-of-pocket payment methods, financial consequences, financial cost-coping).
For financial consequences and financial coping behaviors, logistic regression models were constructed among variables significant in univariate testing (p < 0.05) to explore association with IFDFW score (i.e., overall financial distress), controlling for current age, race/ethnicity, treatment status, education, income, and full-time employment. For financial cost-coping, we considered both medical-related cost-coping (e.g., skipping treatment, not taking prescribed medication) and general cost-coping (e.g., taking on credit card debt, delaying purchases). Because lower scores represent worse outcomes on the IFDFW, we report the inverse of the adjusted odds ratio for ease of interpretation.
Results
Sample
Of 410 potential respondents who clicked on the survey, eight were ineligible due to age ≥ 40 years at diagnosis. Among the remaining 402 eligible respondents, 71 did not start the survey once entering it. Of respondents who started the survey (n = 331), 267 provided evaluable data, which we defined as at least completing the IFDFW and COST measures and including an age-eligible response to the question on age at diagnosis (completion rate = 81%). Mean respondent age was 27.0 years at diagnosis (sd = 7.50) and 35.3 years (sd = 5.30) at time of survey. The sample predominantly identified as women (87%) and included 8% men and 2% non-binary or transgender respondents; 3% did not report their gender. Breast cancer (27%), lymphoma (17%), leukemia (11%), and colorectal cancer (10%) were the most common diagnoses. The majority of the sample (58%) reported they had finished all cancer treatment, with 26% still receiving hormonal therapy and 14% undergoing active treatment; 35% had experienced metastasis, recurrence, or a second cancer after their initial diagnosis. Ninety-seven percent of the sample had health insurance: most (73%) had private insurance, with 12% Medicare and 9% Medicaid.
The sample was comprised of 70% non-Hispanic white respondents, 10% Hispanic/Latino/a/x, 6% non-Hispanic Black, 6% multiple race/ethnicities, and 3% Asian. Overall, 70% had completed at least a bachelor’s degree, and 53% were partnered/married. The most frequently reported income range at diagnosis was $25,000–$49,999 (30%) and $50,000–$100,000 (36%) at survey completion. Among respondents reporting student loan debt (n = 151), mean debt was $63,398 (sd = 72,319.27). Sixty percent of the sample (n = 161) reported having credit card debt: mean debt was $10,243 (sd = 13,593.46). A majority of respondents (55%) was employed full-time at survey completion; 14% were on long-term disability; 9% were students; and 8% were unemployed at survey completion [Respondents could select more than one answer choice]. Complete sample demographics are listed in Table 1.Table 1 Sample demographics and clinical information (N = 267)
No. (%)
Gender
Woman 232 (86.9)
Man 22 (8.2)
Trans man 2 (0.7)
Non-binary 4 (1.5)
Prefer not to respond 7 (2.6)
Race
Non-Hispanic/Latino/a/x White 188 (70.4)
Non-Hispanic/Latino/a/x Black 15 (5.6)
Hispanic/Latino/a/x 27 (10.1)
Asian 7 (2.6)
Native American/American Indian 1 (0.4)
More than once race 17 (6.4)
Prefer not to respond 12 (4.5)
Current relationship status
Single/not living with partner 106 (39.7)
Married/living with partner 141 (52.8)
Widowed, divorced, or separated 11 (4.1)
Prefer not to respond/something else 9 (3.4)
Highest education
High school 9 (3.4)
Some college or vocational training 39 (14.6)
Associate’s degree 22 (8.2)
Bachelor’s degree 81 (30.3)
Graduate or professional degree 108 (40.4)
Prefer not to respond 8 (3.0)
Current household income
Less than $25,000 36 (13.5)
$25,000–$49,999 49 (18.4)
$50,000–$99,999 95 (35.6)
$100,000 or more 63 (23.6)
Prefer not to respond 24 (9.0)
Employment statusa
Working full-time 95 (54.9)
Working part-time 15 (8.7)
Homemaker/stay-at-home parent 14 (8.1)
In school 12 (6.9)
On disability (short or long term) 31 (17.9)
Unemployed 13 (7.6)
Prefer not to respond 10 (5.8)
Diagnosis
Breast 70 (26.2)
Lymphoma 45 (16.9)
Colorectal 27 (10.1)
Brain 19 (7.1)
Leukemia 30 (11.2)
Gynecologic 16 (6.0)
Sarcoma 18 (6.7)
Thyroid 10 (3.7)
Other 22 (8.2)
Prefer not to respond/missing 10 (3.7)
Annual out-of-pocket expenses estimate
< $500 32 (12.0)
$500–$999 25 (9.4)
$1000–1999 33 (12.4)
$2000–4999 75 (28.1)
$5000 + 77 (28.8)
Don’t know 25 (9.4)
Payment methodsa
Checking/general savings 218 (81.6)
Health savings account (HSA) 72 (27.0)
Specific health care savings account (non-HSA) 19 (7.1)
Low or no interest medical credit card 14 (5.2)
Traditional credit card 100 (37.5)
Loan 16 (6.0)
Parent/other family pays full cost 15 (5.6)
Parent/other family pays part of cost 57 (21.3)
Crowdfunding 20 (7.5)
Did not pay some/all costs 49 (18.4)
Treatment status
Active treatment 37 (13.9)
Receiving hormonal/endocrine therapy 70 (26.2)
Completed treatment 155 (58.1)
Prefer not to respond 5 (1.2)
Insurance type
Private 195 (73.0)
Medicaid 25 (9.3)
Medicare 32 (12.0)
Other plan 6 (2.2)
No insurance 8 (3.0)
Don’t know 1 (0.3)
aRespondents could select more than one answer choice
Overall financial distress and financial toxicity
Mean IFDFW score (i.e., overall financial distress) was 4.3 (sd = 2.38): 35% of the sample scored 1–2, which IFDFW authors characterize as “overwhelming/severe financial distress”; 28% scored 3–4, or “high financial distress”; 23% scored 5–6, or “average financial distress”; and 14% scored 7–10, or “low or no financial distress”[16]. Mean COST score (i.e., cancer-related financial toxicity) was 13.7 (sd = 9.09): 54% of respondents had severe financial toxicity (COST < 14); 36% had moderate (COST 14–25); and 11% had low/no financial toxicity (COST ≥ 26).
In univariate correlation testing, IFDFW and COST scores were highly and significantly correlated (r = 0.85, p < 0.001). As such, both lower financial distress and less cancer-related financial toxicity were associated with older age at survey, more education, and higher current income. Lacking full-time employment and having credit card debt were also associated with worse financial distress and worse financial toxicity. Race/ethnicity, relationship status, and student loan debt were not significantly associated with COST scores but were associated with IFDFW scores, such that respondents who identified as Black, Indigenous, or a person of color (BIPOC); single respondents; and those with student loan debt had significantly higher financial distress. Age at diagnosis, treatment status, and recurrence, metastasis, or development of a second cancer were not associated with either IFDFW or COST scores (see Table 2).Table 2 Univariable analyses
Comparison of means IFDFWa mean p-value COSTb mean p-value
Full-time employment < .001 < .001
Yes 4.81 15.75
No 3.66 11.19
Race/ethnicity .012 .15
White non-Hispanic 4.49 13.95
Black, Indigenous, or person of color 3.60 12.12
Student loan debt .012 .07
Yes 3.97 12.95
No 4.92 15.37
Credit card debt < .001 < .001
Yes 3.57 11.19
No 6.55 20.98
Marital/partner status .02 .05
Single 3.76 11.94
Married/partnered 4.63 14.75
All others 4.88 13.38
Recurrence, metastasis, second cancer .56 .70
Yes 4.44 13.42
No 4.24 13.88
Formal education < .001 < .001
Bachelor’s degree or higher 4.79 15.00
Less than bachelor’s degree 2.93 9.68
Current annual income < .001 < .001
< $25,000 2.29 6.05
$25,000–$49,999 3.29 11.12
$50,000–$99,999 4.32 13.98
$100,000 or more 6.24 19.25
Treatment status .36 .15
Active treatment 3.80 11.21
Receiving hormonal therapy 4.20 13.41
Finished with all treatment 4.46 14.41
Did not pay some/all of out-of-pocket expenses < .001 < .001
Yes 2.68 9.10
No 4.69 14.76
Took out a loan to pay medical bills < .001 < .001
Yes 2.16 6.31
No 4.43 14.19
Receive family help with out-of-pocket costs .001 < .001
Yes 3.42 9.58
No 4.59 15.00
Paid for bills with a health savings account < .001 < .001
Yes 5.31 17.43
No 3.92 12.35
Used crowdfunding to pay medical bills .013 .15
Yes 2.87 10.92
No 4.41 13.94
Correlationsc IFDFW p-value COST p-value
Age at diagnosis .05 .47 .04 .50
Age now .14 .04 .15 .02
Education .35 < .001 .25 < .001
Income .43 < .001 .40 < .001
aInCharge Financial Distress/Financial Well-Being Scale, scored 1 = 10 with lower scores indicating worse financial well-being
bComprehensive Scale for Financial Toxicity, scored 0–44 with lower scores indicating worse financial toxicity
cPearson r correlation
Material financial burden: financial consequences
Financial consequences related to medical expenses included debt collection contact (39%), spending more than 10% of income on medical expenses (39%), lacking money to pay for basic necessities (23%), loan denial (20%), and thoughts about and/or filing for bankruptcy (14%). Of respondents who could report their credit status (n = 209), 44% said their credit score went down after cancer (vs. 29% went up and 27% stayed the same). Experiencing any of these events was associated with worse overall financial distress and cancer-related financial toxicity in univariable testing; in multivariable models, worse financial distress was associated with experiencing any negative financial consequences, including lacking money for basic necessities (aOR = 2.31, 95% CI = 1.64, 3.26) and debt collection contact (aOR = 1.52, 95% CI = 1.27, 1.83) (see Table 3 for complete results).Table 3 Multivariable associations of IFDFW with financial coping behaviors and financial consequences
Odds ratio estimate 95% Confidence interval p-value
Financial coping behaviors
Lifetimeb
Skipped/delayed cancer treatment 1.46 1.16 1.85 < .001
Skipped/delayed survivorship care 1.35 1.14 1.91 < .001
Did not take medication as prescribed 1.43 1.20 1.71 < .001
Past yearc
Skipped medical test or appointment 1.64 1.35 2.01 < .001
Had a health problem but did not see provider 1.63 1.33 1.99 < .001
Skipped/delayed preventative care 1.41 1.19 1.68 < .001
Skipped/delayed dental care 1.33 1.14 1.56 < .001
Skipped/delayed vision care 1.20 1.03 1.39 0.02
Skipped/delated mental health care 1.40 1.19 1.66 < .001
Did not see a specialist 1.71 1.38 2.11 < .001
Did not fill a prescription 1.38 1.12 1.69 0.002
Took fewer pills than prescribed 1.49 1.16 1.92 0.001
In 2019 (Pre-Covid)
Put off purchase 1.32 1.13 1.55 < .001
Borrowed money 1.47 1.24 1.76 < .001
Took on credit card debt 1.97 1.58 2.45 < .001
Financial consequences
In 2019 (Pre-Covid)
Could not afford basic necessities 2.31 1.64 3.26 < .001
Took money from savings 1.38 1.17 1.62 < .001
Spent more than 10% of income on healthcare 1.46 1.22 1.74 < .001
Contacted by debt collector 1.52 1.27 1.83 < .001
Thought about or filed for bankruptcy 2.62 1.69 4.07 < .001
Denied a loan 1.75 1.32 2.30 < .001
InCharge Financial Distress/Financial Well-Being Scale, scored 1 = 10 with lower scores indicating worse financial well-being; models controlled for current age, race/ethnicity, education, treatment status, income, full-time employment, and reported findings represent odds of engaging in practice for each one point decrease in scale
bRespondents reported if they had ever engaged in the named practice because of the cost
cRespondents reported if they had engaged in the named practice because of the cost in the past year
Nearly all respondents (94%) reported they were financially responsible for their health care costs, as opposed to a parent or someone else. Among estimates of annual out-of-pocket expenses, 19% of respondents reported expenses “greater than $5000” and 28% endorsed out-of-pockets costs between $2000 and $5000 (28%); 39% of the sample estimated they spent > 10% of their annual income on healthcare costs (see Table 1).
Frequently endorsed methods of payment of out-of-pocket expenses were from a checking account/general savings (82%), traditional credit card (38%), and/or a designated health savings account (27%) [categories not exclusive]. Twenty-four percent of respondents received help with some or all of their costs from parents/family; 18% reported that they did not pay some portion of their out-of-pocket costs; 8% used crowdfunding methods; and 6% took out a loan for medical bills.
In multivariable analysis (see Table 3), controlling for current age, race/ethnicity, treatment status, education, income, and full-time employment, more financial distress was associated with an increased odds of not paying out-of-pocket expenses (aOR = 1.51, 95% CI = 1.17, 1.94), taking out a loan to pay medical bills (aOR = 1.97, 95% CI = 1.17, 3.72), and having other people pay some/all of medical costs (aOR = 1.23, 95% CI = 1.02,1.47). Less financial distress was associated with an increased likelihood of using a health savings account (aOR = 1.20, 95% CI = 1.02, 1.41).
Material financial burden: financial coping behaviors
General financial coping behaviors included taking money out of savings (55%), taking on credit card debt (45%), putting off a major purchase (45%), and borrowing money (42%). Related to healthcare, respondents endorsed whether they had ever skipped or delayed cancer care (23%) or survivorship care (36%) because of the cost, and if, in the past year, they skipped or delayed seeing a specialist (30%); seeing a provider for a medical problem (35%); or utilizing preventative care (37%), vision care (38%), dental care (53%), or mental health care (45%) because of the cost. Skipping or delaying any element of healthcare was associated with worse financial distress and worse financial toxicity in univariate testing. Respondents also reported ever skipping or delaying prescribed medication (40%) and doing so in the past year (29%). Both practices were associated with worse financial distress and toxicity in univariate testing.
In multivariable models controlling for current age, race/ethnicity, treatment status, education, income, and full-time employment, worse financial distress led to increased odds of engaging in any healthcare-related cost-coping (e.g., skipping survivorship care [aOR = 1.35, 95% CI = 1.14, 1.91]; forgoing mental health care [aOR = 1.40, 95% CI = 1.19, 1.66]) or general cost-coping behavior [(e.g., putting off major purchases [aOR = 1.32, 95% CI = 1.13, 1.55]; borrowing money [aOR = 1.47, 95% CI = 1.24, 1.76]) (see Table 3 for complete results).
Discussion
Our findings demonstrate the long-term financial consequences experienced by AYA survivors and highlight their financial coping mechanisms, including limiting their use of healthcare. Respondents, who were on average 8.3 years from their diagnosis, faced both healthcare- and non-healthcare-related financial consequences, as well as high levels of financial hardship (i.e., overall financial distress and cancer-specific financial toxicity). This hardship increased the odds of engaging in general and medical-related financial cost-coping behaviors, both with potentially negative outcomes. This study also highlights the association of overall financial distress with ongoing healthcare needs potentially necessitated by late and long-term effects of treatment (e.g., mental health care, dental treatment, vision care) and with non-medical financial concern [10, 13].
In our sample, cancer-related financial toxicity, as measured by the COST tool, was worse than that reported elsewhere in AYA samples, likely owing to our recruitment strategies [9, 10, 22]. We found that BIPOC race/ethnicity, lower education, and lower income were all associated with worse financial hardship in this AYA sample—findings that align with prior research and demonstrate the systemic effects of structural inequalities and discriminatory practices [2, 23]. For AYAs, given their age and developmental stage, financial challenges include education-associated debt, the costs associated with starting and raising a family (which can be exacerbated by treatment-related infertility), and achieving financial independence despite having a “bad” or limited credit history, low/no savings, and a disrupted employment history [24]. These challenges, combined with other concerns that may disproportionally affect young adults (YA) (e.g., insurance instability, job lock, employment turnover), create an environment that reinforces ongoing financial hardship and stymies adult financial stability [25–27].
Despite a recent emergence of commentaries and reviews addressing financial hardship among AYA survivors, the issue—and, more importantly, interventions to address it—remain understudied, particularly among historically and systematically excluded populations [6, 11, 28–30]. Promising efforts have been made toward disease- and treatment-focused research and among specific populations, including YA survivors in the military and YA women in the workforce; these studies demonstrate a need for tailored interventions to address the unique concerns experienced within disparate populations [31, 32]. Findings from our study highlight a key theme for future AYA financial hardship-related research: expanding samples to include family, caregivers, and care partners, as loan denials, bankruptcy, and other negative effects may impact the entire family unit [30, 33]. Another ongoing need for AYA financial hardship research, as others have noted, is a measurement tool that is specifically tailored to and/or validated in the AYA population, given that currently available tools cover topics that may not yet be directly applicable to younger AYAs or those who are not yet financially independent (e.g., retirement savings, contributions to household incomes) and do not include topics that are more likely to be relevant to younger respondents (e.g., childcare costs, student loan repayment) [34]. In the absence of such a tool, our use of both the IFDFW and COST was supported by their high internal consistency (IFDFW: α = 0.95; COST: α = 0.87), which we have seen in our previous work as well, and our study was the first, to our knowledge, to use both tools in an AYA sample [10, 15].
Financial hardship, particularly among AYAs, is a multifaceted problem, and future intervention work must reach across systems in order to achieve maximum impact [35]. Findings from this study demonstrate the hardship AYA survivors face nearly a decade post-diagnosis. We, as well as others, have previously highlighted the need to provide cancer patients with financial navigation and increase their health cost literacy (i.e., ability to understand financial concepts related to care) and health insurance literacy [36–39]. For AYAs, who may still be developing their financial capability and may have limited experience with the healthcare system, these tools help them to engage in cost-related discussions with their providers, which we have shown to be promising in reducing out-of-pocket expenses [39, 40]. These interventions, however, must be embedded within broader systemic efforts to effect meaningful, sustainable change. While empowering AYAs with the knowledge to make informed decisions about insurance type and participate in cost-related discussions with their healthcare teams may improve their self-efficacy to manage healthcare and other expenses, the current flaws of the US healthcare system, including a lack of cost transparency and insurance coverage variations due to erosion of Affordable Care Act policies, impede meaningful progress [41, 42]. Frameworks to understand financial hardship, such as the conceptualization used in this study by Jones and colleagues and recently published, patient-centered work by Danhauer and colleagues, will be useful in structuring research that considers systemic effects [20, 43].
Our findings are limited by the cross-sectional nature of our study design, which precludes inferences about causation. In addition, we are limited by our use of a convenience sample and the resulting lack of gender, racial/ethnic, and educational diversity, which influences the generalizability of our results, although even with limited numbers we do demonstrate that groups typically under-represented or excluded show worse financial hardship, which is consistent with prior research. Our use of a convenience sample may have also caused us to attract and recruit respondents who were experiencing extreme hardship, as evidenced by our comparably high levels of financial hardship. Furthermore, our sample was comprised mostly of women, who, in prior research, have been found to be at higher risk for financial hardship [2, 5]. Findings in this study, particularly those related to employment, financial toxicity and distress, and elements of financial hardship, were also likely influenced by the COVID-19 pandemic, as our data collection occurred in late 2020 and early 2021. As noted in our methodology, we attempted to mitigate this impact by structuring the survey so that respondents were asked to recall events prior to the pandemic, and we included specific questions about the economic impact of COVID-19 (e.g., job/insurance loss because of the pandemic, credit card debt increase since the pandemic). Nonetheless, it is highly likely that responses were shaped by individual experiences during the COVID-19 pandemic, and it may be impossible to fully disentangle pre-COVID events, feelings, and practices.
Conclusion
These findings illustrate the profound, durable consequences of financial hardship after cancer treatment among AYA cancer survivors. Comprehensive interventions are needed to provide AYAs the requisite tools to navigate financial aspects of the healthcare system; connect them with resources toward gaining financial independence; and create systems-level solutions to address healthcare affordability.
Appendix. Survey questions
Author contribution
Conceptualization, study design, data collection: BT, DNF, CB, SEW, MSZ, FC; data analysis: BT, EMA; data interpretation, manuscript writing and revision, final manuscript approval: all authors.
Funding
This manuscript was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 and the Chanel Endowment to Fund Survivorship Research.
Data availability
De-identified data that support the findings of this study are available on request from the corresponding author, BT, pending permission from the Memorial Sloan Kettering (MSK) Institutional Review Board (IRB) and a signed data sharing agreement between institutions. The data are not publicly available due to the privacy of research participants.
Declarations
Ethics approval
The MSK IRB reviewed this study and determined it to be exempt per 45 CFR 46.104(d)(2).
Consent to participate
Because the MSK IRB classified this study as exempt, written consent was not obtained; however, potential participants were informed of the anonymous and voluntary nature of the research and that they could leave the study at any time.
Competing interests
The authors have no conflicts of interest.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Zafar SY Abernethy AP Financial toxicity, Part I: a new name for a growing problem Oncology 2013 27 2 80 81 23530397
2. Yabroff KR Financial hardship associated with cancer in the United States: findings from a population-based sample of adult cancer survivors J Clin Oncol 2016 34 3 259 267 10.1200/JCO.2015.62.0468 26644532
3. Landwehr MS, Watson SE, Dolphin-Krute M. Healthcare costs and access for young adult cancer survivors: a snapshot post ACA. Am J Manag Care. 2018;24(10 Spec No.):Sp440-sp441.
4. Landwehr MS The cost of cancer: a retrospective analysis of the financial impact of cancer on young adults Cancer Med 2016 5 5 863 870 10.1002/cam4.657 26853096
5. Altice CK, et al. Financial hardships experienced by cancer survivors: a systematic review. J Natl Cancer Inst. 2017;109(2).
6. Ghazal LV Financial toxicity in adolescents and young adults with cancer: a concept analysis Cancer Nurs 2021 44 6 E636 e651 10.1097/NCC.0000000000000972 34694089
7. Lu AD Medical financial hardship in survivors of adolescent and young adult cancer in the United States J Natl Cancer Inst 2021 113 8 997 1004 10.1093/jnci/djab013 33839786
8. Zheng Z Medical financial hardship among cancer survivors in the United States Cancer 2019 125 10 1737 1747 10.1002/cncr.31913 30663039
9. Abdelhadi OA Psychological distress and associated additional medical expenditures in adolescent and young adult cancer survivors Cancer 2022 128 7 1523 1531 10.1002/cncr.34064 35001391
10. Thom B, Benedict C. The impact of financial toxicity on psychological well-being, coping self-efficacy, and cost-coping behaviors in young adults with cancer. J Adolesc Young Adult Oncol. 2019.
11. Salsman JM Understanding, measuring, and addressing the financial impact of cancer on adolescents and young adults Pediatr Blood Cancer 2019 66 7 e27660 10.1002/pbc.27660 30756484
12. Smith AW Understanding care and outcomes in adolescents and young adult with cancer: a review of the AYA HOPE study Pediatr Blood Cancer 2019 66 1 e27486 10.1002/pbc.27486 30294882
13. Kaul S Cost-related medication nonadherence among adolescent and young adult cancer survivors Cancer 2017 123 14 2726 2734 10.1002/cncr.30648 28542734
14. Harris PA The REDCap consortium: Building an international community of software platform partners J Biomed Inform 2019 95 103208 10.1016/j.jbi.2019.103208 31078660
15. Thom B, et al. Economic distress, financial toxicity, and medical cost-coping in young adult cancer survivors during the COVID-19 pandemic: findings from an online sample. Cancer. 2021.
16. Prawitz AD InCharge financial distress/financial well-being scale: development, administration, and score interpretation Financ Couns Plan 2006 17 1 34 50
17. de Souza JA, et al. Measuring financial toxicity as a clinically relevant patient-reported outcome: the validation of the COmprehensive Score for financial Toxicity. Cancer. 2016.
18. Esselen KM, et al. Evaluating meaningful levels of financial toxicity in gynecologic cancers. Int J Gynecol Cancer. 2021.
19. Souza JAD Validation of a financial toxicity (FT) grading system J Clin Oncol 2017 35 15_suppl 6615 6615 10.1200/JCO.2017.35.15_suppl.6615
20. Jones SM A theoretical model of financial burden after cancer diagnosis Future Oncol 2020 16 36 3095 3105 10.2217/fon-2020-0547 32976048
21. Agency for Healthcare Research and Quality. Medical Expenditure Panel Survey (MEPS). 2021 [cited 2022; Available from: https://www.ahrq.gov/data/meps.html.
22. Ou JY, et al. Financial burdens during the COVID-19 pandemic are related to disrupted healthcare utilization among survivors of adolescent and young adult cancers. J Cancer Surviv. 2022;1–12.
23. Panzone J, et al. Association of race with cancer-related financial toxicity. JCO Oncol Pract. 2021;Op2100440.
24. Kayser K Living with the financial consequences of cancer: a life course perspective J Psychosoc Oncol 2021 39 1 17 34 10.1080/07347332.2020.1814933 32876547
25. Parsons HM Young and uninsured: Insurance patterns of recently diagnosed adolescent and young adult cancer survivors in the AYA HOPE study Cancer 2014 120 15 2352 2360 10.1002/cncr.28685 24899580
26. Parsons HM Early impact of the patient protection and affordable care act on insurance among young adults with cancer: analysis of the dependent insurance provision Cancer 2016 122 11 1766 1773 10.1002/cncr.29982 26998967
27. Kirchhoff AC, et al. “Job lock” among long-term survivors of childhood cancer: a report from the childhood cancer survivor study. JAMA Oncol. 2017.
28. Cheung CK A call to action: antiracist patient engagement in adolescent and young adult oncology research and advocacy Future Oncol 2021 17 28 3743 3756 10.2217/fon-2020-1213 34263658
29. Doherty MJ Thom B Gany F Evidence of the feasibility and preliminary efficacy of oncology financial navigation: a scoping review Cancer Epidemiol Biomarkers Prev 2021 30 10 1778 1784 10.1158/1055-9965.EPI-20-1853 34341051
30. Kirchhoff A, Jones S. Financial toxicity in adolescent and young adult cancer survivors: proposed directions for future research. J Natl Cancer Inst. 2021.
31. Cheung CK, et al. Capturing the financial hardship of cancer in military adolescent and young adult patients: a conceptual framework. J Psychosoc Oncol. 2021;1–18.
32. Meernik C Material and psychological financial hardship related to employment disruption among female adolescent and young adult cancer survivors Cancer 2020 127 1 137 148 10.1002/cncr.33190 33043464
33. Nightingale CL, et al. Financial burden for caregivers of adolescents and young adults with cancer. Psychooncology. 2022.
34. Salsman JM Systematic review of financial burden assessment in cancer: evaluation of measures and utility among adolescents and young adults and caregivers Cancer 2021 127 11 1739 1748 10.1002/cncr.33559 33849081
35. Salsman JM, Kircher SM. Financial hardship in adolescent and young adult oncology: the need for multidimensional and multilevel approaches. JCO Oncol Pract. 0(0):OP.21.00663.
36. Waters AR “I thought there would be more I understood”: health insurance literacy among adolescent and young adult cancer survivors Support Care Cancer 2022 30 5 4457 4464 10.1007/s00520-022-06873-2 35107600
37. Aviki EM Patient-reported benefit from proposed interventions to reduce financial toxicity during cancer treatment Support Care Cancer 2022 30 3 2713 2721 10.1007/s00520-021-06697-6 34822002
38. Thom B The intersection of financial toxicity and family building in young adult cancer survivors Cancer 2018 124 16 3284 3289 10.1002/cncr.31588 29924381
39. Zafar SY Cost-related health literacy: a key component of high-quality cancer care J Oncol Pract 2015 11 3 171 173 10.1200/JOP.2015.004408 25829522
40. Zafar SY The utility of cost discussions between patients with cancer and oncologists Am J Manag Care 2015 21 9 607 615 26618364
41. Moss HA Declines in health insurance among cancer survivors since the 2016 US elections Lancet Oncol 2020 21 11 e517 10.1016/S1470-2045(20)30623-9 33069279
42. Chino F, Johnson J, Moss H. Compliance with price transparency rules at US national cancer institute-designated cancer centers. jaMA Oncol. 2021.
43. Danhauer SC, et al. Stakeholder-informed conceptual framework for financial burden among adolescents and young adults with cancer. Psychooncology. 2021.
| 36472761 | PMC9734817 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Cancer Surviv. 2022 Dec 6;:1-11 | utf-8 | J Cancer Surviv | 2,022 | 10.1007/s11764-022-01280-2 | oa_other |
==== Front
AIDS Behav
AIDS Behav
AIDS and Behavior
1090-7165
1573-3254
Springer US New York
36471205
3922
10.1007/s10461-022-03922-z
Original Paper
Impact of COVID-19 on HIV Prevention Access: A Multi-platform Social Media Infodemiology Study
Xu Qing 12
McMann Tiana 123
Godinez Hector 1
Nali Matthew C. 123
Li Jiawei 1
Cai Mingxiang 1
Merenda Christine 4
Lee Christine 4
Araojo Richardae 4
http://orcid.org/0000-0002-2191-7833
Mackey Tim K. [email protected]
123
1 S-3 Research LLC, San Diego, CA USA
2 Global Health Policy and Data Institute, Sang Diego, CA USA
3 grid.266100.3 0000 0001 2107 4242 Global Health Program, Department of Anthropology, University of California, San Diego, San Diego, CA USA
4 grid.417587.8 0000 0001 2243 3366 Office of Minority Health and Health Equity, U.S. Food and Drug Administration, Silver Spring, MD USA
5 12 2022
111
1 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
This study seeks to identify and characterize key barriers associated with PrEP therapy as self-reported by users on social media platforms. We used data mining and unsupervised machine learning approaches to collect and analyze COVID-19 and PrEP-related posts from three social media platforms including Twitter, Reddit, and Instagram. Predominant themes detected by unsupervised machine learning and manual annotation included users expressing uncertainty about PrEP treatment adherence due to COVID-19, challenges related to accessibility of clinics, concerns about PrEP costs and insurance coverage, perceived lower HIV risk leading to lack of adherence, and misinformation about PrEP use for COVID-19 prevention.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10461-022-03922-z.
Keywords
Infodemiology
HIV/AIDS
Minority health
PrEP
Social media
Food and Drug Administration (FDA) Office of Minority Health and Health Equity (OMHHE) of the U.S. Department of Health and Human Services (HHS)BAA-SSBSWP#155 Contract #75F40120C00181 Mackey Tim K.
==== Body
pmcIntroduction
The end of 2019 introduced new global challenges with the sudden emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the weeks and months following its detection in the United States and other parts of the world, day-to-day activities of patients began to experience significant interruption due to implementation of stay at home, and social distancing measures needed to slow the escalating pandemic. While these measures reduced in-person interactions of disease transmission, they also created new challenges, including for HIV prevention [1, 2].
Prioritizing triage of COVID-19 cases created a shift in allocation of certain healthcare services [3]. Those most affected included patients seeking routine care, which includes individuals seeking HIV prevention services that require strict adherence to therapy, such as pre-exposure prophylaxis (PrEP) [4]. HIV negative individuals rely on PrEP to maintain negative HIV serostatus, yet many patients experienced reduced clinical visits during COVID-19, thus interrupting their PrEP therapy [5–7]. Those not on PrEP but at elevated HIV risk, require consultation with a healthcare professional to confirm negative status to be prescribed PrEP [8]. However, treatment barriers associated with commuting to appointments, completing necessary blood/lab work, and filling prescriptions, were all negatively impacted by COVID-19 [9, 10].
Supporting the importance of maintaining access to HIV prevention services, a 2021 study used simulation models to estimate the benefits of continuing certain HIV prevention services (e.g., male circumcision, HIV diagnostic testing, viral load testing, and program to prevent mother-to-child transmission) and found that the risk of additional COVID-19-related deaths was at least 100 times less than HIV-related mortality that would be averted by prevention services [11]. Further, as more individuals at risk for HIV become sexually active due to removal of COVID-19 restrictions, the possibility of HIV transmission during a post-pandemic period may increase, necessitating more comprehensive understanding of barriers associated with PrEP access [10, 12]. This may also coincide with a time period where an increased number of HIV-negative individuals are reportedly engaging in riskier sexual and unsafe behaviors [13]. Hence, research examining the impacts of the COVID-19 pandemic on HIV prevention behavior is needed to address post-pandemic challenges, but interventions will also need to be tailored to specific vulnerable populations and diverse experiences.
Current HIV and COVID-19 research has documented interruption of HIV services and widening health disparities, yet few studies have attempted to identify the unique socioecological barriers that may have arisen due to COVID-19-related restrictions and its associated implications [14–16]. Hence, to better understand the evolving environment at the intersection of HIV and COVID-19, this study seeks to identify and characterize key barriers associated with PrEP therapy access using infodemiology approaches (i.e., the science of distribution and determinants of information in an electronic medium, with the aim of informing public health) [17]. Specifically, we conducted analysis of publicly available user-generated data from multiple social media platforms associated with PrEP and HIV prevention attitudes, beliefs, and experiences during the pandemic.
Methods
Data Collection
Data was collected from Twitter, Reddit, and Instagram simultaneously over a 60-day period (October 2020, until December 2020), including both retrospective (limited to posts after March 13, 2020, when COVID-19 was declared a national emergency in the United States) and prospective data. We chose these platforms based on their general popularity, accessibility of data, and diversity in user base and different methods of online communication and interaction (e.g., a microblogging site [Twitter], a news aggregation and discussion site [Reddit], and a photo and video platform [Instagram]). We first generated a list of PrEP and HIV associated keywords and hashtags by manually searching posts on selected social media platforms, which generated a baseline set of terms associated with HIV, PrEP, and approved medications. This was accomplished by conducting structured searches of a set of initial keywords and then collecting additional hashtags and keywords associated with HIV prevention and treatment content from the first 100 post results. This allowed us to generate the final list of selected keywords and hashtags used for this study’s data collection phase (see Supplementary File). We used multiple data collection approaches including the public streaming Twitter API and automated data mining approaches built in the programming language Python to collect posts from Reddit and Instagram. This study focused on analysis of English-language posts but did not include a geographic restriction. As this study only utilized secondary publicly available data, it was deemed exempt by WCG IRB. WCG IRB is registered with the Office for Human Research Protections and US Food and Drug Administration (FDA) as IRB00000533. Data was collected for purposes of aggregation, and no results contained in this study include individually identifiable information.
Data Analysis
Content and Statistical Analysis
In this study, relevant “signal” posts were defined as user-generated posts from Twitter, Instagram, or Reddit accounts discussing PrEP and/or general HIV prevention practices and also mention of COVID-19. To identify signal posts, we adopted a combination of keyword filtering, unsupervised machine learning using the Biterm Topic Model (BTM), as well as manual annotation by further filtering our dataset for COVID-19-related keywords in the text of user posts (e.g., “covid19,” “corona,” “coronavirus,” and “coronavid19” [18]). The Biterm Topic Model is an unsupervised machine learning approach used to detect patterns in data and can summarize the entire corpus of text into distinct highly correlated categories. BTM can be used to sort short text into highly prevalent themes without the need for predetermined training data and has been previously used for exploration of other public health topics [19–24]. The methodological approach of using BTM for detection of HIV and PrEP-related topics is also detailed in a separate published paper [25].
The inclusion criteria for signal posts included user-generated conversations where knowledge, attitudes, behaviors, or experiences regarding PrEP or general HIV prevention methods were discussed, as well as information associated with public service announcements and health promotion and education messages specifically posted or shared from an individual user account. Public service announcements, health promotion and education messages posted from organizations (i.e., not individual accounts), advertisements for HIV prevention services/clinics that were posted by an organization, and other conversations not related to HIV prevention or that appeared not to be user-generated were excluded.
A general deductive coding schema using the socio-ecological perspective outline (SEPO) [26] that outlines three intervention levels for PrEP including the “Individual and Relationships Domains: Provider Level”, “Individual and Relationships Domains: Patient Level” and “Community Domains: Healthcare-System Level”, were selected as parent codes as used in a prior PrEP infodemiology study [25]. All posts were reviewed by first and second author, and notes were taken on general themes of posts from which an initial code list was created. SEPO categories of PrEP barriers were adopted as subcodes throughout our deductive coding and subcodes not detected were excluded from the final codebook. Emergent themes that did not present in existing subcodes were added to the codebook under the three parent codes based on the conceptual domain and intervention level of the new theme. First and second author achieved a strong intercoder reliability (Cohen’s kappa coefficient ≈ 0.88) for codes generated. For inconsistent results, all authors reviewed the posts and reached consensus on correct classification.
Chi-square tests were used to examine if the proportion of user conversations varied among: (i) provider-level; (ii) patient-level; and (iii) community-level between Twitter and Instagram. Fisher’s exact tests were used to determine significant proportional differences in user conversations on Reddit due to smaller sample size. All statistical analyses were conducted using RStudio version 4.1.2. A p-value of < 0.05 was considered statistically significant.
User Race, Ethnicity, and Sexual Minority Assessment
Given the disproportionate impact of COVID-19 on HIV treatment access, disease burden, and pre-existing socio-economic and health disparity-related barriers, we also reviewed publicly available information from users to assess self-reported information related to: (1) a racial and ethnic group; and (2) a specific sexual minority group. We reviewed user profile metadata and the content of the last 10 posts from each user account for any self-reported racial, ethnic, or sexual minority affiliation (e.g., “As a sexually active black gay man in a major metropolitan area”, and “ I am a black man in New York…”). The racial and ethnic groups categorized included: Black or African American, American Indian or Alaska Natives, Asian, Native Hawaiian or other Pacific Islander, and Hispanic or Latino. The five sexual and gender minority classification were lesbian, gay, bisexual, transgender, and queer (LGBTQ) and were grouped as a single sexual minority affiliation class. In addition to racial, ethnic, and sexual minority self-reported data, we also reviewed user account information and posts for any mention of geographic location. User data are users who reported their location in the United States.
Results
A total of 267,689 posts were collected from Twitter, Reddit, and Instagram using our HIV and PrEP-related keywords and hashtags between March 13, 2020 and December 11, 2020, a time of relatively high COVID-19 pandemic activity and when vaccines had not been readily available or administered to the general public. The dataset comprised of 254,122 (94.93%) Twitter posts, 11,218 (4.19%) Instagram posts, and 2349 (0.88%) Reddit posts. After filtering for COVID-19-related terms, the total corpus of posts was reduced to 11,222 (4.19% of the total dataset) comprised of 7620 (67.90%) Twitter, 3278 (29.21%) Instagram, and 324 (2.89%) Reddit posts. After using BTM on the higher volume of Twitter posts, and manual annotation for Instagram and Reddit posts, a total of 317 signal posts were detected (2.82% or entire dataset), of which we detected 190 (59.94% of signal posts) signal posts from Twitter, 109 (34.38%) from Instagram, and 18 (5.68%) from Reddit (See Supplementary File), which were then content coded for further in-depth analysis. A summary of SEPO parent and sub-code results are reported in Table 1 with corresponding de-identified examples from different sexual minority and racial and ethnic minority users.Table 1 Deductive code list and identified sub-codes based on SEPO
Topic level Code number Description Examples (de-identified and paraphrased) Twitter Instagram Reddit Total
Provider level
(31.55% of all signals)
A-1 Providing free HIV self-test kits “During the time of COVID, it is important to continue to test yourself for any HIV infection. Today, we are offering free HIV home tests mailed directly to you confidentially. All information submitted will be anonymously. #HIVtest #gettested #hivawareness #hivprevention #hivpositive #hivtesting #gay #lesbian #bisexual #trans #transgender” 2 41 0 43 (43.00%)
A-2 Providing free STD prevention (condom) “Protect yourself from potential infections. It’s important to rubber up before engaging in activities. Message us today so we can send you free condoms. You never know when you will need to use them.” 0 15 0 15 (15.00%)
A-3 Providing HIV medical and prevention services (HIV test and PrEP) “At home testing kits for long term adherence to #PrEP is one way to verify if PrEP has been working well for you to prevent #HIV. Contact us to see how we can assist you! #COVID #telehealth” 7 10 0 17 (17.00%)
A-4 Concerns regarding reduced operation of STD and HIV clinics during COVID “Testing for your status for HIV is important. The pandemic may have impacted availability and locations to go near you, but there are options to test yourself. If that isn’t an option you can also do virtual PrEP clinic with a pharmacist available 7 days a week. #queer #prep #theprepclinic # hivprevention #harmreduction #knowyourstatus #hivtesting #safersex 17 8 0 25 (25.00%)
Total 26 74 0 100
Patient Level (36.59% of all signals) B-1 Distrust of HIV prevention “B******! It’s all about control. Covid is no different than HIV. They want you to take something into your body because it can prevent you from illness. What’s next? They can’t take my rights away. I decide what goes into my body 6 0 0 6
(5.17%)
B-2 Experienced lack of access to PrEP and HIV treatment during COVID “Ever since COVID-19 began, its been very difficult to get tested for HIV in hospitals . I think clinics are a better option.” 22 7 2 31 (26.72%)
B-3 Concern of lack of funding and resources for HIV prevention “@******* @******* @ *****, I overheard a few people at my clinic talking about how they might double count patients who visit for HIV, so they don’t lose funding. I wonder if they do that for other diseases?” 2 0 0 2
(1.72%)
B-4 User claims in support of PrEP therapy “Mask up during COVID. Been on PrEP for years and I can say the medication works well. It’s HIV blocking abilities are a life saver. However, I did het Hep-c a few years back from sex alone. That was disappointing but oh well. Just you PrEP. It works!” 4 0 0 4
(3.45%)
B-5 Patient reacquiring access to PrEP treatment “Now that the lockdowns are over and our case counts are near 0 maybe it’s time to get back on PrEP. Its time to have fun this year!” 2 0 0 2
(1.72%)
B-6 Expressions that users should be aware of COVID-19-related risks (people having sex and at risk) “Screaming at this F**** who told me he doesn’t hookup without condoms, and he feels like he did something for denying a guy he met on grinder who didn’t want condoms because he uses PrEP. Like honey, condoms won’t protect you from COVID. What are you doing?” 3 0 0 3
(2.59%)
B-7 Recommend other users to engage in HIV prevention efforts (testing, PrEP, condom use) “If you test negative for #HIV that doesn’t mean you no longer need condoms, PrEP or other effective prevention strategy. Kinda like a negative #COVID test doesn’t mean you don’t have to socially distance.” 13 18 0 31
(26.72)
B-8 Self-perceived reduced risk due to reduced sexual behavior “I stopped using PrEP (COVID) since I can’t do anything with these lockdowns” 19 1 3 23
(19.83%)
B-9 Users think they immune to COVID because they are on PrEP “People are crazy today. They think taking one medication will protect them from others diseases. Come on people. Taking PrEP doesn’t protect you from STD like chlamydia or the COVID virus. Hell, it won’t save you from your own stupidity ” 14 0 0 14
(12.07%)
Total 85 26 5 116
Community Level (31.86% of all signals) C-1 Opinion that COVID lowers rate of HIV (due to social distancing) “While COVID is terrible overall, I think all these lockdowns may have a benefit towards lowering STI rates. Can you imagine” 1 0 0 1
(0.99%)
C-2 Financial impact caused by COVID Pandemic increased sex worker number and could lead to higher STI and HIV rates “One of the saddest things I have seen is the increase funds for boys and girls. In 24 h, I have been contacted by 9 people offering sex for money. Some are people who lost their jobs because of covid. I decline them and try to give them support, but it sad that 93% of sex workers have contracted at least one STI before. I feel that this pandemic will increase the overall percentage. #HIV #HIVprevention #NoPrEPforme #gettested2020 #safesex #sexwork” 0 1 0 1
(0.99%)
C-3 Health resources being prioritized for COVID-19 instead of HIV “Hospitals are being overrun by COVID patients. I was watching the news that emergency vehicles likes ambulances will have to treat those who are positive for covid before other patients. What if I have a broken bone that needed to be looked at. Or what if I have a heart attack? Am I supposed to wait until the pandemic is over for help? Will this affect any of my medication like PrEP or my typical screening with my primary doctor? I hope I can still get medical help when it’s needed. If not, I’ll be pissed.” #covid19 #covid19PH #coronavirus #safesex #SafeSexAwareness #RH #RHLaw #birthcontrol #HIV #HIVprevention #womenshealth #genderequality #genderequalityforall #genderequalitymatters 9 2 0 11
(10.89%)
C-4 Lack of focus on HIV prevention “COVID hasn’t put HIV or STI infections to sleep. They are still being transmitted and we need adequate sexual health services for them!” 7 0 0 7
(6.93%)
C-5 New technology discussions for PrEP “Exciting news! New covid taskforce discussed a highly effective two-dose COVID vaccine! Also, a more effective PrEP drug for HIV! It’s about time! ” 26 1 0 27
(26.73%)
C-6 PrEP used as a prevention method for COVID-19 “Lots of distrust circling on social media. People are taking anything to prevent COVID. Heck, some of my friends think that PrEP can also protect them from COVID since it protects them from HIV transmission.” 31 0 12 43
(42.57%)
C-7 Sharing knowledge on HIV prevention when users lack access to PrEP “In some way we have several layers of protection to prevent the spread of HIV. Even if you can’t get access to PrEP, many organizations provide condoms for those who are on a budget. #SafeSexAlways #StopTheStigma” 3 2 1 6
(5.94%)
C-8 Sharing general PrEP knowledge “Pre-exposure prophylaxis (PrEP) is a medication that preventions HIV infection. PrEP is free for those who are considered to be substantial high risk of contracting HIV via sex. However, because of COVID, some appointments services may be affected. #sexwellbeing” 1 3 0 4
(3.96%)
C-9 Discussion of stigma experienced by use of PrEP “I can understand why people look at me differently when I tell them I’m on PrEP. It’s not that I have HIV, but I’m trying to prevent myself from acquiring it. I wish that people would think and educate themselves before they speak.” 1 0 0 1
(0.99%)
Total 79 9 13 101
Content and Statistical Analysis
SEPO provider-level conversations generated 100 posts (31.55% of all signals) and were focused on perceived provider decision making barriers reported by social media users. PrEP-related user discussions focused on concerns about accessibility to STD and HIV clinics due to reduced operation during COVID-19, with the highest volumes occurring on Twitter (68%, n = 17) and Instagram (32%, n = 8). Another PrEP-related topic focused on the provision of HIV testing and prevention services (i.e., HIV testing in conjunction with PrEP) and made up the third-highest volume of user conversations at the provider level. However, more than half (58%, n = 58) of topics in this level focused on information and resources for non-PrEP HIV prevention approaches, including access to free HIV self-testing kits and condoms, aimed at mitigating spread due to unsafe sex during COVID-19.
Patient-level user conversations, which focused on barriers at the patient decision-making level, had the highest total signal in the dataset (n = 116, 36.59% posts). The majority of these posts came from Twitter (73.28%, n = 85), followed by Instagram (22.41%, n = 26), and Reddit (4.31%, n = 5). A major theme that emerged was widespread discussion of resource allocation, with concerns that resources were being taken away from PrEP due to the COVID-19 surge (26.72%, n = 31). Another topic included discussions encouraging consistent HIV testing, PrEP adherence, and condom use to prevent HIV transmission (n = 31, 26.72%). Users also discussed their relative risk associated with HIV and COVID-19 (19.83%, n = 23), including self-reporting reduced sexual behavior and perceived lower risk due to social distancing, leading to termination of PrEP and other HIV prevention methods. A final sub-topic included incorrect information about the use of PrEP in providing immunity for COVID-19 (12.07%, n = 14).
Community-level conversations accounted for 101 (31.86%) signal posts and focused on perceived barriers influenced at the macro community level. Prominent sub-topics included similar incorrect conversations that PrEP could be used as a prevention method or precaution against COVID-19 infection (42.57%, n = 43) and discussions of new technology for PrEP (26.73%, n = 27) (e.g., clinical trials investigating alternatives to delivering PrEP therapy, including administration via injection in lieu of daily adherence to medication). Specifically, Reddit conversation threads included many questions about PrEP being effective as a protective measure against COVID-19 infection. Other themes included opinions that there was a general lack of commitment to HIV prevention services, including PrEP, due to COVID-19.
Between Twitter and Instagram, provider-level user conversations were significantly more likely on Instagram and patient-level user conversations were significantly more likely on Twitter, X2 (1, N = 211) = 51.96, p < 0.001. Community-level user conversations were significantly more likely on Twitter compared to provider-level conversations on Twitter, X2 (1, N = 188) = 74.64, p < 0.001. Patient-level user conversations were significantly more likely on Twitter than Instagram compared to community-level user conversations, X2 (1, N = 199) = 5.02, p = 0.03. Overall, comparing Instagram and Reddit, the proportion of patient-level user conversations was significantly more likely on Instagram and community-level user conversations were significantly more likely on Reddit (Fisher’s exact test p = 0.002).
Self-reported Racial/Ethnic/Sexual Minority Data and Location Data
Using publicly available data from user accounts and their metadata, we were also able to identify 34 (10.73%) users that reported affiliation with one or more of the five sexual minority classifications. Additionally, we also classified users based on affiliation with racial minorities, which included 13 (4.10%) Black or African American and 2 (0.63%) Asian users; and affiliation with ethnic minorities including 2 (0.63%) Hispanics or Latino social media users. A total of 253 (79.81%) unique users did not have sufficient information available to be identified into a specific racial group, 288 (90.85%) users were not able to be identified into a specific ethnic group, and 283 (89.27%) users were not able to be identified into a sexual minority group. We also did not assess if users self-reported as non-Hispanic white users. No users self-identified as Native Hawaiian and other Pacific Islander (See Table 2). Additionally, we were able to collect self-reported location data from 154 Twitter users, and 12 Instagram users. We observed that users reported they resided in 23 countries, and based on the number of users, the top three countries were the United States (89 Twitter users and 8 Instagram users), United Kingdom (31 Twitter users and 3 Instagram users), and Australia (10 Twitter users).Table 2 User identified minority status breakdown
Platform Racial categories Ethnic categories Sexual minority
African American/Black Asian White Missing identification Hispanics or Latino Not Hispanics or Latino Missing identification LGBTQ Non- sexual minority Missing identification
Instagram
(% of Instagram users)
0
(0%)
0
(0%)
5
(4.59%)
104
(95.41%)
1
(0.92%)
6
(5.50%)
102
(92.58%)
3
(2.75%)
0
(0%)
106
(97.25%)
Reddit
(% of Reddit users)
1
(5.56%)
0
(0%)
0
(0%)
17
(9.44%)
0
(0%)
0
(0%)
18
(100%)
10
(55.56%)
0
(0%)
8
(44.44%)
Twitter
(% of Twitter users)
12
(6.32%)
2
(1.1%)
44
(23.16%)
132
(69.47%)
1
(0.53%)
21
(11.05%)
168
(88.42%)
21
(11.05%)
0
(0%)
169
(88.95%)
Total 13
(4.10%)
2
(0.63%)
49
(15.46%)
253
(79.81%)
2
(0.63%)
27
(8.52%)
288
(90.85%)
34
(10.73%)
0
(0%)
283
(89.27%)
Conclusions
Findings from this exploratory infodemiology study largely confirm what is already known; the COVID-19 pandemic contributed to disruptions for HIV prevention services that may impact uptake and adherence to PrEP therapy and other HIV prevention services. Importantly, these challenges are accentuated for ethnic, racial, and sexual minority populations. Our analysis of just over a quarter million social media posts from three platforms yielded 317 specific user-generated posts expressing attitudes, knowledge, and experiences associated with PrEP, HIV prevention services, and COVID-19. Thirty-seven users reported a sexual minority affiliation (LGBTQ status), making this the largest online user group we detected engaged directly in these conversations. Additionally, 17 users self-reported as a racial or ethnic minority group.
Results from this study provide insights into the specific barriers experienced across the HIV/AIDS PrEP care continuum during the COVID-19 pandemic as expressed by users from different social media platforms. Results indicate that certain barriers to PrEP are reported, experienced, perceived, and shared by users across multiple socioecological levels, while other barriers are unique to specific levels. For example, all levels reported perceived barriers to HIV prevention and PrEP access due to resource constraints (e.g., reduced clinic operation, not being able to access treatment due to lockdowns, resources being diverted or prioritized for COVID-19 instead of HIV prevention), while users also actively shared resources about HIV testing, PrEP, and other prevention methods. Shared challenges and information sharing requires a more comprehensive and coordinated approach to promoting HIV prevention, including targeted patient and provider advocacy for PrEP therapy and active community engagement, including through social media channels.
Shared experiences across all SEPO levels may also help to characterize the overall risk environment that emerged due to COVID-19 and its impact on PrEP. This impact appears to be most acutely expressed at the patient level, where users reported a number of different topics ranging from changing behaviors and attitudes with PrEP and HIV prevention (including disruption and even deciding to forego PrEP) and also reassessing their own HIV/AIDS risk in response to pandemic conditions (deciding they were at lower risk for HIV and ceasing PrEP). Unfortunately, users at the patient-level also expressed distrust and circulated incorrect and misinformation about the use of PrEP to prevent COVID-19 transmission, a phenomenon also detected at the community-level, even though there is no evidence to support these claims. These concerns mirror warnings issued by public health officials on various forms of misinformation related to COVID-19 prevention and treatment [18]. In response, tailored education and “debunking” of these claims specific to the HIV community is needed in alignment with other efforts to combat growing health misinformation online [27].
Additionally, the provider, patient, and community level challenges we detected may serve to exacerbate other documented challenges with HIV prevention uniquely experienced by ethnic, racial, and sexual populations, including ongoing stigma, deep rooted fear of HIV, increased stress and mental health impact, lack of equitable access to treatment and lower adherence rates, and overall disproportionate HIV burden [28]. Hence, generating better understanding and addressing the specific barriers that may disproportionally impact these vulnerable groups needs to be addressed synergistically across all socio-ecological levels and across the HIV prevention and care continuum, particularly during health emergencies [29].
Limitations
This study is primarily exploratory and has certain limitations. We only collected data from three social media platforms and limited our analysis to English language keywords and filtered terms to a specific time period during the COVID-19 pandemic. Hence, the findings are not generalizable to all social media users who discuss and experience PrEP-related barriers or can be generalized to all stages of the pandemic. Specifically, data analyzed in this study covered a period after COVID-19 was declared a U.S. public health emergency until the date when the first COVID-19 vaccine became readily available to the public. Hence, access to and maintenance of HIV prevention services, such as PrEP, may have been impacted by different pandemic developments, necessitating additional analysis at specific stages of the pandemic to assess cumulative impacts on at-risk HIV populations. Future studies should also expand data collection to different languages and phrases associated with HIV prevention and risk behavior, as well as longer time periods, to generate a more representative corpus of social media conversations. We also used keywords to filter posts for manual annotation after applying an unsupervised topic modeling approach. However, posts that did explicitly contain COVID-19-related keywords that occurred during the pandemic or that may have occurred outside our study period, may have also yielded valuable insight into additional PrEP-related barriers experienced by online users. Future studies should analyze a larger dataset of user-generated conversations by developing additional supervised and unsupervised machine learning approaches to classify content. Additionally, the oversampling of tweets in our dataset due to greater data availability from the Twitter API could result in a bias sample of posts when compared to other platforms. Finally, we used self-identified or self-reported racial or ethnic minority affiliation and sexual minority affiliation and did not further cross-validate this user representation, which may further limit the applicability of findings specific to these groups.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 16 KB)
Acknowledgements
We thank Cortni Bardier and Vidya Purushothaman for useful discussion, input, and assistance during the conduct of the project.
Clearance: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
Author Contributions
QX, TMM, HG, MCN, JL, MC, CL, CM, RA and TKM jointly conceived the study, drafted the study, conducted data collection and analysis, and wrote and agreed to the final version of this manuscript.
Funding
This publication was supported by the Food and Drug Administration (FDA) Office of Minority Health and Health Equity (OMHHE) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award Broad Agency Announcement (BAA-SSBSWP#155, Contract #75F40120C00181), totaling $104,500 with 100 percent funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.
Data Availability
Not applicable.
Code Availability
Not applicable.
Declarations
Conflict of interest
QX, TMM, HG, MCN, MC, JL, and TKM are employees of the startup company S-3 Research LLC. S-3 Research is a startup funded and currently supported by the National Institutes of Health – National Institute of Drug Abuse through a Small Business Innovation and Research contract for opioid-related social media research and technology commercialization. Authors reports no other conflicts of interest associated with this manuscript.
Ethical Approval
As this study only utilized secondary publicly available data, it was deemed exempt by WCG IRB. WCG IRB is registered with the Office for Human Research Protections and US Food and Drug Administration (FDA) as IRB00000533. Data was collected for purposes of aggregation, and no results contained in this study include individually identifiable information.
Consent to Participate
Not applicable.
Consent to Publication
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. EL P, DR R, H G, ALW M, N A, AR W, et al. Characterizing Health Care Delays and Interruptions in the United States During the COVID-19 Pandemic: Internet-Based, Cross-sectional Survey Study. Journal of Medical Internet Research [Internet]. https://www.jmir.org/2021/5/e25446/
2. Hojilla JC Hurley LB Marcus JL Silverberg MJ Skarbinski J Satre DD Characterization of HIV preexposure prophylaxis use behaviors and HIV incidence among US adults in an Integrated Health Care System JAMA Netw Open 2021 4 e2122692 10.1001/jamanetworkopen.2021.22692 34436609
3. Panocchia N D’ambrosio V Corti S Presti EL Bertelli M Scattoni ML COVID-19 pandemic, the scarcity of medical resources, community-centred medicine and discrimination against persons with disabilities J Med Ethics 2021 47 362 366 10.1136/medethics-2020-107198
4. Arrington-Sanders R Hailey-Fair K Wirtz AL Morgan A Brooks D Castillo M Role of structural marginalization, HIV stigma, and mistrust on HIV prevention and treatment among young black latinx men who have sex with men and transgender women: perspectives from youth service providers AIDS Patient Care STDs 2020 34 7 15 10.1089/apc.2019.0165 31944853
5. Sanchez TH Zlotorzynska M Rai M Baral SD Characterizing the impact of COVID-19 on men who have sex with men across the United States in April, 2020 Aids Behav 2020 24 2024 2032 10.1007/s10461-020-02894-2 32350773
6. Gatechompol S Avihingsanon A Putcharoen O Ruxrungtham K Kuritzkes DR COVID-19 and HIV infection co-pandemics and their impact: a review of the literature Aids Res Ther 2021 18 28 10.1186/s12981-021-00335-1 33952300
7. Wion RK Miller WR The impact of COVID-19 on HIV self-management, affective symptoms, and stress in people living with HIV in the United States Aids Behav 2021 25 3034 3044 10.1007/s10461-021-03335-4 34129142
8. Pinto RM Park S COVID-19 pandemic disrupts HIV continuum of care and prevention: implications for research and practice concerning community-based organizations and frontline providers AIDS Behav 2020 24 2486 2489 10.1007/s10461-020-02893-3 32347403
9. D’Angelo AB Lopez-Rios J Flynn AWP Holloway IW Pantalone DW Grov C Insurance- and medical provider-related barriers and facilitators to staying on PrEP: results from a qualitative study Transl Behav Med 2020 11 573 581 10.1093/tbm/ibz191
10. Calabrese SK Earnshaw VA Underhill K Hansen NB Dovidio JF The impact of patient race on clinical decisions related to prescribing HIV Pre-exposure prophylaxis (PrEP): assumptions about sexual risk compensation and implications for access AIDS Behav 2014 18 226 240 10.1007/s10461-013-0675-x 24366572
11. Stover J Kelly SL Mudimu E Green D Smith T Taramusi I The risks and benefits of providing HIV services during the COVID-19 pandemic PLoS ONE 2021 16 e0260820 10.1371/journal.pone.0260820 34941876
12. Taggart T Liang Y Pina P Albritton T Awareness of and willingness to use PrEP among Black and Latinx adolescents residing in higher prevalence areas in the United States PLoS ONE 2020 15 e0234821 10.1371/journal.pone.0234821 32628674
13. Holt M Chan C Broady TR Mao L MacGibbon J Rule J Adjusting behavioural surveillance and assessing disparities in the impact of COVID-19 on gay and bisexual men’s HIV-related behaviour in Australia AIDS Behav 2022 27 1 17
14. Beima-Sofie K Ortblad KF Swanson F Graham SM Stekler JD Simoni JM “Keep it going if you can”: HIV service provision for priority populations during the COVID-19 pandemic in Seattle, WA AIDS Behav 2020 24 2760 2763 10.1007/s10461-020-02902-5 32385679
15. Qiao S Li Z Weissman S Li X Olatosi B Davis C Disparity in HIV service interruption in the outbreak of COVID-19 in South Carolina AIDS Behav 2021 25 49 57 10.1007/s10461-020-03013-x 32856176
16. Harkness A Behar-Zusman V Safren SA Understanding the impact of COVID-19 on Latino sexual minority men in a US HIV hot spot AIDS Behav 2020 24 2017 2023 10.1007/s10461-020-02862-w 32300989
17. Eysenbach G Infodemiology and infoveillance: framework for an emerging set of public health informatics methods to analyze search, communication and publication behavior on the Internet J Med Internet Res 2009 11 e11 10.2196/jmir.1157 19329408
18. Mackey TK Purushothaman V Haupt M Nali MC Li J Application of unsupervised machine learning to identify and characterise hydroxychloroquine misinformation on Twitter Lancet Digital Heal 2021 3 e72 e75 10.1016/S2589-7500(20)30318-6
19. Kalyanam J Katsuki T Lanckriet GRG Mackey TK Exploring trends of nonmedical use of prescription drugs and polydrug abuse in the Twittersphere using unsupervised machine learning Addict Behav 2017 65 289 295 10.1016/j.addbeh.2016.08.019 27568339
20. Li J Xu Q Shah N Mackey TK A machine learning approach for the detection and characterization of illicit drug dealers on Instagram: model evaluation study J Med Internet Res 2019 21 e13803 10.2196/13803 31199298
21. Xu Q Li J Cai M Mackey TK Use of machine learning to detect wildlife product promotion and sales on Twitter Front Big Data 2019 2 28 10.3389/fdata.2019.00028 33693351
22. Li J Chen W-H Xu Q Shah N Kohler JC Mackey TK Detection of self-reported experiences with corruption on twitter using unsupervised machine learning Soc Sci Hum Open 2020 2 100060
23. Bardier C Yang JS Li J Mackey TK Characterizing alternative and emerging tobacco product transition of use behavior on Twitter BMC Res Notes 2021 14 303 10.1186/s13104-021-05719-0 34372926
24. Haupt MR Jinich-Diamant A Li J Nali M Mackey TK Characterizing twitter user topics and communication network dynamics of the “Liberate” movement during COVID-19 using unsupervised machine learning and social network analysis Online Soc Netw Media 2021 21 100114 10.1016/j.osnem.2020.100114
25. Xu Q Nali MC McMann T Godinez H Li J He Y Unsupervised machine learning to detect and characterize barriers to pre-exposure prophylaxis therapy: a multiplatform social media study JMIR Infodemiol. 2022 2 1 e35446 10.2196/35446
26. Pinto RM Berringer KR Melendez R Mmeje O Improving PrEP implementation through multilevel interventions: a synthesis of the literature AIDS Behav 2018 22 3681 3691 10.1007/s10461-018-2184-4 29872999
27. Corey L Corbett-Detig R Beyrer C Expanding efforts and support to respond to the HIV and COVID-19 intersecting pandemics JAMA 2022 327 1227 10.1001/jama.2022.3517 35275202
28. Koester K Amico RK Gilmore H Liu A McMahan V Mayer K Risk, safety and sex among male PrEP users: time for a new understanding Cult Health Sex 2017 19 1 13 10.1080/13691058.2017.1310927 27297661
29. Kim EJ Marrast L Conigliaro J COVID-19: magnifying the effect of health disparities J Gen Intern Med 2020 35 2441 2442 10.1007/s11606-020-05881-4 32394141
| 36471205 | PMC9734820 | NO-CC CODE | 2022-12-14 23:28:30 | no | AIDS Behav. 2022 Dec 5;:1-11 | utf-8 | AIDS Behav | 2,022 | 10.1007/s10461-022-03922-z | oa_other |
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Clin Drug Investig
Clin Drug Investig
Clinical Drug Investigation
1173-2563
1179-1918
Springer International Publishing Cham
36462104
1231
10.1007/s40261-022-01231-w
Review Article
Therapeutic Polypeptides and Peptidomimetics: Powerful Tools for COVID-19 Treatment
Liu Xinyu 1
Shi Jian 1
Wang Deyang 1
Su Ying 2
Xing Zhen 2
Sun Fei 3
http://orcid.org/0000-0002-2578-7159
Chen Fei [email protected]
1
1 grid.449428.7 0000 0004 1797 7280 Department of Physiology, Jining Medical University, 133 Hehua Rd, Jining, 272067 China
2 grid.513202.7 Dongping County People’s Hospital, Tai-an, China
3 Qilu Medical University, Zibo, China
3 12 2022
110
17 11 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has swept the whole world and brought about a public health crisis of unprecedented proportions. To combat the rapid transmission and possible deaths due to the disease, researchers and companies around the world are developing all possible strategies. Due to the advantages of safety, specificity, and fewer adverse effects, polypeptide and peptidomimetic drugs are considered promising strategies. This review comprehensively summarizes and discusses the progress in development of peptide drugs for use in the treatment of COVID-19. Based on the latest results in this field, we divided them into clinically approved drugs, clinical trial drugs, and clinically ineffective drugs, and outlined the molecular targets and mechanisms of action one by one to reveal their feasibility as promising therapeutic agents for COVID-19. Notably, monoclonal antibodies have shown beneficial effects in the early stages of infection, while Paxlovid can significantly reduce hospitalization and mortality among non-vaccinated patients. Among clinical experimental drugs, both the interleukin-1 receptor antagonist anakinra and the bradykinin B2 receptor antagonist icatibant are well tolerated and effective in patients with COVID-19, but long-term trials are needed to confirm the durability of efficacy.
http://dx.doi.org/10.13039/501100007129 Natural Science Foundation of Shandong Province ZR2020QC100 Chen Fei
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pmcKey Points
Polypeptide and peptidomimetic drugs are key tools to reduce hospitalization and mortality in COVID-19 patients.
Therapeutic polypeptides and peptidomimetics can act through multiple targets, such as viral proteins, ACE2 receptors, and virus-induced pro-inflammatory cytokines.
Introduction
The coronavirus disease 2019 (COVID-19) pandemic has emerged as a threat to global health, social stability, and the global economy. After identification and isolation of the virus, previous studies confirmed that it belongs to the genus β-coronavirus and is approximately 79% similar to the severe acute respiratory syndrome coronavirus (SARS-CoV) at the nucleotide level [1]. Based on this, the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses named the RNA virus as SARS-CoV-2 [2]. Although vaccines are considered to be the most powerful weapon to fight against viral invasion at present, they are usually used as a preventive measure for uninfected individuals rather than as a treatment. Therefore, there is an urgent requirement to develop effective antiviral therapeutics that can not only treat COVID-19 patients rapidly and effectively but also prevent the further spread of the virus [3]. Notably, the slow efficacy of conventional drugs has failed to address the need for timely treatment. As a result, conventional drugs are not considered an effective option in the case of an outbreak. Compared with traditional small molecule drugs, peptide drugs are smaller fragments of proteins that are more suitable for synthesis in terms of time efficiency and cost. In addition, peptide drugs present several advantages as therapeutic approaches, including increased specificity and affinity for the target and low toxicity [4]. Hence, polypeptide and peptidomimetic drugs may be appropriate as a treatment for COVID-19.
Recent studies on the molecular biology of SARS-CoV-2 have also revealed the possibility of using peptide drugs. Infection is initiated when the receptor binding domain (RBD) of SARS-CoV-2 binds to the human angiotensin-converting enzyme 2 (ACE2) receptor [5]. After the virus enters the host cell, its RNA is released. Subsequently, host ribosomes are hijacked to produce the two viral replicase polyproteins, which can further be processed into 16 mature non-structural proteins (NSPs) through two virus-encoding proteases: main protease (Mpro) and papain-like protease. These NSPs are able to assemble into the replication and transcription complex to initiate viral RNA replication and transcription [6]. Moreover, the progression of COVID-19 is associated with a severe increase in inflammatory factors [7]. All these mean that peptide drugs may play a role through multiple mechanisms, including inhibiting the protein–protein interactions between SARS-CoV-2 spike glycoprotein and cellular receptors, inhibiting the proteases associated with viral replication and transcription and preventing the release of inflammatory cytokines.
Methods of Literature Search
Literature sources included the PubMed and Google Scholar databases (date of last search: August 14, 2022). The keywords included in the search were ‘COVID-19’ and ‘drugs’, ‘monoclonal antibodies’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘bamlanivimab etesevimab’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘casirivimab imdevimab’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘regdanvimab’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘sotrovimab’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘Paxlovid’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘tocilizumab’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘aviptadil’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘dalbavancin’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘anakinra’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘icatibant’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘solnatide’ and ‘COVID-19’ or ‘SARS-CoV-2’, ‘lopinavir ritonavir’ and ‘COVID-19’ or ‘SARS-CoV-2’.
Currently Approved Drugs
The use of monoclonal antibodies (mAbs) dates back more than three decades. The first approved mAb, muronomab, was used primarily for graft rejection in renal transplant patients [8]. Over the years, the use of mAbs has expanded from the treatment of autoimmune diseases and cancer therapeutics to communicable diseases [9]. A large number of mAbs for COVID-19 treatment have been developed at breakneck speed over the past 2 years. Currently, the following four SARS-CoV-2 RBD-specific mAbs are in clinical use: casirivimab (REGN10933) plus imdevimab (REGN10987) authorized by the US Food and Drug Administration (FDA) on November 21, 2020, sotrovimab (VIR-7831) authorized by the FDA on May 26, 2021, bamlanivimab (LY-CoV555) plus etesevimab (LY-CoV016) authorized by the FDA on February 9, 2021, and regdanvimab (CT-P59) approved in Korea on September 17, 2021 [10–13] (Table 1). These neutralizing mAbs can block the binding of ACE2 to the spike glycoprotein, thereby preventing the virus from infecting human cells (Fig. 1, created with biorender.com). Clinically, sotrovimab, bamlanivimab plus etesevimab, and casirivimab plus imdevimab have been demonstrated to be beneficial among outpatients with COVID-19 [14–16]. However, clinical studies of sotrovimab and casirivimab plus imdevimab have reported ineffective outcomes in the overall population of patients hospitalized with COVID-19 [17, 18]. In addition to trials of patients hospitalized with COVID-19 probably having a greater proportion of patients with endogenous anti-SARS-CoV-2 antibodies than outpatient trials, increased use of concomitant COVID-19 therapies for inpatients is considered to be an alternative or supplementary explanation for this phenomenon [17]. The additional antiviral activity from neutralizing mAb therapies might not provide incremental benefit above background therapy with other drugs. Thus, these therapies seem to be more suitable for use in the early infective phase of SARS-CoV-2 infection.Table 1 Peptide drugs for the treatment of COVID-19 infections
Name Discovery approach Type Latest status Manufacturer Route of administration Adverse events Treatment stage Antiviral mechanisms References
Bamlanivimab + etesevimab Developed for SARS-CoV-2 mAb EUA (2/9/2021) Eli Lilly Intravenous infusion Anaphylaxis and infusion-related reactionsa Mild-to-moderate illness They target the RBD and block the binding of spike protein to ACE2 [10]
Casirivimab + imdevimab Developed for SARS-CoV-2 mAb EUA (11/21/2020) Regeneron Pharmaceuticals Intravenous infusion or subcutaneous injection Anaphylaxis and infusion-related reactionsa Mild-to-moderate illness They target the RBD and block the binding of spike protein to ACE2 [11]
Regdanvimab Developed for SARS-CoV-2 mAb Approved (9/17/2021) Celltrion Intravenous infusion Elevated liver enzyme levels and hypertriglyceridemia Elderly with mild illness and adults with moderate illness It targets the RBD and blocks the binding of spike protein to ACE2 [12]
Sotrovimab Developed for SARS-CoV-2 mAb EUA
(5/26/2021)
GSK and Vir Biotechnology Intravenous infusion Rash and diarrhea Mild-to-moderate illness It targets the RBD and blocks the binding of spike protein to ACE2 [13]
Paxlovid Developed for SARS-CoV-2 Peptidomimetic EUA (12/22/2021) Pfizer Oral Impaired sense of taste, diarrhea, high blood pressure and muscle aches Mild-to-moderate illness It can inhibit viral replication by binding to the active site of Mpro [24]
Tocilizumab Repurposed IL-6 inhibitor mAb Approved (3/3/2020) Roche Intravenous infusion Allergic reactions Severe illness It binds to IL-6 receptors, thereby inhibiting the cytokine release syndrome [21]
Aviptadil Repurposed VIP Polypeptide Granted Orphan Drug Designationb (7/14/2020) NeuroRx and Relief Therapeutics Intravenous infusion Tachycardia, flushing, hypotension, diarrhea and alterations in electrocardiogram (bigeminy) Severe illness It protects alveolar type II cells by binding to the VPAC1 and prevents the apoptosis indicated by coronavirus [30]
Dalbavancin Repurposed glycopeptide antibiotic Glycopeptide antibiotic In animal models Durata Therapeutics N/A N/A N/A It binds to human ACE2 and blocks the interaction with SARS-CoV-2 spike proteins [55]
Anakinra Repurposed IL-1 inhibitor IL-1 receptor antagonist Phase III Swedish Orphan Biovitrum AB (publ) Subcutaneous injection In experiment In experiment It reduces the inflammatory response and tissue damage caused by IL-1 [37]
Icatibant Repurposed bradykinin B2 receptor inhibitor Polypeptide Phase II Shire Subcutaneous injection In experiment In experiment It inhibits bradykinin and SARS-CoV-2 Mpro [44]
Solnatide Developed for the ARDS subjects 17-mer cyclic peptide Phase II APEPTICO Inhalation In experiment In experiment It acts on the lower respiratory tract and activates the epithelial sodium ion channels [53]
Lopinavir + ritonavir Repurposed HIV-1 inhibitor Peptidomimetic Discontinued (6/29/2020) AbbVie Oral Diarrhea, nausea and vomiting N/A They inhibit the activity of Mpro by occupying its active site, causing a competitive inhibition [59]
ACE2 angiotensin-converting enzyme 2, ARDS acute respiratory distress syndrome, EUA emergency use authorization, GSK GlaxoSmithKline, IL interleukin, mAb monoclonal antibody, Mpro main protease, N/A not applicable, RBD receptor binding domain, VIP vasoactive intestinal polypeptide, VPAC1 vasoactive intestinal peptide receptor 1
aSigns and symptoms of infusion-related reactions may include fever, difficulty breathing, reduced oxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, weakness, altered mental status, nausea, headache, bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, vasovagal reactions (e.g., presyncope, syncope), dizziness and diaphoresis
bFDA declined EUA for aviptadil for critically ill COVID-19 patients at immediate risk of death from respiratory failure despite receiving approved therapy
Fig. 1 Key drug targets of SARS-CoV-2. a Neutralizing mAbs target the receptor binding domain to block the binding of ACE2 to the spike glycoprotein. b Inhibition of viral genome replication. c Inhibition of virus-induced pro-inflammatory cytokines. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, IL interleukin
Interleukin-6 (IL-6) is one of the key cytokines involved in infection-induced cytokine storm [19]. Tocilizumab, an IL-6 receptor antagonist, showed significant benefits in critically ill patients with COVID-19 [20]. It was officially added to the COVID-19 diagnosis and treatment program (7th edition) of the National Health Care Commission of China on March 3, 2020 [21] (Table 1). However, some trials did not show any mortality benefit [22, 23]. The conflicting results may be due to differences in timing, indication, dose of reinjection and the use of biomarkers. Thus, large-scale randomized controlled trials are still required to further confirm the clinical efficacy of tocilizumab in the treatment of patients with COVID-19.
Paxlovid attained emergency use authorization on December 22, 2021 (Table 1). The treatment includes nirmatrelvir and ritonavir [24]. The nitrile group of nirmatrelvir can covalently bind to the important Cys-145 residue of the Mpro through a Pinner-like reaction. Moreover, it is further stabilized by hydrophobic interactions and hydrogen bonding networks, which enhance its binding to the active site of SARS-CoV-2 Mpro [25, 26] (Fig. 1, created with biorender.com). Ritonavir is a potent inhibitor of microsomal cytochrome P450 3A4 enzyme that metabolizes several drugs. Therefore, the addition of ritonavir can reduce the degradation rate of nirmatrelvir [27] (Fig. 2, created with biorender.com). In non-vaccinated COVID-19 patients, treatment with Paxlovid resulted in a risk of progression to severe disease that was 89% lower than the risk with placebo [28]. Another study found that Paxlovid prescription within 5 days of diagnosis had a faster clearance of viral load and a shorter time to viral elimination in patients who are immunocompromised. Moreover, the correlation between timing of Paxlovid initiation and viral elimination is linear [29]. Thus, Paxlovid should be considered for introduction into primary care for high-risk patients who are immunocompromised, including those who are hospitalized, and unvaccinated in particular, in order to facilitate viral eradication.Fig. 2 Paxlovid’s mechanism of action against SARS-CoV-2. ACE2 angiotensin-converting enzyme 2, Mpro main protease, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
Aviptadil has been granted orphan drug designation by the FDA for the treatment of COVID-19 (Table 1). It is a synthetic form of human vasoactive intestinal polypeptide [30] and can bind to NSP16 at a specific site to inhibit the 2'-O-methyltransferase activity of the NSP10/NSP16 complex, which plays a role in evading the immune recognition process [31] (Fig. 1, created with biorender.com). Moreover, aviptadil could protect alveolar type II cells by binding to vasoactive intestinal peptide receptor 1 and preventing the action of caspase induced by the coronavirus [32]. In addition to this, aviptadil reduces the production of cytokines such as IL-6 to prevent acute respiratory distress syndrome (ARDS) in COVID-19 patients [30]. Furthermore, Li et al. (2007) found it can upregulate the expression of c-fos protein in alveolar type II cells, thereby increasing the synthesis of pulmonary surfactant phospholipids [33] (Fig. 3, created with biorender.com). In a prospective, multicenter, randomized, placebo-controlled trial of 196 patients admitted to intensive care at 10 US hospitals, it was observed that patients in the aviptadil group showed improvement which included the likelihood of recovering from failure, surviving to 60 days, and reducing hospital stay when compared with placebo [34]. In another case series, 21 confirmed SARS-CoV-2 patients treated with intravenous aviptadil showed significant radiological and clinical improvement. All of them had significantly lower inflammatory markers, such as ferritin, D-dimer, and IL-6 [35]. Notably, the FDA declined emergency use authorization for aviptadil for critically ill COVID-19 patients at immediate risk of death from respiratory failure [36]. Thus, more robust data on a larger target sample in different populations will be immensely helpful to confirm its safety and effectiveness in treating COVID-19 patients.Fig. 3 Mechanism of action of aviptadil for the treatment of COVID-19. ACE2 angiotensin-converting enzyme 2, COVID-19 coronavirus disease 2019, IL-6 interleukin-6, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, VPAC1 vasoactive intestinal peptide receptor 1
Drugs in Clinical Trials
Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra) composed of 153 amino acid residues (Table 1) [37]. Unlike native human IL-1Ra, anakinra has an additional methionine residue at the amino terminus. Of note, severe COVID-19 patients may develop pulmonary edema [38]. This is due to the activation of bradykinin B1 receptor and bradykinin B2 receptor (B2R) on lung endothelial cells [39]. IL-1 can upregulate the expression of bradykinin B1 receptor protein [40]. However, anakinra can inhibit the activity of IL-1α and IL-1β by binding to IL-1R [41], thereby reducing the inflammatory response and tissue damage caused by IL-1 (Fig. 1, created with biorender.com). A retrospective cohort study in Italy (ClinicalTrials.gov identifier: NCT04341584) showed that high-dose anakinra treatment resulted in a 77% reduction in mortality at 21 days compared with a control group of patients with COVID-19 who received usual care in the same hospital [42]. Furthermore, anakinra improved overall survival and was well tolerated in patients with ARDS associated with COVID-19 [43]. However, these studies have small sample sizes. The results need to be validated by a longer-term controlled trial to examine the long-term efficacy.
Icatibant is a selective bradykinin B2 receptor antagonist with an affinity for the B2R as bradykinin itself (Table 1) [44]. The binding of bradykinin to B2R leads to more vasodilation and increased vascular permeability, resulting in fluid accumulation in the interstitial tissue [45, 46]. Based on the inhibitory effects of icatibant on bradykinin and Mpro, it has the potential to treat patients with COVID-19 [47]. Mansour et al. (2020) found that icatibant promoted significant improvement of lung computed tomography scores and increased blood eosinophils, which has been reported as an indicator of disease recovery [48]. In line with this, a case-control study in patients with COVID-19 also concluded that icatibant was excellently tolerated and improved the oxygenation [49]. Given the short half-life of icatibant [50], there is uncertainty regarding the most appropriate dose of icatibant to administer. Therefore, further research is still needed for clinical application.
Solnatide is a synthetic cyclic peptide composed of 17 amino acids that mimics the lectin-like structure of tumor necrosis factor-α. It can activate the lung epithelial sodium channel to directly affect alveolar liquid clearance and to reduce the leakage of blood and fluids from the capillaries in the airspace, that is, accelerate the resolution of alveolar edema and reduce barrier injury in the lung [51, 52]. Recently, based on the conformational studies and in the analysis of charge distribution of the peptide surface, Martin-Malpartida et al. (2022) described how solnatide interacts with the cytoplasmic C-terminal domain of the epithelial sodium channel α-subunit via electrostatic complementarity [53]. Additionally, as solnatide lacks pro-inflammatory activity, its intratracheal instillation does not stimulate chemokine production or increase neutrophil infiltration in lungs [51]. In 2013, APEPTICO, a privately held biotechnology company, fruitfully concluded a phase I clinical study in healthy subjects, verifying the safety of solnatide [54]. Furthermore, a phase IIb, randomized, placebo-controlled, double-blind, dose-escalation study (EUDRACT No. 2017-003855-47) is underway to access the safety and preliminary efficacy of sequential multiple ascending doses of solnatide in patients with moderate-to-severe ARDS and pulmonary permeability edema [51].
The glycopeptide antibiotic dalbavancin binds to human ACE2 with high affinity and blocks the interaction with SARS-CoV-2 spike protein (Table 1). Wang et al. (2021) found dalbavancin could effectively prevent SARS-CoV-2 replication in Vero E6 cells with a half maximal effective concentration of ~12 nM. In addition, histopathological injuries caused by SARS-CoV-2 infection in mouse and rhesus macaque models are significantly inhibited by its administration [55]. In combination with its good safety and long plasma half-life (5–7 days), dalbavancin should be considered as a promising anti-COVID-19 drug candidate.
Clinically Ineffective Drugs
Lopinavir/ritonavir (LPV/r) is a peptidomimetic molecule (Table 1) that inhibits the activity of Mpro by occupying its active site, causing a competitive inhibition [56] (Fig. 1, created with biorender.com). However, most human immunodeficiency virus protease inhibitors show poor bioavailability. This is because they can also be extensively metabolized by the P450 3A4 enzyme [57]. In the trial by Cao et al. (2020), adding LPV/r treatment did not reduce viral RNA loads or duration of viral RNA detectability as compared with the standard care group. Notably, a significant proportion of patients were unable to complete treatment due to severe gastrointestinal adverse effects [58]. In addition, the results of the Randomised Evaluation of COVID-19 Therapy (RECOVERY trial) showed that among patients admitted to hospital with COVID-19, LPV/r was not associated with reductions in 28-day mortality, length of hospital stay, or risk of progression to invasive mechanical ventilation or death. Subgroup analyses found no evidence for a time-to-treatment effect or benefit in those with less severe disease [59]. The World Health Organization has halted the LPV/r treatment groups involved in its Solidarity trial [60].
Conclusion
As previously mentioned, polypeptide and peptidomimetic drugs can act through multiple targets, such as the RBD, the Mpro, the ACE2 receptor, and virus-induced pro-inflammatory cytokines. Due to their satisfactory therapeutic efficacy, they appear to be effective drugs against SARS-CoV-2 at different stages of viral infection. In mild to moderate disease stages, neutralizing mAbs and Paxlovid have been shown to be effective drugs. Tocilizumab and aviptadil showed efficacy in patients with severe illness. Among these drugs, neutralizing mAbs can block protein–protein interactions between cellular receptors and SARS-CoV-2 spike glycoprotein. Paxlovid and aviptadil can inhibit proteases associated with viral replication. Several peptide drugs are still in small-sample, short-duration clinical trials. Therefore, many questions remain unanswered, including identifying the most effective drugs for mild, moderate, and severe disease; the best time to start treatment; ideal dosage; adverse effects; duration of treatment; and the most beneficial combination therapy. In summary, peptide drugs have many advantages in the prevention, control and treatment of COVID-19, and deserve further in-depth study.
Declarations
Authors’ Contribution
The first draft of the manuscript was written by Xinyu Liu, Jian Shi and Deyang Wang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by the Natural Science Foundation of Shandong Province (Grant no. ZR2020QC100).
Conflict of Interest
All authors have no financial interests or potential conflicts of interests to declare.
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Availability of Data and Material
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Code Availability
Not applicable.
Xinyu Liu, Jian Shi, Deyang Wang have contributed equally to this work and share first authorship.
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References
1. Lu R Zhao X Li J Niu P Yang B Wu H Wang W Song H Huang B Zhu N Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding The lancet 2020 395 565 574 10.1016/S0140-6736(20)30251-8
2. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Nat Microbiol 2020 5 536 544 10.1038/s41564-020-0695-z 32123347
3. Huang X Pearce R Zhang Y De novo design of protein peptides to block association of the SARS-CoV-2 spike protein with human ACE2 Aging (Albany NY). 2020 12 11263 10.18632/aging.103416 32544884
4. VanPatten S He M Altiti A Cheng FK Ghanem MH Al-Abed Y Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics Future Med Chem 2020 12 1647 1656 10.4155/fmc-2020-0180 32672061
5. Wrapp D Wang N Corbett KS Goldsmith JA Hsieh C-L Abiona O Graham BS McLellan JS Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science 2020 367 1260 1263 10.1126/science.abb2507 32075877
6. Harrison AG Lin T Wang P Mechanisms of SARS-CoV-2 transmission and pathogenesis Trends Immunol 2020 41 1100 1115 10.1016/j.it.2020.10.004 33132005
7. Chen N Zhou M Dong X Qu J Gong F Han Y Qiu Y Wang J Liu Y Wei Y Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study The lancet 2020 395 507 513 10.1016/S0140-6736(20)30211-7
8. Ecker DM Jones SD Levine HL The therapeutic monoclonal antibody market 2015 MAbs, Taylor & Francis 9 14
9. Chatterjee S Choudhury S Das D An update of antispike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies Indian J Pharmacol 2022 54 51 10.4103/ijp.ijp_519_21 35343208
10. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19-0. Accessed 26 Sep 2022.
11. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19. Accessed 25 Sep 2022.
12. Ministry of Food and Drug Safety. Regdanivmab full Korean approval. 2021. https://www.mfds.go.kr/brd/m_99/view.do?seq=45778. Accessed 26 Sep 2022.
13. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Monoclonal Antibody for Treatment of COVID-19. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-monoclonal-antibody-treatment-covid-19. Accessed 24 Sep 2022.
14. Gupta A Gonzalez-Rojas Y Juarez E Casal MC Moya J Falci DR Sarkis E Solis J Zheng H Scott N Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial JAMA 2022 327 1236 1246 10.1001/jama.2022.2832 35285853
15. Dougan M Nirula A Azizad M Mocherla B Gottlieb RL Chen P Hebert C Perry R Boscia J Heller B Bamlanivimab plus etesevimab in mild or moderate Covid-19 N Engl J Med 2021 385 1382 1392 10.1056/NEJMoa2102685 34260849
16. Weinreich DM Sivapalasingam S Norton T Ali S Gao H Bhore R Musser BJ Soo Y Rofail D Im J REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19 N Engl J Med 2021 384 238 251 10.1056/NEJMoa2035002 33332778
17. Self WH Sandkovsky U Reilly CS Vock DM Gottlieb RL Mack M Golden K Dishner E Vekstein A Ko ER Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial Lancet Infect Dis 2022 22 622 635 10.1016/S1473-3099(21)00751-9 34953520
18. Abani O Abbas A Abbas F Abbas M Abbasi S Abbass H Abbott A Abdallah N Abdelaziz A Abdelfattah M Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial The Lancet 2022 399 665 676 10.1016/S0140-6736(22)00163-5
19. Zhang C Wu Z Li J-W Zhao H Wang G-Q Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality Int J Antimicrob Agents 2020 55 105954 10.1016/j.ijantimicag.2020.105954 32234467
20. Investigators R-C Interleukin-6 receptor antagonists in critically ill patients with Covid-19 N Engl J Med 2021 384 1491 1502 10.1056/NEJMoa2100433 33631065
21. Wei P-F Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7) Chin Med J 2020 133 1087 1095 10.1097/CM9.0000000000000819 32358325
22. Salvarani C Dolci G Massari M Merlo DF Cavuto S Savoldi L Bruzzi P Boni F Braglia L Turrà C Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial JAMA Intern Med 2021 181 24 31 10.1001/jamainternmed.2020.6615 33080005
23. Rosas IO Bräu N Waters M Go RC Hunter BD Bhagani S Skiest D Aziz MS Cooper N Douglas IS Tocilizumab in hospitalized patients with severe Covid-19 pneumonia N Engl J Med 2021 384 1503 1516 10.1056/NEJMoa2028700 33631066
24. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Accessed 26 Sep 2022.
25. Menéndez JC Approaches to the potential therapy of COVID-19: a general overview from the medicinal chemistry perspective Molecules 2022 27 658 10.3390/molecules27030658 35163923
26. Zhao Y Fang C Zhang Q Zhang R Zhao X Duan Y Wang H Zhu Y Feng L Zhao J Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332 Protein Cell 2022 13 689 693 10.1007/s13238-021-00883-2 34687004
27. Extance A Covid-19: what is the evidence for the antiviral Paxlovid? BMJ 2022 377 o1037 10.1136/bmj.o1037 35477536
28. Hammond J Leister-Tebbe H Gardner A Abreu P Bao W Wisemandle W Baniecki M Hendrick VM Damle B Simón-Campos A Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19 N Engl J Med 2022 386 1397 1408 10.1056/NEJMoa2118542 35172054
29. Sun F Lin Y Wang X Gao Y Ye S Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection Lancet Infect Dis 2022 22 1279 10.1016/S1473-3099(22)00430-3 35843259
30. Raveendran A Al Dhuhli KS Kumar GH Role of Aviptadil in COVID-19 BMH Med J 2021 8 77 83
31. Alnomasy SF, Alotaibi BS, Aldosari ZM, Mujamammi AH, Anand P, Akhter YA, and Hasan MR. Inhibitory effects of aviptadil on the SARS-CoV-2 nsp10/nsp16 protein complex. Research Square [Preprint]. 2021. 10.21203/rs.3.rs-191980/v1.
32. Mukherjee T Behl T Sharma S Sehgal A Singh S Sharma N Mathew B Kaur J Kaur R Das M Anticipated pharmacological role of Aviptadil on COVID-19 Environ Sci Pollut Res 2021 29 1 17
33. Li L She H Yue S-J Qin X-Q Guan C-X Liu H-J Luo Z-Q Role of c-fos gene in vasoactive intestinal peptide promoted synthesis of pulmonary surfactant phospholipids Regul Pept 2007 140 117 124 10.1016/j.regpep.2006.11.027 17218027
34. Jayaweera D Park DJ Recovery and survival in covid-19 respiratory failure , when treated with aviptadil Age (years, mean). 2022 60 62 67
35. Youssef JG Al-Saadi M Zahiruddin F Beshay S Bitar M Javitt J Rapid recovery from COVID-19 respiratory failure with comorbidity in 21 patients treated with vasoactive intestinal peptide 2020 Social Science Electronic Publishing
36. NRx Pharmaceuticals, Inc. FDA Declines Emergency Use Authorization for ZYESAMI (aviptadil) for subgroup of Patients with Critical COVID-19 at immediate risk of death from respiratory failure despite treatment with approved therapy, including remdesivir. https://www.prnewswire.com/news-releases/fda-declines-emergency-use-authorization-for-zyesami-aviptadil-for-subgroup-of-patients-with-critical-covid-19-at-immediate-risk-of-death-from-respiratory-failure-despite-treatment-with-approved-therapy-including-remdesivir-301579610.html. Accessed 28 Sep 2022.
37. Kyriazopoulou E Poulakou G Milionis H Metallidis S Adamis G Tsiakos K Fragkou A Rapti A Damoulari C Fantoni M Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial Nat Med 2021 27 1752 1760 10.1038/s41591-021-01499-z 34480127
38. Bahloul M Ketata W Lahyeni D Mayoufi H Kotti A Smaoui F Kallel N Daoud E Bouaziz M Kammoun S Pulmonary capillary leak syndrome following COVID-19 virus infection J Med Virol 2021 93 94 10.1002/jmv.26152 32519786
39. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, and van der Hoeven H. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020; 9.
40. Schanstra JP Bataillé E Castano MM Barascud Y Hirtz C Pesquero JB Pecher C Gauthier F Girolami J-P Bascands J-L The B1-agonist [des-Arg10]-kallidin activates transcription factor NF-kappaB and induces homologous upregulation of the bradykinin B1-receptor in cultured human lung fibroblasts J Clin Investig 1998 101 2080 2091 10.1172/JCI1359 9593764
41. Dinarello CA, van der Meer JW, Treating inflammation by blocking interleukin-1 in humans. Seminars in immunology. 2013;25:469–84.
42. Tharaux P-L Pialoux G Pavot A Mariette X Hermine O Resche-Rigon M Porcher R Ravaud P Bureau S Dougados M Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial Lancet Respir Med 2021 9 295 304 10.1016/S2213-2600(20)30556-7 33493450
43. Franzetti M Forastieri A Borsa N Pandolfo A Molteni C Borghesi L Pontiggia S Evasi G Guiotto L Erba M IL-1 receptor antagonist anakinra in the treatment of COVID-19 acute respiratory distress syndrome: a retrospective, observational study J Immunol 2021 206 1569 1575 10.4049/jimmunol.2001126 33547169
44. Malchair P Otero A Giol J Solanich X Carnaval T Fernández-Nistal A Sánchez-Gabriel A Montoto C Lleonart R Videla S A multicenter, open-label, randomized, proof-of-concept phase II clinical trial to assess the efficacy and safety of icatibant in patients infected with SARS-CoV-2 (COVID-19) and admitted to hospital units without invasive mechanical ventilation: study protocol (ICAT-COVID) Trials 2022 23 1 15 10.1186/s13063-022-06219-7 34980237
45. Tarighi P Eftekhari S Chizari M Sabernavaei M Jafari D Mirzabeigi P A review of potential suggested drugs for coronavirus disease (COVID-19) treatment Eur J Pharmacol 2021 895 173890 10.1016/j.ejphar.2021.173890 33482181
46. Cockcroft J Chowienczyk P Brett S Bender N Ritter J Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist Br J Clin Pharmacol 1994 38 317 321 10.1111/j.1365-2125.1994.tb04360.x 7833220
47. Liu X Wang X-J Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines J Genet Genom 2020 47 119 10.1016/j.jgg.2020.02.001
48. Mansour E Palma AC Ulaf RG Ribeiro LC Bernardes AF Nunes TA Agrela MV Bombassaro B Monfort-Pires M Camargo RL Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19—a proof-of-concept study MedRxiv. 2020 382 1787
49. van de Veerdonk FL Kouijzer IJ de Nooijer AH van der Hoeven HG Maas C Netea MG Brüggemann RJ Outcomes associated with use of a kinin B2 receptor antagonist among patients with COVID-19 JAMA Netw Open 2020 3 e2017708 e2017708 10.1001/jamanetworkopen.2020.17708 32789513
50. European Medicines Agency. EPAR Assessment Report 09-020-2018. https://www.ema.europa.eu/en/medicines/human/EPAR/firazyr. Accessed 9 Nov 2022.
51. Schmid B Kredel M Ullrich R Krenn K Lucas R Markstaller K Fischer B Kranke P Meybohm P Zwißler B Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS—a randomized, placebo-controlled, double-blind trial Trials 2021 22 1 21 10.1186/s13063-021-05588-9 33397449
52. Shabbir W Tzotzos S Bedak M Aufy M Willam A Kraihammer M Holzner A Czikora I Scherbaum-Hazemi P Fischer H Glycosylation-dependent activation of epithelial sodium channel by solnatide Biochem Pharmacol 2015 98 740 753 10.1016/j.bcp.2015.08.003 26254591
53. Martin-Malpartida P Arrastia-Casado S Farrera-Sinfreu J Lucas R Fischer H Fischer B Eaton DC Tzotzos S Macias MJ Conformational ensemble of the TNF-derived peptide solnatide in solution Comput Struct Biotechnol J 2022 20 2082 2090 10.1016/j.csbj.2022.04.031 35601958
54. Apetico, GmbH, Austria. Solnatide has been approved by the Austrian federal office for safety in health care (BASG) for the treatment of COVID-19 patients with severe pulmonary dysfunction. http://www.apeptico.com/index-news. Accessed 7 Nov 2022.
55. Wang G Yang M-L Duan Z-L Liu F-L Jin L Long C-B Zhang M Tang X-P Xu L Li Y-C Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models Cell Res 2021 31 17 24 10.1038/s41422-020-00450-0 33262453
56. Nukoolkarn V Lee VS Malaisree M Aruksakulwong O Hannongbua S Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CLpro inhibitors J Theor Biol 2008 254 861 867 10.1016/j.jtbi.2008.07.030 18706430
57. Singh TU Parida S Lingaraju MC Kesavan M Kumar D Singh RK Drug repurposing approach to fight COVID-19 Pharmacol Rep 2020 72 1479 1508 10.1007/s43440-020-00155-6 32889701
58. Cao B Wang Y Wen D Liu W Wang J Fan G Ruan L Song B Cai Y Wei M A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19 N Engl J Med 2020 382 1787 1799 10.1056/NEJMoa2001282 32187464
59. Horby PW Mafham M Bell JL Linsell L Staplin N Emberson J Palfreeman A Raw J Elmahi E Prudon B Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial The Lancet 2020 396 1345 1352 10.1016/S0140-6736(20)32013-4
60. World Health Organization. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. https://www.who.int/news/item/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19. Accessed 29 Sep 2022.
| 36462104 | PMC9734822 | NO-CC CODE | 2022-12-14 23:28:30 | no | Clin Drug Investig. 2022 Dec 3;:1-10 | utf-8 | Clin Drug Investig | 2,022 | 10.1007/s40261-022-01231-w | oa_other |
==== Front
Qual Sociol
Qual Sociol
Qualitative Sociology
0162-0436
1573-7837
Springer US New York
9525
10.1007/s11133-022-09525-3
Article
An Interpretive Approach to Religious Ambiguities around Medical Innovations: The Spanish Catholic Church on Organ Donation and Transplantation (1954–2014)
http://orcid.org/0000-0002-1434-1493
Sáenz Rebeca Herrero [email protected]
Rebeca Herrero Sáenz
(she/her) is an Assistant Professor at the Department of Sociology and Anthropology at Molloy University. She conducts research on the intersection between health/medicine, culture, and social solidarity. Her most recent research examines the evolution of the media coverage of organ donation and transplantation in Spain and its implications for Spanish nationalism. Her work has appeared in Poetics, Current Sociology and Nursing Clio.
Molloy University, 312 Kellenberg Hall 1000 Hempstead Avenue, NY 11570 Rockville Centre, USA
6 12 2022
132
28 10 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
How do institutionalized religions solve moral ambiguities around controversial medical innovations and public health issues? Most religions have moral guidelines about what can and cannot be done to people’s bodies, but these guidelines are not always straightforward and, when faced with certain scientific advances, can come into contradiction with other doctrinal principles. I address this theoretical puzzle through the empirical case of the Spanish Catholic Church’s discourse on organ donation and transplantation during the second half of the twentieth century. Drawing on an interpretive analysis of official statements by the Spanish Catholic Church, and of the media coverage of the religious debate over organ donation and transplantation in Spain from 1954 onwards, I show that the first experiments in organ transplantation faced the Church with a contradiction between its altruistic teachings and its beliefs in the sacredness of human life. Faced with an interpretive dilemma, the Church produced a context-specific version of its official doctrine friendly to organ donation and transplantation. It did so by activating its altruistic elements and suppressing sacralized meanings of the body, thus aligning organ donation with Catholic values of generosity and fraternal love. My study theorizes this moral alignment as a semantic overlap realized through historically situated institutional discourse. Additionally, it incorporates 24 primary and secondary sources on comparative cases to propose three facilitating factors that enabled and encouraged the Spanish Catholic Church to embrace a controversial medical practice.
Keywords
Medical Innovation
Religion
Catholic Church
Spain
Organ Donation
Organ Transplantation
Frame Alignment
Elective Affinity
Graduate Student Association, University at Albany SUNY (US)The Graduate School, University at Albany SUNY (US)
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pmcIntroduction
This article examines how institutionalized religions solve moral ambiguities around controversial medical innovations and public health issues. Most literature on these topics considers religion an individual-level independent variable that directly impacts people’s attitudes, behaviors, and decisions, an approach to understanding religion that sociologists have criticized before (Ammerman 2014; Edgell 2012). Following these authors, I treat religions as complex and fragmentary belief systems that hold multiple—and sometimes contradictory—moral principles of evaluation (Baggett 2006; Dillon 1996a, 1996b). These contradictions, which present challenges for interpretation and evaluation, do not sort themselves out in the abstract but rather in concrete attempts to resolve specific problems (McDonnell et al. 2017).
Building on this perspective, I address the case of the Spanish Catholic Church’s support for organ donation and transplantation during the second half of the twentieth century. The Spanish Catholic Church has historically expressed little reservations about organ transplantation; it frequently encourages Catholics to donate organs, invoking Christian generosity and fraternal love (Monseñores Álvaréz and Cases 2009; Monseñor Asenjo 2014; Monseñor Martínez Sistach 2008).
However, the Catholic doctrine provides arguments to both support and reject organ donation and transplantation. Catholicism promotes altruistic behavior, encourages believers to give without expecting compensation, and praises generosity and self-sacrifice. Such principles overlap with the “gift of life” paradigm that dominates discourses on organ donation and that defines it as an intrinsically altruistic act (Healy 2004a; Vernale and Packard 1990). But certain elements in the Catholic doctrine are incompatible with organ procurement. Literal interpretations of the Resurrection dogma—part of the Catholic Eschatological doctrine—imply that dead bodies must be buried whole, so that they can resurrect in flesh. Additionally, Catholicism defends the sacredness of human life, which can raise questions about the medical definition of brain death (Brown 2007; Byrne 1999; Furton 2002).
How did the Spanish Catholic Church negotiate this contradiction? My analysis of official statements by the Spanish Catholic Church and of the media coverage of the religious debate over organ donation and transplantation shows that the first experiments in organ transplantation confronted the Spanish Catholic Church with an interpretive dilemma. As one of Spain’s highest moral authorities, the Spanish Catholic Church was expected to provide non-specialists with a moral framework to evaluate this new medical practice (Ecklund et al. 2017), but organ transplantation called forth a contradiction between Catholicism’s altruistic values and its beliefs in the sacredness of the human life and body. Furthermore, it did so at a moment when the Spanish Catholic Church’s legitimacy was declining. Changes in the Church’s position within the Francoist regime, and Spain’s rapid secularization during the late 1960s and 70s (Pérez-Agote 2012), put the Spanish Catholic Church in a delicate predicament. Supporting organ donation and transplantation allowed the Spanish Catholic Church to recast itself as a modern institution compatible with a democratic regime, but required extensive interpretive work to produce a historically and contextually specific version (Edgell 2012, 251) of the Catholic doctrine favorable to organ transplantation by activating some of its normative evaluations and suppressing others.
To uncover and situate the processes of meaning-making that underpin the Spanish Catholic Church’s support for organ donation and transplantation, I translate religious principles of evaluation into the vocabularies that they deploy. By doing so, I employ an interpretive, language-based approach to concepts like elective affinity (Howe 1978; Swedberg and Agevall 2016; Weber 2003) and frame alignment (Benford and Snow 2000; Snow et al. 1986), conceptualizing them as overlaps between vocabularies that make certain combinations of beliefs and practices compatible. To facilitate my analysis, I group similar elements of the Catholic doctrine—and the evaluative principles and the vocabularies that they invoke—in “packages” (Beckett 1996; Gamson and Lasch 1983; Gamson and Modigliani 1989; Garrison 1988) and assess how they relate to organ donation and transplantation. My findings show that, by invoking an altruistic interpretive package centered around principles of altruism and generosity, and deactivating a sacralized body interpretive package centered around the sacredness of the human life and body, the Spanish Catholic Church materialized an “elective affinity” (Swedberg and Agevall 2016; Weber 2003) and counteracted a potential “negative affinity” (Löwy 2006) between Catholicism and organ procurement, aligning organ donation with Catholic values of generosity and fraternal love.
To move beyond the Spanish case, I rely on 24 primary and secondary sources on comparative cases to propose three facilitating factors that enabled and encouraged the Spanish Catholic Church to show an early and continued support for organ donation and transplantation despite the moral and religious controversies that surrounded this medical practice. First, the very content of religions’ theological and moral principles places limits for reinterpretation. In other words, some religious principles are easier to reinterpret in a way that supports a certain medical innovation, while others resist such reinterpretations. Second, religious institutions and authorities vary in their degree of unity and homogeneity. While some religious groups can provide believers with clear moral guidelines, others face intradenominational disagreements between different approaches, and sometimes leave moral dilemmas to the individual. Finally, the larger sociopolitical context—specifically, the relationship between religion, State, and public—provides background conditions that shape how religious institutions approach controversial medical innovations.
Empirically tracing this process exposes cultural dynamics that, operating at the level of meaning (Kane 1991), define universes of possible institutional discursive action. Simultaneously, it shows how historical contexts shape institution’s discursive choices, making visible the cultural work that institutionalized religions do to position themselves on controversial topics while balancing cultural constrains, historical conditions, and their own interests.
My findings make contributions to several disciplinary literatures. For cultural sociologists, my article builds on an interpretive approach to the relationship between beliefs, discourses and practices that allows for diverse research strategies and approaches to the study of culture. For medical sociologists, it adds to the well-established body of literature on the cultural legitimation of medical innovations (Blume 2013; Joyce 2005), in this case via religious arguments. For public health scholars, it offers an alternative account of the relationship between religion and organ donation and transplantation that illuminates the challenges that institutionalized religions face to position themselves in the face of new, controversial scientific discoveries.
An Interpretive Perspective on Religion and Organ Transplantation: From Cultural Logics to Discursive Contexts
Public health scholars have shown keen interest in whether religious beliefs encourage or prevent people from becoming organ donors. Their studies have yielded contradictory results. While most find that survey respondents mention religious reasons to refuse to donate organs (Berzelak et al. 2019; Hasan et al. 2019; Irving et al. 2012; Siminoff et al. 2020; Tontus 2020; Umair et al. 2020), others find that respondents sometimes consider their religious feelings a reason to donate organs (Demırkiran et al. 2019; de Groot et al. 2012; Irving et al. 2012).
A cultural perspective on the relationship between religion and organ transplantation can solve two epistemological shortcomings that may explain these inconsistent results: First, most of these studies operationalize religion as an isolated, individual-level variable with a direct causal effect on people’s likelihood to become organ donors, a common practice in the study of religion’s role in people’s decision-making that other sociologists have criticized before (Ammerman 2014; Edgell 2012). Second, many of these studies work with an abstract, ahistorical notion of religion—or “religiousness”—that strips it from its local forms and sociohistorical contexts (Santayana 2015). Conceptualizing religions as sets of institutionalized and publicly available discourses (Ammerman 2005, 2014) may be empirically less straightforward, but it’s better suited to analyze the religious and moral ambiguities that surround organ donation and transplantation and other, potentially controversial, medical innovations and public health issues.
Of the variety of models that sociologists have produced to link beliefs and practices, I build on the interpretive tradition that conceptualizes complex, abstract principles of evaluation in terms of the vocabularies and symbolic resources that they deploy to assess overlaps between meanings. As early as in The Protestant Ethic and the Spirit of Capitalism, Weber uses the term “elective affinity” to explain how Protestantism favored the development of a capitalist work ethic (Weber 2003). He defined elective affinity as the mutual attraction of elements, but he used the concept informally (Swedberg and Agevall 2016). Inferring a definition of the term from Weber’s intellectual environment, Howe (1978) proposes a semantic interpretation. He defines elective affinity as a “property of concepts that have features in common with other concepts” (Howe 1978, 376), and suggests conceptualizing these commonalities in terms of affinities in language (Howe 1978, 179). Overlapping vocabularies define universes of possible action, making certain combinations of beliefs and practices compatible or incompatible, and generating both affinities and negative affinities (Löwy 2006).
More recently, the framing approach made a concerted effort to translate ideological positions into vocabularies, symbolic resources, and meanings. Following the work of Erving Goffman, this approach defines collective action frames as “schemata of interpretation” (Goffman cited in Benford and Snow 2000, 614) that make events meaningful. For example, media and public opinion scholars have relied on frames and framing as tools to understand how cultural discourses -or texts- influence people’s consciousness (Entman 1993; Garrison 1988). Analytically, this perspective identifies the “linguistic and symbolic resources that make sense of and give meaning to one or more aspects of social issues” (Beckett 1996, 60) and aggregates them in clusters or “packages” (Gamson and Lasch 1983; Gamson and Modigliani 1989; Garrison 1988). In addition, social movements scholars have applied a “framing perspective” to understand constituents’ mobilization by highlighting movement actors’ interpretive work and attending to its processual character (Benford and Snow 2000). These scholars use the term “frame alignment” to refer to the efforts by movement actors to link “individual and social movement interpretive orientations, such that some set of individual interests, values, and beliefs and SMO [social movement organization] activities, goals, and ideology are congruent and complementary” (Snow et al. 1986, 464).
The combination of Howe’s reinterpretation of Weber’s elective affinities, and the notion of alignment proposed by the framing perspective, is especially useful for the case at hand, given the overlapping moral and sociopolitical goals that I argue the Spanish Catholic Church was pursuing in its attempt to legitimize and support organ transfer. On one hand, elective affinity, when approached from an interpretive perspective, captures the extent to which there is an overlap in language, vocabulary, and meaning between two distinct spheres of social life. On the other hand, frame alignment captures the interpretive work performed by individual or collective actors to create that overlap in language, vocabulary, and meaning.
The interpretive processes that I analyze here were oriented, primarily, to generating a compatibility—this is, an affinity—between two different areas of social life, the Catholic doctrine and the dominant paradigms of organ donation, procurement, and transplantation, something I argue was achieved by creating an overlap in vocabularies. In addition, as transplantation became an accepted therapeutic option and the transplant organ shortage became a pressing social problem, creating this overlap also involved mobilizing the Church’s constituents to donate their organs. This, in turn, provided the Spanish Catholic Church with considerable secondary gains, for it gave it the opportunity to recast itself as a modern, democratic actor invested in Spain’s scientific and social development.
Beyond the particularities of the empirical case at hand, dissecting abstract principles of evaluation into the vocabularies they deploy has several advantages. First, it makes cultural dynamics empirically traceable. Incommensurability is a salient issue in the sociology of culture (Ghaziani 2017), which highlights the importance of anchoring cultural dynamics in observable units of analysis.
Second, cultural dynamics, while operating with a degree of autonomy, depend on institutional discursive action that is embedded in sociohistorical contexts (Kane 1991). Tracing cultural dynamics on concrete texts makes it possible to situate said dynamics in their sociocultural environments and link them to broader historical processes that are “largely beyond actors’ direct control” (Diani 1996, 1055) and that affect the potential success of a particular framing. Institutional discourses are embedded in discursive fields, which contain the symbolic resources for discourse elaboration and reflect a pattern of relations between the actors that participate in them (Snow 2008). In this case, the Spanish Catholic Church’s discourse on organ transfer plays against the backdrop of the changing relationship between the Church itself, the Spanish state, and the Spanish public during the second half of the twentieth century. Changes in the cultural preeminence of the Spanish Catholic Church, then, provide the discursive context in which its public discourse on organ donation and transplantation unfolds.
In summary, this approach to the relationship between religion and organ procurement accounts, on one hand, for the internal logics of religions as symbolic systems that affect public life (Alexander 1990; Ammerman 2005, 2014; Geertz 1973). On the other hand, it situates those logics within social, political, and historical contexts (Alexander and Smith 2006; Kane 1991), explaining the role of religious institutions as intentional actors that “constrain the emergence and impact of certain cultural meanings and, at the same time, allow others to become enormously significant” (Baggett 2006, 297).
Data and Methods
I analyzed 80 primary sources (see Appendix 1). They include official statements about organ donation and transplantation by Spanish Catholic authorities, newspaper articles covering the religious debate on organ procurement on three leading national newspapers (ABC, La Vanguardia, and Ya), from 1954 until 2014, and Dominican priest José Todoli’s book Ética de los Trasplantes (“The Ethics of Transplantation”), which received some media attention at the time of its publication. I included the press coverage of the debate in my analysis because it reflects the role of Spanish Catholic authorities -theologians, moralists, bishops, etc.- in the public debate around organ procurement. Additionally, Catholic authorities’ appearances in the press were central to the Church’s communicative strategy to influence public opinion, given that, for lay people, the press and other media was their main point of access to theological debates about organ transfer.
The newspapers I selected do not represent a comprehensive picture of Spain’s media ecology. However, the three of them were leading opinion centers around the time the public discussion about organ transplantation was at its peak. Besides, the newspapers’ conservative editorial views make them more likely to report on the Catholic Church’s opinions. During the Francoist dictatorship, these publications were friendly to the regime without being part of the state-sponsored media. After Franco’s death, La Vanguardia moved towards a pro-catalan perspective, but retained its conservative character. Ya belonged to Editorial Católica, a publishing company property of the Spanish Catholic Church. Although in 1988 the Spanish Episcopal Conference sold Ya to another publishing group, the newspaper remained primarily a Catholic outlet. Articles from both ABC and La Vanguardia were available through their online archives. Articles from Ya were available at the Spanish National Library in Madrid, and only from 1970 until 1996 (when the newspaper closed down).
I analyzed my data through multiple rounds of close reading. In the first stage, I inductively classified the arguments that Catholic authorities invoked in the public discussion about religion and organ transplantation that took place in Spain since the 1950s, and organized them in two “packages” (Altomonte 2020; Beckett 1996; Gamson and Lasch 1983; Gamson and Modigliani 1989), summarized in Table 1. Each package is anchored in a specific set of doctrinal sources, invokes a specific set of associated principles of evaluation, deploys a specific vocabulary, and implies a moral position towards organ transfer. The first package, which I call sacralized body, clusters around questions about the nature of life and death and about the divine ownership over the human body. The second package, which I call altruistic, clusters around Catholic social ethics and notions of generosity, self-sacrifice and fraternal love. Although other moral and doctrinal arguments appear in the discussion, their presence is not as salient compared to the ones highlighted here. Table 1 Sacralized body and altruistic interpretive packages. Doctrinal sources, associated principles of moral evaluation, vocabulary examples, and moral positions towards organ transplantation
Package Doctrinal anchorsa Associated Principles of Evaluation Vocabulary examples Moral position
Sacralized body St. Thomas Aquinas’ Dogma (Summa Contra Gentiles, 3) God’s exclusive sovereignty over the human life and body Contemplates bodily resurrection Law, lawful, lawfulness, norms, right, property, respect, mutilation, mutilate, owner, ownership, expropriate, extirpate, inviolable, inviolability, kill, dignity, sovereignty, (body-soul) unity, homicide, suicide, doctrine, preserve, preservation, sacred, sacrilege, integrity, tradition Organ transplantation is a violation of the integrity, dignity, and sacredness of the human body and therefore should be opposed or at least strictly limited
Sixth Commandment
(Exodus 20:13; Matthew 5:21; Matthew 19:19; Mark 10:19; Luke 18:20)
“Thou shalt not kill” Prohibition of homicide and mutilation (including voluntary). Mandate to preserve all life
Resurrection Dogma (Eschatological doctrine) (1 Corinthians 15:54–55; Matthew 4:17; Acts 23:6, 24:15, 24:21) Bodily resurrection
Altruistic Virtue of Charity (John 4:8; Peter 4:8; Summa Theologica, 2–2.23–46, Catechism of the Catholic Church, 2nd edition (1997), n. 1822) “Love God above all things for His own sake, and our neighbor as ourselves for the love of God” Give, give back, need, love, fellow, comfort, hope, help, charity, suffering, offer, exemplar, heal, restore, selfless, social value, society, generous, generosity, consciousness, human, humanitarian, Humankind, Mankind, serve, service, Christian duty, virtue, solidarity, common good, fraternity, Christian call, sacrifice Organ transplantation is a life-saving medical procedure that aids fellow ailing humans, and organ donation is an expression of Christian charity and fraternal love
Great Commandment (Matthew 22:35–40, Mark 12:28–34, Luke 10:27) “You shall love thy neighbor as you love thyself”
Great Commandment, (John 15:13) “Greater love has no one than this: to lay down one's life for one's friends”
aAll Bible references taken from the King James Version (KJV).
Each package overlaps and clashes, respectively, with the two dominant cultural paradigms of organ donation (Moloney and Walker 2000, 2002). The altruistic package overlaps with the “gift of life” paradigm that, as has been thoroughly researched, dominates the public discourse about organ donation in Western and Westernized societies and highlights its altruistic nature (Galasiński and Sque 2016; Gerrand 1994; Healy 2004b, 2004a, 2006; Joralemon 1995; Lock 1999, 2002; Siminoff and Chillag 1999). The sacralized body package clashes with representations of the body as a machine made of interchangeable parts, of the cadaver as “waste”, and of organ extraction as “harvesting” that other scholars have identified as part of the organ procurement imaginary (Hogle 1999; Lock 2002; Sharp 2006). The intersection between the gift of life paradigm and the altruistic package creates points of affinity (Howe 1978) between Catholic beliefs and organ procurement. Meanwhile, the clash between the sacralized body package and medical resignifications of the body generates a moral incompatibility -a “negative affinity” (Löwy 2006)- between Catholicism and organ transplantation. Aligning organ procurement and Catholicism required Catholic leaders to do extensive cultural work to neutralize the sacralized body package and to activate the altruistic one (Fig. 1). Fig. 1 Elective and negative affinities between cultural paradigms of organ donation and transplantation and altruistic and sacralized body interpretive packages
In the next analytical stage, and after observing a chronological evolution in the salience of each package, I analyzed the data interpretively, producing a “thick description” (Geertz 1973) of the transformations in the Spanish Catholic’s Church discourse on organ procurement. This approach, which combines the analytical leverage of classification and the attention to texture and detail of interpretive analysis, is the most appropriate one for the type and amount of data in this study. It allows me to hermeneutically reconstruct the religious debate on organ donation and transplantation in Spain since the 1950s and to situate it in its sociohistorical context (Alexander and Smith 2006).
Finally, and for comparative purposes, I examined 24 primary and secondary sources exploring how other religious denominations have reacted to and interpreted organ donation and transplantation to provide comparative cases and build a more general argument about religious interpretations of medical innovations.
Findings
Interest in the religious debate on organ donation and transplantation spikes at moments of rapid change, like the first heart transplant in 1967 and the subsequent experiments in solid organ transplantation, the approval of the Spanish transplantation law in 1979, and the discovery of cyclosporine in the early 80 s and the consequent shortage of transplant organs. In “unsettled times” (Swidler 1986), the Spanish Catholic Church worked to elucidate the moral character of organ transplantation, and to establish normative guidelines for action for its followers.
The religious conversation around organ procurement declined since the late eighties and early nineties. By the year 2000, the question was settled. Although the Spanish Catholic Church has continued to show public support for organ donation (see, for example, Monseñores Álvaréz and Cases 2009; Monseñor Asenjo 2014; Monseñor Martínez Sistach 2008), by then organ procurement was already a routine medical and social practice and the Church had clarified its position. Additionally, the creation of the Organización Nacional de Trasplantes (“National Organization for Transplants”)—the state-run institution that manages organ procurement in Spain—in 1989 imposed a higher degree of institutional control over the promotion of organ donation and transplantation. Finally, in the next few years organ donation rates in Spain soared, and Spain became the global leader in organ donation in 1992, making the shortage of transplant organs less urgent than it had been a few years before.
In the next few pages, I present my analysis of the interpretive work that the Spanish Catholic Church did to align organ donation with the Catholic doctrine. I show that moral negotiations of sacralized notions of the body dominate the debate in the 1950s and 1960s. As organ transplantation becomes a routine medical practice and transplant organ shortages emerge as a social problem, the debate evolves towards an open dominance of the altruistic package, and an open rejection of the sacralized body package as “unscientific barriers”, “allegedly religious prejudices” or “pseudo religious atavisms”. Since the 1970s, the focus shifted to the promotion of organ donation as a charitable act (Table 2). Table 2 Summary of changes in the religious debate around organ transplantation in the Spanish national press
Years Transplantation-related events State of the religious debate
1956 Controversy around Father Carlo Gnocchi’s cornea donation in Italy Sets terms of debate and pushes the Vatican towards acceptance of cadaveric organ donation
1960–1967 First kidney transplants performed in Spain Less attention paid to organ transplantation
1967–1971 First heart transplant
Global transplantation race
Transplants are still experimental and not always successful, mostly due to immunological rejection
Discussion about the morality of organ transplantation in the light of Catholic theological principles: What is acceptable to do to a dead or dying body? Does brain death equal real death? Where does the soul reside? Who owns the human body?
Increase in press articles, many reporting on conferences and symposia discussing the morality of organ transplantation
The Spanish Catholic Church takes a pro-transplant stance and leaves the question of determining death to physicians
1971–1978 Immunological rejection still unresolved
Temporary suspension of organ transplants
Less attention paid to organ transplantation
1978—2000 Cyclosporine solves immunological rejection
Organ shortage emerges as a social problem
Construction of the Spanish organ procurement system
The Spanish Catholic Church begins actively promoting organ donation as an act of Christian charity and fraternal love
Concerns about the sacrality of the body are dismissed as “superstitions” and “pseudorreligious atavisms.”
2000 and beyond Transplantation is a routine medical procedure
New biomedical innovations attract media attention (cloning, xenotransplantation, stem cell research)
Religious debate around organ transplantation is settled
Theological controversies about other biomedical innovation arise
Desacralizing the Body in Times of Medical Discovery
During the 1950s and 1960s, the religious debate about organ donation and transplantation centers around desacralizing the body. In these two decades, the Spanish Catholic Church worked on deactivating the sacralized body package, questioning or at least limiting its validity. This includes questioning the religious rights of cadavers, limiting the applicability of the Sixth Commandment, and accepting a separation between body and spirit—and between science and Church—that makes medical definitions of brain death acceptable. Although the altruistic package is present, the charitable nature of organ donation is not the core of the conversation.
This dilemma appears in my data for the first time in 1956, when Father Gnocchi—an Italian Catholic priest famous for his charity work—donated his corneas after his death (Cortés-Cavanillas 1956a; Efe 1956a; Moriones 1956). The Italian law prohibited cadaveric organ donation at the time. Father Gnocchi's illegal act pressured the Vatican to clarify the Catholic Church’s position. An ABC article published March 9th, 1956, explains that the Pope would have to choose between a strict interpretation of St. Thomas of Aquinas’ writings, which mandates that only God can dispose of the person’s body, and a moderate position claiming that St. Thomas’ dogma only applies to living individuals, not to cadavers (Cortés-Cavanillas 1956b). The article itself suggests that the Vatican should opt for the more moderate position, describing cornea donation and transplantation as “a highly valuable social work, benevolent under God’s and society’s eyes, because it constitutes one of the most sublime examples of Christian Charity”. Implied is the idea that sacralized notions of the body hinder a “sublime” form of generosity, and that the possibility of exercising charity through organ donation renders them outdated.
Although its altruistic character appears as an argument for organ donation, the Vatican’s dilemma is framed as a choice between a strict and a moderate approach to St. Thomas’ dogma and to the sacred character of the body. On May 15th, 1956, both ABC and La Vanguardia (Efe 1956b, 1956c) published Pope Pious XII’s statement, where he questions the religious rights of the cadaver and proclaims that, for Catholicism, “there is no religious obstacle that impedes transplanting a cadaver’s cornea into the eye of a patient” because “a cadaver is not, strictly, a subject of rights […] Organs do not constitute goods for the cadaver, because the cadaver does not need them”. This utilitarian argument dismisses St. Thomas’ dogma, and questions literal interpretation of the Catholic Eschatological doctrine, specifically of bodily resurrection.
In Spain, theologians and members of the Catholic Church took interest in the debate, but because Spain lacked the technical and human resources to perform transplants, it soon died down. The question came back to the public interest almost ten years later, as cornea and kidney transplants became a reality in Spain and elsewhere. On April 13th, 1966, for example, ABC published a review of Jesuit doctor and priest Thomas J. O’Donnell’s book, Medical Ethics (P. C. 1966). The review praises how O’Donnell applies a modern reading of the Code of Canon Law to current practices such as organ donation. It explains that voluntary mutilation, prohibited by the Sixth Commandment (“thou shall not kill”), does not include voluntary organ donation. This exception limits the applicability of one of the most important components of the Catholic doctrine, smoothing the path for future discussions about brain death.
Dr. Christian Barnard’s first heart transplant in 1967 generated a new spike of interest in organ transplantation. On December 7th, 1967, ABC echoed an article published in L’Osservatore Romano -the Vatican City State’ daily newspaper- reflecting on the relationship between the body and the spirit: “To which extent -the author ponders- is the fusion of soul and body indispensable? It would be better to say that the human being is spiritual, and that bodily organs are physically part of us, but they are not us” (Efe 1967). Embracing the cartesian divide between body and spirit signals a transit between sacralized and medicalized notions of the body that will become important to establish a definition of brain death as death.
The distinction between body and spirit, and between religion and science is even clearer Father Antonio Arza’s—Chair of Canon Law at the University of Deusto, in Navarre (Spain)- statement published in La Vanguardia on December 8th, 1967 (La Vanguardia 1967). Father Arza claims that it is admissible for Catholics to give non-vital organs, like a kidney or a cornea, in life. He adds that donation of vital organs is legitimate only if the donor is dead, but that it pertains to physicians to determine what constitute death. The morality of cadaveric donation, then, rests on physicians having the adequate scientific tools to determine death, not primarily on religious principles.
The debate remained active despite these efforts to secularize the body. For example, on May 22nd, 1968, ABC reports on a Symposium on organ transplantation held in Madrid during that week, where Father Gonzalo Higuera and theologian Narciso Tibau Durán insisted that higher moral norms and laws, not science for its own sake, must govern organ transplantation (ABC 1968b). Father Tibau also mentions that the results of organ transplantation contribute to determine their morality. Given the mixed results of organ—especially heart—transplants in the following months, this will become a central point of discussion. While transplants as a viable therapeutic option with a certain guarantee of success are morally acceptable, transplants as human experiments are not. This is a much more cautious position than the ones presented before, as it still considers sacralized notions of the body as viable tools to evaluate the moral character of organ transplantation.
This lingering ambiguity is particularly visible in Dominican Priest José Todoli’s book Ética de los Trasplantes (“Transplantation Ethics”), published in the Spring of 1968 and subject of some debate in the upcoming months (ABC 1968d; Fernández de la Mora 1968:; La Vanguardia 1968b; Ponce 1968; Todoli 1968). Father Todoli, who had studied Saint Thomas’ dogma in detail, insists that the Catholic Church no longer considers organ donation a form of mutilation, because the “principle of solidarity” overcomes the “principle of self-preservation” and justifies donating an organ to save someone else’s life. This applies to double organs, and to vital organs when the donor is dead. According to Father Todoli, however, terminal illness and brain death do not equate to death, since doctors have the moral mandate to prolong life as much as they can. He claims that only cardiac death constitutes death. His conservative views on the moral nature of life and death contrast with his claim that organs should be considered social goods, and with his support for opt-out systems.1
Although ambiguities remained unresolved for a few years, the Spanish Catholic Church progressively embraced a position favorable to organ transplantation. In the summer of 1969, Madrid hosted the first Global Conference on Organ Transplantation (ABC 1969a; 1969b, 1969c, 1969d, 1969e; La Vanguardia 1969a, 1969b, 1969c). As published in ABC on July 15th of 1969, one of the Conference’s goals was to reflect on the moral and religious dimension of organ transplantation (ABC 1969b). On the same day, La Vanguardia reproduced the conclusions of the Conference’s Deontology section, comprised by Catholic theologians such as Father Gonzalo Higuera and Father Manuel Cuyás, and theologians from other religions (La Vanguardia 1969a). The main question, again, was the nature of death, left for science to determine.
Coverage of the Conference included a short interview with Father Manuel Cuyás, a Spanish Catholic priest known for his friendly views on organ transplantation (La Vanguardia 1969a). In the interview, he claims that the common good, and not just the donor’s family’s desires, should determine what to do with people’s organs. He even claims that, in some cases, physicians go too far trying to prolong irrecuperable patients’ lives, implying that it is acceptable to stop life support to extract organs for transplantation. Father Cuyás’ statement relies on a medicalized definition of the body that accepts scientific authority and the use of medical technologies as criteria to determine death.
This decisiveness contrasts with the Vatican’s enduring ambivalence. In 1972 -three years after Madrid’s Global Conference- Pope Paul VI’s message to doctors and surgeons was still cautious. In his message, he appeals to “moral sensitivity” and avoids a straightforward answer about brain death, explaining that the Catholic Church “is in no condition to discuss these issues in a specific and scientific manner”, but to “interpret God’s law as it pertains to the defense of all human life since its beginning until its end.” (Efe 1972). Meanwhile, the Spanish Catholic Church had moved away from elucidating the moral character of organ transplantation and had embraced the promotion of organ donation.
Promoting Organ Donation: Generosity, Self-Sacrifice, and Fraternal Love
The altruistic package was present since the beginning of the religious debate around organ procurement, even if it did not become dominant until the 1970s. For example, ABC and La Vanguardia’s praise of Father Gnocchi’s cornea donation draws on this package, and so do later defenses of the morally positive character of organ donation. Additionally, on January 30th, 1965, ABC published a review of Somatic Law, a book where Father Félix García, a Catholic priest, defends organ donation referring to the Great Commandment and to John 15:13 (ABC 1965). Both biblical sources emphasize fraternal love and self-sacrifice and will become central to the discussion in the following decades.
By the early 1970s, the Spanish Catholic Church had adopted a position favorable to organ procurement, participating in Conferences and events whose goal was, among others, to overcome “unscientific barriers” to transplantation (La Vanguardia 1972). From then on, the debate shifts from negotiating the validity of the sacralized body package to embracing the altruistic package.
When the new democratic government announced a long-awaited Transplantation Law in 1979, the Spanish Catholic Church backed it and started to actively promote organ donation. For example, in January of 1979 several regional dioceses released statements encouraging Catholics to donate organs (Monseñor Ramón Buxarrais 1979; La Vanguardia 1979). In a pastoral letter, bishop of Malaga Monsignor Buxarrais exhorts believers to maintain a “Christian attitude” towards transplantation and invokes the “sad and worrisome” situation of kidney patients awaiting a transplant. He suggests different options for Catholics to help solve this problem, including leaving written testament of one’s willingness to donate organs, and allowing family members to donate their deceased relative’s organs so that “even after death, they can be of service to others”. In another letter, the Diocese of Oviedo’s Health Pastoral describes organ donation as an expression of Christian charity. The letter claims that, given the shortage of transplant organs, “everyone’s effort” is necessary, and so is to “create a conscience of urgency and of duty of charity to offer to our fellow men what we can dispense with without endangering ourselves” (La Vanguardia 1979). While in previous decades religion guided scientific progress and limited potential moral excesses, now science offers new moral possibilities to realize religious altruistic principles.
Following these regional initiatives, reporters questioned president of the Spanish Episcopal Conference Monsignor Vicente Enrique y Tarancón—known for his efforts to establish a positive relationship between the Spanish Catholic Church and Spain’s democratic forces after Franco’s death- about the high proportion of Catholics that refused to donate organs for religious reasons. In his statement to ABC (ABC 1979), he repeats that the Catholic Church does not oppose organ transplantation. On the contrary, he says, the Church had already endorsed it before. Furthermore, Monsignor Tarancón promises that the Episcopal Conference would release an official statement, coinciding with parliamentary discussions about the new Transplantation Law.
The law, which passed in October of 1979, establishes an opt-out procurement system based on presumed consent from the patient (Ley 30/1979). It raised less controversy than one would expect from a society that had just come out of a traditionalist military dictatorship. However, on October 10th, 1979, ABC and Ya reported on a man who, following the Catholic Eschatological doctrine—particularly the Resurrection dogma—had signed an official document prohibiting medical authorities to extract his organs (Efe 1979; Ya 1979b). In the following years, the Spanish Catholic Church would dedicate considerable efforts to dismiss such claims, championing the altruistic, charitable nature of organ donation.
Once the Law passed, the transplant organs shortage became Spain’s organ procurement system’s main problem. Many patients died waiting to receive an organ. In this context, the Spanish Catholic Church doubled down in its efforts to promote organ donation. For instance, in the Summer of 1980 Archbishop of Valencia Monsignor Roca Cabanellas released a pastoral exhortation explaining believers that “through organ donation we can show our desire to serve Humanity; for Christians, it is a testament to the fraternal love that Jesus Christ demands from us, and for both believers and others with a good will, it manifests their right conscience”. The Law, he adds, is a great opportunity for charity, expressed as the will to offer one’s own body to save or improve someone else’s life (Monseñor Roca Cabanellas 1980). On August 6th, 1980, Ya echoed this statement, mentioning how Monsignor Roca Cabanellas had specifically dismissed eschatological concerns (Cruz Román 1980).
A few months later, in January of 1981, La Vanguardia reported that Bishop of the Canary Islands Monsignor Ramón Echarren had released a pastoral letter promoting kidney donation (Europa Press 1980). In the letter, he claims that “in the light of the Gospel, in the light of our faith, the great call that we need to feel like a call for love is that many of these patients could heal permanently with a kidney transplant.” He then adds that, when “God calls us to His side, we no longer need them [kidneys]”, and asks, “is there anything more Christian than giving ourselves? Is there any Christian reason that opposes offering our kidneys in the very moment we are giving our life to God?”. Monsignor Echarren bypasses here any possible religious objection to organ donation, framing it exclusively in terms of its altruistic character.
The discovery of cyclosporine -a powerful anti-rejection drug- in the early 80 s stimulated the public conversation around transplantation and organ shortages. For example, on June 6th, 1984, on the “Religion” section of ABC, Catholic priest and journalist Father José Luis Martín Descalzo shared his experience with kidney disease and how it had made him aware of the dire reality of kidney patients -whom he refers to as “brothers” (Martín Descalzo 1984). Father Martín, addressing those who refused organ donation on religious grounds, explains that Resurrection has nothing to do with preserving one’s organs after death. He adds, paraphrasing John 15:13, that there is no greater charity and proof of fraternity than to give one’s life for a fellow human. He also states that organ donation results directly from a charitable and solidary spirit between fellow Men and insists that the Catholic Church has found no moral obstacles for organ donation, and that refusing donation based on religious motives is not consistent with the “Christian spirit”.
A few weeks later, on July 24th, 1984, Ya reported in its “Religion” section on a document titled “Solidarity with the sick: Kidney donation”, by a group of Galician Bishops (Ya 1984a). The Bishops argue that religious objections to organ donation are not in line with a Christian spirit and call them “misguided sentimentalisms”. “Christians”, they add, “must convince ourselves that [organ] donation is fully consistent with the line of love and service to fellow Men”. They even deem organ donation “demandable”. Both documents openly dismiss sacralized notions of the body that may hinder organ donation and highlight its altruistic character.
The Spanish Episcopal Conference finally released a long-awaited, official, nation-wide pastoral exhortation, titled “On organ donation and transplantation”, in October of 1984 (Conferencia Episcopal Española 1984). The document defines organ transplantation as a “scientific miracle”, that achieves a “higher form of fraternity”. Transplantation is, then, not only a scientific advancement, but also a moral one, because it allows people to exercise new, previously unthinkable, forms of charity. For the Episcopal Conference, the Catholic Church has the moral obligation to dispel religious objections to organ donation. The Catholic faith, they explain, finds no moral obstacles to organ transplantation. On the contrary, the Church sees it as a precious way to imitate Jesus, who sacrificed his life for others. Through organ donation Men can “come closer to the gratuitous and effective love that God feels for us”. They consider organ donation a “living example of solidarity” and “proof that Mens’ bodies can die, but that the love that sustains them never dies”. This statement appeared on all ABC, La Vanguardia, and Ya in the following weeks (ABC 1984b; La Vanguardia 1984a, 1984b; Ya 1984b) showcasing the official victory of the altruistic package over the sacralized body package.
The organ shortage persisted throughout the 1980s, and the Spanish Catholic Church continued insisting on the Christian and charitable character of organ donation. For example, ABC published an interview with Father Javier Gafo, Jesuit priest and professor of Ethics at Comillas Pontifical University (Spain’s main Catholic University) on October 1st, 1986 (Fernández Rubio 1986). In the interview, Father Gafo explains that “the [Catholic] Church encourages Christians to support organ donation” from both deceased and living donors. As for religious motives to refuse organ donation—specifically the Resurrection dogma—Father Gafo deems them “fake religious concepts”. He adds that “the best service and the highest respect for a cadaver is that its organs can help other people live” and quotes John 15:13. Sacralized notions of the body that had dominated the religious discussion of organ donation two decades earlier are now downgraded to the category of “fake”.
During this period, members of the Spanish Catholic Church also provided exemplars that consolidated organ donation and transplantation as a reasonable course of action. For example, several bishops signed organ donor cards (Europa Press 1979; La Vanguardia 1981), and some members of the Church disclosed their transplant candidate status (Martín Descalzo 1984).
Mentions of the religious aspect of organ procurement and interventions by Catholic authorities became less frequent after that. While the Spanish Catholic Church continued to publicly support and promote organ donation, by the early 1990s the interpretive dilemma was settled. In the following decade, new bioethical debates displaced organ procurement as objects of controversy.
What Can We Learn from this Case? Discursive Contexts and Facilitating Factors
The case of the Spanish Catholic Church’s support for organ donation and transplantation is not, by far, the only place where a religious group has had to navigate competing theological strands in the public policy arena. Furthermore, even within the discussion of organ transfer, it is possible that the Spanish Catholic Church’s acceptance of this medical practice responds to a global trend—within Christianity or even just within the Catholic Church—towards a greater openness. To elucidate which features make the case at hand particularly illuminating, I examined 24 sources of both primary and secondary literature that explore the relationship between religion and organ transfer in different contexts. While several authors have examined how different religions approach organ transplantation, detailed studies that incorporate historical, cultural, social, and political factors are less common. However, surveying this literature has allowed me to identify what makes the Spanish Catholic Church different from other organized religions in its approach to organ transfer, and a series of facilitating factors that may explain these differences.
The main circumstance that sets the Spanish Catholic Church apart is its early, unequivocal, and continued support for organ transfer which, as shown in the previous section, manifested itself first as an effort to dispel religious objections to organ transplantation and then moved towards an active promotion of organ donation as an expression of Catholic values. Although the II Vatican Council had put some pressure on national Catholic Churches to abandon traditionalist positions and to focus on earthly matters, and although the Vatican has expressed support for organ donation as an act of fraternal love (Abdeldayem et al. 2016; Messina 2015; Oliver et al. 2011)—something that would arguable have created a global incentive for national Catholic Churches to embrace organ transplantation and other scientific innovations—this does not directly translate into immediate and continued support for organ transplantation by individual national Churches and Catholic congregations. For example, as reported in ABC on an article from January 14th, 1968, Mexican Bishop Monsignor Orozco Lomeli considered that transplants were “immoral” (Efe-Upi 1968). Even in cases where Christian authorities showed initial support for organ transplantation, like was the case of the United States (Efe 1968b), that does not mean that support is unequivocal. In recent years, some American Christian outlets have expressed some concerns about the morality of organ transplantation (Byrne 1999; Kuhn 2008; Meilaender 2007, 2008; Paris 2002; Smith 2013). Not only are there disagreements regarding whether transplants are morally acceptable, but also around what is the most ethically sound way of procuring organs. While the Vatican—and other Christian religious authorities—has repeatedly decried organ sale and organ trafficking as morally reprehensible, some scholars interpret that Thomas Aquinas’ writings on bodily autonomy allow for organ sale (Cherry 2000a, 2000b).
Outside of Christianity, reformist Islamic authorities in Egypt, for example, have also shown early and consistent support for organ transplantation (Hamdy 2012, 2016). However, their approach has revolved mainly around dispelling religious objections to organ donation and transplantation, whereas the Spanish Catholic Church supplemented that strategy over time with a clear and active embrace of organ donation as an expression of Catholic values. In Egypt it would be activists and revolutionaries who, in 2011, would connect cadaveric cornea donation to notions of sacrifice and religious martyrdom in the context of the protests against Hosni Mubarak’s regime (Hamdy 2016).
The Spanish Catholic Church’s level of commitment to support organ transplantation, then, sets it apart from other religious institutions. Comparison with other Catholic and non-Catholic contexts reveals three facilitating factors that enabled and encouraged the Spanish Catholic Church to embrace the controversial medical practice of organ transplantation. First, it is likely that the content of the Catholic doctrine lent itself to the type of reinterpretation that the Spanish Catholic Church performed more than other religious doctrines. Neutralizing the sacredness of the body reinforces a separation between body and soul that was not alien to the Catholic doctrine, and emphasizing altruism and self-sacrifice amplifies a widely known Catholic principle. Besides, the ritual of communion may have acquainted Catholics with the idea of sharing blood and tissues, while the concept of the Holy Trinity may have familiarized them with the notion of an expanded self. Finally, stories like that of St. Cosmas and St. Damian, two Catholic physicians and martyrs who, in the Catholic hagiography, are considered to have performed the first transplant in History, may have helped portray the transplantation of organs and tissues in a positive light.
Comparatively, for Jehovah Witnesses, for example, the notion of organ transplantation may be harder to make culturally acceptable considering their beliefs about blood transfusion. Although technically possible, imagining an organ transplant that does not involve blood transfer is counterintuitive and difficult to convey to believers (Abdeldayem et al. 2016; Messina 2015; Oliver et al. 2011). Similarly, anthropologist Margaret Lock found that popular beliefs about brain death and death informed by Shintoism have historically impeded support for organ transfer in Japan (Lock 2002). In addition to abstract theological principles, it seems like funerary rituals that require a quick burial or that require manipulating the corpse in specific ways are harder to reinterpret. For example, some Muslim traditions mandate that the body should be buried 24 h after the death, which can impede some procurement processes (Abdeldayem et al. 2016; Messina 2015; Oliver et al. 2011).
Some religions, however, may be similarly “friendly” to the idea of organ transplantation. The Hindu mythology, for example, includes several instances of using body parts to help others (Abdeldayem et al. 2016; Messina 2015; Oliver et al. 2011), and some scholars of Buddhism claim that the state of mind in which one dies is more important than the moment of death itself, which would be an argument to support cadaveric donation (Becker 1990). The degree of potential theological compatibility, then, does not suffice to explain why the Spanish Catholic Church embraced organ transfer with such distinctive, early, and persistent enthusiasm.
In that venue, a second factor may have contributed to this outcome. It is worth noting that the Spanish Catholic Church is a unified religious authority that has enjoyed high levels of cultural hegemony throughout Spain’s history. The Spanish Monarchy and the Catholic Church have historically been closely intertwined. Successive Spanish monarchs relied on the Catholic Church to legitimize their power and, in exchange, granted the Spanish Catholic Church a great degree of control over public and private affairs. At the same time, the Spanish Monarchy favored the formation of a national ecclesiastic hierarchy to limit Vatican control. The relationship between the Spanish Catholic Church and the Spanish state was, at least until the late twentieth century, one of mutual dependency.2
The Church’s internal -or at least, apparent- unity, hegemonic position, and relative independence allowed it to make a concentrated effort of interpretation and to avoid the type of intradenominational disputes that have arisen within other religious groups characterized by higher levels of decentralization. For example, the Orthodox Church does not have unified criteria regarding organ donation and transplantation, and it leaves the decision to donate to individuals, who are encouraged to consult with their spiritual advisors. Similarly, and although Protestant denominations tend to support organ donation, most of them consider the decision to donate -and to receive an organ- a strictly individual matter. In the case of Judaism, controversies around brain death have not been resolved, which means that some people of Jewish faith disapprove of organ transfer altogether, while others agree to brain-dead donation, and others indicate that procurement should not begin until their hearts have stopped beating (Abdeldayem et al. 2016; Messina 2015; Oliver et al. 2011). In the United States, for example, positions on organ transfer also vary by denomination, with liberal branches of Judaism expressing more support for organ donation than Orthodox Jews, who are more concerned with the moral validity of brain death (Baeke et al. 2011). Finally, in Islam, the sources of Islamic law do not address organ transplantation nor brain death, scholarly consensus around these issues does not exist, and the existing, non-binding fatwa often contradict each other. In this scenario, families apply independent reasoning, sometimes with help from Ulemas (interpreters of the Islamic law) (Ali and Maravia 2020; Miller 2016; Padela and Basser 2012; Padela and Duivenbode 2018; Padela et al. 2013).
In fact, in context where other religious groups have attempted to lend support to and promote organ transfer, part of their strategy has been to move towards some form of centralization of religious authority, or at least a consensus in bioethical matters. For example, since the nineteenth century, state-aligned reformist Islamic scholars in Egypt have tried to encourage the population to donate their corneas—and later, other organs—after death by dispelling religious concerns around organ transfer and providing them with a unitary set of guidelines (Hamdy 2012, 2013, 2016). Organizations like the Islamic Organization for Medical Sciences (IOMS), the British Islamic Medical Association (BIMA), and the Turkish religious organization Milli Görüs and the Contact Group for the Relations between Muslim Organizations and Government (CMO) in the Netherlands have also tried to reach some degree of consensus to support organ transfer (Ali and Maravia 2020; Ghaly 2012). However, attempts to reinterpret religious texts are often met with resistance by scholars who oppose the idea of manipulating religious doctrine in order to provide support for organ transfer (Rady and Verheijde 2014).
Finally, the sociopolitical context of Spain during the 1960s, 70 s, and 80 s (when most of the theological debate around organ transfer took place) provided a conducive background for the Spanish Catholic Church to both embrace organ transplantation and to actively promote it. On one hand, organ transfer enjoys a peculiar cultural salience in Spain, and has done so since its early days (Herrero Sáenz 2022). The Francoist regime made a considerable effort to publicize Spanish surgeons’ achievements in transplantation, with the intention of counteracting negative perceptions of Spain and signaling development to both domestic publics and the international community (Danet 2013; Danet and Medina-Doménech 2014, 2015; Herrero Sáenz 2020). Later, successive democratic governments have made a substantial investment in building an effective organ procurement system and in encouraging the population to donate their organs (or, more often, their relatives’). Resulting from these efforts, organ donation rates have increased dramatically in Spain in the last 30 years, and the country currently occupies an undisputed leading position in the global organ donation rankings. Internationally recognized actors such as the World Health Organization (WHO), the Council of Europe, and the leading scientific journal American Journal of Transplantation consider the “Spanish Model” (Matesanz 2008) the gold standard of global procurement (Matesanz et al. 2009; Sharif 2017). This amount of recognition and praise has resulted in an outstanding social acceptance of organ transplantation (Centro de Investigaciones Sociológicas 2001, 2004, 2012).
On the other hand, during the second half of the twentieth century, the social influence of Catholicism in Spain declined. First, Church and State grew apart, especially after dictator Francisco Franco’s death in 1975, when Spain’s democratic transition reduced the Catholic Church’s privileges. During the Civil War and the first stages of the Francoist dictatorship, the Catholic Church had supported the regime, participating in the post-war repression and becoming an integral part of the Francoist establishment (Astor et al. 2017). “National Catholicism” was a central component of Franco’s official State ideology and identity. After the Second Vatican Council (1962–1965), which encouraged national churches to move away from transcendental positions and embrace their role in solving earthly social problems, the Spanish Catholic Church moved towards more open positions (Montero García 2009). After Franco’s death in 1975, the Church -led by Cardinal Monsignor Vicente Enrique y Tarancón, president of the Spanish Episcopal Conference- supported Spain’s democratic transition, even if that meant giving up some of the prerogatives that the Spanish Catholic Church had acquired during the dictatorship and softening some of its more traditionalist stances. In exchange, the Spanish Catholic Church maintained a privileged political and social position.
Second, a rapid process of secularization started in the 1960s and grew during the 1970s and 1980s. Religious practice declined, and so did religion’s importance in people’s lives and decisions. On one hand, by participating in the Francoist regime the Spanish Catholic Church alienated a good portion of the population, who saw Spain’s democratization as an opportunity to move away from religion in general and Catholicism in particular. On the other hand, younger generations were losing interest in religion and religious practice (Pérez-Agote 2012).
In that sense, the Spanish Catholic Church attempted to make Catholic beliefs more compatible with the current social, cultural, and historical milieu (Swart 1995). The link between sociopolitical contexts and religious interpretations of medical innovations, and specifically of organ transfer, has not been studied in detail. However, authors like Margaret Lock and Sherine Hamdy have found that in Japan and Egypt, respectively, religious opposition to organ transfer has to do with wider crises of authority and trust in institutions (Hamdy 2012, 2013, 2016; Lock 2002), which in the case of Egypt changed with the 2011 uprising and the symbolic connection between mass eye trauma, cornea donation, and religious martyrdom (Hamdy 2016). In his study “Islam and organ donation in the Netherlands”, Mohammed Ghaly found that it is not possible to understand Muslim organization’s interest in supporting organ donation without considering ongoing accusations against the Muslim population of not donating enough organs and taking advantage of the Dutch organ procurement system and, more widely, without considering the rise of islamophobia in the region (Ghaly 2012). In these examples, the social, cultural, and political milieu is, in itself, a condition of possibility for institutional religious support for organ transfer.
In sum, the first experiments in organ transplantation put the Spanish Catholic Church in a delicate predicament. As one of Spain’s highest moral authorities, it was expected to provide non-specialists with a coherent moral framework to evaluate this new medical practice (Ecklund et al. 2017, 294), which meant working through the contradictions between the altruistic and the transcendental elements of its doctrine. In this scenario, the Spanish Catholic Church had at least four potential courses of discursive action (see Table 3) based on whether it would emphasize or neutralize each of its doctrinal interpretive packages: Table 3 The Spanish Catholic Church’s potential courses of discursive action in relation to organ donation and transplantation
Altruistic package
Neutralize (-) Emphasize ( +)
Sacralized body package Neutralize (-) (A) Distance (C) Alignment
Emphasize ( +) (B) Opposition (D) Inconsistency
The Spanish Catholic Church could have (A) distanced itself from the debate and left moral decisions about organ donation and transplantation in the hands of individuals. Other religious institutions and leaders have taken that path (Ali and Maravia 2020; Baeke et al. 2011; Miller 2016; Padela and Basser 2012; Padela and Duivenbode 2018; Padela et al. 2013). However, this would have weakened the Spanish Catholic Church’s position as a moral arbiter and would have been a missed opportunity to maintain its cultural relevance. It could have (B) opposed organ transfer, highlighting Catholic beliefs about the sacredness of the human body, but that would have put it at odds with Spain’s political elites. People’s increasing disinterest in religion was also a factor in pushing the Spanish Catholic Church towards a more open position regarding certain forms of scientific and medical progress, especially as controversial questions like divorce and abortion became a point of friction between the Church and Spain’s progressive forces. Alternatively, the Spanish Catholic Church could have (D) tried to hold on to and reinforce both its beliefs about generosity and charity and its beliefs about the sacredness of the body, but that would not have solved the contradiction and could have sparked some degree of backlash. Aligning Catholic beliefs with discourses around organ transfer by suppressing sacralized notions of the body and emphasizing values of charity, altruism, and generosity (C) avoided the potential pitfalls implied in all the other options, and therefore was the best course of discursive action for the Spanish Catholic Church.
Discussion
Organ transplantation confronted the Catholic Church with a contradiction between its altruistic principles and its ideas about the sacred character of the human life and body. My findings show that, faced with this interpretive dilemma, the Spanish Catholic Church did extensive interpretive work to align organ donation and transplantation with Catholic beliefs, but did so within the limits established by the internal logics of preexisting meaning structures that made organ donation and transplantation both potentially acceptable—as a form of altruistic behavior—and unacceptable—as a practice that contradicts sacralized meanings of the body—for Catholicism.
The cultural dynamics I described above, however, do not completely determine institutional agency. The interests of the Spanish Catholic Church, and the sociohistorical factors that surrounded it during the time organ transplantation emerged as a therapeutic option, shaped its institutional discursive strategies. In this case, the relationship between the Catholic Church and organ procurement in Spain is one of reciprocal legitimation. On one hand, aligning organ procurement with Catholic beliefs contributed to legitimize and normalize it. On the other hand, publicizing its support for organ donation gave the Spanish Catholic Church the chance to recast itself as a modern social and political actor, at a time where it was facing a legitimacy crisis.
Comparing the Spanish case with other instances of religious interpretation of organ donation and transplantation reveals three facilitating factors that enabled and encouraged the Spanish Catholic Church to embrace organ donation and transplantation. The degree of potential theological compatibility between a religious doctrine and the practices and discourse of organ transfer, the degree of consensus and unity within institutionalized religions, and the larger social, political, and cultural climate both encourage and constrain religious institutions’ support for organ transfer. While none of these factors are a sufficient condition for religious institutions to take a particular stance about a new medical practice, they provide background conditions that facilitate religious agreement with scientific innovations.
My findings, and their theoretical implications, can be fruitful for various scholarly fields. For sociologists of culture, they build on an interpretive approach to the relationship between beliefs and practices that respects the relative independence of cultural dynamics operating at the level of meaning, while also accounting for institutional discursive agency and situating it in a concrete sociohistorical context (Alexander and Smith 2006; Kane 1991). For medical sociologists, my findings add to the well-established literature on the cultural legitimation of medical practices (Blume 2013; Joyce 2005), in this case focusing on how religious arguments can contribute to normalize an initially shocking medical procedure. Finally, public health scholars can benefit from my findings to understand the challenges that institutionalized religions face when confronted with controversial medical practices that raise conflicts within their own doctrines. This, in turn, can foster a better understanding and smoother avenues for collaboration between medical institutions—such as organ procurement organizations—and religious authorities (Randhawa and Neuberger 2016). Given that, for many, organ donation—of their organs or their relatives’—elicits religious dilemmas, understanding these more profoundly is crucial to explain and mitigate the perennial transplant organ shortage.
Besides interpreting discursive processes, my findings raise questions of causal efficacy: Did the support of the Spanish Catholic Church contribute to increase the social acceptance of organ transplantation in Spain? My study does not directly address how the Church’s messages affected people’s subjective experience, but it is possible. Making the altruistic package more readily available for people to employ as a resource for their moral evaluation of organ transplantation (Ecklund et al. 2017) may have stirred Catholics towards supporting organ procurement by providing them with “religiously-based rationales for social action” (Edgell 2012, 251). Furthermore, media made this cultural repertoire publicly available to Catholics and non-Catholics, amplifying its reach beyond religious individuals (Lichterman 2012). In a context like Spain where the Catholic Church had enjoyed centuries of hegemony, it wouldn’t be surprising for these moral evaluations, initially of religious origin, to become “culturalized” (Astor and Mayrl 2020), and relevant for non-believers.
It is also possible that the Church’s campaign had little impact on people’s actions. Although the Spanish Catholic Church’s leadership supported organ transplantation unequivocally, the institution is not ideologically homogeneous (Pérez-Agote 2012), and believers were probably exposed to competing claims about both the moral character of organ donation and to different interpretations of what it means to be Catholic (Baggett 2006). The messages that priests across the country were circulating among their parishioners might have differed from what the Episcopal Conference was preaching. Although previous scholarship has addressed the ideological heterogeneity within the Spanish Catholic Church (Montero García, 2009), to the best of my knowledge its impact on the debate on organ procurement remains underexplored.
Besides, although we can presuppose that the Church’s messages had a certain influence on the public, my findings do not speak to how people engaged with these messages and whether they shaped their attitudes and actions. People engage actively with cultural meanings, including religious messages (Fisher 2012), and actors can draw on different interpretations of the Catholic doctrine and mobilize them towards opposed goals. Furthermore, Catholics may also employ secular principles of evaluation to assess the moral character of organ transplantation (Edgell and Hull 2017).
Despite its limitations, an approach focused on contextually situated meaning-making processes is also applicable to other cases of religious interpretations of medical innovations and public health issues. While religious controversies about abortion, euthanasia, or stem cell research immediately come to mind, other medical and public health issues with less obvious religious ramifications are worth exploring. For example, authors have found that religious ideas are shaping people’s likelihood to get vaccinated against COVID-19 (Corcoran et al. 2021; Garcia and Yap 2021; Milligan et al. 2021) and against other diseases. To understand the linkage between religion and vaccine hesitancy it is crucial to examine how certain religious groups and organizations interpret these medical innovations and the public health rationales for vaccination, and in what sociopolitical context they produce these interpretations.
In sum, controversial medical innovations and public health issues sometimes reveal moral contradictions that face religious organizations with interpretive challenges. In such moments, religious institutions generate context-specific creeds and moral guidelines, but they do so while navigating doctrinal, institutional, and sociopolitical conditions that enable, constrain, and shape the reinterpretation of religious texts.
Appendix 1: Primary sources
ABC. 1963. “Symposium sobre Trasplante de Riñón.” ABC, May 30, 68.
ABC. 1965. “Juicio Crítico en el Ateneo.” ABC, January 30, 51–52.
ABC. 1968a. “Próximos Coloquios sobre ‘La Muerte y los Trasplantes de Órganos.’” ABC, April 28th, 85.
ABC. 1968b. “Los Trasplantes, en la Teología y en la Moral.” ABC, May 22nd, 89.
ABC. 1968c. “Los Trasplantes en Derecho Somático y la ‘Lege Condenda.’” ABC, May 23rd, 92-93.
ABC. 1968d. “‘Ética de los Trasplantes.’” ABC, June 22, 96.
ABC. 1969a. “Próximo Congreso Mundial de Trasplantes, en Madrid.” ABC, June 19, 58.
ABC. 1969b. “Franco Inauguró Ayer el I Simposio Internacional de Trasplantes de Órganos.” ABC, July 15, 45-46.
ABC. 1969c. “Los Injertos Cardíacos, Problemas Legales y Aspectos Ético-Morales Fueron los Temas Debatidos en la Primera Jornada de Trabajo.” ABC, July 16, 67.
ABC. 1969d. “Se hacen Públicas las Primeras Conclusiones Provisionales del Simposio.” ABC, July 17, 55-56.
ABC. 1969e. “Opiniones al Cierre del Simposio.” ABC, July 18, 43.
ABC. 1979a. “Interés del Cardenal Tarancón en por los Enfermos de Riñón.” ABC, June 30, 21.
ABC. 1984a. “Dialogo entre Ciencia y Moral en la Semana Teológica.” ABC, August 28, 28.
ABC. 1984b. “‘La Iglesia ve en la Donación de Órganos una Preciosa Forma de Amor y Solidaridad’” ABC, October 28, 41.
ABC. 1986. “Día del Donante.” ABC, October 1, 16.
C., P. 1966. “O’Donnel: ‘Ética Médica.’” ABC, April 13, 93.
Conferencia Episcopal Española. 1984. “Sobre la Donación y el Trasplante de Órganos.” Retrieved June 7th, 2020: http://donacion.organos.ua.es/info_sanitaria/religiones/catolicismo.htm
Cortés Cavanillas, Julián. 1956a. “Ha Muerto En Milán El ‘Ángel de Los Niños.’” ABC, March 3, 25–26.
Cortés Cavanillas, Julián. 1956b. “Silvio y Amabile Han Vuelto a Ver, Gracias a Don Carlo Gnocchi.” ABC, March 9, 31.
Cuyás, Manuel. 1967. “La Moral de Los Trasplantes Orgánicos.” La Vanguardia, December 14, 30.
Efe. 1956a. “Ha Fallecido En Milán El Padre Gnocchi.” ABC, March 1, 28.
Efe. 1956b. “El Papa Habla del Trasplante de la Córnea.” ABC, May 15, 42.
Efe. 1956c. “Definición de su Santidad sobre El Trasplante de Córnea.” La Vanguardia, May 15, 13.
Efe. 1967. “Opiniones de ‘L’Osservatore Romano.’” ABC, December 7, 70.
Efe. 1968a. “Pablo VI Recibio en Audiencia Privada al Doctor Barnard.” ABC, January 30, 32.
Efe. 1968b. “Apoyo a los trasplantes de corazón.” La Vanguardia, February 27, 18.
Efe. 1972. “‘Hemos de Defender la Vida desde su Comienzo hasta su Ocaso.’” La Vanguardia, June 2, 25.
Efe. 1979. “Se Opone a que Utilicen su Cadaver en Trasplantes.” ABC, October 10, 38.
Efe-Upi. 1968. “El Obispo Auxiliar de Méjico Considera Inmorales los Trasplantes.” ABC, January 14, 52.
Europa Press. 1979. “Monseñor Iniesta Dona sus Riñones.” La Vanguardia, June 15.
Europa Press. 1980. “La Cesión de Órganos.” La Vanguardia, January 28, 35.
Fernández de la Mora. 1968. “‘Ética de los Trasplantes.’” ABC, May 30, 38-39.
Fernández Rubio, Francisco. 1986. “Apoyo Decidido de la Iglesia a la Donación de Órganos para Trasplantes.” ABC, October 1:46.
Formica, Mercedes. 1968. “La Voz de Dios, en el Trasplante de San Cosme y San Damian.” ABC, April 7th, 93.
Garrido, Cristina. 2011. “Un Religioso Inaugura la Primera Cadena de Trasplantes en España.” ABC, April 29, 62-63.
Gurbindo, Fermin. 1979. “Opina un Beneficiario de los Trasplantes.” ABC, October 26, 78.
Hérnandez, Salvador. 1994. “Ayuda para un Joven.” ABC, December 11, 22.
Hospital Rodes, Joaquín. 1972. “El Quinto, No Matar.” La Vanguardia, December 6, 61.
Ibáñez, Jesús. 1984. “En el 60 por 100 de los Casos de Posibles Donantes, los Familiares Niegan la Extracción.” Ya, November 23, 27.
La Vanguardia. 1967. “Es Moral el Trasplante de Corazón si la Muerte del Donante se Ha Producido.” La Vanguardia, December 8, 8.
La Vanguardia. 1968a. “La Moral Católica y los Trasplantes de Corazón” La Vanguardia, May 25, 22.
La Vanguardia. 1968b. “‘Ética de los Trasplantes.’” La Vanguardia, June 20, 52.
La Vanguardia. 1968c. “‘Los Trasplantes.’” La Vanguardia, June 27, 47.
La Vanguardia. 1968d. “‘Arbor, Num. 268, M.’” La Vanguardia, July 18, 40.
La Vanguardia. 1968e. “En Septiembre se Celebrarán las IX Conversaciones Intelectuales, en Poblet.” La Vanguardia, August 24, 20.
La Vanguardia. 1968f. “Las Próximas Conversaciones Intelectuales de Poblet.” La Vanguardia, September 11, 22.
La Vanguardia. 1968g. “Finalizaron las IX Conversaciones de Intelectuales, de Poblet.” La Vanguardia, September 17, 28.
La Vanguardia. 1968h. “El Prelado Celebró una Misa para los Enfermos del Hospital Clínico.” La Vanguardia, December 31st, 25.
La Vanguardia. 1969a. “Prosiguen los Trabajos del Simposio Internacional de Trasplantes de Organos.” La Vanguardia, July 16, 5.
La Vanguardia. 1969b. “Sesiones del I Simposio Internacional sobre Trasplantes de Órganos.” La Vanguardia, July 17, 11.
La Vanguardia. 1969c. “Clausura del I Simposio Internacional sobre Trasplantes de Órganos.” La Vanguardia, July 18, 6.
La Vanguardia. 1972. “Problemática y Aspectos Humanos de los Trasplantes.” La Vanguardia, October 31, 28.
La Vanguardia. 1976. “Actitud Cristiana ante los Trasplantes de Organos.” La Vanguardia, January 17, 26.
La Vanguardia. 1981. “Salvar una Vida, Motivo Primordial.” La Vanguardia, July 1.
La Vanguardia. 1984a. “Los Obispos Españoles Apoyan los Trasplantes de Órganos” La Vanguardia, October 24, 21.
La Vanguardia. 1984b. “La Conferencia Episcopal Afirma que la Donación de Órganos es una forma Preciosa de Amor y Solidaridad.” La Vanguardia, November 2, 23.
Maboch, Antonio. 1976. “Juegos Biológicos Arriesgados.” La Vanguardia, September 14, 27.
Martín Descalzo. 1984. “Donación de Órganos y Evangelio.” ABC, June 4, 34.
Martínez Carrero, Delia. 1979. “Trasplantes.” ABC, November 10, 70.
Monseñores Bernardo Álvarez Alonso and Francisco Cases Andreu. 2009. “Donar Órganos es Dar Vida.” Diócesis de Canarias. Retrieved June 7th, 2020: http://www.diocesisdecanarias.es/obispo/monsfranciscocasesandreu/mensajes/donacion-de-organos.html
Monseñor Juan José Asenjo. 2014. “La Donación de Órganos, un Gesto de Alto Valor Cristiano.” Archidiócesis de Sevilla. Retrieved June 7th, 2020: https://www.archisevilla.org/la-donacion-de-organos-un-gesto-precioso-de-alto-valor-cristiano/
Monseñor Lluís Martínez Sistach. 2008. “Donación de Órganos.” La Vanguardia, April 6, 38.
Monseñor Miguel Roca Cabanellas. 1980. “La Donación de Órganos para Trasplante.” Índice del Boletín Oficial del Arzobispado de Valencia, 273.
Monseñor Narciso Jubany Aranu. 1987. “Trasplantes de Órganos.” La Vanguardia, September 13, 44.
Monseñor Ramón Buxarrais. 1979. “Sobre los Trasplantes de Riñón”. Diócesis de Málaga. Retrieved June 7tn, 2020: https://www.diocesismalaga.es/cartas-pastorales-mons-buxarrais/2012081064/sobre-los-trasplantes-de-rinon/
Moriones, Julio. 1956. “Dos Ciegos Menos, y Un Santo Más.” La Vanguardia, March 4, 21.
Moriones, Julio. 1968. “Roma: Audiencia de Paulo VI al Doctor Barnard.” La Vanguardia, January 30, 13.
Ortega, Narciso. 1979. “Los Trasplantes y la Resurrección.” ABC, October 23, 95.
Ovidio. 1986. “Donación y Trasplantes.” ABC, October 8, 17.
Ponce, Fernando. 1968. “Los Profesores Roberto Saumells y José Todoli, en el Curso de Problemas Contemporáneos.” ABC, August 13, 47.
Rebollar, Mónica. 1996. “Javier Gafo: ‘La Donación Debe Ser un Acto Altruista.’” Ya, April 15, 25.
Sanz, Rosario. 1985. “Donación de Órganos.” ABC, December 22, 27-32.
Todoli, José. 1968. Ética de los Trasplantes. Pamplona: Editorial OPE.
Trujillo, Isabel. 1994. “Un Franciscano Salta a la Televisión para Presentar el Primer ‘Reality Show’ Solidario.” ABC, July 22, 115.
Valeri, Luis. 1971. “La Eutanasia.” La Vanguardia, January 14, 43.
Ya. 1979a. “Monseñor Iniesta Donó sus Riñones.” Ya, June 15, 43.
Ya. 1979b. “Un Valenciano se Niega, ante Notario, al Trasplante de sus Órganos.” Ya, October 10, 39.
Ya. 1984a. “La Donación de Riñones no Plantea Problema Moral.” Ya, July 24, 17.
Ya. 1984b. “Los Obispos Exhortan a la Donación de Órganos.” Ya. October 28, 28.
Yagüe, Antonio M. 1985. “El Culto al Cadáver Sigue Frenando los Trasplantes de Órganos.” Ya, December 15, 1985.
Acknowledgements
I collected part of the data for this study during my stay as a Visiting Researcher at the Department of History of Science (Spanish National Research Council) in the summer of 2019. My gratitude goes to the Department, and especially to Dr. Leoncio López-Ocón Cabrera, for their material and intellectual support. I am also indebted with my advisor and dissertation chair, Dr. Ronald Jacobs, and to the anonymous reviewers, for their helpful feedback and comments.
Funding
Data collection for this project was partially funded by a “Graduate Student Association Research Grant”, awarded by and the University at Albany Graduate Student Association (GSA), and a “University at Albany Dissertation Research Fellowship Award”, granted by the University at Albany SUNY.
Data Availability
All data for this study are available from the author upon request.
Declarations
Conflicts of Interest
I hereby declare no conflicts of interest regarding the present manuscript.
IRB approval
All the data for this study was publicly available. No IRB approval was necessary.
Data Transparency
All data for this study is available from the author upon request.
IRB Approval and Data Transparency
All the data for this study were publicly available. No IRB approval was necessary. All data for this study are available from the author upon request.
1 Systems where brain dead patients are automatically considered organ donors unless they have explicitly manifested their opposition.
2 For a detailed analysis of the changing relations between the Catholic Church, the state, and the public in Spain, see Pérez-Agote 2012.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Abdeldayem, Hesham, Ahmed Farag El-Kased, Ahmed El-Shaarawy, Essam Salah Hammad, Gihan Al-Haddad, OmKolsoum Sobhi, and Naglaa Allam. 2016. Religious concepts in organ transplantation. In Frontiers in transplantology, ed. Hesham Abdeldayem, Ahmed Farag El-Kased, and Ehab El-Shaarawy, 3–22. London: IntechOpen.
Alexander Jeffrey Alexander Jeffrey Seidman Steven Analytic debates: Understanding the relative autonomy of culture Culture and society: Contemporary debates 1990 Cambridge Cambridge University Press 1 27
Alexander Jeffrey Smith Philip Alexander Jeffrey The strong program of cultural cociology Meanings of social life 2006 New York Oxford University Press 24 39
Ali Mansur Maravia Usman Seven faces of a fatwa: Organ transplantation and Islam Religions 2020 11 2 99 121 10.3390/rel11020099
Altomonte Guillermina Exploiting ambiguity: A moral polysemy approach to variation in economic practices” American Sociological Review 2020 85 1 76 105 10.1177/0003122419895986
Ammerman, Nancy T. 2005. Religious narratives in the public square. In Taking faith seriously, ed. by Mary Jo Bane, Brent Coffin, and Richard Higgins, 146–74. Cambridge: Harvard University Press.
Ammerman Nancy T Finding religion in everyday life Sociology of Religion 2014 75 2 189 207 10.1093/socrel/sru013
Astor Avi Burchardt Marian Griera Mar The politics of religious heritage: Framing claims to religion as culture in Spain” Journal for the Scientific Study of Religion 2017 56 1 126 142 10.1111/jssr.12321
Astor Avi Mayrl Damon Culturalized religion: A synthetic review and agenda for research” Journal for the Scientific Study of Religion 2020 59 2 209 226 10.1111/jssr.12661
Baeke Goedele Wils Jean-Pierre Broeckaert Bert American Jewish approaches to contemporary ethical issues in medicine: The case of organ retrieval from brain-dead donors Mortality 2011 16 4 365 379 10.1080/13576275.2011.613271
Baggett Jerome P The Catholic citizen: Perennial puzzle or emergent oxymoron? Social Compass 2006 53 2 291 309 10.1177/0037768606064342
Becker Carl B Buddhist views of suicide and euthanasia Philosophy East & West 1990 40 4 543 556 10.2307/1399357
Beckett Katherine Culture and the politics of signification: The case of child sexual abuse Social Problems 1996 43 1 57 76 10.2307/3096894
Benford Robert D Snow David A Framing processes and social movements: An overview and assessment American Review of Sociology 2000 26 611 639 10.1146/annurev.soc.26.1.611
Berzelak Nejc Avsec Danica Kamin Tanja Reluctance and willingness for organ donation after death among the Slovene general population Slovenian Journal of Public Health 2019 58 4 155 163 10.2478/sjph-2019-0020 31636723
Blume Stuart S Medical innovations: Their diffusion, adoption, and critical interrogation Sociology Compass 2013 7 9 726 737 10.1111/soc4.12062
Brown Grattan T Reading the signs of death: A theological analysis The National Catholic Bioethics Quarterly 2007 7 3 467 476 10.5840/ncbq20077328
Byrne, Paul A. 1999. Catholics and organ donation. Homiletic and Pastoral Review April:62–66. https://www.catholicculture.org/culture/library/view.cfm?recnum=1147. Accessed 29 November 2022.
Centro de Investigaciones Sociológicas. 2001. Estudio no 2412: Opiniones y Actitudes de los Españoles hacia la Biotecnología. Madrid: CIS.
Centro de Investigaciones Sociológicas. 2004. Estudio no 2584: Barómetro de Diciembre de 2004. Expectativas 2005. Madrid: CIS.
Centro de Investigaciones Sociológicas. 2012. Estudio no 2947: Salud (ISSP). Madrid: CIS.
Cherry Mark J Body parts and the market place: Insights from thomistic philosophy Christian Bioethics: Non-Ecumenical Studies in Medical Morality 2000 6 2 171 193 10.1076/1380-3603(200008)6:2;1-7;FT171
Cherry Mark J The body for charity, profit and holiness: Commerce in human body parts Christian Bioethics: Non-Ecumenical Studies in Medical Morality 2000 6 2 127 138 10.1076/1380-3603(200008)6:2;1-7;FT127
Corcoran Katie E Scheitle Christopher P DiGregorio Bernard D Christian nationalism and COVID-19 vaccine hesitancy and uptake Vaccine 2021 39 45 6614 6621 10.1016/j.vaccine.2021.09.074 34629205
Danet, Alina. 2013. Los trasplantes de órganos en España: cuerpo, emociones, e identidad nacional en la prensa contemporánea (1900–1975). PhD dissertation. Universidad de Granada.
Danet Alina Medina-Doménech Rosa M A ‘tale of two countries’: Narratives of hearts, patients and doctors in the Spanish press Public Understanding of Science 2015 24 6 641 657 10.1177/0963662513506144 24164746
Danet Alina Medina-Doménech Rosa M Españolismo, masculinidad y la modernidad científica de los trasplantes de córnea. La representación periodística de Ramón Castroviejo (1930–1975) Journal of Spanish Cultural Studies 2014 15 4 437 53 10.1080/14636204.2014.991490
Demırkiran Oktay Bozbay Suha Elmaagac Merve Agkoç Melek Religious and cultural aspects of organ donation in the Turkish population Transplantation Proceedings 2019 51 7 2158 2162 10.1016/j.transproceed.2019.01.159 31377065
Diani Mario Linking mobilization frames and political opportunities: Insights from regional populism in Italy American Sociological Review 1996 61 6 1053 1069 10.2307/2096308
Dillon Michele Cultural differences in the abortion discourse of the Catholic Church: Evidence from four countries Sociology of Religion 1996 57 1 23 36 10.2307/3712002
Dillon, Michele. 1996b. The American abortion debate: Culture war or normal discourse? In The American Culture Wars: Current Contests and Future Prospects, ed. James L. Nolan Jr, 115–132. Charlottesville: University of Virginia Press.
Ecklund Elaine Howard Peifer Jared L White Virginia Chan Esther Moral schemas in articulation and intuition: How religious people evaluate human reproductive genetic technologies Sociological Forum 2017 32 2 277 297 10.1111/socf.12330
Edgell Penny A cultural sociology of religion: New directions Annual Review of Sociology 2012 38 1 247 265 10.1146/annurev-soc-071811-145424
Edgell Penny Hull Kathleen E Cultural schemas of religion, science, and law in talk about social controversies Sociological Forum 2017 32 2 298 320 10.1111/socf.12331
Entman Robert M Framing: Toward clarification of a fractured paradigm Journal of Communication 1993 43 4 51 58 10.1111/j.1460-2466.1993.tb01304.x
Fisher Gareth Religion as repertoire: Resourcing the past in a beijing buddhist temple Modern China 2012 38 3 346 376 10.1177/0097700411417327
Furton Edward J Brain death, the soul, and organic life The National Catholic Bioethics Quarterly 2002 2 3 455 470 10.5840/ncbq20022332 12854599
Galasiński Dariusz Sque Magi Organ donation agency: A discourse analysis of correspondence between donor and organ recipient families Sociology of Health and Illness 2016 38 8 1350 1363 10.1111/1467-9566.12478 27595861
Gamson William A Lasch Kathryn E Spiro Shimon E Yuchtman-Yaar Ephraim The Political culture of social welfare policy Evaluating the Welfare State: Social and Political Perspectives 1983 New York Academic 397 415
Gamson William A Modigliani A Media discourse and public opinion on nuclear power: A constructionist approach American Journal of Sociology 1989 95 1 1 37 10.1086/229213
Garcia Louiegi L Yap John Federick C The role of religiosity in COVID-19 vaccine hesitancy Journal of Public Health 2021 43 3 e529 e530 10.1093/pubmed/fdab192 34080617
Garrison William A A constructionist approach to mass media and public opinion Symbolic Interaction 1988 11 2 161 174 10.1525/si.1988.11.2.161
Geertz Clifford The interpretation of cultures 1973 New York Basic Books
Gerrand Nicole The notion of gift-giving and organ donation Bioethics 1994 8 2 127 150 10.1111/j.1467-8519.1994.tb00250.x 11654943
Ghaly Mohammed Organ donation and Muslims in the Netherlands: A transnational fatwa in focus Recht Van De Islam 2012 26 39 52
Ghaziani Amin An ‘amorphous mist’? The problem of measurement in the study of culture Theory and Society 2017 38 6 581 612 10.1007/s11186-009-9096-2
de Groot Jack Vernooij-Dassen Myrra Hoedemaekers Cornelia Hoitsma Andries Smeets Wim van Leeuwen Evert Decision making by relatives about brain death and organ donation: An integrative review Transplantation 2012 93 12 1196 1211 10.1097/TP.0b013e318256a45f 23318303
Hamdy Sherine Our bodies belong to God: Organ transplants, Islam, and the struggle for human dignity in Egypt 2012 Berkeley University of California Press
Hamdy Sherine All eyes on Egypt: Islam and the medical use of dead bodies amidst Cairo’s political unrest Medical Anthropology 2016 35 3 220 235 10.1080/01459740.2015.1040879 26131735
Hamdy Sherine F Political challenges to biomedical universalism: Kidney failure among Egypt’s poor Medical Anthropology 2013 32 4 374 392 10.1080/01459740.2013.778255 23768221
Hasan Hania Zehra Arhama Riaz Lubna Riaz Ramsha Insight into the knowledge, attitude, practices, and barriers concerning organ donation amongst undergraduate students in Pakistan Cureus 2019 11 8 e5517 10.7759/cureus.5517 31687293
Healy Kieran Altruism as an organizational problem: The case of organ procurement American Sociological Review 2004 69 June 387 404 10.1177/000312240406900304
Healy Kieran Dobbin Frank Sacred markets and secular ritual in the organ transplant industry The Sociology of the Economy 2004 New York Russell Sage 308 331
Healy Kieran Last best gifts: Altruism and the market for human blood and organs 2006 Chicago University of Chicago Press
Herrero Sáenz, Rebeca. 2020. Heart transplantation, democracy, and collective forgetting in contemporary Spain. Nursing Clio, June 4. https://nursingclio.org/2020/06/04/heart-transplantation-democracy-and-collective-forgetting-in-contemporary-spain/. Accessed 15 November 2022.
Herrero Sáenz, Rebeca. 2022. “'We’re good at tennis, soccer… and organ donation’: The Spanish organ procurement organization as a producer of national identity discourses (2017–2020),” Poetics 92(Part B):101618. 10.1016/j.poetic.2021.101618
Hogle Linda F Recovering the nation’s body: Cultural memory, medicine, and the politics of redemption 1999 New Brunswick Rutgers University Press
Howe Richard Herbert Max Weber’s elective affinities: Sociology within the bounds of pure reason American Journal of Sociology 1978 84 2 366 385 10.1086/226788
Irving Michelle J Tong Allison Jan Stephen Cass Alan Rose John Chadban Steven Allen Richard D Craig Jonathan C Wong Germaine Howard Kirsten Factors that influence the decision to be an organ donor: A systematic review of the qualitative literature Nephrology Dialysis Transplantation 2012 27 6 2526 2533 10.1093/ndt/gfr683
Joralemon Donald Organ wars: The battle for body parts Medical Anthropology Quarterly 1995 9 3 335 356 10.1525/maq.1995.9.3.02a00040 8542438
Joyce Kelly A Appealing images: Magnetic resonance imaging and the construction of authoritative knowledge Social Studies of Science 2005 35 3 437 62 10.1177/0306312705050180
Kane Anne Cultural analysis in historical sociology: The analytic and concrete forms of the autonomy of culture Sociological Theory 1991 9 1 53 69 10.2307/201873
Kuhn, Anita. 2008. Down on the transplantations. Touchstone: A Journal of Mere Christianity, October, 46–47. https://www.touchstonemag.com/archives/article.php?id=21-08-046-c. Accessed 17 October 2021.
Lichterman Paul Religion in public action: From actors to settings Sociological Theory 2012 30 1 15 36 10.1177/0735275112437164
Lock Margaret Cultural aspects of organ donation and transplantation Transplantation Proceedings 1999 31 1345 1346 10.1016/S0041-1345(98)02021-1 10083596
Lock Margaret Twice dead: Organ transplants and the reinvention of death 2002 Berkeley University of California Press
Löwy, Michael. 2006. Catholic ethics and the spirit of capitalism: The unwritten chapter in Max Weber’s sociology of religion. Instituto de Estudos Avançados Da Universidade de São Paulo. http://200.144.254.127:8080/english/texts/lowycatholicethics.pdf. Accessed 29 November 2022.
Matesanz Rafael Matesanz Rafael El Modelo Español de donación y trasplante de órganos: La ONT El Modelo Español de Coordinación y Trasplantes 2008 Madrid Aula Médica 11 26
McDonnell Terence E Bail Christopher A Tavory Iddo A theory of resonance Sociological Theory 2017 35 1 1 14 10.1177/0735275117692837
Meilaender, Gilbert. 2007. Broken bodies redeemed. Touchstone, January/February, 30–37. https://www.touchstonemag.com/archives/article.php?id=20-01-030-f. Accessed 29 November 2022.
Meilaender, Gilbert. 2008. The giving and taking of organs. First Things: A Monthly Journal of Religion and Public Life, March. https://www.firstthings.com/article/2008/03/001-the-giving-and-taking-of-organs. Accessed 29 November 2022.
Messina E Beyond the officially sacred, donor and believer: Religion and organ transplantation Transplantation Proceedings 2015 47 2092 2096 10.1016/j.transproceed.2015.06.031 26361651
Miller Andrew C Opinions on the legitimacy of brain death among Sunni and Shi’a scholars Journal of Religion and Health 2016 55 2 394 402 10.1007/s10943-015-0157-8 26581553
Milligan, Megan A., Danielle L. Hoyt, Alexandra K. Gold, Michele Hiserodt, and Michael W. Otto. 2022. COVID-19 vaccine acceptance: Influential roles of political party and religiosity. Psychology, Health & Medicine 27(9): 1907–1917. 10.1080/13548506.2021.1969026.
Moloney Gail Walker Iain Talking about transplants: Social representations and the dialectical, dilemmatic nature of organ donation and transplantation British Journal of Social Psychology 2002 41 2 299 320 10.1348/014466602760060264 12133230
Moloney Gail Walker Iain Messiahs, pariahs, and donors: The development of social representations of organ transplants Journal for the Theory of Social Behaviour 2000 30 2 203 227 10.1111/1468-5914.00126
Montero García Feliciano La Iglesia: De la colaboración a la disidencia (1956–1975). La oposición durante el franquismo 2009 Madrid Encuentro
Oliver Michael Woywodt Alexander Ahmed Aimun Saif Imran Organ donation, transplantation and religion Nephrology Dialysis Transplantation 2011 26 2 437 444 10.1093/ndt/gfq628
Padela Aasim I Arozullah Ahsan Moosa Ebrahim Brain death in Islamic ethico-legal deliberation: Challenges for applied Islamic bioethics Bioethics 2013 27 3 132 139 10.1111/j.1467-8519.2011.01935.x 22150919
Padela Aasim I Basser Taha A Brain death: The challenges of translating medical science into Islamic bioethical discourse Medicine and Law 2012 31 3 433 450 23248843
Padela Aasim I Duivenbode Rosie The ethics of organ donation, donation after circulatory determination of death, and xenotransplantation from an Islamic perspective Xenotransplantation 2018 25 e12421 e12433 10.1111/xen.12421
Paris, John J. 2002. Harvesting organs from cadavers: An ethical challenge. America Magazine, April, 9–12. https://www.americamagazine.org/issue/370/article/harvesting-organs-cadavers-ethical-challenge. Accessed 29 November 2022.
Pérez-Agote Alfonso Cambio religioso en España: Los avatares de la secularizacion 2012 Madrid Centro de Investigaciones Sociológicas
Rady Mohamed Y Verheijde Joseph L The moral code in Islam and organ donation in western countries: Reinterpreting religious scriptures to meet utilitarian medical objectives Philosophy, Ethics, and Humanities in Medicine 2014 9 11 10.1186/1747-5341-9-11
Randhawa Gurch Neuberger James Max Role of religion in organ donation - Development of the United Kingdom faith and organ donation action plan Transplantation Proceedings 2016 48 3 689 694 10.1016/j.transproceed.2015.10.074 27234715
Santayana George The life of reason, or the phases of human progress: Reason in religion 2015 Cambridge The MIT Press
Sharif Adnan Viva España - Lessons from the Spanish organ donation system American Journal of Transplantation 2017 17 6 1694 10.1111/ajt.14246 28235159
Sharp Lesley A Strange harvest: Organ transplants, denatured bodies, and the transformed self 2006 Los Angeles University of California Press
Siminoff Laura A Bolt S Gardiner HM Family first: Asian Americans’ Attitudes and behaviors toward deceased organ donation Journal of Racial and Ethnic Health Disparities 2020 7 1 72 83 10.1007/s40615-019-00635-3 31493296
Siminoff Laura A Chillag Kata The fallacy of the ‘gift of life’ Hastings Center Report 1999 29 6 34 41 10.2307/3527870 10641243
Smith, Wesley J. 2013. Medicinal murder. First Things: A Monthly Journal of Religion and Public Life, May. https://www.firstthings.com/article/2013/05/medicinal-murder. Accessed 29 November 2022.
Snow David A Elaborating the discursive contexts of framing: Discursive fields and spaces Studies in Symbolic Interaction 2008 30 3 28 10.1016/S0163-2396(08)30001-5
Snow David A Burke Rochford E Worden Steven K Benford Robert D Frame alignment processes, micromobilization, and movement participation American Sociological Review 1986 51 4 464 481 10.2307/2095581
Swedberg, Richard and Ols Agevall. 2016. Elective affinities. In The Max Weber dictionary: Key words and central concepts, eds. Richard Swedberg and Ols Agevall, 114–115. San Francisco: Stanford University Press.
Swart William J The league of nations and the Irish question: Master frames, cycles of protest, and 'master frame alignment' The Sociological Quarterly 1995 36 3 465 81 10.1111/j.1533-8525.1995.tb00448.x
Swidler Ann Culture in action: Symbols and strategies American Sociological Review 1986 51 2 273 286 10.2307/2095521
Tontus H. Omer Educate, re-educate, then re-educate: Organ donation-centered attitudes should be established in society Transplantation Proceedings 2020 52 1 3 11 10.1016/j.transproceed.2019.10.028 31898938
Umair, Sonia, Jo Ann Ho, Norazlyn Kamal Basha, Serene Siew-Imm Ng, and Umair Waqas. 2020. Understanding the attitudes and factors influencing organ donation decisions among university students in Pakistan: A qualitative study. Humanities & Social Sciences Reviews 8(1):52–59. 10.18510/hssr.2020.818
Vernale, Garla and Sheila A. Packard. 1990. Organ donation as gift exchange. Image: The Journal of Nursing Scholarship 22(4):239–42. 10.1111/j.1547-5069.1990.tb00221.x
Weber Max The Protestant ethic and the spirit of capitalism 2003 Mineola Dover Publications
| 0 | PMC9734823 | NO-CC CODE | 2022-12-14 23:28:30 | no | Qual Sociol. 2022 Dec 6;:1-32 | utf-8 | Qual Sociol | 2,022 | 10.1007/s11133-022-09525-3 | oa_other |
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J Racial Ethn Health Disparities
J Racial Ethn Health Disparities
Journal of Racial and Ethnic Health Disparities
2197-3792
2196-8837
Springer International Publishing Cham
36472807
1465
10.1007/s40615-022-01465-6
Article
Antiracism Training for Nutrition Professionals in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC): a Promising Strategy to Improve Attitudes, Awareness, and Actions
http://orcid.org/0000-0001-8352-0826
Santoro Christine M. [email protected]
1
Farmer Mari-Carmen 2
Lobato Gloria 13
James Monica 3
Herring Sharon J. 14
1 grid.264727.2 0000 0001 2248 3398 Program for Maternal Health Equity, Center for Urban Bioethics, Department of Urban Health and Population Science, Lewis Katz School of Medicine at Temple University, 3223 N. Broad Street, Suite 175, Philadelphia, PA USA
2 grid.412726.4 Department of Obstetrics and Gynecology, Thomas Jefferson University Hospital, Philadelphia, PA USA
3 grid.477556.2 0000 0004 0579 4372 NORTH, Inc., Managers of the Philadelphia WIC Program, Philadelphia, PA USA
4 grid.264727.2 0000 0001 2248 3398 Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA USA
6 12 2022
18
21 10 2021
12 3 2022
21 11 2022
© W. Montague Cobb-NMA Health Institute 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Introduction
Women, Infants and Children (WIC) nutrition professionals serve as frontline providers for Black families who disproportionately experience poor perinatal outcomes. With racism driving inequities, we developed an antiracism training tailored to WIC. This report describes the training framework, design, components, and evaluation.
Methods
In 2019, with feedback from WIC providers, we created a 3-h antiracism training for Philadelphia WIC nutrition professionals that included an identity reflection, key concept definitions, workplace scenario and debrief, a model for repair and disruption, and an action tool. We implemented this training in August 2019 and surveyed WIC staff trainees’ awareness of racism and skills to address bias before, immediately after, and 6 months post-training, comparing responses at each time point.
Results
Among 42 WIC staff trainees, mean age was 30 years, 56% were white, 91% female, and 74% had no prior antiracism training. Before the training, 48% felt quite a bit or extremely aware of the role of racism in the healthcare system; this increased to 91% immediately after and was 75% 6 months later. Similar increases in confidence identifying and addressing interactions that perpetuate racism were achieved immediately after training, although the magnitude decreased by 6 months. One-third felt quite a bit or extremely confident the training improved participant interactions at the 6-month timepoint. Qualitative feedback reinforced findings.
Discussion
Results suggest antiracism training may improve WIC nutrition professionals’ attitudes, awareness, and actions and could be valuable in efforts to advance health equity. More work is needed to examine how changes translate into improvements for WIC participants.
Keywords
WIC
Antiracism training
Health equity
Cultural humility
Perinatal health disparities
http://dx.doi.org/10.13039/100000062 National Institute of Diabetes and Digestive and Kidney Diseases R01DK115939 Herring Sharon J. http://dx.doi.org/10.13039/100000050 National Heart, Lung, and Blood Institute R01HL130816 Herring Sharon J.
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pmcIntroduction
In recent years, with the exception of how the police mistreat, harm, and kill Black people, perhaps no other issue around racial justice and inequities has received as much attention and scrutiny as the crisis in Black maternal health [1]. This is due in large part to the organizing and scholarship by Black women and birthing people who, through their own lived experience, research, and community-based efforts, have exposed the racism that has resulted in the extant racial health inequities impacting Black families [2]. Regardless of good intentions, racism impacts the health care environment, the health care provider’s practice, and the participant/patient experience [2, 3]. Many well-intentioned healthcare institutions (e.g., hospitals, nursing homes and health service agencies (e.g., Special Supplemental Nutrition Program for Women, Infants and Children [WIC] struggle with the reality that with regard to perinatal health equity, they are not simply part of the solution but also part of the problem [4, 5, 6]).
This time of increased consciousness around perinatal health inequities and systemic racism is a crucial opportunity to provide needed training, tools, and support to all staff in the maternal child health workforce [7]. Antiracism initiatives have begun in healthcare institutions. However, one overlooked health services agency with a key role in the perinatal landscape for Black birthing people in cities like Philadelphia is WIC. Data reveal that more of the lowest income (i.e., 100% or less of Federal Poverty Level) WIC participants are disproportionately Black and Indigenous families who have significant financial need and corresponding higher incentive to utilize WIC services [8]. While improvements are necessary in how demographic data are collected at WIC, particularly around racial identity [9], nationally, the majority of WIC participants identify as white or non-Black Hispanic people. Contrasting to national demographics of participants, in 2017, almost 75% of all Pennsylvania WIC participants were Black (including those who identify as Black and Hispanic), which is equal to or lower than the proportion in Philadelphia [10]. Black-led advocacy groups as well as the National WIC Association view racial biases as malleable and suggest training staff on racial inequities, antiracism, and bias [11–13], yet neither clear guidelines nor a standard approach for antiracism training targeting WIC staff exist. This lack of antiracism training has significant implications—as of 2017, nationwide eligibility for WIC included more than 2.4 million non-Hispanic Black people [14], indicating that a substantial number of families could be impacted by racism in the WIC program.
While there are promising models being developed for antiracism trainings, such as Crawford Bias Reduction Theory & Training [15] and 5Rs of Cultural Humility [16], there is not yet a specific antiracism methodology or training identified in the literature as having demonstrated consistent, significant, and sustained effectiveness or widespread implementation and dissemination. However, recent meta-analyses [17, 18] reveal several characteristics associated with effective diversity and bias trainings that are likely to translate to antiracism trainings as well: opportunities for social interaction,in-person sessions (ideally at the workplace); disseminated practice (i.e., trainings over more than one session); employer-mandated attendance; and trainings as one part of larger institutional equity efforts. These same studies also recommend strategies to deal with biases that include supporting metacognition, active “debiasing,” and practicing within the framework cultural humility. While there are critiques of implicit bias training efforts in healthcare (e.g., potentially activating rather than mitigating biases) [19, 20], this seems to be a risk if the approach only focuses on awareness of one’s bias and not concrete tools to recognize and manage the impact of the bias on others [20].
Informed by this evidence, in 2019 we developed and implemented an antiracism training for Philadelphia WIC staff, tailored to nutrition professionals, who have the role of counseling all WIC participants. To the best of our knowledge, this report is the first describing an antiracism training for WIC staff and delineates the (a) training framework, (b) design and key training components, and (c) evaluation, including results from 6 months post-training. This work was determined to be non-human subjects research by the Institutional Review Board at Temple University.
Methods
Training Framework
Informed by the lessons from the literature on effective bias trainings, we chose cultural humility as our training’s guiding framework. First developed in the late 1990s by Melanie Tervalon and Jann Murray-García to help address health disparities and institutional inequities in medicine, cultural humility is currently conceptualized as “the ability to maintain an interpersonal stance that is other-oriented in relation to aspects that are most important to the person” [21], p. 354). Key principles of cultural humility include: (1) a lifelong commitment to self-evaluation, -reflection, and -critique,(2) a willingness to right imbalances in power for respectful partnerships; and (3) a recognition of the need for institutional accountability [22]. According to Masters et al. [16], the practice of cultural humility helps promote empathy, mitigate bias, and allows providers to recognize the individuality of the person in their care. Using a cultural humility framework inherently brings more awareness into clinical encounters and incorporates skills identified as reducing biases in healthcare, such as perspective-taking, metacognition, and partnership-building [23, 24], all of which are equally germane to encounters in health service agencies like WIC.
Design and Key Training Elements
Between March and August of 2019, our training team of an Afro-Latinx, hospital-based midwife and antiracism educator and a White, community-based midwife with experience in public health research and bioethics, developed the foundational didactic 3-h antiracism training. In preparation, we held a focus group with WIC staff to elicit their feedback on the training content, including interactive scenarios based on their workplace experiences. Our intention in developing the training was to increase awareness and provide skills to reduce experiences of bias, prejudice, and racism at WIC as well as to make WIC visits more meaningful and less stressful for participants and staff. The five core components of the training are described below.Identity Web Reflection Exercise
We chose to begin the training with an “Identity Web Reflection” exercise to help participants consider how their identity shapes their worldview and an introduction to the concept of cultural humility. This exercise asks WIC staff trainees to: (1) draw a circle around their name in the middle of their paper; (2) put their most important identities, with at least three identities being ones they did not choose (e.g., immigrant, Black, oldest child) in five circles around their name; (3) reflect on questions like “Has belonging to one of these groups ever cost you, either personally or professionally?” and “Are there identity groups to which others assume (correctly or incorrectly) you belong?”; (4) partner with a colleague to share responses, considering which answers offered new insights; and (5) discuss with the group about if/how having more awareness of their personal identities can help them find common ground with one another as well as with WIC participants.
Definitions and Concepts in the Context of WIC, Philadelphia, and Perinatal Health Data
We intended to ground antiracism work in the specific context of Philadelphia (e.g., high poverty rates, racially diverse), the role and functions of WIC (e.g., participation coverage rates), and national and local perinatal health data (e.g., Black maternal mortality and morbidity rates). Framing these sobering statistics from a place of empathy acknowledges that WIC staff are being asked to do more with less, just as families experiencing poverty and health inequities are (e.g., they can partner with families to find creative, practical ways to still improve health/outcomes even in the context of less institutional and individual resources). We then planned to define racism, privilege/white privilege, white supremacy, implicit bias and cultural humility, as well as introduce a multilevel framework based on the socio-ecological model of behavior change examining individual, interpersonal, and institutional influences on interactions at WIC.
Workplace Scenario and Debrief
Based on focus group input, we prepared an interactive group discussion and debrief about how knowledge of health inequities and social/structural determinants of health impact the care given at WIC using “A Very Busy Day at WIC…” scenario (Fig. 1). WIC staff trainees were asked to apply a cultural humility framework to consider what they would say and do the same or differently in this scenario, and to think through how their response may be impacted by their personal identity and positionality in the workplace, as well as if the WIC participant in the scenario was, for example, White versus Black, or a Muslim person in garb versus a Spanish-speaking participant.
Review of a Model for Healing, Repair, and Disruption
Building on this increased awareness of cultural humility in their interactions with WIC participants and/or other staff, we decided to follow the workplace scenario with a simple, effective model for healing and repair, which deconstructs the different roles (e.g., mistake maker, upstander, and bystander) people play in social interactions, especially during conflicts [25]. In order to offer some specific avenues for taking action, we briefly reviewed the 5 Ds of Bystander Intervention (Delay, Delegate, Direct, Distract, Document) drawn from the violence prevention and community safety literature [26], but applied to situations involving racism and bias at WIC.
CARE Card Action Tool
We chose to conclude the training with the introduction of a novel action tool, the CARE Card (Fig. 2), intended to be visible at one’s desk at WIC as a reminder that this work is ongoing and lifelong. The double-sided, laminated card is designed to prompt WIC staff to be mindful and culturally humble in their interactions with participants and each other, rather than a linear checklist. The back of the card provides a visual of the individual, interpersonal, and institutional level framework we revisit throughout the session.
Fig. 1 Workplace scenario: “A very busy day at WIC”
Fig. 2 CARE card action tool
Assessment of the Program
To evaluate the antiracism training, we developed a series of 13 questions to assess WIC staff trainees’ knowledge of core concepts, awareness of their own identity, biases and privilege, and understanding of the role of racism in the US healthcare system. During implementation, we asked WIC staff trainees these questions at three timepoints (just before training, immediately after training, and 6 months post-training). We additionally created questions for trainees to rate their confidence to identify and address interactions that perpetuate racism at the individual, interpersonal, and institutional levels using a 5-point Likert Scale for responses, where 1 was “not at all,” 2 was “a little bit,” 3 was “somewhat,” 4 was “quite a bit,” and 5 was “extremely” confident. We framed our training and assessments in the context of the socio-ecological model for behavior change (at the individual, interpersonal, and institutional levels), as this model is often utilized by healthcare institutions and health service agencies to understand the many influences on health outcomes, and it is familiar to WIC staff. Right after the training, we additionally queried WIC staff trainees for feedback about each component and the training overall, assessing usefulness via a 5-point Likert scale for responses, where 1 was “not at all,” 2 was “a little bit,” 3 was “somewhat,” 4 was “quite a bit,” and 5 was “extremely” useful along with offering opportunities to give qualitative feedback. Surveys were available via a REDCap link to be completed by smartphone with paper copies available onsite for those who preferred that method. Responses were collected anonymously, managed using REDCap electronic data capture tools, and summarized as means/frequencies. We did not link individual trainee responses at each timepoint, limiting the examination of data to the cohort level only. Therefore, we used two-sided z-tests for independent proportions to compare responses before the training (baseline) to responses immediately after training, as well as responses at baseline to 6 months post-training. SAS version 9.4 [27] was utilized to carry out all analyses. While all WIC staff trainees (n = 42) completed the 3-h training session, we acknowledge there was attrition in the response rate for the posttest immediately after the training (n = 34), as well as in the number of responses we received at 6 months post-training (n = 32).
Results
We implemented the training in August 2019 on the required bimonthly education day for Philadelphia WIC nutrition professionals at agency headquarters. Our team provided lunch, administered a pre-assessment, and established community agreements (e.g., willingness to take risks, speak from one’s own experiences, etc.) before beginning didactics. Among 42 WIC staff trainees, the mean age was 30 years, 55% self-identified as white, 32% as Black or African American, 9% as Asian, 4% as other, 91% were female, and 74% had no prior antiracism training. Forty percent had worked at WIC for less than 1 year, 30% between 1 and 2 years, 12% between 3 and 5 years, 9% for 6–10 years, and 9% greater than 10 years. Eighty-six percent of staff trainees were WIC Nutrition Professionals (other remaining staff trainees were managers or administrators who worked at the WIC site where the training was conducted; they were not required to attend but chose to join the session). According to management at NORTH, Inc, there were approximately 44 Nutrition Professionals employed across all Philadelphia WIC offices at the time of the training. Thirty-six nutritional professionals attended the training, which is approximately 82% of the group required to attend.
Before the training, 48% of WIC staff trainees felt quite a bit or extremely aware of the role of racism in the US healthcare system; this increased to 91% immediately after and remained high at 6 months (75%) (p < 0.05 for changes from baseline to immediate posttest and from baseline to 6 months post-training using two-sided z-tests for independent proportions). At baseline, only 56% of trainees reported being quite a bit or extremely aware of their own biases and privilege. This increased to 91% immediately after the training and remained above baseline (81%) at the 6-month post-training assessment (p < 0.05 for changes from baseline to immediate posttest and from baseline to 6 months post-training using two-sided z-tests for independent proportions). While nutrition professionals reported increased confidence in identifying and addressing interactions that perpetuate racism at the individual, interpersonal, and institutional levels immediately after the training, their confidence in identifying and addressing interactions that perpetuate racism decreased at 6 months post-training at all levels (Table 1).Table 1 WIC nutrition professionals’ confidence in identifying and addressing interactions that perpetuate racism•
Pre-training
(n = 42) Immediately
post-training
(n = 34) Six months
post-training
(n = 32)
% trainees that reported “quite a bit” or “extremely” confident
Confidence in IDENTIFYING interactions that perpetuate racism at the individual level 49% 74%* 72%*
Confidence in ADDRESSING interactions that perpetuate racism at the individual level 37% 74%* 45%
Confidence in IDENTIFYING interactions that perpetuate racism at the interpersonal level 44% 77%* 61%
Confidence in ADDRESSING interactions that perpetuate racism at the interpersonal level 22% 64%* 52%*
Confidence in IDENTIFYING interactions that perpetuate racism in work setting (e.g., at the institutional level) 42% 76%* 65%
Confidence in ADDRESSING interactions that perpetuate racism in work setting (e.g., at the institutional level) 29% 73%* 45%
•For some responses, data were missing for one WIC staff trainee
*Changes from baseline to this time point were statistically significant (p < 0.05) using two-sided z-tests for independent proportions
Table 2 summarizes feedback immediately after the training about the usefulness of each program component as well as key qualitative feedback about each component. When queried about how their practice might change as a result of attending the workshop, WIC staff reflections included, “Learning to pause and think about my own implicit biases and try to be even more understanding of the participants situations,” and “I hope that I can have more mindful moments, where I'm taken back, or surprised by participants, who suffer and have such diverse experiences”. At 6 months post-training, one-third of WIC staff trainees felt quite a bit or extremely confident that the workshop content led to real changes in their interactions with WIC participants.Table 2 Evaluation of training components immediately post-training
Training components % trainees that reported “quite a bit” or “extremely” useful Qualitative feedback
Identity web exercise 88% “I thought it was very helpful and I was able to see things from a different perspective. I feel like I have more awareness now.”—Trainee 7
“I liked that I got to talk and explain an experience to a fellow coworker who is not from my background”—Trainee 3
“It made me think of things I was unaware of about my identity.”—Trainee 11
Definitions and discussion of concepts 90% “It (was) very helpful to define words and phrases that have a lot of political and racial tension around them. This invites clarity and understanding, rather than reactivity and division.”—Trainee 15
“Scholarly definitions help bring the words back from overly sensationalized click bait news articles. These words are thrown all over social media and the news so it’s great to remind ourselves what we are actually taking about.”—Trainee 22
A very busy day at WIC scenario 70% “We become immune to these situations rather than see each participant as an individual.”—Trainee 4
“This can be complicated because there are so many different people and angles to try and understand. Each of us suffer, and we act out when we don’t take care of ourselves.”—Trainee 21
CARE card action tool 90% “I find this to be a very helpful tool to find calm and to maintain self-care, as well as care for those different from you.”—Trainee 36
“Using the CARE card, (I’m) thinking about how the things participants go through affects our session.”—Trainee 40
Discussion
These findings suggest that a 3-h antiracism training grounded in cultural humility can change attitudes and awareness as well as confidence among WIC staff in identifying and addressing interactions that perpetuate individual, interpersonal, and systemic racism. WIC staff reported sustained increases in awareness of systemic racism and of their own biases and privilege for at least 6 months post didactics. Similar increases in confidence identifying and addressing interactions that perpetuate racism were achieved immediately after the training, although the magnitude decreased by 6 months. While WIC staff trainees’ reflections indicated they could see making changes to their practice as a result of the content presented, and one-third reported that the workshop led to changes in their interactions with WIC participants, we did not objectively assess whether changes in provider behaviors occurred (e.g., through observation) or query patients on their experiences.
Our results are aligned with those from a newly published paper, “Implementing a graduate medical education antiracism workshop at an academic university in the Southern USA” [28]. Similar to our training, content covered microaggressions, colorblindness, tokenism, stereotypes, levels of racism, the impact of racism on health, and antiracism concepts. A majority of participants who completed the post-training assessment reported they could apply knowledge to their work (95%) and found the workshop useful (95%). Over two-thirds reported being able to better identify disparities and better identify and communicate about racism. After the workshop, 75% thought differently about the healthcare impact of institutionalized racism. While Simpson and colleagues did not assess participants at 6 months post-training, many participants requested a longitudinal curriculum to build and sustain momentum around culture change. The consistent drop in WIC staff trainees’ confidence to identify and address interactions that perpetuate racism at 6 months post-training in our study further validates this need for disseminated practice in antiracism efforts.
Despite the fact that WIC staff trainees found the core training components in our study quite a bit or extremely useful, the workplace scenario and debrief elicited a wide range of responses and feelings among WIC staff trainees, including defensiveness. Trainees pointed out the competing priorities of accommodating challenges that participants face while still meeting agency expectations to follow protocols and rules, e.g., allowing participants who arrive late due to issues beyond their control such as public transportation challenges to still be seen on the same day versus following agency protocol to reschedule if more than 30 min late. This highlights how institutional level policies influence interactions between WIC participants and providers as well as among WIC staff [29], further demonstrated by the WIC enrollment process. Until the COVID-19 pandemic accelerated the passage of waivers at the federal level to allow for remote enrollment and issuance of benefits [30], the bureaucratic and protocol driven nature of WIC meant there had not been institutional acknowledgement of how the life context that positions families in need of WIC benefits may work against them having the agency, time, and skills needed to physically produce what is required [31]. However, remote enrollment has been an antiracist institutional change that took WIC participants’ social context into account and reduced the opportunity for WIC staff implicit and explicit biases about the person applying for benefits. Therefore, it felt significant that WIC staff trainees recognized the need for an integrated approach linking individual, interpersonal, and institutional efforts toward equity, not solely placing the onus for change on individual staff members working on their biases or addressing interpersonal racism in the workplace.
In order to address confidentiality concerns, we did not link individual trainee responses at each timepoint, limiting the examination of data on changes in attitudes, awareness, and behaviors to the cohort level only (necessitating the use of z-tests for independent proportions in analyses). Therefore, we could stratify by neither demographic variables (e.g., race, time at WIC) nor the impact of higher baseline competencies in the areas covered to determine which trainee characteristics were associated with attrition or survey completion. Further, while our original intention was to do an annual core training with three quarterly follow-up sessions, due to Pennsylvania WIC transitioning to electronic benefit transfer cards in the fall of 2019 followed by the onset of the COVID-19 pandemic, plans for ongoing sessions were indefinitely suspended. This could explain why confidence in addressing interactions that perpetuate racism at multiple levels was not sustained at 6 months. Lastly, evidence reviewed earlier in this report describes antiracism training as most impactful in the context of larger institutional efforts to advance equity, which is not yet happening in a comprehensive manner at Philadelphia WIC.
Despite limitations, the initial findings from the training remain promising and indicate further work is needed to study if and how these demonstrated changes in WIC staff trainees’ attitudes, actions, and awareness translate into improved care experiences for WIC participants. As such, these findings can inform institutional-level changes at Philadelphia WIC, including implementing antiracism trainings for all staff at Philadelphia WIC (with possible statewide dissemination); creating a confidential means for WIC participants to give feedback about their experiences that can inform both the agency’s policies and antiracism work; and advocating as an agency for inclusion of WIC staff in legislation that mandates antiracism training for perinatal providers. In this seminal moment of attention to Black maternal mortality and systemic racism, we believe offering ongoing antiracism training is a valuable step toward building the capacity of WIC staff to improve the participant experience and advance a culture of health equity.
Acknowledgements
We would like to thank NORTH, Inc., managers of the Philadelphia WIC program, for allowing us to offer the antiracism training as part of their professional development offerings.
Author Contribution
CS, MCF, GL, and MJ participated in the training design. CS and MCF implemented the training. CS and SH participated in the acquisition and analysis of data. CS, MCH, and SH participated in the drafting of the final manuscript. All authors participated in the critical review of the manuscript. All authors have given final approval to the manuscript.
Funding
Members of the study team were supported by grants from the National Institutes of Health (R01DK115939, R01HL130816).
Data Availability
Data is available upon request.
Declarations
Ethics Approval
This work was determined to be non-human subjects research by the Institutional Review Board at Temple University.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Conflict of Interest
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Villarosa L. 2018. Why America’s black mothers and babies are in a life-or-Death crisis: the answer to the disparity in death rates has everything to do with the lived experience of being a black woman in America. New York Times Magazine. https://www.nytimes.com/2018/04/11/magazine/black-mothers-babies-death-maternal-mortality.html. Accessed 15 Sept 2021.
2. Crear-Perry J (2018) Race isn’t a risk factor in maternal health. Racism is. Rewire News. https://rewire.news/article/2018/04/11/maternal-health-replace-race-with-racism/. Accessed 15 Sept 2021.
3. Bailey ZD Krieger N Agénor M Graves J Linos N Bassett MT Structural racism and health inequities in the USA: evidence and interventions The Lancet 2017 389 10077 1453 1463 10.1016/S0140-6736(17)30569-X
4. Hardeman RR Medina EM Kozhimannil KB Structural racism and supporting Black lives—the role of health professionals N Engl J Med 2016 375 22 2113 2115 10.1056/NEJMp1609535 27732126
5. Society of Maternal-Fetal Medicine (2020) Strategies to overcome racism’s impact on pregnancy outcomes. Society of Maternal-Fetal Medicine. smfm.org/equity.
6. Scott, K. A., Britton, L., McLemore, M. R. (2019). The ethics of perinatal care for Black Women: dismantling the structural racism in “Mother Blame” narratives. Journal Perinatal Neonatal Nursing, 33(2), 108–115. 10.1097/JPN.0000000000000394
7. Milner A Franz B Henry Braddock II J We need to talk about racism—in all of its forms—to understand COVID-19 disparities Health Equity 2020 4 1 397 402 10.1089/heq.2020.0069 32999950
8. United States Department of Agriculture (2018) WIC participant and program characteristics 2018—charts. USDA Food and Nutrition Services. https://www.fns.usda.gov/wic/participant-and-program-characteristics-2018-charts#1. Accessed 15 Sept 2021.
9. Gamblin M, Brooks C, Bassam N, Abu Khalaf NB (2019) Applying racial equity to U.S, federal nutrition assistance programs: SNAP, WIC and child nutrition. A Bread for the World Institute special report. Bread for the World Institute. https://www.paperturn-view.com/us/bread-for-the-world/applying-racial-equity-to-u-s-federal-nutrition-assistance-programs?pid=NTg58712&v=3. Accessed 15 Sept 2021.
10. March of Dimes (2017) PERISTATS Pennsylvania. Healthy moms. Strong babies. https://www.marchofdimes.org/Peristats/ViewSubtopic.aspx?reg=42&top=11&stop=448&lev=1&slev=4&obj=36. Accessed 15 Sept 2021.
11. Howell EA Reducing disparities in severe maternal morbidity and mortality Clin Obstet Gynecol 2018 61 2 387 399 10.1097/GRF.0000000000000349 29346121
12. Muse S, Dawes Gay E, Doyinsola Aina A, et al. (2018) Setting the standard for holistic care of and for Black women. Black Mamas Matter Alliance. http://blackmamasmatter.org/wp-content/uploads/2018/04/BMMA_BlackPaper_April-2018.pdf. Accessed 15 Sept 2021.
13. National WIC Association (2021a) How we can build a more modern WIC experience. National WIC Association. https://www.nwica.org/blog/take-action-how-we-can-build-a-more-modern-wic-experience#.Yh0iHJPMJhE. Accessed 15 Sept 2021.
14. United States Department of Agriculture (2017) WIC 2017 eligibility and coverage rates. USDA Food and Nutrition Services. https://www.fns.usda.gov/wic-2017-eligibility-and-coverage-rates. Accessed 15 Sept 2021.
15. Crawford, D. Crawford bias reduction theory and training (CBRT). Dr. Dana E. Crawford. http://drdanacrawford.com/home/cbrt/. Accessed 15 Sept 2021.
16. Masters, C., Robinson, D., Faulkner, S., Patterson, E., McIlraith, T., Ansari, A. (2019). Addressing biases in patient care with the 5Rs of cultural humility, a clinician coaching tool. Journal of General Internal Medicine, 34(4), 627–63. 10.1007/s11606-018-4814-y
17. FitzGerald C Martin A Berner D Hurst S Interventions designed to reduce implicit prejudices and implicit stereotypes in real world contexts: a systematic review BMC psychology 2019 7 1 29 10.1186/s40359-019-0299-7 31097028
18. Kalinoski ZT Steele-Johnson D Peyton EJ Leas KA Steinke J Bowling NA A meta-analytic evaluation of diversity training outcomes J Organ Behav 2013 34 8 1076 1104 10.1002/job.1839
19. Green TL, Hagiwara N (2020) The problem with implicit bias training. Scientific American: Behavior & Society Opinion. https://www.scientificamerican.com/article/the-problem-with-implicit-bias-training/. Accessed 15 Sept 2021.
20. Hagiwara N Kron FW Scerbo MW Watson GS A call for grounding implicit bias training in clinical and translational frameworks Lancet (London, England) 2020 395 10234 1457 1460 10.1016/S0140-6736(20)30846-1 32359460
21. Hook JN, Davis DE, Owen J, Worthington Jr EL, Utsey SO (2013) Cultural humility: measuring openness to culturally diverse clients. Journal of Counseling Psychology ®. 10.1037/a0032595.
22. Tervalon M Murray-García J Cultural humility versus cultural competence: a critical distinction in defining physician training outcomes in multicultural education J Health Care Poor Underserved 1998 9 2 117 125 10.1353/hpu.2010.0233 10073197
23. Balakrishnan K Arjmand EM The impact of cognitive and implicit bias on patient safety and quality Otolaryngol Clin North Am 2019 52 1 35 46 10.1016/j.otc.2018.08.016 30245040
24. Chapman EN Kaatz A Carnes M Physicians and implicit bias: how doctors may unwittingly perpetuate health care disparities J Gen Intern Med 2013 28 11 1504 1510 10.1007/s11606-013-2441-1 23576243
25. The Philadelphia School (2016) Tools for friendship. TPS Blog. https://www.tpschool.org/blog/2016/1/9/tools-for-friendship. Accessed 15 Sept 2021.
26. Center of Urban Pedagogy (2017) Show up: your guide to bystander intervention. https://www.ihollaback.org/app/uploads/2016/11/Show-Up_CUPxHollaback.pdf.
27. SAS Institute Inc (2013) SAS/ACCESS 9.4 Interface to ADABAS: Reference. Cary, NC: SAS Institute Inc.
28. Simpson T Evans J Goepfert A Elopre L Implementing a graduate medical education anti-racism workshop at an academic university in the Southern USA Med Educ Online 2022 27 1 1981803 10.1080/10872981.2021.1981803 34813390
29. Nazroo JY Bhui KS Rhodes J Where next for understanding race/ethnic inequalities in severe mental illness? Structural, interpersonal and institutional racism Sociol Health Illn 2020 42 2 262 276 10.1111/1467-9566.13001 31562655
30. National WIC Association. (2021b) The state of WIC: healthier pregnancies, babies and young children during COVID-19. National WIC Association. https://s3.amazonaws.com/aws.upl/nwica.org/state-of-wic-report-march-2021.pdf. Accessed 15 Sept 2021.
31. Violante, A. &Yates-Berg, A. (n.d.). Could temporary, behaviorally informed changes to WIC be program fixtures? IDEAS 42 Blog. https://www.ideas42.org/blog/could-temporary-behaviorally-informed-changes-to-wic-be-program-fixtures/. Accessed 15 Sept 2021.
| 36472807 | PMC9734826 | NO-CC CODE | 2022-12-14 23:28:30 | no | J Racial Ethn Health Disparities. 2022 Dec 6;:1-8 | utf-8 | J Racial Ethn Health Disparities | 2,022 | 10.1007/s40615-022-01465-6 | oa_other |
==== Front
Mol Biol
Mol Biol
Molecular Biology
0026-8933
1608-3245
Pleiades Publishing Moscow
8418
10.1134/S002689332206005X
Cell Molecular Biology
High Heterogeneity of Virus-Neutralizing and RBD-Binding Activities of COVID-19 Convalescent Sera
Astakhova E. A. 12
Byazrova M. G. 123
Yusubalieva G. M. 4
Larichev V. F. 5
Baklaushev V. P. 4
Filatov A. V. [email protected]
12
1 grid.465277.5 National Research Center “Institute of Immunology”, Federal Medical-Biological Agency, 115522 Moscow, Russia
2 grid.14476.30 0000 0001 2342 9668 Immunology Department, Biological Faculty, Moscow State University, 119234 Moscow, Russia
3 grid.77642.30 0000 0004 0645 517X Рeoples Friendship University of Russia (RUDN University) of Ministry of Science and Higher Education of Russia, 117198 Moscow, Russia
4 grid.465277.5 Federal Research and Clinical Center for Specialized Types of Medical Care and Medical Technologies, Federal Medical-Biological Agency, 115682 Moscow, Russia
5 grid.415738.c 0000 0000 9216 2496 Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia
9 12 2022
2022
56 6 10281035
4 6 2022
5 7 2022
5 7 2022
© Pleiades Publishing, Inc. 2022, ISSN 0026-8933, Molecular Biology, 2022, Vol. 56, No. 6, pp. 1028–1035. © Pleiades Publishing, Inc., 2022.Russian Text © The Author(s), 2022, published in Molekulyarnaya Biologiya, 2022, Vol. 56, No. 6, pp. 1095–1103.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
The parameters of the humoral response are an important immunological characteristic of donors who recovered from COVID-19 and vaccinated individuals. Analysis of the level of virus-binding antibodies has become widespread. The most accurate predictor of effective immune protection against symptomatic SARS-CoV-2 infection is the activity of virus-neutralizing antibodies. We determined virus-neutralizing activities in plasma samples of individuals (n = 111) who had COVID-19 from April to September 2020. Three independent methods were used: conventional with live virus, with virus-like particles pseudotyped with spike protein, and a surrogate virus-neutralization test (cVNT, pVNT and sVNT, respectively). For comparison, the levels of IgG, IgA and IgM antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein were also evaluated. The levels of virus-binding as well as virus-neutralizing antibodies in cVNT and pVNT showed high heterogeneity. A comparison of cVNT and pVNT results showed a high correlation, sVNT results also correlated well with both cVNT and pVNT. To the greatest extent, the level of IgG antibodies correlated with the results of cVNT, pVNT and sVNT. These results can be used in the selection of plasmas that are best suited for transfusion and treatment of acute COVID-19. In addition, data on the virus-neutralizing activity of plasma are important for the selection of potential donors, for the isolation of SARS-CoV-2-specific B-lymphocytes, in order to further generate monoclonal virus-neutralizing antibodies.
Keywords:
COVID-19
SARS-CoV-2
virus neutralizing antibodies
human plasma
convalescents
issue-copyright-statement© Pleiades Publishing, Inc. 2022
==== Body
pmcIn the context of the current COVID-19 pandemic, serological analysis of biological samples has great importance. The humoral immune response is an important characteristic for both naturally recovered and vaccinated individuals [1]. Monitoring antibody levels against SARS-CoV-2 is essential to predict the risk of reinfection and assess the effectiveness of vaccination. In addition, these parameters are used for retrospective contact tracing of sick patients, estimates of the number of asymptomatic carriers, and for estimating the level of herd immunity.
In serological assays for SARS-CoV-2, two viral proteins are commonly used as antigens: the nucleoprotein (N) and the spike protein (S). SARS-CoV-2 binds to its receptor on the host cell through the receptor-binding domain (RBD) of the S-protein, therefore RBD is considered the main target for neutralizing antibodies [2]. Thus, the level of S- and RBD-binding antibodies may indirectly indicate the neutralizing activity of the serum. A high level of virus-neutralizing antibodies is a good predictor of effective immune protection against the symptomatic course of COVID-19 [3, 4], so the determination of virus-binding antibodies should be supplemented by direct measurement of the level of virus-neutralizing antibodies. Note that the analysis for virus-binding antibodies is well developed and widely used in laboratory practice, while the determination of virus-neutralizing antibodies is available only to specialized laboratories.
In the early stages of the SARS-CoV-2 pandemic, when there was an acute lack of reliable therapeutic agents for the treatment of COVID-19, plasma transfusion of convalescents was the only possible etiotropic therapy. Transfusion of plasma from donors who have recovered from COVID-19 has the potential to provide immediate passive immunization and protection against SARS-CoV-2 infection. However, the effectiveness of plasma therapy was ambiguous. The most successful method is the use of convalescent plasma in the early stages of the disease ‒ shortly after hospitalization. The use of plasma with a high titer of anti-S protein or RBD antibodies is also a prime factor. Transfusion of convalescent plasma provided a more than twofold increase in patient survival compared to control groups with properly selected parameters [5]. All this indicates that the plasma intended for transfusion must be strictly controlled for virus-neutralizing activity.
There are several methods for determining the virus-neutralizing activity of sera, each of which is divided into several sub-variants. These are, firstly, a method using a native live SARS-CoV-2 virus—a conventional virus neutralization test (cVNT), secondly, using virus-like particles pseudotyped with an S protein (pVNT) [6], and finally surrogate VNT (sVNT) [7].
The aim of the study was to compare the virus-neutralizing activity of convalescent plasma samples determined by three different methods: cVNT, pVNT and sVNT. An attempt was made to assess the variability in the virus-neutralizing activity of plasma samples and compare it with the virus-binding activity of the same samples.
EXPERIMENTAL
Characteristics of patients. The study included volunteers (n = 111) who suffered from COVID-19 between April and September 2020. Most of the patients (86%) received inpatient treatment at the FRCC FMBA of Russia, some patients—in other medical institutions in Moscow or at home. All participants were diagnosed with COVID-19 based on PCR testing and/or clinical findings. 1–3 months after recovery, volunteers donated blood plasma to the FRCC of the FMBA of Russia for subsequent transfusion to sick patients. Plasma harvesting was performed by plasmapheresis, the volume of plasma harvested was 640 mL for each donor. In our study, 100 microliter aliquots of plasma were used.
Patients who recovered from COVID-19 ranged in age from 18 to 52 years (median 38 years, interquartile range (IQR) 21 to 43 years); 68 of them were men (61.2%) and 43 women (38.8%). The comparison group included healthy donors (n = 25). The comparison group in terms of age and the ratio of men and women corresponded to the COVID-19 recovered group. Venous blood from healthy volunteers was collected into heparinized tubes (Sarstedt, Germany), then the tubes were centrifuged for 10 min at 300 g and plasma was collected. Plasma samples (100 µL aliquots) were frozen and stored at –70°C.
ELISA quantification of anti-RBD antibodies. The levels of anti-RBD antibodies in plasma was determined by ELISA using commercial plates coated with RBD (#K153G, Xema Medica, Russia) according to the manufacturer’s instructions. Antibodies against human IgG, IgA, and IgM conjugated with horseradish peroxidase (Cat. nos. 109-036-088, 109-035-129, 109-035-011, Jackson Immuno Research, USA) were used as detection reagents. 100 μL of the peroxidase substrate, 3,3',5,5'-tetramethyl benzidine (TMB), was added to each well and incubated until a blue color appeared. The reaction was stopped by adding 100 μL of stop reagent. The optical density of the solution was measured using a BioRad iMark Microplate Absorbance Reader photometer (Bio-Rad, United States).
All samples were titrated to find the linear region on the plot of absorbance (OD450) versus plasma dilution. A point in the middle of the linear section of the titration curve was used to determine the level of antibodies. The concentration of anti-RBD IgG antibodies was determined in absolute units (ng/mL), using the human monoclonal antibody 34B12 with a known concentration as a standard (kindly provided by Doctor of Biological Sciences A.V. Taranin, Institute of Molecular and Cell Biology SB RAS, Novosibirsk [8]). The levell of anti-RBD IgA and IgM antibodies were determined in relative units, using the plasma of one of the donors as a standard.
cVNT (conventional virus-neutralizing test). The analysis was performed on Vero E6 cells that were infected with authentic SARS-CoV-2 (strain hCoV-19/Russia/Moscow-PMVL-12/2020) at a dose of 100 TCID50 (50% tissue cytopathic infectious dose). The cytopathic effect was assessed visually after 96 h using an inverted microscope. The virus-neutralizing activity of plasma samples was determined by the suppression of the cytopathic effect of the virus. The cytopathic effect of the virus in the absence of plasma was taken as 100%. Plasma was titrated starting from a dilution of 1 : 10. The highest dilution of plasma, at which no cytopathic effect on 100 TCID50 of the virus had yet developed, was taken as the antibody titer. Experiments on neutralization were accompanied by control of the working dose of the virus, the toxicity and the sterility of sera.
pVNT (pseudovirus-based virus-neutralizing test). This assay was performed on HEK-293 cells stably transfected with a plasmid expressing angiotensin converting enzyme-2 (ACE2). Lentiviral virus-like particles (VLPs) pseudotyped with SARS-CoV-2 S‑protein were added to target cells. The VLPs carried the green fluorescent protein (GFP) reference gene, which was expressed in infected cells. The dose of VLPs was selected so that in the absence of antibodies, 50% of target cells were infected—they were detected by GFP fluorescence using a CytoFLEX S flow cytometer (Beckman Coulter, USA). When the infection was completely inhibited, the target cells did not give a fluorescent signal. For each serum, five 5-fold serial dilutions were made, starting at 1 : 4. The results were presented as the serum dilution at which 50% inhibition (ID50) of cell infection was observed, calculated from the Sigmoidal titration plot, 5PL, in the GraphPad Prism program (USA).
sVNT (surrogate virus-neutralizing test). This assay was performed using the SARS-CoV-2 VNAFA K533 kit (#2104, Xema Medica) according to the manufacturer’s recommendations. Plasma samples were diluted 10-fold with sample buffer and a solution of RBD conjugate with horseradish peroxidase (RBD-HRP) was added to them in a ratio of 1 : 10 (v/v). The mixture was incubated for 30 min at 37°C, after which 100 μL of the reaction mixture was transferred to an ACE2-coated plate and incubated for another 30 min at 37°C. The wells were washed 5 times with wash buffer. The reaction was shown and recorded in the same way as described above when performing ELISA. Data were analyzed using Zemfira 4.0 software.
Statistical analysis. The data were processed using the GraphPad Prism software version 8.4.3 (GraphPad, USA). The significance of differences between samples was assessed using the Mann–Whitney test. Differences in the compared parameters were considered statistically significant at p < 0.05. The graphs show medians (middle line), third, and first quartiles (rectangles), whiskers show a 1.5-fold interquartile range. A quantitative assessment of the statistical relationship between the parameters was carried out by calculating the coefficients of linear regression, as well as Spearman’s rank correlation (r).
RESULTS
The study included patients who had COVID-19 between April and September 2020. At that time, the Wuhan strain of SARS-CoV-2 or its variant with the D614G substitution in the S protein circulated in Russia [9–11].
Level of RBD-Binding Antibodies
First of all, the level of RBD-binding antibodies was determined in the plasma of patients who recovered from COVID-19. The results of IgG quantitation and semiquantitative IgA and IgM levels of anti-RBD antibodies are shown on Fig. 1. The results for healthy donors are represented as a negative control.
Fig. 1. Distribution of IgG (a), IgA (b), and IgM (c) antibodies to SARS-CoV-2 spike protein RBD in patients who recovered from COVID-19. Box plots on the left and violin plots on the right. Each dot represents a plasma sample. Gray dots indicate samples obtained from patients who recovered from COVID-19; white dots are from healthy volunteers. The horizontal dotted lines represent the cutoff threshold.
For IgG antibodies in recovered patients, the median was 1819.7 ng/mL (IQR 635.3–4753.4), while for healthy donors it was 16.9 ng/mL (IQR 2.0–27.4) (p < 0.0001). For IgA antibodies, these values were 118.0 rel. units (IQR 52.72–208.9) and 13.5 rel. units (IQR 3.9–18.3), respectively (p < 0.0001); for IgM antibodies, 251.8 rel. units (IQR 103.5–669.9) and 10.3 rel. units (IQR 1.44–20.41), respectively (p < 0.0001).
The analysis of the distribution of the level of antibodies in a cohort of patients showed high heterogeneity of this parameter. The content of RBD-binding antibodies varied quite widely, within 5, 3, and 4 orders of magnitude, respectively, for IgG, IgA, and IgM antibodies. At the same time, the distribution of RBD-specific IgG and IgM antibodies differed markedly from a normal distribution, which was confirmed by analysis by the D’Agostino-Pearson method (p < 0.0001). We hypothesized that the reason for the deviation from the normal distribution is the presence of several null values of RBD-specific IgG and IgM antibodies. When zero values were excluded from the samples, the distribution of values for IgG and IgM antibodies approached a normal distribution (p = 0.8170 and p = 0.0504, respectively). For IgA antibodies, the initial distribution was close to normal (p = 0.2911).
Level of Virus-Neutralizing Antibodies
The virus-neutralizing activity of plasma samples was determined using three independent methods: cVNT, pVNT and sVNT. Most of the participants had neutralizing antibodies: 101/111 (91%), 91/111 (82%) and 88/111 (79%) patients, respectively.
The levels of virus-neutralizing antibodies determined by the cVNT and pVNT methods were heterogeneous (Fig. 2), while the sVNT results varied within two orders of magnitude. This is understandable, since sVNT results are represented as percentage of virus neutralization, which, by definition, does not exceed 100%. The actual distribution of sVNT results could be wider, which was not observed, since plasma samples with high titers fell into the saturation region.
Fig. 2. Distribution of levels of virus-neutralizing antibodies in patients who recovered from COVID-19. The results of the cVNT (a), pVNT (b), and sVNT (c) methods are presented. The horizontal dotted lines represent the cutoff threshold.
The distribution of virus-neutralizing activity of plasma samples, as well as the levels of RBD-binding antibodies, deviated from a normal distribution. The presence of points with zero neutralizing activity was one of the characteristics of this distribution. It can be assumed that the zero points appeared as a result of the erroneous inclusion in the study group of individuals who did not have COVID-19. In this case, the plasma samples taken would give zero values at once in several tests, but this was not observed.The appearance of zero points was probably due to the different sensitivity and/or specificity of the test systems used.
Correlation between the Levels of RBD-Binding Antibodies and Virus-Neutralizing Activity
We conducted a correlation analysis in order to assess the relationship between the results obtained by different methods. First of all, we evaluated the relationship between data on the binding of antibodies to RBD and virus neutralizing activity (Fig. 3a). The level of IgG antibodies correlated to the greatest extent with the results of cVNT, pVNT, and sVNT (r = 0.677, p < 0.0001; r = 0.624, p < 0.0001; r = 0.615, p < 0.0001, respectively). A slightly lower correlation was found between cVNT, pVNT, sVNT and the level of IgA antibodies (r = 0.63, p < 0.0001; r = 0.581, p < 0.0001; r = 0.444, p < 0.0001, respectively). Finally, the IgM level weakly correlated with sVNT (r = 0.367, p = 0.001) with good correlation with cVNT and pVNT (r = 0.671, p < 0.0001; r = 0.716, p < 0.0001, respectively).
Fig. 3. Correlation analysis of the activity of convalescent plasma samples. (a) Comparison of the results of virus neutralization tests: cVNT, pVNT, and sVNT with data on the determination of IgG, IgA, and IgM antibodies against RBD. (b) Comparison of the results of tests for virus neutralization: cVNT, pVNT and sVNT—with each other. (c) Heat map of correlation coefficients according to Spearman. Straight lines represent linear regression trend lines. On the subpanels, the numbers indicate the coefficients of linear regression, as well as the rank correlation according to Spearman (r). Responses with low values when presented on logarithmic scales were taken equal to 1.
Comparison of the results obtained by different modifications of the virus-neutralization tests is shown in Fig. 3b. As expected, the highest correlation of results was found for cVNT and pVNT (r = 0.841, p < 0.0001), and it was somewhat weaker for cVNT and sVNT (r = 0.643, p < 0.0001) and pVNT and sVNT (r = 0.665, p < 0.001).
DISCUSSION
The most adequate approach to determine the virus-neutralizing activity of plasma is using live SARS-CoV-2 virus. The cVNT method is one of the most accurate and informative approaches because it reveals the effect of antibodies that neutralize the virus by various mechanisms [12]. The cVNT method is based on the use of a replication-competent virus, and therefore it is carried out in laboratories with a biosafety level of at least BSL3 (according to the International Biosafety Level Classification), and this greatly limits its use. The disadvantages of cVNT also include subjectivity in assessing the cytopathic effect of target cells and the discrete nature of the received data. While the first drawback is leveled by many years of experience and qualifications of the researcher, the lack of continuity of the results obtained complicates subsequent statistical analysis.
Virus-like particles pseudotyped with the SARS-CoV-2 S-protein mimic the initial stages of the virus life cycle: its binding and fusion with the target cell [6]. The pVNT method is much easier to perform than the cVNT method and allows work in laboratories with a BSL2 biosafety level. As a result of these circumstances, pVNT has become widespread in research laboratories.
It should be noted that both cVNT and pVNT require living cells; in addition, an important factor is the qualification of the performer. Due to these limitations, the above methods are not widely used in clinical diagnostic practice. As an additional method, we used the so-called surrogate virus neutralization test, sVNT [7]. It can be classified as a rapid test, as it allows assessment of the virus-neutralizing effect of plasma samples in just 1–2 hours, while cVNT and pVNT take several days. The disadvantages of sVNT include limited specificity: it can detect only antibodies that work exclusively by the mechanism of blocking the binding of RBD with ACE2 [7].
It is interesting to note that a small proportion of convalescents had practically no virus-neutralizing antibodies. This observation is consistent with previously published data that 2% of patients who recovered from COVID-19 do not produce neutralizing antibodies [13]. Notably, the largest number of such patients (n = 23) was detected using sVNT, a test that detects only RBD-neutralizing antibodies. It can be assumed that some plasma samples from this group of recovered patients contained neutralizing antibodies that bind to the S protein outside the RBD region [14]. Indeed, it has been previously shown that antibodies to the N-terminal domain or the S2 region of the S-protein can also be involved in the neutralization of the virus [15].
Despite the noted differences revealed by us, as well as in some other studies, different methods of virus neutralization correlate well with each other [16–18]. The highest correlation coefficient was found between the values obtained in the cVNT and pVNT tests (r = 0.841). This means that the cVNT test can in most cases be replaced by the pVNT test when assessing the SARS-CoV-2 neutralizing activity of antibodies in donor plasma. With certain reservations, all three tests can be used to evaluate the neutralizing activity of plasma samples. Comparison of the results on virus-neutralizing activity and the content of RBD-specific antibodies makes it possible to evaluate the contribution of different isotypes to the neutralizing ability of a particular plasma sample. For each neutralization test used, the highest correlation coefficients were obtained for IgG antibodies. This indicates the predominant role of IgG antibodies, over IgM and IgA, in blocking the interaction of the virus RBD with its receptor, ACE2. It is interesting to compare these results with published data for other groups of convalescents, as well as for emerging variants of SARS-CoV-2.
Note that recently our compatriots, D. Kolesov et al. [14], published work similar to that presented here. Their study was also performed on the Moscow population and with the participation of patients who had been infected with Wuhan or similar variants of SARS-CoV-2 [14]. However, in our study, we obtained lower correlation coefficients between the results of cVNT, sVNT, and the anti-RBD test. Perhaps this is due to the different sVNT formats. It can also be noted that our correlation coefficient between sVNT and anti-RBD test is comparable to that for vaccinated individuals [17].
On a sufficiently large sample, we found a high heterogeneity of convalescent plasmas. Samples with high virus-neutralizing activity attract the most attention - titers exceeded 1000 in cVNT, and ID50 values were above 1000 in pVNT. These plasma samples are among the most promising for subsequent transfusion in patients in the acute phase of COVID-19. The percent of such samples is small (no more than 5%). Plasma with a moderate amount of virus-neutralizing antibodies (titers in the range from 90 to 300 in cVNT and ID50 values in the range from 100 to 1000 in pVNT) prevailed in the sample. Previously, it was suggested that heterogeneity in the virus-neutralizing activity of plasma/serum in patients with COVID-19 may be associated with severity of disease [19, 20], as well as with different timing of sampling. The variability in the virus-neutralizing activity of plasma samples was most clearly manifested when comparing different mutant variants of SARS-CoV-2 [16]. The low virus-neutralizing activity of blood plasma/serum in some patients with COVID-19 may be one of the reasons for re-infection [21].
Thus, a comparison of tests to assess the virus-neutralizing activity of plasma samples of COVID-19 convalescents allows us not only to answer the question of the mutual substitution of one or another test, but also to identify samples that contain antibodies against SARS-CoV-2 that work through different neutralization mechanisms. It seems important to use such test systems for the preliminary selection of donors for sorting single SARS-CoV-2-specific B-lymphocytes in order to generate human monoclonal virus-neutralizing antibodies.
FUNDING
This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement no. 075-15-2021-1086, contract no. RF-193021X0015, 15.IP.21.0015).
COMPLIANCE WITH ETHICAL STANDARDS
Conflict of interests. The authors declare that they have no conflicts of interest.
Statement of compliance with standards of research involving humans as subjects. All research involving humans comply with the ethical standards of the institutional and/or national research ethics committee and the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. Informed consent was obtained from each of the participants included in the study. The study protocol was approved by the local ethics committee of the FRCC FMBA of Russia (protocol #4-2020 April 28, 2020).
Abbreviations: cVNT, conventional virus neutralization test; ID50, half-maximal inhibitory dilution; IQR, interquartile range; RBD, receptor-binding domain; pVNT, pseudovirus-based virus neutralization test; S, spike protein of SARS-CoV-2; sVNT, surrogate virus neutralization test; VLP, virus-like particles.
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REFERENCES
1 Qi H. Liu B. Wang X. Zhang L. The humoral response and antibodies against SARS-CoV-2 infection Nat. Immunol. 2022 23 1008 1020 10.1038/s41590-022-01248-5 35761083
2 Premkumar L., Segovia-Chumbez B., Jadi R., Martinez D.R., Raut R., Markmann A., Cornaby C., Bartelt L., Weiss S., Park Y., Edwards C.E., Weimer E., Scherer E.M., Rouphael N., Edupuganti S., Weiskopf D., Tse L.V., Hou Y.J., Margolis D., Sette A., de Silva A.M. 2020. The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci. Immunol. 5 (48), eabc8413.
3 Cromer D. Steain M. Reynaldi A. Schlub T.E. Wheatley A.K. Juno J.A. Kent S.J. Triccas J.A. Khoury D.S. Davenport M.P. Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis Lancet Microbe. 2022 3 e52 e61 10.1016/S2666-5247(21)00267-6 34806056
4 Khoury D.S. Cromer D. Reynaldi A. Schlub T.E. Wheatley A.K. Juno J.A. Subbarao K. Kent S.J. Triccas J.A. Davenport M.P. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection Nat. Med. 2021 27 1205 1211 10.1038/s41591-021-01377-8 34002089
5 Baklaushev V.P. Averyanov A.V. Sotnikova A.G. Perkina A.S. Ivanov A.V. Yusubalieva G.M. Novikova O.N. Shikina V.E. Dupik N.V. Kedrova A.G. Sanjarov A.E. Shirshova E.V. Balionis O.I. Valuev-Elliston V.T. Zakirova N.F. Glazov Ya.N. Panukhina I.A. Solov’ev N.A. Vinokurov A.G. Ivanov Yu.V. Vasiliev V.N. Klypa T.V. Troitskiy A.V. Safety and efficacy of convalescent plasma for COVID-19: the first results of a clinical study Klin. Prakt. 2020 11 38 50
6 Bewley K.R. Coombes N.S. Gagnon L. McInroy L. Baker N. Shaik I. St-Jean J.R. St-Amant N. Buttigieg K.R. Humphries H.E. Godwin K.J. Brunt E. Allen L. Leung S. Brown P.J. Penn E.J. Thomas K. Kulnis G. Hallis B. Carroll M. Charlton S. Quantification of SARS-CoV-2 neutralizing antibody by wild-type plaque reduction neutralization, microneutralization and pseudotyped virus neutralization assays Nat. Protoc. 2021 16 3114 3140 10.1038/s41596-021-00536-y 33893470
7 Tan C.W. Chia W.N. Qin X. Liu P. Chen M.I. Tiu C. Hu Z. Chen V.C. Young B.E. Sia W.R. Tan Y.J. Foo R. Yi Y. Lye D.C. Anderson D.E. Wang L.F. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction Nat. Biotechnol. 2020 38 1073 1078 10.1038/s41587-020-0631-z 32704169
8 Gorchakov A.A. Kulemzin S.V. Guselnikov S.V. Baranov K.O. Belovezhets T.N. Mechetina L.V. Volkova O.Y. Najakshin A.M. Chikaev N.A. Chikaev A.N. Solodkov P.P. Larichev V.F. Gulyaeva M.A. Markhaev A.G. Kononova Y.V. Alekseyev A.Y. Shestopalov A.M. Yusubalieva G.M. Klypa T.V. Ivanov A.V. Taranin A.V. Isolation of a panel of ultra-potent human antibodies neutralizing SARS-CoV-2 and viral variants of concern Cell Discov. 2021 7 96 10.1038/s41421-021-00340-8 34667147
9 Gushchin V.A. Dolzhikova I.V. Shchetinin A.M. Odintsova A.S. Siniavin A.E. Nikiforova M.A. Pochtovyi A.A. Shidlovskaya E.V. Kuznetsova N.A. Burgasova O.A. Kolobukhina L.V. Iliukhina A.A. Kovyrshina A.V. Botikov A.G. Kuzina A.V. Grousova D.M. Tukhvatulin A.I. Shcheblyakov D.V. Zubkova O.V. Karpova O.V. Gintsburg A.L. Neutralizing activity of sera from Sputnik V-vaccinated people against variants of concern (VOC: B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3) and Moscow endemic SARS-CoV-2 variants Vaccines 2021 9 779 10.3390/vaccines9070779 34358195
10 Komissarov A.B. Safina K.R. Garushyants S.K. Fadeev A.V. Sergeeva M.V. Ivanova A.A. Danilenko D.M. Lioznov D. Shneider O.V. Shvyrev N. Spirin V. Glyzin D. Shchur V. Bazykin G.A. Genomic epidemiology of the early stages of the SARS-CoV-2 outbreak in Russia Nat. Commun. 2021 12 649 10.1038/s41467-020-20880-z 33510171
11 Matsvay A, Klink G.V., Safina K.R., Nabieva E., Garushyants S.K., Biba D., Bazykin G.A., Mikhaylov I.M., Say A.V., Zakamornaya A.I., Khakhina A.O., Lisitsa T.S., Ayginin A.A., Abramov I.S., Bogdan S.A., Kolbutova K.B., Oleynikova D.U., Avdeenko T.F., Shipulin G.A., Yudin S.M., Skvortsova V.I. 2021. Genomic epidemiology of SARS-CoV-2 in Russia reveals recurring cross-border transmission throughout 2020. medRxiv. 2021, 10.1101/2021.03.31.21254115
12 Saade C. Gonzalez C. Bal A. Valette M. Saker K. Lina B. Josset L. Trabaud M.A. Thiery G. Botelho-Nevers E. Paul S. Verhoeven P. Bourlet T. Pillet S. Morfin F. Trouillet-Assant S. Pozzetto B. Live virus neutralization testing in convalescent patients and subjects vaccinated against 19A, 20B, 20I/501Y.V1 and 20H/501Y.V2 isolates of SARS-CoV-2 Emerg. Microbes Infect. 2021 10 1499 1502 10.1080/22221751.2021.1945423 34176436
13 Fafi-Kremer S. Bruel T. Madec Y. Grant R. Tondeur L. Grzelak L. Staropoli I. Anna F. Souque P. Fernandes-Pellerin S. Jolly N. Renaudat C. Ungeheuer M.N. Schmidt-Mutter C. Collongues N. Bolle A. Velay A. Lefebvre N. Mielcarek M. Meyer N. Fontanet A. Serologic responses to SARS-CoV-2 infection among hospital staff with mild disease in eastern France EBioMedicine. 2020 59 102915 10.1016/j.ebiom.2020.102915 32747185
14 Kolesov D.E. Sinegubova M.V. Dayanova L.K. Dolzhikova I.V. Vorobiev I.I. Orlova N.A. Fast and accurate surrogate virus neutralization test based on antibody-mediated blocking of the interaction of ACE2 and SARS-CoV-2 spike protein RBD Diagnostics 2022 12 393 10.3390/diagnostics12020393 35204485
15 Jiang S. Hillyer C. Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses Trends Immunol. 2020 41 355 359 10.1016/j.it.2020.03.007 32249063
16 Jaafar R. Boschi C. Aherfi S. Bancod A. Le Bideau M. Edouard S. Colson P. Chahinian H. Raoult D. Yahi N. Fantini J. La Scola B. High individual heterogeneity of neutralizing activities against the original strain and nine different variants of SARS-CoV-2 Viruses. 2021 13 2177 10.3390/v13112177 34834983
17 Krüttgen A. Lauen M. Klingel H. Imöhl M. Kleines M. Two novel SARS-CoV-2 surrogate virus neutralization assays are suitable for assessing successful immunization with mRNA-1273 J. Virol. Methods. 2022 299 114297 10.1016/j.jviromet.2021.114297 34563583
18 Wisnewski A.V. Liu J. Lucas C. Klein J. Iwasaki A. Cantley L. Fazen L. Campillo Luna J. Slade M. Redlich C.A. Development and utilization of a surrogate SARS-CoV-2 viral neutralization assay to assess mRNA vaccine responses PLoS One. 2022 17 e0262657 10.1371/journal.pone.0262657 35041700
19 Chen X. Pan Z. Yue S. Yu F. Zhang J. Yang Y. Li R. Liu B. Yang X. Gao L. Li Z. Lin Y. Huang Q. Xu L. Tang J. Hu L. Zhao J. Liu P. Zhang G. Chen Y. Ye L. Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19 Signal. Transduct. Target. Ther. 2020 5 180 10.1038/s41392-020-00301-9 32879307
20 Legros V. Denolly S. Vogrig M. Boson B. Siret E. Rigaill J. Pillet S. Grattard F. Gonzalo S. Verhoeven P. Allatif O. Berthelot P. Pélissier C. Thiery G. Botelho-Nevers E. Millet G. Morel J. Paul S. Walzer T. Cosset F. L. Pozzetto B. A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity Cell. Mol. Immunol. 2021 18 318 327 10.1038/s41423-020-00588-2 33408342
21 Gallais F. Gantner P. Bruel T. Velay A. Planas D. Wendling M. J. Bayer S. Solis M. Laugel E. Reix N. Schneider A. Glady L. Panaget B. Collongues N. Partisani M. Lessinger J. M. Fontanet A. Rey D. Hansmann Y. Kling-Pillitteri L. Fafi-Kremer S. Evolution of antibody responses up to 13 months after SARS-CoV-2 infection and risk of reinfection EBioMedicine. 2021 71 103561 10.1016/j.ebiom.2021.103561 34455390
| 0 | PMC9734827 | NO-CC CODE | 2022-12-14 23:28:30 | no | Mol Biol. 2022 Dec 9; 56(6):1028-1035 | utf-8 | Mol Biol | 2,022 | 10.1134/S002689332206005X | oa_other |
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Learn Environ Res
Learn Environ Res
Learning Environments Research
1387-1579
1573-1855
Springer Netherlands Dordrecht
9443
10.1007/s10984-022-09443-9
Original Paper
Development and validation of the online learning process questionnaire (OLPQ) at home for primary-school children and their caregivers
Lam Joseph Hin Yan
Tong Shelley Xiuli [email protected]
grid.194645.b 0000000121742757 Human Communication, Development, and Information Sciences, Faculty of Education, The University of Hong Kong, Pokfulam Road, Hong Kong, China
6 12 2022
124
4 6 2021
17 11 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Despite the increasing use of virtual modalities in schools since the COVID-19 pandemic, no systematic tools exist to evaluate the process of online learning. We developed and validated an Online Learning Process Questionnaire (OLPQ) for assessing online at-home learning among 219 Hong Kong primary-school students and 474 caregivers. Exploratory and confirmatory factor analyses of caregivers’ data classified the 58-item OLPQ into 11 subscales: (1) learning aims, (2) environmental structuring, (3) learning environment, (4) time management, (5) engagement in learning activities, (6) persistence, (7) interaction between teachers and students, (8) interaction among students, (9) feedback from the interface, (10) application of learning, and (11) meaning of learning under three learning phases. Confirmatory factor analysis of students’ data further categorized the 11-subscale framework into three learning phases: preparatory, performance, and transfer. The OLPQ demonstrated excellent reliability and discriminant validity across caregiver (Cronbach’s alpha = 0.98) and student samples (alpha = 0.98). These findings indicate that the OLPQ is a valid and reliable instrument for assessing the online at-home learning process among both students and their caregivers.
Keywords
At-home online learning
Caregivers and students
Scale development
School-age children
Virtual modalities
Equal Opportunities Commission, Hong KongR-2020/21-111 Tong Shelley Xiuli Research Grant Council, Hong Kong SAR RFS2021-7H05 17620520 Tong Shelley Xiuli
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pmcIntroduction
Online learning has become an increasingly-popular model of instruction in primary schools around the world, especially during the COVID-19 pandemic. Compared with traditional classroom-based instruction, online learning advantageously transcends geographical barriers, allows for flexible learning speeds, and improvesstudents’ technological skills (e.g., Allen & Seaman 2014; Livingstone & Bober, 2004; Picciano & Seaman, 2007). However, as online learning requires students to be more self-motivated and self-sufficient, it places higher demands on students’ metacognitive and behavioral skills (Cho et al., 2010). Despite the increasing adoption of online learning and its advantages, no learning-specific tool exists to evaluate students’ experience and their perception of the online learning process. To address this issue, we developed and validated an Online Learning Process Questionnaire (OLPQ) to systematically assess various aspects of online learning and its underlying componential structure from both student and caregiver perspectives.
A conceptual framework for the OLPQ
The three-phase model of learning lays the theoretical foundation for understanding the online learning process. According to this model, the three phases are (1) the preparatory phase, referring to understanding of what is being learned and connecting it to prior knowledge; (2) the performance phase, describing engagement in learning activities and interactions; and (3) the transfer phase, applying what one has learned to real-life situations (Anderson, 2008; Puustinen & Pulkkinen, 2001). All three phases require metacognitive skills, such as strategies planning, regulation of strategies used, and monitoring learning process (Jansen et al., 2017). Moreover, some metacognitive skills are connected to an extent across different phases of learning, for example, planning in the preparatory phase, executing and monitoring the plan in the performance phase, and evaluating it in the transfer phase. Figure 1 presents an overview of the theoretical components of the three-phase model of learning.
Figure 1 An Overview of the Theoretical Three-phase Online Learning Model and Its Scales
The preparatory phase usually involves teachers’s providing an outline of the learning activities before starting. Students then access their prior knowledge and skills to establish a basic understanding, and they become intellectually prepared for upcoming learning activities (Anderson, 2008). However, the challenges encountered by students and their caregivers differ between online home learning and face-to-face instruction in two key aspects. First, a classroom environment, by default, is set up for learning, whereas a home environment contains many distractions that can hinder concentration, especially for young students (Lau & Lee, 2020). Second, the paper-based format of learning is more familiar to students and their caregivers compared with the diverse learning tools available to complete online learning activities, such as real-time learning platforms, learning management systems, and e-mail clients, which take time to become accustomed to (Jansen et al., 2017; Lau & Lee, 2020).
The subsequent performance phase of learning involves students’ engagement in learning activities. Unlike face-to-face teaching for which the timetable is pre-assigned by schools and teachers can motivate students more easily, online learning offers students greater flexibility. Therefore, self-regulatory skills, such as time management, persistence, and engagement, become more crucial (Jansen et al., 2017; Puustinen & Pulkkinen, 2001). Because online learning is more individually-based (Toven-Lindsey et al., 2015), greater interaction and assistance are necessary to enhance students’ motivation to learn and complete online learning activities (Nicpon et al., 2006). According to Moore (1989), three types of instruction are critical to online learning: the interaction between students and interfaces; the interaction between students and teachers; and the interaction among students. The first one facilitates the learning of tasks and elicits immediate feedback, while the second one promotes help-seeking and allows teachers to motivate students. The third one permits students to share thoughts, provide feedback, and learn from each other, which prevents loneliness during online learning (Cho & Cho, 2017; Nicpon et al., 2006).
After completing learning activities, students proceed to the transfer phase of learning by retaining what they have learned and applying it to real life. During learning activities, information and skills are stored in students’ working memory and consolidated into long-term memory for application (Anderson, 2008). By applying the acquired knowledge and skills to real-life situations that possess personal meaning, students can engage with their learning experiences positively (Anderson, 2008). The transfer phase is thus crucial not only for learning in the present, but also has potential impacts on future attitudes towards learning and how students adapt their learning-related behaviors in the preparatory and performance phases of subsequent learning experience (Hsu et al., 2009).
A review of previous studies regarding the online learning process
To date, several instruments have been developed for evaluating different aspects of the online learning process among high-school and tertiary students. For example, the Self-Regulated Online Learning Questionnaire (SROLQ) assesses adults’ self-regulated behaviors and metacognitive activities in large-scale open online courses. The 36-item SROLQ consists of five subscales of metacognitive skills, environmental structuring, time management, help seeking, and persistence (Jansen et al., 2017). The Online Self-Regulation Questionnaire (OSRQ) focuses on three types of interactions experienced by university students, namely, the interaction between students and learning content, the interaction between teacher and students, and the interaction among students (Cho & Cho, 2017). The Distance Education Learning Environments Survey (DSELES) targets students’ psychological and social perception of online learning environments in higher education and consists of 34 items, covering instructor support, student interaction and collaboration, personal relevance, authentic learning, active learning, and student autonomy (Walker & Fraser, 2005). The Web-Based Learning Environment Inventory (WBLEI) measures post-secondary students’ perception of four features of the online learning environment, including accessibility, interaction, responsiveness and results (Chang & Fisher, 2003). The Business Statistics Computer Learning Environment Inventory (BSCLE) assesses university students’ perceptions of online learning environment in practical subjects (i.e., business statistics) with five subscales focusing on students’ readiness to apply the skills after learning interactions (Nguyen-Newby & Fraser, 2021).
One noticeable limitation of all aforementioned instruments is their inadequacy for evaluating the three preparatory-performance-transfer phases of learning comprehensively. Specifically, the scope of the existing tools is limited in terms of the phases of learning captured and their distinctions. For example, in the SROLQ, items from the preparatory and appraisal phases of learning are merged into the larger domain of metacognitive skills without assessing learning environment and other prerequisites (Jansen et al., 2017). This results in a lack of distinction between the preparation and transfer of learning.
Furthermore, very few questionnaires consider all three phases of learning, and the performance phase is broadly given greater attention than other phases. For example, the OSRQ emphasizes different types of online interaction during the performance phase of learning only (Cho & Cho, 2017). Similarly, the DELES targets the learning performance stage only (Walker & Fraser, 2005). However, even when the performance phase of online learning is frequently considered, it is often incomplete or less well-defined . For example, the WBLEI (Chang & Fisher, 2003) focuses only on the interaction dimension of the performance phase in online learning, without evaluating students’ self-regulatory skills. Considering the low social presence resulting from the online medium, self-regulatory skills and autonomy are especially important for students to engage in the learning activities, compared with traditional classroom learning (Jansen et al., 2017; Puustinen & Pulkkinen, 2001; Richardson et al., 2017). Thus, self-regulation should be a critical component for any evaluation tools for online learning.
With emphasis placed on performance, the transfer phase has often been neglected. For example, the BSCLEI prioritizes the preparedness of students for online learning (i.e., integration and technology adequacy) and students’ learning interaction (i.e., student cohesiveness, involvement, and task orientation without considering transfer of learning (Nguyen-Newby & Fraser, 2021). This neglects the agentic role of students in their own learning. To capture this, real-life applications and meaning of learning should be included.
Another significant limitation is that most of these instruments target secondary and college students who have greater mastery of self-regulation skills and more sophisticated technological skills than primary-school students. Thus, these existing tools might not be directly applicable to young primary-school students. Given the increasing use of online learning as a mode of instruction in this age group, it is necessary to develop and validate an age-appropriate questionnaire to evaluate the process of online learning among primary-school students. Additionally, while students themselves are central to their learning, it is also important to consider those who assist in the process, such as caregivers. Existing measures have only been validated with a student sample, but not among caregivers. This is justified, considering that available measures have been designed for use among secondary and college students via a self-report format. However, given the age of primary-school students, the inclusion of caregivers is important because they tend to be actively engaged in their children’s online learning activities, such as to provide encouragement (Lau & Lee, 2020). Considering that caregivers are likely to facilitate their children’s online learning in the home environment and thus observe their children’s learning of behavioral skills, such as time management, interaction during learning, and determination to learn (An & Lee, 2010; Lau & Lee, 2020), they can provide accurate evaluations of their children’s online learning process and difficulties. Therefore, in addition to the students themselves, caregivers are also ideal respondents.
Context and objectives of this study
The rise of online learning can be attributed to two main phenomena, namely, technological advances and the COVID-19 pandemic. With internet accessibility increasing among children and the convenient format of online learning, students are able to engage with education outside of the regular classroom environment and explore their own interests (Allen & Seaman, 2014; Livingstone & Bober, 2004). While this shift has been accelerated by school closures and social-distancing policies associated with the COVID-19 pandemic (Armitage & Nellums, 2020), the trend of online learning is likely to continue beyond the pandemic, given the development of various courses and contents in this flexible format, accompanied by the growing attention to students’ digital literacy (Dhawan, 2020). Therefore, assessing the process of online learning at home not only might be relevant during the pandemic, but also for the future of education.
In addressing this practical need, this study was designed to develop and validate the Online Learning Process Questionnaire (OLPQ) which can assess the online learning process at home and be completed by both primary-school students and their caregivers. Two research questions were addressed. First, is the three-phase model of learning applicable to primary school students for measuring their online learning process? Second, what is the underlying factor structure of the OLPQ? The development of this questionnaire involved questionnaire formulation and content validation. During the validation process, the factor structure was first suggested and validated using the caregiver sample. Afterwards, it was cross-validated using a student sample. The validity and reliability of the questionnaire were evaluated for each sample.
Method
Questionnaire formulation
In line with the three-phase model of learning (Puustinen & Pulkkinen, 2001), several subscales were developed to assess the process of online learning under the preparatory phase, performance phase, and transfer phase. Specifically, the preparatory phase section comprises the four subscales of (1) Learning Goals, (2) Prerequisites, (3) Environmental Structuring, and (4) Learning Environment. The performance phase section includes the six subscales of (1) Time Management, (2) Engagement in Learning Activities, (3) Persistence, (4) Interaction between Teachers and Students, (5) Interaction among Students, and (6) Feedback from the Interface. The transfer phase consists of the three subscales of (1) Maintenance of Skills and Knowledge, (2) Application of Skills and Knowledge, and (3) Meaning of Learning. The items for each subscale were first constructed during the literature review stage and further selected based on a systematic review of various measures of the online learning process, as well as the online learning situation in Hong Kong. Specifically, five items (Items 22, 23 and 24 from Environment Structuring and Item 27 and 28 from Persistence) were adopted and modified from the SROLQ (Jansen et al., 2017). Similarly, two items (Items 7 and 9 from Environment Structuring) were adopted and modified from the OSRLQ (Barnard et al., 2009). Additionally, three items (Items 1 and 2 from Self-Regulation in Interaction between Students and Teachers and Item 9 from Self-Regulation in Interaction between Students and Students) were adopted and modified from the OSRLQ (Cho & Cho, 2017). Moreover, one item (Item 4 from Self-efficacy to Handle Tools) was adopted and modified from the Self-Efficacy Questionnaire for Online Learning (Shen et al., 2013). Additionally, each subscale contained multiple items to minimize possible measurement errors. The authors discussed and modified the items before the questionnaire then underwent a content validation process.
Content validation
To establish content validity, or the evaluation of whether the items are supported on theoretical grounds (Trochim & Donnelly, 2001), four education researchers and three experienced Hong Kong primary-school teachers were invited via email to comment on the definitions of the subscales and questionnaire items in the first draft of the questionnaire in English. Based on their comments, three items were revised for clarity and one new item was added to the subscale of Interaction between Teachers and Students. The revised questionnaire consisted of 67 items. Figure 1 shows the distribution of questions of various subscales under the three phases of learning. The questionnaire was then translated into Chinese by a research assistant in Chinese language education, and a back translation was prepared by a research assistant in English language education from the research laboratory in our university. Because the questionnaire was expected to be used in Hong Kong primary schools, two Chinese language teachers and one English language teacher were invited to further assess the content validity and language conformity, as well as the suitability and appropriateness of items for the context of online learning in Hong Kong.
Sample and procedures
A total of 474 caregivers of primary-school students and 219 primary-school students from Hong Kong participated in this study. Recruitment was conducted on a Facebook page managed by the authors’ laboratory, and most of the audience consisted of caregivers. Informed consent was obtained from all participants. The participants were then invited to complete the online questionnaire via Qualtrics, with the whole process taking approximately 15–20 min. The order of all questions was randomized, except for those in the demographics section. Ethical approval was granted for this study by the Human Research Ethics Committee at the University of Hong Kong. Table 1 shows the participants’ demographic information and online learning experience. As reported by both caregivers and students, most primary-school students (over 90%) carried out online learning at home.
Table 1 Frequency of demographic variables for participants
Variable Frequency
Caregiver sample
(N = 474)
Student sample
(N = 219)
Grade of student
Grade 1 70 (14.8%) 28 (12.8%)
Grade 2 69 (14.6%) 24 (11.0%)
Grade 3 86 (18.1%) 38 (17.4%)
Grade 4 76 (16.0%) 38 (17.4%)
Grade 5 94 (19.8%) 55 (25.1%)
Grade 6 79 (16.7%) 36 (16.4%)
Sex of student
Female 181 (38.2%) 90 (41.1%)
Male 293 (61.8%) 129 (58.9%)
Relationship with studenta
Mother 36 (7.6%)
Father 430 (90.7%)
Others 8 (1.7%)
Online learning method(s) usedb
Real-time online teaching 431 (90.9%) 197 (90.0%)
Online learning platform 363 (76.6%) 162 (74.0%)
Learning management system 337 (71.1%) 156 (71.2%)
Learning video 321 (67.7%) 135 (61.6%)
Online assessment 215 (45.4%) 106 (48.4%)
E-mail 170 (35.9%) 87 (39.7%)
Place for conducting online learning activities
Home 432 (91.1%) 197 (90.0%)
School 32 (6.8%) 20 (9.1%)
Library 3 (0.6%) 1 (0.5%)
Others 7 (1.5%) 1 (0.5%)
Note. aThis question was included in the caregivers’ questionnaire only. bParticipants can choose more than one option
Data analysis
Exploratory factor analysis (EFA) was first performed to extract the hypothesized factors to identify the proposed questionnaire. Promax rotation was chosen because of the factor intercorrelations and its suitability for factor correlations larger than .15 (Tabachnick & Fidell, 2013). Items were retained or eliminated based on the following criteria: (1) factor eigenvalues larger than 1 and item loadings larger than .4; (2) the removal of items with significant factor loadings on multiple factors; and (3) factors consisting of not fewer than three items (Hair et al., 2006; Straub, 1989). Next, confirmatory factor analysis (CFA) was conducted to examine the internal validity of the items (Joreskog & Sorbom, 2018). Six goodness-of-fit indices were used: chi-square, chi-squared divided by degrees of freedom, comparative fit index (CFI), Incremental Fit Index (IFI), standardized root mean square residual (SRMR), and root-mean-square error approximation (RMSEA). Furthermore, we assessed the reliability and discriminant validity. Finally, CFA, reliability, and discriminant validity analyses were carried out with the student data to cross-validate the factor structure with the caregiver data.
Results
Identifying the underlying factor structure of Online Learning Process Questionnaire (OLPQ): Exploratory factor analysis with a Hong Kong Chinese caregiver sample
To determine factor loadings and their dimensions for the 67-item online questionnaire, EFA was performed on the caregiver data. Bartlett’s sphericity test yielded a significant result, χ2(2, 211) = 26466.38, p < .001, indicating that the intercorrelation matrix had sufficient common variance for the EFA analysis. The Kaiser-Meyer-Olkin value was .97, indicating that the factorable matrix had adequate sampling (Kaiser, 1958). By using eigenvalues larger than 1 and factor loadings greater than .4 as the criteria, 12 factors that explained 67.30% of the total variance were extracted. However, the 12th factor, which explained 1.30% of the variance and contained two questions, was removed because of multiple loadings on the factors. Seven further items were removed because of low factor loadings (smaller than .4). The final 11-factor structure, consisting of 58 items, explained 66.00% of the variance and demonstrated satisfactory fit to the data (Kline, 2014).
Table 2 summarizes the factor loadings of all items and their dimensions. Items from Learning Goals and Prerequisites in the preparatory phase were merged into one factor called Learning Aims. Items from Maintenance of Skills and Knowledge and Application of Skills and Knowledge in the transfer phase were merged into one factor called Application of Learning. For the remaining factors, the items matched their previously-assigned subscales, which showed that the convergent validity and dimensionality were acceptable. Figure 2 and Table 3 present the final 11-factor structure, the definitions of the subscales, and sample items, as well as the three subscales in the preparatory phase, six subscales in the performance phase, and two subscales in the transfer phase. The final items included in the questionnaire are presented in Appendix. As shown in Tables 2, factor loadings for Learning Aims, Environmental Structuring, and Learning Environment in the preparatory phase were between .41 and .80, between .65 and .84, and between .53 and .71, respectively. Factor loadings for the subscales in the performance phase were as follows: Time management (.61–.87), Engagement in Learning Activities (.63–.90), Persistence (.51–.60), Interaction between Teachers and Students (.59–.89), Interaction among Students (.54–.91), and Feedback from the Interface (.76–.91). Factor loadings for Application of Learning and Meaning of Learning in the transfer phase were between .43 and .93 and between .47 and .81, respectively. No cross-loading of the remaining items exited among the 11 factors, thus supporting the discriminant validity of the questionnaire.
Table 2 Factor loadings of rotated component matrix for caregiver sample (N = 474) and regression coefficients of items for caregiver and student sample (N = 219)
Item Component factor loadings Regression coefficient
AL ITS LA TM ELA IS FI ES LE ML P Caregivers Students
AL2 .93 .90 .89
AL3 .83 .85 .84
AL6 .82 .81 .83
AL1 .81 .88 .89
AL4 .81 .87 .83
AL5 .77 .81 .88
AL7 .56 .78 .79
AL8 .47 .71 .77
AL9 .43 .71 .80
ITS4 .89 .85 .86
ITS6 .87 .87 .85
ITS2 .86 .85 .88
ITS1 .80 .80 .87
ITS3 .69 .77 .81
ITS5 .59 .70 .80
LA2 .80 .85 .82
LA1 .78 .84 .80
LA4 .74 .86 .88
LA3 .74 .81 .85
LA5 .72 .86 .84
LA6 .49 .55 .70
LA7 .43 .57 .75
LA8 .41 .64 .75
TM2 .87 .81 .79
TM3 .85 .84 .86
TM4 .76 .83 .81
TM1 .70 .68 .82
TM5 .61 .70 .79
ELA3 .90 .82 .83
ELA1 .68 .87 .83
ELA2 .66 .84 .84
ELA4 .63 .75 .75
IS4 .91 .92 .90
IS1 .89 .87 .93
IS2 .88 .89 .94
IS3 .78 .80 .86
IS5 .54 .73 .87
FI1 .91 .89 .91
FI4 .86 .87 .87
FI2 .84 .87 .90
FI5 .82 .86 .91
FI3 .76 .88 .86
ES3 .84 .77 .90
ES4 .81 .85 .84
ES1 .77 .82 .85
ES2 .65 .63 .74
LE2 .71 .76 .81
LE4 .62 .76 .73
LE1 .61 .78 .74
LE3 .53 .57 .70
ML1 .81 .76 .79
ML2 .78 .87 .88
ML4 .68 .74 .85
ML3 .53 .78 .77
ML5 .47 .75 .83
P3 .60 .85 .74
P1 .53 .75 .77
P2 .51 .83 .87
Eigenvalues 29.43 3.66 3.19 2.62 2.47 1.99 1.81 1.66 1.58 1.37 1.06
% of variance 38.23 4.75 4.14 3.40 3.21 2.59 2.35 2.15 2.05 1.78 1.37
Cumulative % of variance 38.23 42.97 47.11 50.50 53.72 56.30 58.65 60.80 62.85 64.63 66.00
Note. Extraction method: principal component analysis; rotation method: Promax rotation with Kaiser normalization, rotation converged in 15 iterations. AL = application of learning, ITS = interaction between teachers and students, LA = learning aims, TM = time management, ELA = engagement in learning activities, IS = interaction among students, FI = feedback from the interface, ES = environmental structuring, LE = learning environment, ML = meaning of learning, P = persistence. The number under the component column indicates the item number. ps < .001 for all regression coefficients
Figure 2 An Overview of the Exploratory Three-phase Online Learning Model and Its Scales
Table 3 Each subscale’s description and its sample item for Online Learning Process Questionnaire (OLPQ)
Learning phases and subscales Description Sample items
Learning preparatory phase
Learning aims Extent to which students are aware of the outline and knowledge required to complete online learning activities I am aware of the learning objective of online learning services/programs.
Environmental structuring Extent to which students can participate in online learning activities in a comfortable physical environment I am satisfied with the learning environment where I access online learning services.
Learning environment Extent to which students are at ease using the online learning platform The online learning platform(s) is(are) easy to use.
Learning performance phase
Time management Extent to which students can manage their time to complete online learning activities I can allocate sufficient time suitably for online learning activities.
Engagement in Learning Activities Extent to which students have attentive interest and participate actively in the online learning activities I am engaged in the online learning activities.
Persistence Extent to which students can overcome difficulties and continue to complete the online learning activities I can finish the required online learning activities even if I find the content challenging.
Interaction between teachers and students Extent to which students can interact with, seek help and receive feedback from teachers during the online learning process The interaction between me and my teachers is adequate during online learning activities.
Interaction among students Extent to which students can interact with and learn from their peers during online learning activities I can learn from my classmates during online learning activities.
Feedback from the interface Extent to which feedback from the learning platform is supportive and facilitates learning The feedback received from the learning platform(s) is helpful for me to learn.
Learning transfer phase
Application of learning Extent to which students can maintain the knowledge and skills learned, then apply them in real-life situations I feel satisfied when I can apply the skills and knowledge learned from online learning activities to other subjects.
Meaning of learning Extent to which students understand the aim of learning and facilitate their own academic learning process The skills and knowledge learned from online learning activities are meaningful to my personal life.
Verifying the 11-factor structure of OLPQ: Confirmatory factor analysis with both caregiver and student samples
To verify the identifying factor structure of the OLPQ, CFA was performed with the caregiver sample. As shown in Table 2, significant regression coefficients ranged from .55 to .92, ps < .001. The model fit indices were acceptable, with χ2(1874, N = 474) = 4242.80 (p < .001), χ2/df = 2.26, SRMR = .051, CFI = .90, IFI = .91, and RMSEA = .05 (Hu & Bentler, 1999; Ullman & Bentler, 2013).
To cross-validate the dimensionality and relationships within the 58-item OLPQ, a 11-factor model was specified and tested using data from the student sample. As shown in Table 2, the regression coefficients of all items ranged from .70 to .94, ps < .001. The model fitted the data well, as indicated by all fit indices: χ2(1540, N = 219) = 2947.68 (p < .001), χ2/df = 1.91, SRMR = .05, CFI = .90, IFI = .89, and RMSEA = .07. This indicates that the 11-factor structure identified using data from the caregiver sample was stable and can be generalized to the student sample.
Reliability and discriminant validity of OLPQ
To evaluate the internal consistency of all 58-items in the OLPQ from the caregiver sample, Cronbach’s alpha was calculated. The alpha coefficient for the 58-item questionnaire was 0.98, indicating excellent reliability, exceeding the minimum requirement of .70 (Hair et al., 2006). Table 4 shows reliability coefficients of each subscale and their correlations. Reliability coefficients of the subscales, ranging from .81 to .95, are classified as good to excellent (Cronbach, 1951). All of the correlations between the subscales (ranging from .02 to .67) and the mean correlations (ranging from .18 to .47) were lower than the reliability coefficients, suggesting that the subscales assessed distinct yet interrelated aspects of the online learning process.
Table 4 Internal consistency reliability (Cronbach’s alpha coefficient) and discriminant validity (correlation with other scales) for caregiver sample (N = 474)
Scale Number of items Reliability Mean correlation Correlations
LA ES LE TM ELA P ITS IS FI LT ML
LA 8 .95 .45 —
ES 4 .85 .43 .65 —
LE 4 .81 .36 .38 .40 —
TM 5 .88 .37 .66 .59 .26 —
ELA 4 .89 .32 .40 .33 .32 .27 —
P 3 .85 .18 .13 .04 .34 .12 .18 —
ITS 6 .92 .44 .56 .53 .36 .46 .50 .20 —
IS 5 .92 .46 .55 .58 .50 .45 .46 .17 .59 —
FI 5 .94 .34 .38 .40 .32 .29 .23 .19 .43 .41 —
AL 9 .95 .47 .67 .64 .43 .59 .38 .25 .59 .60 .43 —
ML 5 .89 .18 .08 .16 .30 .02 .12 .18 .21 .24 .32 .16 —
Note. LA = learning aims, ES = environmental structuring, LE = learning environment, TM = time management, ELA = engagement in learning activities, P = persistence, ITS = interaction between teachers and students, IS = interaction among students, FI = feedback from the interface, AL = application of learning, ML = meaning of learning
The same psychometric analysis of the OLPQ was conducted using data from the student sample. Cronbach’s alpha coefficient of the 58-item questionnaire was .98, indicating excellent reliability. Table 5 shows the reliability coefficients of each subscale and their correlations for the student sample. The reliability coefficients of the subscales ranged from .83 to .95, which can be classified as good to excellent (Cronbach, 1951). All correlations between the subscales (ranging from .35 to .82) and the mean correlations (ranging from .49 to .69) were lower than the reliability coefficients, which indicates that the subscales assessed distinct yet interrelated aspects of the online learning process.
Table 5 Internal consistency reliability (Cronbach’s alpha coefficient) and discriminant validity (correlation with other scales) for student sample (N = 219)
Scale Number of items Reliability Mean correlation Correlations
LA ES LE TM ELA P ITS IS FI LT ML
LA 8 .93 .62 —
ES 4 .83 .49 .46 —
LE 4 .83 .57 .56 .58 —
TM 5 .91 .56 .62 .46 .50 —
ELA 4 .89 .63 .66 .52 .64 .65 —
P 3 .84 .54 .48 .47 .62 .63 .63 —
ITS 6 .94 .62 .65 .52 .56 .52 .68 .55 —
IS 5 .95 .53 .62 .35 .48 .42 .52 .38 .72 —
FI 5 .95 .64 .67 .52 .57 .61 .66 .60 .73 .65 —
AL 9 .95 .69 .75 .58 .63 .65 .73 .61 .72 .62 .75 —
ML 5 .91 .60 .72 .46 .55 .55 .62 .47 .59 .56 .61 .82 —
Note. LA = learning aims, ES = environmental structuring, LE = learning environment, TM = time management, ELA = engagement in learning activities, P = persistence, ITS = interaction between teachers and students, IS = interaction among students, FI = feedback from the interface, AL = application of learning, ML = meaning of learning
Discussion
In this study, we developed and validated the OLPQ to assess the process of online learning at home from the perspectives of primary school students and their caregivers. By assessing a large sample of primaryschool students and their caregivers in Hong Kong, an 11-factor structure for 58-items in the OLPQ questionnaire was developed and verified. The final OLPQ consists of the subscales of (1) learning aims, (2) environmental structuring, (3) learning environment, (4) time management, (5) engagement in learning activities, (6) persistence, (7) interaction between teachers and students, (8) interaction among students, (9) feedback from the interface, (10) application of learning, (11) meaning of learning in preparatory, performance and transfer phases. EFA conducted on the caregiver sample suggested an 11-factor structure that explained 66.00% of the variance, while CFA confirmed the factor structure for the caregiver sample and cross-validated it for the student sample. The discriminant validity was indicated by lower correlations between subscales than their internal consistency for both caregiver and student samples. The internal reliabilities of all 11 subscales in the OLPQ were acceptable to excellent for both caregiver and student samples.
In line with previous research (Anderson, 2008; Puustinen & Pulkkinen, 2001), the OLPQ clarifies that online learning involves the preparatory, performance and transfer phases. The identification of these three phases of learning in the QLPQ not only supports the notion that different metacognitive skills and learning behaviors are required before, during and after the learning task to achieve the learning outcomes (Puustinen & Pulkkinen, 2001), but it also suggests that online learning is a continuous and dynamic process and any effective evaluation tools should not be limited to the skills and outcome of the performance phase (i.e., the learning activities).
More importantly, the development and validation of the OLPQ for primaryschool students extends previous studies which focused on online learning among college and postgraduate students who have better mastery of self-control and self-learning skills (e.g., Prior et al., 2016). Specifically, the QLPQ has taken into consideration the characteristics of primaryschool students, such as the relatively lower level of attention during online learning and the greater need for academic and behavioral support from teachers and caregivers (Lau & Lee, 2020). Furthermore, different from most existing self-regulation questionnaires which are primarily course-based (Jansen et al., 2017; Nguyen-Newby & Fraser, 2021), the OLPQ considers the higher prevalence of hybrid learning (i.e., the use of both face-to-face teaching and online learning) experienced by primary students by placing emphasis on their unique online learning context. Additionally, the OLPQ is the first to measure the online learning process from both the students’ and caregivers’ perspectives. As caregivers plays an important role in online learning among primary school students, such as providing academic and technological support, and monitoring learning process (Lau & Lee, 2020), the validation of the QLPQ in both samples enables this assessment tool to be comprehensive in evaluating the online learning process among primary-school students.
Educational and theoretical implications
The development of the OLPQ has far-reaching implications. First, the OLPQ can be easily adopted by schools as a tool for teachers for better understanding students’ learning processes and potential challenges that they might encounter. This is critically important because most online learning takes place outside school and involves a lower social presence from teachers (Richardson et al., 2017). Because the OLPQ is structured using the three learning phases, teachers can focus on the processes with which they are most concerned. Specifically, previous research has been reported that learning preparation, students’ interaction during online learning, and their engagement in learning activities are harder to observe during online learning (Appana, 2008). By utilizing the OLPQ, teaching staff and schools can be more involved in evaluating how teacher-designed online learning materials and resources are implemented at home. Additionally, based on findings from the OLPQ, teachers can obtain professional advice to enhance students’ online learning at home.
From a caregiver’s perspective, the OLPQ is an important platform of expression. Given the critical role of caregivers in supporting their young students’ learning at home and the increasing importance of their connection with schools, it is of great significance to include their genuine feedback on how online learning is implemented at home (Lau & Lee, 2020; Ma et al., 2016). By discussing findings from the OLPQ together, caregivers become more involved and can feel that their children’s development at school is prioritized by school staff (Chenhall et al., 2011; Choi, 2017). Together, one of the practical implications of OLPQ is the inclusion of caregivers in the evaluation process, enhancing school-caregiver relationships.
From a research perspective, educational researchers can utilize results of the OLPQ to develop programs that enhance the effectiveness of online learning at home. As the process of online learning is also related to students’ learning attitudes, motivation, and learning experience (Hsu et al., 2009), the OLPQ promotes educators’ comprehensive understanding of tudents’ learning and provide insight into how online learning can be modified. While the OLPQ was developed with the context of COVID-19 , research on online learning is much needed so that it can become more effective for students (Lau & Lee, 2020; Lestari & Gunawan, 2020; Picciano & Seaman, 2007).
Limitations and future directions
Despite its significant theoretical and educational implications, three limitations of the OLPQ include the sample, the lack of test-retest reliability, and other potential factors. Specifically, the OLPQ was only validated by Hong Kong primary school students and their caregivers . Given the rise of online learning, the questionnaire would benefit from validation among secondaryschool students in other places. Also, given the time constraint, no test-retest reliability was established for the QLPQ. Future research should extend this work by examining measuring stability, correlation coefficients, and the coefficient alpha of the OLPQ. Additionally, several other factors such as age, socioeconomic status, online learning methods, special educational needs, and online learning attitudes might affect the process of online learning (Lam & Tong, 2022). Future research could explore the roles of these factors by testing different age samples.
Conclusion
This study involved developing and validating the OLPQ for assessing the process of online learning at home for both primary school students and their caregivers . The 58-item questionnaire consisted of 11 factors:(1) learning aims, (2) environmental structuring, (3) learning environment, (4) time management, (5) engagement in learning activities, (6) persistence, (7) interaction between teachers and students, (8) interaction among students, (9) feedback from the interface, (10) application of learning, and (11) meaning of learning under three phases of learning, namely the preparatory phase, the performance phase, and the transfer phase. The 11 factors of three phases of learning were validated for both the caregiver and student samples with good to excellent reliability. The QLPQ is the first instrument to evaluate the online learning processing from both students’ and caregivers’ perspectives. Schools can adopt this tool and administer it to caregivers and students to gather information regarding how to adjust the implementation of online learning for enhancing students’ learning experiences and effectiveness.
Appendix
The Online Learning Process Questionnaire (OLPQ) in English and Chinese.
A) The Preparatory Phase of Learning.
I. Learning aims.
I am aware of the learning objectives of online learning services/programs.
我意識到網上學習的學習目標。
I understand the learning objectives of online learning services/programs.
我明白網上學習的學習目標。
The learning objectives are appropriate for online learning services/programs.
網上學習的學習目標是合適的。
The learning objectives help me understand the content of online learning services/programs.
學習目標幫助我理解網上學習的内容。
I am confident that I will achieve the learning goals after engaging in online learning services.
在進行網上學習後, 我有信心可以達到學習目標。
The prerequisite questions or learning activities are provided in the online learning services.
網上學習會提供預習問題或學習活動。
The prerequisite questions or learning activities enhance the effectiveness of online learning.
預習問題或學習活動能提高網上學習的效率。.
I will review the prerequisite skills and knowledge before I start online learning activities, if necessary.
當我進行網上學習前, 如有需要, 我會預習相關技巧和知識。
II. Environmental structuring.
I can find a place where I can concentrate when accessing online learning services.
我找到一個可以專心進行網上學習的地方。
I have a regular place for engaging in online learning services.
我有固定的地方來進行網上學習。
The place for online learning services has minimal distractions.
在我進行網上學習的地方有著最少的干擾。
I am satisfied with the learning environment where I access online learning services.
我對進行網上學習時的學習環境感到滿意。
III. Learning environment.
The online learning platform(s) is(are) easy to use.
網上學習平台容易使用。
The layout of the online learning platform(s) is(are) organized.
網上學習平台的設計是有條理的。
The online learning platform(s) has(have) minimally excessive sounds or graphical information.
網上學習平台有著最少多餘的聲音或影像。
I am capable of using different online learning platform(s).
我能使用不同的網上學習平台。
B) The Performance Phase of Learning.
I. Time management.
I know how much time I need to spend on online learning services.
我知道我在網上學習需要花了多少時間。
I can allocate enough time for online learning services without clashing with other activities.
我可以分配足夠的時間給網上學習, 而且不會與其他活動的時間有衝突。
I can allocate sufficient time suitably for online learning activities.
我可以分配合適的時間用來進行網上學習。
It is easy for me to schedule my time to access online learning services.
分配時間進行網上學習, 對我而言是一件容易的事。
I can complete online learning activities on time.
我能夠準時完成網上學習的活動。
II. Engagement in learning activities.
I am engaged in the online learning activities.
我投入於網上學習。
I feel a sense of participation while completing online learning activities.
當我進行網上學習時, 我感受到“參與”的感覺。
I feel that I can concentrate during online learning activities.
我專注於進行網上學習。
I am eager to learn during online learning activities.
我渴望在進行網上學習時學習。
III. Persistence.
I can finish the required online learning activities even if I do not like the content.
即使我不喜歡其中的内容, 我也能完成網上學習。
I can finish the required online learning activities even if I find the content challenging.
即使我認爲内容具有挑戰性, 我也能完成網上學習。
I find ways to force myself to complete the online learning activities.
我會用不同方法去迫使自己完成網上學習。
IV. Interaction between teachers and students.
I am able to interact with my teachers during online learning activities.
在進行網上學習時, 我能與老師互動。
The interaction between me and my teachers is adequate during online learning activities.
在進行網上學習時, 我與老師有足夠的互動。
The interaction between me and my teachers can facilitate online learning.
我與老師的互動能促進網上學習。
I can seek help from my teachers during online learning activities whenever I need it.
在進行網上學習時, 我能尋求老師的幫助。
I know how to seek help from my teachers during online learning activities.
在進行網上學習時, 我知道怎樣可以尋求老師的幫助。
My teachers can provide timely responses to my questions during online learning activities.
在進行網上學習時, 老師能適時回應我的問題。
V. Interaction among students.
I am able to interact with my classmates during online learning activities.
在進行網上學習時, 我能與同學互動。
The interaction between me and my classmates is adequate during online learning activities.
在進行網上學習時, 我與同學有足夠的互動。
I enjoy my interaction with classmates during online learning activities.
在進行網上學習時, 我享受與同學的互動。
It is easy to interact with my classmates during online learning activities.
在進行網上學習時, 我能容易地與同學互動。
I can learn from my classmates during online learning activities.
在進行網上學習時, 我能夠從同學身上學習。
VI. Feedback from the interface.
I am able to receive feedback from the learning platform(s) during online learning activities.
在進行網上學習時, 我能夠收到學習平台給我的回饋意見。
The feedback received from the learning platform(s) is easy to find during online learning activities.
在進行網上學習時, 我能輕易找到學習平台給我的回饋意見。
The feedback received from the learning platform(s) is adequate for me to continue to learn.
學習平台給我的回饋意見, 足夠讓我繼續學習。
The feedback received from the learning platform(s) is helpful for me to learn.
學習平台給我的回饋意見, 對於我的學習是有幫助的。
The feedback received from the learning platform(s) allows me to further study the topic.
學習平台給我的回饋意見, 讓我繼續深入學習某個課題。
C) The Transfer Phase of Learning.
I. Application of learning.
I can apply the skills and knowledge learned from online learning activities to other subjects.
我能我從網上學習中所學習到的技巧和知識應用到其他科目。
I can apply the skills and knowledge learned from online learning activities to daily life.
我能我從網上學習中所學習到的技巧和知識應用到日常生活。
It is easy to apply the skills and knowledge learned from online learning activities to other subjects.
將我從網上學習所學習到的技巧和知識應用到其他科目是一件容易的事。
It is easy to apply the skills and knowledge learned from online learning activities to daily life.
將我從網上學習所學習到的技巧和知識應用到日常生活是一件容易的事。
I feel satisfied when I can apply the skills and knowledge learned from online learning activities to other subjects.
當我將從網上學習所學習到的技巧和知識應用到其他科目, 我會感到滿足。
I feel satisfied when I can apply the skills and knowledge learned from online learning activities to daily life.
當我將從網上學習所學習到的技巧和知識應用到日常生活, 我會感到滿足。
I know what I have learned through online learning activities.
我知道我從網上學習中學習到什麽。
I can recall the skills and knowledge learned from online learning activities via verbal reminders.
只要有口頭的提示, 我就能記起我從網上學習中所學習到的技巧和知識。
I can use the skills and knowledge learned from online learning activities in assessments and examinations.
我能夠將我從網上學習中所學習到的技巧和知識運用於評估和考試。
II. Meaning of learning.
Learning online broadens my horizon.
網上學習拓闊了我的視野。
I feel more motivated to learn when it is done online.
網上學習能推動我學習。
Learning online makes me an independent learner.
網上學習令我獨立學習。
The skills and knowledge learned from online learning activities are meaningful to my personal life.
我從網上學習中所學習到的技巧和知識, 對於我的個人生活是有幫助。
I understand how I learn best when learning online.
我明白怎樣才能在網上學習裏學習得最好。
Acknowledgements
We thank Joanna Lee and Nicole Law for their assistance in translation of questionnaire. Additionally, we would like to thank Justine Wai for their English editing and proofreading.
Funding
This research was in part supported by the Funding Programme for Research Projects on Equal Opportunities 2020/21 (R-2020/21–111) granted by the Equal Opportunities Commission, the Research Fellow Scheme (RFS2021-7H05) and General Research Fund (17609518, 17620520) granted by Research Grant Council, Hong Kong SAR to Dr. Shelley Xiuli Tong.
Code availability
Not applicable.
Availability of data and material
Derived data supporting the findings of this study are available from the corresponding author upon request.
Declarations
Conflict of interest
The author declare no conflict of interest.
Ethics approval
This study was granted ethics approval by the Human Research Ethics Committee, the University of Hong Kong.
Consent to participate
Informed online written consent was obtained from the parents for their own and their children’s participation in the study before testing began.
Consent for publication
The authors give their consent for this submitted manuscript to be published in the journal.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Allen, I. E., & Seaman, J. (2014). Grade change: Tracking online education in the United States Babson Survey Research Group. https://eric.ed.gov/?id=ED602449
An SK Lee D An integrated model of parental mediation: the effect of family communication on children’s perception of television reality and negative viewing effects Asian Journal of Communication 2010 20 4 389 403 10.1080/01292986.2010.496864
Anderson, T. (2008). The theory and practice of online learning (2nd ed.). Athabasca University (AU) Press.
Appana S A review of benefits and limitations of online learning in the context of the student, the instructor and the tenured faculty International Journal on E-learning 2008 7 1 5 22
Armitage R Nellums LB Considering inequalities in the school closure response to COVID-19 The Lancet Global Health 2020 8 5 e644 10.1016/S2214-109X(20)30116-9 32222161
Barnard L Lan WY To YM Paton VO Lai SL Measuring self-regulation in online and blended learning environments The Internet and Higher Education 2009 12 1 1 6 10.1016/j.iheduc.2008.10.005
Chang V Fisher DL Khine MS Fisher DL The validation and application of a new learning environment instrument for online learning in higher education Technology-rich learning environments: a future perspective 2003 Singapore World Scientific Publishing 1 20
Chenhall, R. D., Holmes, C., Lea, T., Senior, K., & Wegner, A. (2011). Parent-school engagement: exploring the concept of ‘invisible’ indigenous parents in three north australian school communities. The Northern Institute. https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2457&context=sspapers Charles Darwin University.
Cho MH Cho Y Self-regulation in three types of online interaction: a scale development Distance Education 2017 38 1 70 83 10.1080/01587919.2017.1299563
Cho MH Demei S Laffey J Relationships between self-regulation and social experiences in asynchronous online learning environments Journal of Interactive Learning Research 2010 21 3 297 316
Choi JA Why I’m not involved: parental involvement from a parent’s perspective Phi Delta Kappan 2017 99 3 46 49 10.1177/0031721717739593
Cronbach LJ Coefficient alpha and the internal structure of tests Psychometrika 1951 16 3 297 334 10.1007/BF02310555
Dhawan S Online learning: a panacea in the time of COVID-19 crisis Journal of Educational Technology Systems 2020 49 1 5 22 10.1177/0047239520934018
Hair, J. F., Black, W. C., Babin, B. J., Anderson, R. E., & Tatham, R. (2006). Multivariate data analysis. Pearson Prentice Hall.
Hsu MK Wang SW Chiu KK Computer attitude, statistics anxiety and self-efficacy on statistical software adoption behavior: an empirical study of online MBA learners Computers in Human Behaviour 2009 252 412 420 10.1016/j.chb.2008.10.003
Hu LT Bentler PM Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives Structural Equation Modeling: A Multidisciplinary Journal 1999 6 1 1 55 10.1080/10705519909540118
Jansen RS Van Leeuwen A Janssen J Kester L Kalz M Validation of the self-regulated online learning questionnaire Journal of Computing in Higher Education 2017 29 1 6 27 10.1007/s12528-016-9125-x
Joreskog, K., & Sorbom, D. (2018). LISREL 10.1. Scientific Software International.
Kaiser HF The varimax criterion for analytic rotation in factor analysis Psychometrika 1958 23 3 187 200 10.1007/BF02289233
Kline, P. (2014). An easy guide to factor analysis. Routledge.
Lam, J. H. Y., & Tong, S. X. (2022). Development and validation of the online learning attitude questionnaire (OLAQ) among primary school children and caregivers. Interactive Learning Environments, 1–15. 10.1080/10494820.2022.2043911.
Lau EYH Lee K Parents’ views on young children’s distance learning and screen time during COVID-19 class suspension in Hong Kong Early Education and Development 2020 33 1 18 10.1080/10409289.2020.1843925
Lestari PAS Gunawan G The impact of COVID-19 pandemic on learning implementation of primary and secondary school levels Indonesian Journal of Elementary and Childhood Education 2020 1 2 58 63
Livingstone, S., & Bober, M. (2004). UK children go online: surveying the experiences of young people and their parents. LSE Research Centre. http://eprints.lse.ac.uk/395/.
Ma X Shen J Krenn HY Hu S Yuan J A meta-analysis of the relationship between learning outcomes and parental involvement during early childhood education and early elementary education Educational Psychology Review 2016 28 4 771 801 10.1007/s10648-015-9351-1
Moore MG Editorial: three types of interaction American Journal of Distance Education 1989 3 1 7 10.1080/08923648909526659
Nguyen-Newby TH Fraser BJ Computer laboratory workshops as learning environments for university business statistics: validation of questionnaires Learning Environments Research 2021 24 389 407 10.1007/s10984-020-09324-z
Nicpon MF Huser L Blanks EH Sollenberger S Befort C Kurpius SER The relationship of loneliness and social support with college freshmen’s academic performance and persistence Journal of College Student Retention: Research Theory & Practice 2006 8 3 345 358 10.2190/A465-356M-7652-783R
Picciano, A. G., & Seaman, J. (2007). K-12 online learning: a survey of US school district administrators. Sloan Consortium.
Prior DD Mazanov J Meacheam D Heaslip G Hanson J Attitude, digital literacy and self-efficacy: Flow-on effects for online learning behavior The Internet and Higher Education 2016 29 91 97 10.1016/j.iheduc.2016.01.001
Puustinen M Pulkkinen L Models of self-regulated learning: a review Scandinavian Journal of Educational Research 2001 45 3 269 286 10.1080/00313830120074206
Richardson JC Maeda Y Lv J Caskurlu S Social presence in relation to students’ satisfaction and learning in the online environment: a meta-analysis Computers in Human Behavior 2017 71 402 417 10.1016/j.chb.2017.02.001
Shen D Cho MH Tsai CL Marra R Unpacking online learning experiences: online learning self-efficacy and learning satisfaction The Internet and Higher Education 2013 19 10 17 10.1016/j.iheduc.2013.04.001
Straub DW Validating instruments in MIS research MIS Quarterly 1989 13 2 147 169 10.2307/248922
Tabachnick, B. G., & Fidell, L. S. (2013). Using multivariate statistics: Pearson new international edition. Pearson.
Toven-Lindsey B Rhoads RA Lozano JB Virtually unlimited classrooms: pedagogical practices in massive open online courses The Internet and Higher Education 2015 24 1 12 10.1016/j.iheduc.2014.07.001
Trochim, W. M., & Donnelly, J. P. (2001). Research methods knowledge base (2 vol.). Atomic Dog Pub.
Ullman, J. B., & Bentler, P. M. (2013). Structural equation modeling. In J. A. Schinka, W. F. Velicer, & I. B. Weiner (Eds.), Handbook of psychology: Research methods in psychology (pp. 661–690). John Wiley & Sons, Inc.
Walker SL Fraser BJ Development and validation of an instrument for assessing distance education learning environments in higher education: the Distance Education Learning environments Survey (DELES) Learning Environments Research 2005 8 3 289 308 10.1007/s10984-005-1568-3
| 0 | PMC9734829 | NO-CC CODE | 2022-12-14 23:28:30 | no | Learn Environ Res. 2022 Dec 6;:1-24 | utf-8 | Learn Environ Res | 2,022 | 10.1007/s10984-022-09443-9 | oa_other |
==== Front
Nat Nanotechnol
Nat Nanotechnol
Nature Nanotechnology
1748-3387
1748-3395
Nature Publishing Group UK London
36482240
1292
10.1038/s41565-022-01292-0
News & Views
Gene delivery beyond the liver
Pastore Chiara [email protected]
Nature Nanotechnology, https://www.nature.com/naturenanotechnology
8 12 2022
2022
17 12 12391239
© Springer Nature Limited 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
issue-copyright-statement© The Author(s), under exclusive licence to Springer Nature Limited 2022
==== Body
pmcLipid nanoparticles (LPNs) are used to carry therapeutic nucleic acids, such as mRNA (as in the case of the mRNA-based COVID-19 vaccines), short interfering RNA, and gene editing complexes. Researchers have investigated them for a long time, in pursuit of therapies for untreatable genetic diseases (K. Hajj et al. Nat. Rev. Mater. 2, 17056; 2017 and R. Kanasty et al. Nat. Mater. 12, 967–977; 2013), but their almost exclusive liver localisation upon intravenous injection has limited widespread application of LPNs in gene therapy.Created with BioRender.com.
In a paper published in Nature Nanotechnology in April 2020 (Q. Cheng et al. Nat. Nanotechnol. 15, 313–320; 2020) the authors addressed this limitation and proposed an approach dubbed SORT, a short for Selective ORgan Targeting, to extend LPNs targeting to organs other than liver. Daniel Siegwart, corresponding author of the paper from the University of Texas Southwestern Medical Center in Dallas, USA, recounts: “We started this project because we wanted to understand the mechanisms that drove liver tropism and then made specific changes designed to avoid liver delivery”. Key observations came when investigating the physico–chemical characteristics of liver-targeting LPNs: they noticed that their apparent global pKa was always between 6.2 and 6.5, and were highly enriched in Apolipoprotein E, just like very-low-density lipoprotein found in nature.
LPNs are traditionally made of four components: ionizable cationic lipids, zwitterionic phospholipids, cholesterol and PEG lipids (Fig. 1). To control and tune their physico-chemical properties, Cheng et al. included a fifth component in their formulation, such as a quaternary lipid DOTAP (red SORT lipid in the figure). LPNs containing increasing percentages of DOTAP displayed altered biodistribution profiles, with 50% DOTAP delivering mRNA preferably to the lungs. Notably, Cheng et al. proceeded directly to carry out animal experiments bypassing cell culture experiments, in this way deviating from the conventional dogma of nanoparticle design for biomedical applications. This bold move was rendered necessary because cell cultures do not recapitulate the complexity of living models, as the plasma components that contribute to the protein corona are absent.
Another key property of SORT is that it can in principle allow delivery of therapeutically relevant genetic material to specific cells within the targeted organs. A single dose of LNPs directed to the lungs for example, target around 40% of all epithelial cells and 65% of endothelial cells in this organ. “A major accomplishment is to be able to achieve gene editing in the specific cell types relevant to treating a specific disease” says Siegwart, who expects that cell selectivity will be determined in follow-up clinical trials.
Siegwart and his group are now exploring how to deliver LPNs to several other organs, such as the bone marrow, lymph nodes, kidneys and pancreas. At the same time, the start-up ReCode Therapeutics (https://recodetx.com/about/), which has acquired the licence to the technology, is performing preclinical assessments to determine the safety, tolerability and optimal therapeutic window of SORT for two genetic diseases affecting the lungs: cystic fibrosis and primary ciliary dyskinesia. Early phase clinical trials for the application of SORT to treat primary ciliary dyskinesia will start in 2023.
The implications for gene therapy and personalised medicine here are significant, because cystic fibrosis is a debilitating genetic disease caused by mutations in an ion channel protein, expressed on the surface of lung epithelial cells. Having the possibility of targeting these cells to correct the channel protein mutations provides hope for the development of cystic fibrosis treatments.
| 36482240 | PMC9734830 | NO-CC CODE | 2022-12-14 23:52:11 | no | Nat Nanotechnol. 2022 Dec 8; 17(12):1239 | utf-8 | Nat Nanotechnol | 2,022 | 10.1038/s41565-022-01292-0 | oa_other |
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J Ambient Intell Humaniz Comput
J Ambient Intell Humaniz Comput
Journal of Ambient Intelligence and Humanized Computing
1868-5137
1868-5145
Springer Berlin Heidelberg Berlin/Heidelberg
4496
10.1007/s12652-022-04496-3
Original Research
Revisiting natural user interaction in virtual world
Nguyen Tam V. [email protected]
1
Raghunath Shreyas 1
Phung Kim Anh 1
Ongwere Tom 1
Tran Minh-Triet 234
1 grid.266231.2 0000 0001 2175 167X University of Dayton, Dayton, OH USA
2 grid.454160.2 0000 0004 0642 8526 University of Science, Ho Chi Minh City, Vietnam
3 grid.444808.4 0000 0001 2037 434X John von Neumann Institute, VNU-HCM, Ho Chi Minh City, Vietnam
4 grid.444808.4 0000 0001 2037 434X Vietnam National University, Ho Chi Minh City, Vietnam
7 12 2022
111
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28 11 2022
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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Natural user interaction in virtual environment is a prominent factor in any mixed reality applications. In this paper, we revisit the assessment of natural user interaction via a case study of a virtual aquarium. Viewers with the wearable headsets are able to interact with virtual objects via head orientation, gaze, gesture, and visual markers. The virtual environment is operated on both Google Cardboard and HoloLens, the two popular wireless head-mounted displays. Evaluation results reveal the preferences of users over different natural user interaction methods.
Keywords
Mixed reality
Virtual reality
User interaction
Evaluation
http://dx.doi.org/10.13039/100000001 National Science Foundation 2025234 Nguyen Tam V. VINIFVINIF.2019.DA19 Tran Minh-Triet
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pmcIntroduction
Fig. 1 The conventional real-life aquarium (left—image courtesy of Georgia Aquarium) vs. virtual aquarium (right—our work) with the tiger shark
In recent years, mixed reality (MxR) applications including virtual reality and augmented reality have become very popular in various domains such as education, knowledge dissemination, healthcare, entertainment, and manufacturing. The most common thing in these applications is a display in the form of a smartphone or a headset. These applications mainly focus on providing good graphics for immersive environment. In fact, the user interaction is also important since it connects the users to the virtual world. In practice, the MxR users are able to engage with virtual objects in the applications via various interaction interfaces such as tangible, devices, or sensors.
The existence of aquariums in most regions of the world creates knowledge dissemination opportunities across a diverse and multi-cultural audience. The aquarium provides a great experience to encounter the wonders of marine life. However, the recent COVID-19 pandemic (COVID-19 pandemic 2022) radically transforms the real world. The pandemic has since affected our daily life. Many restaurants, bars, gyms, parks, and recreational areas are closed. People are wearing masks and avoiding crowds. These directives could lead to an increased demand for mixed-reality applications. Besides, the recent reports show that the need for mixed-reality applications will boost over the next decade (Augmented Reality Gets Pandemic Boost 2022). While most aquariums in the US are closed to the public in compliance with health orders for zoos and aquariums (Columbus Zoo and Aquarium 2022), in this study, we aim to offer ways for people to continue connecting with sea animals and learn about marine life. Figure 1 illustrates the setting of the real-life aquarium and the virtual aquarium. The virtual aquarium offers several new virtual opportunities to meet animals in close proximity. In that, people (viewers) may have virtual meet-ups with a live guest appearance such as a fish, sea lion, penguin, or sea otter. Viewers learn more about their favorite animals via interaction such as gesture, or visual markers. Therefore, a virtual aquarium is an ideal platform for us to evaluate the natural user interaction in virtual environment.
Our contributions are summarized as follows. We first introduce the main components of a feasible solution of a virtual aquarium, which can be utilized as an efficient and interesting approach for education and knowledge dissemination. We integrate various interaction methods in order to enhance the user experience. We later study the impact of different interaction methods in mixed reality applications. In particular, we conduct an extensive user study to evaluate different interaction methods.
The remainder of this paper is structured as follows. We conduct a brief review of related works in Sect. 2. Then, Sect. 3 introduces the virtual aquarium application with different interaction methods. Next, Sect. 4 presents the experiments and discusses the experimental results. Finally, the paper is concluded in Sect. 5 and we further present some prospective future works.
Related work
Mixed reality applications
In this subsection, we explore different mixed reality (MxR) applications including virtual reality (VR) and augmented reality (AR).
Virtual reality offers an experience of a fully artificial environment to users. The users are totally immersed in such a virtual world and interact with virtual objects via game controllers, sensors, or gestures. As an example, Nguyen and Sepulveda (2016) used gestures to support user interaction inside the virtual environment. Since the users only view the virtual world, there have been many efforts to integrate other human senses. Ranasinghe et al. (2017) integrated thermal and wind modules in order to help users perceive the ambient temperatures and wind conditions in the virtual environment. Similarly, Zhu et al. (2019) developed a thermal haptic feedback in a form of a smart ring. They found that the users are able to feel the temperature accurately. In another work, Tran et al. (2018) studied the users’ speed change perception via cycling in VR. In particular, they developed a bike prototype that simulates cycling techniques such as bike pedaling or throttling.
Meanwhile, augmented reality attempts to expand reality by overlaying virtual objects into the real environment. Kato and Billinghurst (2004) released AR Toolkit which overlays virtual objects on top of a binary marker. Later, Fiala (2005) developed ARTag markers with bi-tonal planar patterns to improve the marker’s recognition and pose estimation rate. Liu et al. (2012) introduced an AR system, magic closet, for autonomously pairing and rendering clothes based on the input occasion.
There have been efforts to define mixed reality (Speicher et al. 2019; Mystakidis 2022). In practice, mixed reality applications involve both physical reality and virtual reality. In such a hybrid environment, the virtual objects are overlaid and mapped to the real world (as in augmented reality) and users are allowed to interact with objects via devices, sensors, or gestures (as in virtual reality). Nguyen et al. (2016) introduced a mixed reality application allowing users to design interactive reparation manuals by using Moverio smart glasses (Epson 2022). Then, other users can download the designed manuals to fix their own items via pre-designed instructions.
There have been many mixed reality applications in education and training. In fact, the visualization of 3d content and the manipulation of virtual object is an entry level in taxonomies of immersive instructional design methods (Mystakidis et al. 2022; Cruz et al. 2021). Kim et al. (2020) developed a theoretical framework including authentic experience, cognitive and affective responses, attachment, and visit intention with tourism education using a stimulus-organism-response model. Nguyen et al. (2020) developed a MxR system on HoloLens (2022) for nondestructive evaluation training (NDE). The users interact with virtual objects such as ultrasound transducer and inspection objects within an NDE session via gestures and gaze. Butail et al. (2012) created a virtual environment where fish is put in the fish tank. However, the setting is simple with only one fish and there is no user study. Recently, Wißmann et al. (2020) introduced an approach to fish tank virtual reality with semi-automatic calibration support. However, the system only works properly if the glasses are front-facing the monitor. Small head rotations to the left or right are possible, but more extensive rotations may cause shutter synchronization errors. In addition, they did not conduct the user study to evaluate the user interaction. Araiza-Alba et al. (2021) used 360-degree virtual reality videos to teach water-safety skills to children. However, there is no user interaction with 360-degree videos. Čejka et al. (2020) and Sinnott et al. (2019) proposed AR/VR underwater systems. Cejka et al. developed a prototype run on a smartphone sealed in a waterproof case and uses a hybrid approach (markers and inertial sensors) to localize the diver on the site. Sinnott et al. (2019) created an underwater head mounted display by adapting a full-face scuba mask to house a smartphone and lenses. Here, these systems are impractical since they require actual water environment such as a swimming pool which is not always available to the end users.
User interaction in virtual world
User interaction in virtual world plays a crucial role in mixed reality applications. User interaction nurtures a contextual user engagement with the virtual content. Previously the VR headsets blocked the natural view of the user to the real environment. Due to this engineering problem, the users were not able to directly interact with the real world. However, the release of modern see-through headsets, such as HoloLens allowed the interaction between users and the physical world. As reviewed in Bekele and Champion (2019), there are four primary interaction methods, namely, tangible, device-based, sensor-based, and multimodal interaction methods.Fig. 2 The system overview of the virtual aquarium used in this research
Tangible interaction involves physical objects to support the user interaction with virtual objects. For example, Araújo et al. (2016) developed a tangible VR using an interactive cube. The cube side has special line patterns for ease of recognition. Later, Harley et al. (2017) added visual and auditory haptic feedback into the cube. The tangible interfaces must be customized, therefore, these interfaces are not available to massive users.
Device-based interaction adopts graphical user interfaces and/or external devices, for example, computer mouse, gamepad, joystick to help the user engage with virtual objects. Here, the visual marker can be considered as a device-based interface. As an example, Henderson and Feiner (2009) used visual markers in an AR prototype for vehicle maintenance.
Sensor-based interaction utilizes sensing devices such as motion tracker and gaze tracker to understand user inputs. For example, Avgoustinov et al. (2011) developed an NDE training simulation by analyzing the gaze and gesture from users.
Multimodal interaction fuses aforementioned methods, i.e., tangible, device-based, sensor-based interaction techniques to sense and perceive human interaction. For example, this kind of interaction allows devices along with gestural, and gaze-based to engage in interaction with virtual objects.
Bekele and Champion (2019) compared different interaction methods for cultural learning in virtual reality. However, there was no user study conducted. Recently, Yang et al. (2019) reviewed different interaction methods in the virtual environment. They also discussed the application of gesture interaction system in virtual reality. However, there is no evaluation from actual users. FaceDisplay Gugenheimer et al. (2018) is a modified VR headset consisting of three tangible displays and a depth camera attached to its back. Surrounding people can perceive the virtual world through the displays and interact with the headset-worn user via touch or gestures. However, this touch screen-based interaction is unnatural and inconvenient for both the user wearing headset and surrounding people. Meanwhile, Kang et al. (2020) only analyzed the simple interaction such as moving (translation) in virtual reality.
Experience of mixed reality users
The MxR experience is often determined by powerful hardware and actuators (Pittarello 2017). The hardware provides an engagement for the visual experience. Actuators provide user inputs and outputs, and support mapping users’ actions in their real-life experience to their actions in the virtual experience. The implementation of these experiences in VR and AR technologies has been reported in some studies. For example, there are (i) animal-free aquariums that provide visitors with an authentic in-the-wild experience (Jung et al. 2013), and (ii) storytelling virtual theaters that provide visitors an engaging and educational experience about endangered animal species (Dooley 2017; Daut 2020). However, these technologies are installed and are operating in designated and often expensive areas. We have yet to see work that discusses how such technologies can engage users in a less expensive and personal way. The research that has explored user interaction with MxR tools is still complex and has failed to detail the standards for user engagement and interaction preferences (Pittarello 2017). User engagement, interaction, and preferences are important components of MxR and are relevant in describing the MxR experience. In this paper, we adapt six parameters to explore various interaction modes and capture several facets of the MxR usage when connecting with and learning about marine life. These parameters include ease of use, convenience, preference, engagement, and motivation.Fig. 3 The headsets in mixed reality applications. From left to right: Google Cardboard, Oculus Rift, HTC Vive, Epson Moverio, and Microsoft HoloLens. Note that Google Cardboard and Microsoft HoloLens are under wireless setting
Virtual aquarium application
Overview
Here we briefly introduce our virtual aquarium framework. We designed our framework following a modular design approach for the extensibility and re-usability purposes in different application domains. The main components of the framework are shown in Fig. 2.
As a quick glimpse, the object renderer is responsible for rendering virtual objects and superimposing them into the real or virtual scene. Meanwhile, the interaction handler analyzes the user input/interaction and provides the corresponding feedback. For example, users may interact with virtual objects using the gaze, gesture, and visual marker. The object transformation is used to perform certain Affine transformation on the virtual objects such as scaling, translating, rotating according to the user interaction. Besides, the headsets are used to display the virtual environment to the users. The details of different components are listed in the following subsections.
Headsets
A headset is one of the essential devices for any mixed reality application. It comprises a tiny display optic in front of one eye (monocular vision) or each eye (binocular vision) to render stereoscopic views and head motion tracking sensors.
Google Cardboard (2022) is the most simple yet effective VR headset (The Best VR Headsets for PC 2022). As shown in Fig. 3, a smartphone serves as the display and the main processor of the headset, and a cardboard box is a holder. To enhance the usability for users, various extra features such as trackers, stereo sound, and controllers have been integrated into other VR headsets, i.e.,Rift (2022) and Vive (2022). In most VR headsets, the main computation and visual rendering processes are performed in an external PC/laptop connected to the headsets via wired connections. Besides, the VR users cannot feel the real environment since they are immersed in the virtual world. Thus, it is inconvenient for users to walk naturally in VR, and they should simulate their movement via a gamepad or joystick.
To overcome issues with VR headsets, the Epson Moverio glasses (Epson 2022) comprises two components, the binocular and mini-projectors. The binocular has a see-through capability via the transparent display, and mini-projectors are responsible for rendering virtual objects. In this setting, users can see the virtual objects augmented in the real environment. However, its bulky setup, such as a separate heavy battery, main processor, and external controller, prevents users from long working sessions. Therefore, Microsoft introduced HoloLens (2022) which integrates the display, processor, and battery within the same unit. It also has a built-in eye tracker for gaze detection, front-facing cameras for gesture recognition, and a depth sensor for spatial mapping.Fig. 4 The underwater 3D models used in our virtual aquarium
From the list above, we opt to use Google Cardboard and HoloLens for two reasons. First, they are both wireless headsets which are more convenient for viewers than wired ones. Second, they represent two extreme settings, i.e., Google Cardboard for the fully immersive virtual environment whereas HoloLens for the mixed reality environment of the real world and the overlaid virtual content.
Integration of interaction methods
In this work, we specifically focused on the interactions related to head orientation, hand gestures, gaze, and visual markers. Below we provide the details of each interaction method.
Head orientation
When detecting the orientation of the user’s head, the headset uses data from accelerometers and gyroscopes for inertial tracking. In particular, the output of the accelerometers is used to find the velocity and then estimate the position. Meanwhile, the angular velocity is measured by gyroscopes to determine the angular position relative to the initial point.
In our system, the important modality for input is user gaze. A user can target and select a virtual object in the mixed reality environment via user gaze. The gaze determines the location where the user is looking at. Here the gaze direction can be formed via the camera position and the center point of the viewport. This can be considered as the fixed gaze.
Human gaze input
Unlike the fixed gaze mentioned above, the modern headset such as HoloLens integrates a built-in eye tracker. During the spatial mapping phase. HoloLens continuously scans through the real surrounding environment to map spatial meshes in the real world with those meshes in the virtual world. Then, the built-in eye tracker detects the human gaze, namely, the position vector g(xg,yg,zg) and the direction vector f(xf,yf,zf). Here, the gaze direction vector f is a ray casting straight through the gaze vector g.
Gesture input
In our prior work (Nguyen et al. 2020), we show how users engage with virtual content and applications by using their hand gestures. The users may initiate the interactions via simple gestures, for example, raising and tapping down the index finger. Users manipulate the virtual objects or navigate the virtual environment using the relative motions of their hands.
Visual marker input
Visual markers can be in the form of binary markers or natural images. They are pre-scanned models of feature points (the key points detected in the markers). The integrated computer vision component such as dos Santos (2016) performs marker detection and marker tracking. When the marker is detected and tracked, the marker’s feature points are used to estimate the pose of the marker from the user viewpoint. Thanks to the estimated pose, virtual objects can be augmented (superimposed) into the scene on the visual markers.Fig. 5 The interface of different interaction methods. From left to right, top to bottom: Google Cardboard, HoloLens with gaze only, HoloLens with gaze and gesture, HoloLens with gaze, gesture, and visual markers
System implementation
Object renderer and transformation
The virtual aquarium is composed of three sets of rendered objects. These include fish species, non-fish species, and landscape items. Figure 4 illustrates some 3D models used in our virtual aquarium. Each object has an origin point and a transformation matrix. The matrix stores and manipulates the position, rotation, and scale of the object.
We follow Huth and Wissel model (1992) to simulate the fish movement. Each fish swims either individually or in a school. Every fish swims within the school that has the same behavior model. The motion of the model fish school is not affected by external influences. Here, we consider the position pi, orientation oi, and velocity vi for each fish i. The position pi(xi,yi,zi) at each time-step Δt is defined based on the Huth and Wissel (1992):1 pi(t+Δt)=pi(t)+Δt×vi(t+Δt),
where vi(t+Δt) and oi(t+Δt) are defined as follows:2 vi(t+Δt)=oi(t+Δt)×vi(t),
3 oi(t+Δt)=cosαi(t)-sinαi(t)0sinαi(t)cosαi(t)0001×oi(t).
To facilitate the implementation, we permit each fish to swim at a certain depth zi. Meanwhile, the turning angle, αi, is determined using the same behavior model described by Huth and Wissel (1992).Table 1 The configuration comparison of different interaction modes in our experiments
Device Head orientation Gaze Gesture Visual marker
Mode 1 Google Cardboard ✓ c
Mode 2 HoloLens ✓ ✓
Mode 3 HoloLens ✓ ✓ ✓
Mode 4 HoloLens ✓ ✓ ✓ ✓
Interaction handler
Regarding the user gaze, we compute the hit point h(xh,yh,zh) The hit point is the intersection between the gaze vector g with the direction f and the object’s mesh:4 h=g+d×f,
where d is the distance between the gaze and object hit point. Algorithm 1 describes the pseudo code to identify the attentive virtual object (aquarium animals). Note that the attentive object must contain animations and gaze handler implementation. Then, the attentive object will provide the feedback, for example, it performs certain animation and a narrative sound raises to introduce the animal. Regarding the visual marker, we opt to natural images for the markers instead of using binary images. In particular, we adopt Vuforia Engine dos Santos (2016) as mentioned earlier.
System integration
We adopt Unity3D engine1 to implement the proposed system. The engine provides packages for mixed reality development and also supports cross-platform features. These packages allow developers to run the applications onto different devices, including smartphones (used in Google Cardboard) and HoloLens.
We first insert the 3D models, i.e., fish, non-fish, and landscape object instances, into the Unity3D scenes. Each object instance is attached with a C# programming script. For example, each object is assigned to a random trajectory. We also group several schools of fish to simulate the actual aquarium. Regarding the interaction feedback, we display the pop-up information and play the voice for the models designed based on the ray cast hit point h. For the visual marker, we adopted dos Santos (2016) to detect and track the marker. Note that our framework can be easily adopted to different education domains. For example, the underwater 3D models can be replaced as models of paintings or sculptures for a virtual museum. Another application example is the virtual heritage where monuments, buildings and objects with historical, archaeological, or anthropological value can be integrated into our system. Figure 5 illustrates the user interface of the virtual aquarium system in different interaction modes, namely, Google Cardboard, HoloLens with gaze-only, HoloLens with gaze and gesture, HoloLens with multimodal of gaze, gesture, and visual markers.Fig. 6 The average rating scores from the user study evaluation
Evaluation
Participants and experimental settings
Our study received approval from the IRB at the University of Dayton. We follow (Kaur 1997) and (Suárez-Warden et al. 2015) for the design methodology and sample size, respectively. The participants who have no or limited prior knowledge in using mixed reality headsets (e.g., Google Cardboard and HoloLens) are eligible to take part in the user study. The mixed reality application was designed to be simple enough for the novice to contribute to without compromising the integrity of the results. In total, 51 people participated in this study, 18 of these participants identified themselves as female. The participants are university students and staff, whose ages range from 18 to 60 (μ=29.4). We provided participants the instructions for the experiment after they completed the consent form. Table 1 lists the configuration comparison of different interaction modes. Each participant took part in a session, namely, a 5-min trial followed by 1-min break for each interaction method. We observed no cybersickness from participants after every 5-min short trials. We then showed the questionnaire and asked for feedback regarding the following perspectives:Ease of use: How easy is the method?
Convenience: How convenient is the method?
Experience: How much does the interaction mode help you experience the environment?
Preference: How much do you prefer a certain interaction mode over the others?
Engagement: How much does the method engage the user?
Motivation: How much does the method increase the involvement of the user?
The ‘ease of use’ is the most popular criterion in literature (Venkatesh 2000; Ahn et al. 2017; Gopalan et al. 2016). Meanwhile, ‘convenience’ and ‘experience’ were included in Nguyen and Sepulveda (2016) and Kim et al. (2020). In addition, the ’preference’ criterion was studied in Nguyen et al. (2018) and Cicek et al. (2021). Also, the criteria ‘engagement’ and ‘motivation’ were included in Gopalan et al. (2016), Huang et al. (2021) and Bekele and Champion (2019). Therefore, we included all the aforementioned criteria in our study. The participant rated each interaction mode on a 5-point Likert scale (Likert 1932) from the best (5) to the worst (1) for each criterion.
Experimental results
Figure 6 shows the average scores of different interaction modes for the aforementioned criteria. Mode 1 (Google Cardboard) is highly rated for ease of use. There is not much instruction on using Google Cardboard. The participants simply wear the Google Cardboard and use head rotation to observe the virtual environment. Meanwhile, the participants need to learn how to use HoloLens, such as focusing gaze or using gestures. Note that the consecutive wrong gestures that are not recognized by HoloLens frustrate the users.
Regarding the convenience and experience, Mode 3 (HoloLens with gaze and gesture) and Mode 1 achieve the highest and the second highest rates, respectively. The two modes are convenient to users. Meanwhile, Mode 2 (HoloLens with gaze only) is not as convenient as Mode 1 since the device is heavier and there is not much different in terms of functionality. However, Mode 3 (HoloLens with gaze and gesture) is preferred due to the usage of human gestures.
In terms of engagement and motivation, Mode 3 and Mode 4 (HoloLens with gaze, gesture, and visual marker) obtain the top-2 rates. The main reason that Mode 3 outperforms Mode 4 can be explained via the usage of the visual marker itself. Actually, the use of visual markers is very interesting to participants. However, it interrupts the user experience. Indeed the participant needs to use one hand to hold the visual marker. Therefore, it is inconvenient to use the other hand for gesture-based interaction. Meanwhile, Mode 1 and Mode 2 achieve the lowest rates due to the limited interaction.Table 2 Wilcoxon signed rank test with p-values of every two compared mode ratings w.r.t. ease of use and convenience
Convenience (CV)
Ease of use (EU)
Mode 1 – 0.608 0.676 0.189
Mode 2 0.014 – 0.239 0.444
Mode 3 0.475 0.068 – 0.117
Mode 4 0.023 0.635 0.043 –
Mode 1 Mode 2 Mode 3 Mode 4
p-values ≤ 0.05 are marked in boldface
Regarding the preference, the participants favor Mode 3 and Mode 4 over Mode 2 (HoloLens with gaze only) and Mode 1 (Google Cardboard). The participants appreciate the usage of gestures and no strict spatial requirement when using HoloLens.
Next, we apply a statistical significance test to verify if the user ratings of two interaction modes are equivalent. This is regarded as the null hypothesis, for example, H0:r(CVMode1)=r(CVMode2), where r(CVMode1) and r(CVMode2) are the user ratings with regards to the convenience from Mode 1 and Mode 2, respectively. In other words, the significance test verifies whether there is no difference between two sets of user ratings. Given a null hypothesis, we compute the p-value, namely, the probability of obtaining the observed ratings if the null hypothesis is true. In this work, we compute p-values via the Wilcoxon signed rank test (Wilcoxon 1992).
Table 2 presents the p-values of every pair of interaction mode ratings in terms of ease of use (in the lower diagonal) and convenience (in the upper diagonal). We note that the p-values of (EUMode1,EUMode3) and (EUMode1,EUMode4) are ≤0.05 meaning that the null hypothesis is rejected to the two interaction modes. Therefore, the differences between Mode 1 and Mode 2/Mode 4 are statistically significant. Likewise, the null hypothesis is rejected to (Mode 1 and Mode 2) and (Mode 1 and Mode 4) in terms of EU. However, the p-value of (Mode 1 and Mode 3) with regard to EU is >0.05 meaning that the null hypothesis is true. In other words, Google Cardboard and HoloLens (with gaze and gesture) share the similar ease of use. All p-values with regard to CV are >0.05 meaning that the four interaction modes have similar convenience ratings.
For the remaining criteria, Tables 3 and 4 show p-values of every pair of mode ratings (XA and XB), where X is the rating in terms of experience (XP), preference (PR), engagement (EN), and motivation (MV), and A and B are the two interaction modes considered. The differences between Mode 3 (HoloLens with gaze and gesture) and other modes are statistically significant. In particular, the null hypothesis is rejected to (Mode 3 and Mode 2) and (Mode 3 and Mode 4) in terms of experience and preference. In addition, the null hypothesis is also rejected to (Mode 3 and Mode 1) in terms of engagement, motivation, and preference. The results clearly show that the usage of Mode 3 (HoloLens with gaze and gesture) for interaction in mixed reality is preferred by the participants.Table 3 Wilcoxon signed rank test with p-values of every two compared mode ratings w.r.t. experience and preference
Preference (PR)
Experience (XP)
Mode 1 – 0.701 0.063 0.827
Mode 2 0.006 – 0.003 0.537
Mode 3 0.616 0.033 – 0.050
Mode 4 0.031 0.419 0.011 –
Mode 1 Mode 2 Mode 3 Mode 4
p-values ≤ 0.05 are marked in boldface
Table 4 Wilcoxon signed rank test with p-values of every two compared mode ratings w.r.t. engagement and motivation
Motivation (MV)
Engagement (EN)
Mode 1 – 0.108 0.043 0.097
Mode 2 0.960 – 0.310 0.537
Mode 3 0.010 0.004 – 0.831
Mode 4 0.136 0.055 0.492 –
Mode 1 Mode 2 Mode 3 Mode 4
p-values ≤ 0.05 are marked in boldface
Discussion
As mentioned earlier, the demand for mixed reality applications was boosted during the time of the pandemic (Augmented Reality Gets Pandemic Boost 2022). In our experiment, we show that users appreciate the usage of mixed reality applications for virtual aquariums. In particular, we show how the use of HoloLens with gaze and gesture-based interaction was favored by the participants. The participants highly rated the ability to observe and interact with the superimposed objects in the virtual aquarium. The user study indicates that the users prefer the addition of natural interaction such as gesture.
There needs to be an increase in the use of MxR applications in the form of VR and AR, so that experiences, such as a headset that provides 360∘o imagery to the user’s eyes and immersive audio to their ears, is possible. AR creates visual and auditory overlays on top of reality (Augmented Reality Gets Pandemic Boost 2022). During the pandemic, our MxR system (combining VR and AR) could create a new experience through headsets and visual makers that can change based on user preferences. This is an important component of the MxR system and is confirmed in our results section, where all of our participants agreed that head orientation is required for all interaction modes. Furthermore, our participants appreciated the ability to navigate inside the virtual aquarium which is difficult in the real-life aquarium.
We also found that the addition of visual markers is not convenient to the end users. In particular, when visual markers are being used, our results suggest that the visual marker should not be used to trigger the display of virtual objects. Instead, the visual markers should be used for the side information such as manual or in-app instruction. When visual makers are being used, future MxR tools should create an immersive interactive experience for the user and should add to the user’s sense of agency and immersion (in a virtual aquarium for example). The participants also recommended applying our MxR system in a more complicated environment (for example manufacturing, architecture, and healthcare).
Conclusions and future work
In this paper, we revisit the assessment of natural user interaction in virtual world. In particular, we develop a virtual aquarium on two popular wireless headsets, namely, Google Cardboard and HoloLens. Different from other works in literature, we evaluate different user interaction methods such as head orientation, gaze, gesture and visual markers. Our analysis first shows that the ease of use is highly appreciated across the two headsets while the user’s experience, preference, engagements and motivations vary from one mode to another. Our second finding is that the users prefer the addition of natural interaction such as gesture. Another finding is that the addition of visual markers is not convenient to the end users.
In the future, we will investigate methods to further improve the current system. In particular, we aim to extend this work from the aquarium to different virtual environments. Additionally, future studies should integrate visual markers in an appropriate form to increase engagement and convenience. Finally, we believe this work could attract more future research looking to assess the natural user interaction in mixed reality applications.
Funding
This research is supported by National Science Foundation (NSF) under Grant no. 2025234 and Vingroup Innovation Foundation (VINIF) in project code VINIF.2019.DA19.
Declarations
Conflict of interest
The authors have no conflicts of interest to declare that are relevant to the content of this article.
1 https://unity3d.com.
Publisher's Note
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References
Ahn J Choi S Lee M Kim K Investigating key user experience factors for virtual reality interactions J Ergon Soc Korea 2017 36 267 280
Araiza-Alba P Keane T Matthews B Simpson K Strugnell G Chen WS Kaufman J The potential of 360-degree virtual reality videos to teach water-safety skills to children Comput Educ 2021 163 104096 10.1016/j.compedu.2020.104096
Araújo B, Jota R, Perumal V, Yao J, Singh K, Wigdor D (2016) Snake charmer: physically enabling virtual objects. In: Proceedings of the international conference on tangible, embedded, and embodied interaction, pp 218–226
Augmented Reality Gets Pandemic Boost (2022) https://www.wsj.com/articles/augmented-reality-gets-pandemic-boost-11611866795. Retrieved 28 Feb 2022
Avgoustinov N, Boller C, Dobmann G, Wolter B (2011) Virtual reality in planning of non-destructive testing solutions. In: Bernard A (ed) Global product development, pp 705–710
Bekele MK Champion E A comparison of immersive realities and interaction methods: cultural learning in virtual heritage Front Robot AI 2019 6 91 10.3389/frobt.2019.00091 33501106
Bekele MK Champion E A comparison of immersive realities and interaction methods: cultural learning in virtual heritage Front Robot AI 2019 6 91 10.3389/frobt.2019.00091 33501106
Butail S, Chicoli A, Paley DA (2012) Putting the fish in the fish tank: immersive vr for animal behavior experiments. In: 2012 IEEE international conference on robotics and automation. IEEE, pp 5018–5023
Čejka J Zsíros A Liarokapis F A hybrid augmented reality guide for underwater cultural heritage sites Pers Ubiquit Comput 2020 24 815 828 10.1007/s00779-019-01354-6
Cicek I Bernik A Tomicic I Student thoughts on virtual reality in higher education—a survey questionnaire Information 2021 12 151 10.3390/info12040151
Columbus Zoo and Aquarium canceling events over COVID-19 coronavirus concerns (2022). https://www.dispatch.com/story/news/2020/03/13/columbus-zoo-aquarium-canceling-events/1530300007/. Retrieved 28 Feb 2022
COVID-19 pandemic (2022) https://www.who.int/emergencies/diseases/novel-coronavirus-2019. Retrieved 28 Feb 2022
Cruz A Paredes H Morgado L Martins P Non-verbal aspects of collaboration in virtual worlds: a CSCW taxonomy-development proposal integrating the presence dimension J Univers Comput Sci 2021 27 913 954 10.3897/jucs.74166
Daut M (2020) Immersive storytelling: leveraging the benefits and avoiding the pitfalls of immersive media in domes. In: Handbook of research on the global impacts and roles of immersive media, pp 237–263
Dooley K Storytelling with virtual reality in 360-degrees: a new screen grammar Stud Australas Cine 2017 11 161 171 10.1080/17503175.2017.1387357
dos Santos AB, Dourado JB, Bezerra A (2016) Artoolkit and qualcomm vuforia: an analytical collation. In: Symposium on virtual and augmented reality, pp 229–233
Epson Moverio glasses (2022). https://epson.com/moverio-augmented-reality. Retrieved 28 Feb 2022
Fiala M (2005) Artag, a fiducial marker system using digital techniques. In: Computer vision and pattern recognition, pp 590–596
Google Cardboard (2022) https://arvr.google.com/cardboard/. Retrieved 28 February 2022
Gopalan V Zulkifli AN Abubakar J A study of students motivation based on ease of use, engaging, enjoyment and fun using the augmented reality science textbook J Fac Eng 2016 31 27 35
Gugenheimer J, Stemasov E, Sareen H, Rukzio E (2018) Facedisplay: towards asymmetric multi-user interaction for nomadic virtual reality. In: Mandryk RL, Hancock M, Perry M, Cox AL (eds) Proceedings of the 2018 CHI conference on human factors in computing systems, CHI 2018, Montreal, QC, Canada, April 21–26. ACM, p 54 (2018)
Harley D, Tarun AP, Germinario D, Mazalek A (2017) Tangible VR: diegetic tangible objects for virtual reality narratives. In: Proceedings of the 2017 conference on designing interactive systems, pp 1253–1263
Henderson SJ, Feiner S (2009) Evaluating the benefits of augmented reality for task localization in maintenance of an armored personnel carrier turret. In: IEEE international symposium on mixed and augmented reality, pp 135–144
HTC Vive (2022) https://www.vive.com. Retrieved 28 Feb 2022
Huang W Roscoe RD Johnson-Glenberg MC Craig SD Motivation, engagement, and performance across multiple virtual reality sessions and levels of immersion J Comput Assist Learn 2021 37 745 758 10.1111/jcal.12520
Huth A Wissel C The simulation of the movement of fish schools J Theor Biol 1992 156 365 385 10.1016/S0022-5193(05)80681-2
Jung S, Choi YS, Choi JS, Koo BK, Lee WH (2013) Immersive virtual aquarium with real-walking navigation. In: Proceedings of the 12th ACM SIGGRAPH international conference on virtual-reality continuum and its applications in industry, pp 291–294
Kang HJ, Shin J, Ponto K (2020) A comparative analysis of 3d user interaction: How to move virtual objects in mixed reality. In: IEEE conference on virtual reality and 3D user interfaces, VR 2010, Atlanta, GA, USA, March 22–26, 2020. IEEE, pp 275–284
Kato H, Billinghurst M (2004) Developing AR applications with artoolkit. In: IEEE and ACM international symposium on mixed and augmented reality (ISMAR), p 305
Kaur K (1997) Designing virtual environments for usability. In: International conference on human–computer interaction, pp 636–639
Kim MJ Lee CK Jung T Exploring consumer behavior in virtual reality tourism using an extended stimulus-organism-response model J Travel Res 2020 59 69 89 10.1177/0047287518818915
Likert R A technique for the measurement of attitudes Arch Psychol 1932 22 140 55
Liu S, Nguyen TV, Feng J, Wang M, Yan S (2012) Hi, magic closet, tell me what to wear!. In: Proceedings of ACM multimedia conference, pp 1333–1334
Microsoft HoloLens—Mixed Reality Technology (2022) https://www.microsoft.com/en-us/hololens. Retrieved 28 Feb 2022
Mystakidis S Metaverse Encyclopedia 2022 2 486 497 10.3390/encyclopedia2010031
Mystakidis S Christopoulos A Pellas N A systematic mapping review of augmented reality applications to support STEM learning in higher education Educ Inf Technol 2022 27 1883 1927 10.1007/s10639-021-10682-1
Nguyen TV, Kamma S, Adari V, Lesthaeghe T, Boehnlein T, Kramb V (2020) Mixed reality system for nondestructive evaluation training. In: Virtual reality, pp 1–10
Nguyen TV, Mirza B, Tan D, Sepulveda J (2018) ASMIM: augmented reality authoring system for mobile interactive manuals. In: Proceedings of international conference on ubiquitous information management and communication, pp 3:1–3:6
Nguyen TV, Tan D, Mirza B, Sepulveda J (2016), MARIM: mobile augmented reality for interactive manuals. In: Proceedings of ACM conference on multimedia conference, pp 689–690
Nguyen TV Sepulveda J Augmented immersion: video cutout and gesture-guided embedding for gaming applications J Multimed Tools Appl 2016 75 12351 12363 10.1007/s11042-016-3435-x
Nguyen TV Sepulveda J Augmented immersion: video cutout and gesture-guided embedding for gaming applications Multimed Tools Appl 2016 75 12351 12363 10.1007/s11042-016-3435-x
Oculus Rift (2022) https://www.oculus.com. Retrieved 28 Feb 2022
Pittarello F (2017) Experimenting with playvr, a virtual reality experience for the world of theater. In: Proceedings of the 12th biannual conference on Italian SIGCHI chapter, pp 1–10
Ranasinghe N, Jain P, Karwita S, Tolley D, Do EY (2017) Ambiotherm: Enhancing sense of presence in virtual reality by simulating real-world environmental conditions. In: Proceedings of the 2017 CHI conference on human factors in computing systems, pp 1731–1742
Sinnott C, Liu J, Matera C, Halow S, Jones A, Moroz M, Mulligan J, Crognale M, Folmer E, MacNeilage P (2019) Underwater virtual reality system for neutral buoyancy training: development and evaluation. In: 25th ACM symposium on virtual reality software and technology, pp 1–9
Speicher M, Hall BD, Nebeling M (2019) What is mixed reality?. In: Brewster SA, Fitzpatrick G, Cox AL, Kostakos V (eds) Proceedings of the 2019 CHI conference on human factors in computing systems, CHI 2019, Glasgow, Scotland, UK, May 04–09, 2019. ACM, p 537
Suárez-Warden F Rodriguez M Hendrichs N García-Lumbreras S Mendívil EG Small sample size for test of training time by augmented reality: an aeronautical case Procedia Comput Sci 2015 75 17 27 10.1016/j.procs.2015.12.190
The Best VR Headsets for PC (2022) https://thewirecutter.com/reviews/best-desktop-virtual-reality-headset/. Retrieved 28 Feb 2022
Tran TQ, Tran TDN, Nguyen TD, Regenbrecht H, Tran M (2018) Can we perceive changes in our moving speed: a comparison between directly and indirectly powering the locomotion in virtual environments. In: Proceedings of ACM symposium on virtual reality software and technology (VRST), pp 36:1–36:10
Venkatesh V Determinants of perceived ease of use: integrating control, intrinsic motivation, and emotion into the technology acceptance model Inf Syst Res 2000 11 342 365 10.1287/isre.11.4.342.11872
Wilcoxon F (1992) Individual comparisons by ranking methods. In: Breakthroughs in statistics, pp 196–202
Wißmann N, Mišiak M, Fuhrmann A, Latoschik ME (2020) A low-cost approach to fish tank virtual reality with semi-automatic calibration support. In: 2020 IEEE conference on virtual reality and 3d user interfaces abstracts and workshops (VRW). IEEE, pp 598–599
Yang L Huang J Feng T Hong-An W Guo-Zhong D Gesture interaction in virtual reality Virtual Real Intell Hardw 2019 1 84 112 10.3724/SP.J.2096-5796.2018.0006
Zhu K Perrault ST Chen T Cai S Peiris RL A sense of ice and fire: Exploring thermal feedback with multiple thermoelectric-cooling elements on a smart ring Int J Hum Comput Stud 2019 130 234 247 10.1016/j.ijhcs.2019.07.003
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Jindal Global Law Review
Jindal Global Law Review
0975-2498
2364-4869
Springer India New Delhi
185
10.1007/s41020-022-00185-6
Editorial
Age as a site of law’s meaning-making practices
http://orcid.org/0000-0001-8208-3548
Sanghi Sanskriti [email protected]
grid.449565.f OP Jindal Global University, Sonipat, India
5 12 2022
19
22 11 2022
© The Author(s), under exclusive licence to O.P. Jindal Global University (JGU) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
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pmcAge, ageing, and the law
Age, n.
Typically conceptualised as a fixed characteristic or objective unit signifying the length of time for which someone has lived or something has existed.1
Age, v. (ageing)
Commonly understood as a linear trajectory or process towards becoming older or more mature.2
Age is considered a universal phenomenon. Characteristic of an individual’s biological and social life, it is experienced by all, even though it may neither always be identifiable as such nor the only influential identity marker. Constitutive ideas about age—both, as a characteristic (n.) and process (v.)—shape the manner in which one experiences this phenomenon in society. These ideas often emerge out of or are legitimated by law, which constructs meanings out of and about age in its organisation of society. In doing so, law’s processes of construction are themselves also marked by the very passage of time that suffuses the motion of age through the lives of individuals and communities. The pervasiveness of age as a signifier of the human experience3 that law is interested in regulating renders scholarly inquiry into the relationship between law and age imperative.
The theme of this issue of Jindal Global Law Review (JGLR) is aimed at providing a forum for interdisciplinary reflections on this meaning-making capacity of law through its stated and unstated norms at the site of age. By interrogating whether law acts as a mediating force between the abstract concept of age and its conversion into a collectively held idea that is socially wielded and lived, this issue inaugurates a series of interconnected discourses that illumine, challenge, or subvert embedded notions about and boundaries around age.
These discourses traverse a wide expanse. Considering the universality of age to be punctuated by human variability can, for instance, demonstrate the contingency of seemingly objective units of measuring age utilised by law to draw boundaries.4 Such contemplation can also aid in the examination of the rationality and linearity of these boundaries.5 Similarly, attention to the distinctiveness of context can animate the assumptions and beliefs ingrained within a legal system from which biases, stereotypes, and prejudices founded on age may flow.6 By extension, age may emerge as an identity marker that can systemically be used to ‘other’ and which does not operate in isolation of intersecting identity markers.7 The law’s re/production of language that contains certain imaginations about age is another idea that merits exploration given the valence it carries in perpetuating perceptions about role, capacity, and pace among others. These perceptions can manifest through their superimposition upon identity—individual or collective.
By ruminating about several of these ideas—while by no means being limited by or to them—the contributions in this issue reveal the multifaceted nature of the relationship between law and age as well as the manner in which it is operationalised through legal discourse. From the contributions, age emerges as a plural, complex, and layered site at which law simultaneously constructs many meanings. That law’s processes of meaning-making are, in turn, shaped and altered by the passage of time that characterises the movement of age is also animated by several contributions. Demonstrating that the relationship between law and age is not unidirectional, these contributions urge that ideas about age entrenched in law be scrutinised as law ages.
The contributions
To demonstrate these claims, I discuss the contributions to this issue by organising them under select broad and intertwined constructions of age. These constructions—namely, age as a site for the creation of the ‘Other’, age as a site for demarcation of the inside/outside, and age as a site characterised by and communicative of time—are dwelled upon by each contribution in a distinctive fashion. Despite differences in subject-matter and methodology, the contributions are unified in their treatment of age as a site at which multiple meanings are constructed by law. The coming together of these processes—which work independently and in combination—results in a site at which law (repeatedly) draws meaning out of age. As several contributions showcase, law’s own processes of meaning-making are also concurrently shaped.
Age as a site for the creation of the ‘Other’
Law’s (age-old) influence in the organisation of social life has meant that it has hegemonic power in deciding the (relative) worth of individuals.8 This has ensued through law’s construction of an ‘ideal’ subject, deviation from the norms constituting which results in the creation of the ‘Other’.9 Though the ‘Other’ differs from one context to another, her failure to fit into the image of the idealised subject results in marginalisation. The gap between the ‘ideal’ and the ‘Other’ is characterised by—and may even widen due to—negative stereotypes against the ‘Other’, negation of the rights of the ‘Other’, pressure on the ‘Other’ to conform to the ‘ideal’ (the norm) and the like. Law helps sustain this gap between the ‘ideal’ and the ‘Other’ through its processes of meaning-making. That age is a site for law’s meaning-making regarding the ‘Other’ is demonstrated by the contributions authored by Mallika Ramachandran and Qian Liu.
In Ramachandran’s review of Tracey Gendron’s Ageism Unmasked: Exploring Age Bias and How to End It,10 age is conceptualised as a category undergirded by a complex infrastructure of notions that ‘other’. Though Ramachandran’s emphasis is on bias against older persons and their treatment as the ‘Other’, particularly through a systemic negation of the possible simultaneity of ‘decline, growth, and maintenance’, their review initiates a broader dialogue about the power of ageist narratives to ‘other’ individuals as un/productive and/or in/capable. Law is hardly immune to such ageist narratives. In fact, the infrastructure that ‘others’ often emanates out of and is sustained by law in its interaction with social, economic, political, and medical narratives that are prejudicial against or contain misinformation about age. Ramachandran’s critique of rights discourses in which such ageist narratives are unchallenged acts as an instantiation through its revelation of the danger of older persons being treated as objects instead of as subjects. Through her review, Ramachandran provokes the question of whether challenging these narratives can yield a community cognisant and accommodative of its differences instead of one that ‘others’.
With Liu’s article, our gaze shifts—from older persons to ‘leftover’ women, from ageist societies generally to an authoritarian state with a rapidly ageing population such as China, from systemic obscuration or belittlement to pressure to adhere to a heteronormative timeline in relation to marital and reproductive choices. Yet, much as in Ramachandran’s review, Liu’s article engages with law’s ‘othering’ force in its organisation of social life. Situating the pressure against a backdrop of state policies that have yielded a rapidly ageing population whose responsibility China wishes to shift from the state to the individual, Liu’s discussion reveals the oft-imperceptible role of law in perpetuating notions about age. These notions come alive in the daily negotiations engaged in by women in China as anxiety about not adhering to the heteronormative timeline and of consequently being ‘othered’. Equally, their embeddedness can foreclose alternative imaginations of social organisation. Through their arrangement of these seemingly disparate events and ideas into a complex web through which certain women are ‘othered’, Liu raises the crucial question of whether law has romanticised age-old traditional values that are unsuitable for present times.
Age as a site for demarcation of the inside/outside
Law’s creation of the ‘Other’ at the site of age results in the production of categories that are hierarchically situated vis-à-vis each other. As is evident from Ramachandran’s and Liu’s contributions, the demarcation results in ‘biased thoughts, feelings, and behaviors in relation to [one’s] own age and aging processes as well as in relation to the age and aging process of others.’11 Law’s ‘othering’ process need not, however, operate in isolation. Sometimes, through its treatment of certain individuals as the ‘Other’, it may create an ‘inside’ and an ‘outside’.12 This results in the creation of distinct classes whose segregation is marked by law’s line-drawing authority. This line-drawing authority of law inevitably ousts and is exercised by lawmakers on the basis of a range of reasons other than one’s identity too.13 The interview with Shohini Ghosh and the contributions authored by Khagesh Gautam, Rajashree K and Chetan Singai, Avantika Tiwari, and Sharmila HS and Sunitha Abhay Jain contemplate certain ‘insides’ and ‘outsides’ embedded within law and discuss how age is implicated in or ought to impact these discourses.
Gautam’s review of Linda A. Parker’s Cannabinoids and the Brain14 argues the need for Indian lawmakers to regulate rather than prohibit the consumption of cannabis due to its medicinal value. Citing increasing support for the regulation of cannabis consumption in the United States of America, particularly as a strategy for pain relief management among the elderly, Gautam juxtaposes scientific and experiential evidence against law’s presumption of cannabis as injurious to one’s body and mind. By exhorting lawmakers to regulate cannabis primarily due to its medicinal value for the elderly, Gautam positions age as an overlooked but pivotal consideration. They argue that the inclusion of age as a consideration in decision-making about the status law should accord to cannabis can help lawmakers understand the need to transition from prohibition to regulation, thus altering law’s demarcation of the ‘inside’ from the ‘outside’.
Similarly, Rajashree and Singai advocate that age be considered by the relevant authorities in determining the coverage of legal guarantees so as to create an inclusive society. Drawing on interviews conducted with senior citizens, civil society activists, advocates, district magistrates, and administrative officers, the authors weave a visceral, revelatory, and complex tale of the connections between the absence of legal aid for older persons and their faithlessness in a law insensitive to their vulnerabilities. By prompting a discussion about a much-needed systemic change, the authors raise difficult questions about the responsibility of the state towards older persons in particular and those disenfranchised due to certain identity markers more generally. It follows that inaccessibility of tools that empower and emancipate can relegate the elderly to the peripheries of society.
Tensions about law’s inside/outside are equally evident in instantiations of state paternalism. The interview conducted by Oishik Sircar with Ghosh and the case comment authored by Tiwari exhibit this. Contemplating whether age is treated as determinative in quantifying the harm that censorship is intended to provide protection from, Ghosh remarks that the state’s paternalism in its regulation of the public sphere through censorship is ‘compounded by protectionist impulses from a diversity of non-state players’ when it relates to minors. In the process, childhood—much like womanhood, historically—is considered a homogeneous experience without sufficient consideration for its graded character on the basis of factors such as class and gender. Law, thus, invisibilises children’s capacity to exercise moral judgement as political actors, even under conditions of paternal control exercised by guardians and the state alike.15 It, resultantly, ousts diverse experiences of childhood in favour of a ‘universal’ experience. Through censorship, law also ousts material considered ‘harmful’ for children. In doing so, it negates the unique relationship between the material and its spectator, negatively stereotyping children as ‘the vulnerable, suggestible and dangerous [who live] outside the stockade of maturity and reasonableness that the rest of “us” can take for granted’16 in the process.
These themes recur in Tiwari’s case comment on Anversinh v. State of Gujarat (2021).17 Tiwari frames the judgment as an instance of the Supreme Court of India’s negation of a young girl’s agency due to its paternalistic attitude towards her expression of desire. They argue that law rarely uses age as a carefully considered conceptual category; rather, it is often used as a bulwark against law’s erasure of the coercive social processes that shape an individual’s narrative—particularly when it encounters expressions of female desire. As law relegates the ‘desirous child’ to the realm of immaturity, age becomes a tool used to discipline and obfuscate the ‘complexity of a real human subject’ and the ‘messiness of sexuality’. The demarcation of maturity/immaturity results in an inside/outside that is only formally predicated upon age. In substance, it is an embodiment of law’s desire to discipline.
Tiwari also highlights law’s interest in presenting itself as pragmatic, objective, and neutral. Yet, though law may wish to oust affect from its realm—or, at least present itself as doing so—given that it is wielded and lived by individuals for whom the binary is not as stark implies that affect shapes at least some part of most legal processes. Sharmila and Jain’s contribution empirically analyses where age features in one such process, that of clients’ decision-making regarding their legal representation. Interestingly, given that the law tends to treat those trained in the discipline as being on the inside, the authors’ shift in gaze from lawyers to clients in their consideration of age as a criterion for lawyer-selection throws light on newer dimensions of the relationship that binds the two.
Age as a site characterised by and communicative of time
Law and age, individually and relationally, are never in stasis. Constructions of the ‘Other’ or demarcations of the inside/outside at the site of age are, thus, rarely exempt from the temporalising force of law or the movement of age. Several contributions animate this theme, by focusing on the COVID-19 pandemic as an event that reveals the vulnerabilities of age, standalone and in intersection with other identity markers as well as about states’ prolonged inattention to unique needs arising out of age.18 Deblina Dey’s contribution makes an intervention to discourses around this theme, particularly in the Indian context.
Dey’s article deliberates over the question of whether law metes out injustice or deals in violence with older prisoners through its production of ‘carceral time’. Showcasing law as neglectful and indifferent towards the unique needs of older persons, particularly during the COVID-19 pandemic, Dey critiques its implication about their disposability. In Dey’s analysis, law’s (convenient) omission to consider the age of a prisoner in its construction of time results in derogation of rights and normalisation of daily acts of violence. Law, thus, treats time as a march forward without sufficient regard for a parallel process of ageing in which that passage of time signals an impending end.
With Priyanka Tripathi and Debashrita Dey’s contribution, we shift our focus from law’s linear construction of time in negation of its implications for age to films as receptacles of ‘fictive microjurisprudences’19 that offer an alternative imagination—the non-linear experience of time passing through the body. Writing about the potential of films such as Mai and Maine Gandhi Ko Nahin Mara to shape perceptions, Tripathi and Dey explore the intersection between old age and disability (cognitive degeneration, more specifically) as marking a return to childhood. Intergenerational networks of caregiving are, by extension, implicated, with the adult daughter emerging as the primary caregiver. In contemplating these themes, Tripathi and Dey’s article presents ageing as a process in which the inversion of the parent-child relationship results in responsibilities that are rarely independent of gendered asymmetries. Through their treatment of films as texts that can subvert the prevalent ‘youth-centric, ableist gaze’, the authors position cinema as a medium through which our understanding of certain elderly subjects can be redefined.
It is therefore evident that age is characterised by the passage of time through the human body. Given that time inevitably moves, movement—regardless of its direction—is unavoidably bound with age. Tripathi and Dey analogise this process at the site of an individual’s body to bodies of thought foundational to a society. However, unlike the association of age with the mortality of life in its passage through the human body, the enduring quality of law necessitates engagement with the innumerable mutations law undergoes as it ages. The contribution by Shivangi Gangwar and Aishwarya Pagedar dwells upon law’s visibilisation of this quality through legal metaphors, despite its (frequent) invisibilisation of age as an identity marker meriting attention.
Tracing the ‘living’ metaphor in Indian constitutional discourse from the early 20th century into the present, Gangwar and Pagedar illustrate its frequent use by the Supreme Court to describe the evolutive capacity of the Constitution. In doing so, the authors offer an analysis of an idea that imbues meaning into the common understanding that law is alive and shapes our understanding of the realities we inhabit. The authors’ account is, however, not uncritical of the operationalisation of this metaphor in Indian constitutional discourse. Comparing its use in India with that in Canada, United States of America, and Australia, they attend to the inconsistency in the semantic reference to the metaphor across a set of judgments and its undertheorisation despite a ubiquitous presence. With the provocation that despite its repeated usage over a long span of time, the metaphor may yet be quite vacuous and foment illiberal results, the authors contemplate the maturation of the metaphor into a doctrine that can better guard against illiberal outcomes and yield greater certainty.
Unified by their treatment of age as a site for understanding law’s meaning-making practices, the contributions in this issue reveal the criticality of an engagement with the relationship between law and age. Though no one can definitively foresee the future, it is likely that (some) ‘therapeutic outcomes’20 will ensue through careful attention to the imbrication between law and age. This is highlighted in the interview conducted by Ankita Gandhi with Israel (Issi) Doron. Conceptualising age as a site ripe for social change achieved through law, Doron urges action arising out of and in response to constructions of age (n., v.). From their experience as an academic and activist in the field of ‘elder law’, Doron discusses the many forms such action can take. These include theorisation, human rights’ movements predicated on age, and strategic litigation. Through their interrogation of common conceptions associated with age (n., v.), implications for the development of discourses around the relationship between law and age, and demonstration of the intersection of age with other identity markers, such action can yield social change.
1 See, for instance, ‘age, n’ (Cambridge Dictionary). https://dictionary.cambridge.org/dictionary/english/age. Accessed 13 November 2022, which defines ‘age’ as ‘the period of time someone has been alive or something has existed’; ‘age, n’ (Collins Dictionary). https://www.collinsdictionary.com/dictionary/english/age. Accessed 13 November 2022, which defines ‘age’ as ‘the number of years that you have lived’; ‘age, n’ (Merriam-Webster). https://www.merriam-webster.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘the length of an existence extending from the beginning to any given time’, ‘the time of life at which some particular qualification, power, or capacity arises or rests’, and ‘an individual’s development measured in terms of the years requisite for like development of an average individual’; ‘age, n’ (Macmillan Dictionary). https://www.macmillandictionary.com/dictionary/british/age_1. Accessed 13 November 2022, which defines ‘age’ as ‘the number of years that someone has lived’; ‘age, n’ (Britannica Dictionary). https://www.britannica.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘the amount of time during which a person or animal has lived [or] the amount of time during which a thing has existed’ and ‘the time of life when a person does something or becomes legally able to do something’.
2 See, for instance, ‘age, v’ (Merriam-Webster). https://www.merriam-webster.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘to become old: show the effects or the characteristics of increasing age’ and ‘to bring to a state fit for use or to maturity’; ‘age, v’ (Britannica Dictionary). https://www.britannica.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘to become old or older’; ‘age, v’ (Cambridge Dictionary). https://dictionary.cambridge.org/dictionary/english/ageing. Accessed 13 November 2022, which defines ‘age’ as ‘relating to getting older’ and ‘used to describe a person or thing that is getting old’.
3 This is captured well in Jeff Hearn and Wendy Parkin, Age at Work: Ambiguous Boundaries of Organizations, Organizing and Ageing (SAGE 2021) 31, ‘age [is] something that (potentially) affects all people, whether in terms of time and/or biography, and is a profound social and societal relation and social division.’ At 36-37, Hearn and Parkin discuss the many ‘meanings’ of age. These are particularly telling about the pervasiveness of age as a signifier of the human experience and include ‘calendar age, apparent age, social age, emotional age, perceived age or felt age and [] working, organizational, occupational, professional and even academic age.’
4 See, for instance, Israel Issi Doron, ‘Chronological? Functional? or Subjective? The Legal Search for the Definition of Age’ in Yuval Palgi, Amit Shrira, and Manfred Diehl (eds), Subjective Views of Aging: Theory, Research, and Practice (Springer 2022) 365, 365: ‘Age can be defined “objectively,” through objective units of measurement (e.g., “chronological age,” using time units; “functional age,” using the ability to execute certain daily activities; or “biological time,” using biological and clinical indicators), or “subjectively,” through personal feelings or social norms and cultures...’; Ashton Applewhite, This Chair Rocks: A Manifesto Against Ageism (Celadon Books 2016) 62-63: ‘Human variability makes chronological age an increasingly unreliable benchmark of pretty much anything about a person...Age is real, but it is not a fixed characteristic...Age is an observation used to place ourselves relative to others.’
5 See, for instance, Israel Doron and Asaf Hoffman, ‘Time for Law: Legal Literacy and Gerontological Education’ (2006) 31(8) Educational Gerontology 627, 630-631: ‘From the sociological point of view, law is not only a mirror, passively reflecting social reality. It is also an active tool which takes a dynamic part in the definition of social borders and the structuring of fundamental values. In this context, “old age” and “the elderly” may be seen as artificial constructs of social structuring rooted in the laws.’; RC Morgan, ‘The Future of Elder Law’ in Israel Doron (ed), Theories on Law and Ageing: The Jurisprudence of Elder Law (Springer 2009) 145, 153: ‘Aging is a great universal—everyone does it—every day, but everyone does it differently.’
6 See, for instance, Liat Ayalon and Clemens Tesch-Römer, ‘Introduction to the Section: Ageism—Concept and Origins’ in Liat Ayalon and Clemens Tesch-Römer (eds), Contemporary Perspectives on Ageism (Springer 2018) 1, 1: ‘Human ageing is not solely the biological process of senescence... Human ageing is embedded in social contexts...’.
7 See, for instance, Applewhite, This Chair Rocks (n 4) 15-16: ‘Like all discrimination, ageism legitimizes and sustains inequalities between groups...Different kinds of discrimination—including racism, sexism, ageism, ableism, and homophobia—interact, creating layers of oppression in the lives of individuals and groups. The oppression is reflected in and reinforced by society through the economic, legal, medical, commercial, and other systems that each of us navigates in daily life...Like racism and sexism, ageism is not about how we look. It’s about what people in power want our appearance to mean.’
8 See, generally, Henrique Carvalho, ‘Concept: Hegemony’ in Illan rua Wall et al. (eds), The Critical Legal Pocketbook (Counterpress 2021) 72. Law’s hegemonic power in deciding the relative worth of individuals on the basis of certain identity markers has been discussed by numerous scholars. See, for instance, Fiona Kumari Campbell, Contours of Ableism: The Production of Disability and Abledness (Palgrave Macmillan 2009) 34; Carol Smart, Feminism and the Power of Law (Routledge 1989). It often extends to ‘deviant’ choices made by individuals too. See, for instance, Cheshire Calhoun, Feminism, The Family, and The Politics of the Closet: Lesbian and Gay Displacement (Oxford University Press 2000) 153.
9 See, for instance, Ratna Kapur, Erotic Justice: Postcolonialism, Subjects and Rights (Glasshouse Press 2005); Dipika Jain and Kavya Kartik, ‘Unjust Citizenship: The Law that Isn’t’ (2020) 13(2) NUJS Law Review 3; Corey Rayburn, ‘To Catch a Sex Thief: The Burden of Performance in Rape and Sexual Assault Trials’ (2006) 15(2) Columbia Journal of Gender and Law 436; Bill Hughes, ‘Invalidating Emotions in the Non-disabled Imaginary: Fear, Pity and Disgust’ in Nick Watson and Simo Vehmas (eds), Routledge Handbook of Disability Studies (2nd edn, Routledge 2020) 89. In the context of age, discourses about ‘othering’ are prominent in research pertaining to prejudices against older persons. Though these are not legal discourses, they represent narratives law interacts with. See, for instance, Ateret Gewirtz-Meydan et al., ‘Ageism and Sexuality’ in Ayalon and Tesch-Römer (eds), Contemporary Perspectives on Ageism (n 6) 149, 151: ‘The dominant, idealized notion of remaining young-looking, physically attractive and sexually active was highlighted [by an analysis of how Canadian newspapers and magazines portray and construct older people’s sexuality], which marginalized older people who chose not to conform to that ideal or were unable to do so’ and at 152: ‘The gaps between the idealized images of ageing and the subjective experience can harm older people’s self-image’; Martha C Nussbaum and Paul Levmore, Aging Thoughtfully: Conversations about Retirement, Romance, Wrinkles, and Regret (Oxford University Press 2017) 101: ‘We know of societies that glorify age, but ours has a strong preference for youth and therefore, individually, for bodily interventions that preserve the appearance of youth.’
10 Tracey Gendron, Ageism Unmasked: Exploring Age Bias and How to End It (Penguin Random House 2022).
11 Liat Ayalon, ‘Ageism Towards Oneself vs. Ageism Towards Others in the Context of Views of Aging’ in Palgi, Shrira, and Diehl (eds), Subjective Views of Aging (n 4) 41, 41.
12 See, for instance, Cathryn Costello, ‘Migrants and Forced Labour: A Labour Law Response’ in Alan Bogg et al., The Autonomy of Labour Law (Hart Publishing 2015) 189, 227: ‘The increasingly punitive and carceral aspects of migration control focused on “outsiders” are politically coherent with the insecurity of economic life for “insiders”’; Donna J Haraway, Modest_Witness@Second_Millennium. FemaleMan©_Meets_OncoMouseTM (Routledge 1997) 269: ‘Valid witness depends not only on modesty but also on nurturing and acknowledging alliances with a lively array of others, who are like and unlike, human and not, inside and outside what have been the defended boundaries of hegemonic selves and powerful places.’
13 Campbell, Contours of Ableism (n 8) 11: ‘For every outside there is an inside that demands differentiation...’.
14 Linda A Parker, Cannabinoids and the Brain (MIT Press 2018).
15 See, generally, Oishik Sircar and Debolina Dutta, ‘Beyond Compassion: Children of Sex Workers in Kolkata’s Sonagachi’ (2011) 18(3) Childhood 333 and Debolina Dutta and Oishik Sircar, ‘Notes on Unlearning: Our Feminisms, Their Childhoods’ in Rachel Rosen and Katherine Twamley (eds), Feminism and the Politics of Childhood: Friends or Foes? (UCL Press 2018) 83 for an account of how state and non-state actors instrumentalise the law to create and sustain the essentialist image of the vulnerable child—in this case, children of sex workers—in the name of compassion, to effectively depoliticise and flatten diverse forms of childhoods.
16 Graham Murdoch, ‘Reservoirs of Dogma: An Archaeology of Popular Anxieties’ in Martin Baker and Julian Petley (eds), Ill Effects: The Media Violence Debate (Routledge 1997) 83. Ghosh cites Murdoch in their interview with Sircar.
17 Anversinh v State of Gujarat AIR 2021 SC 477.
18 See, Applewhite, This Chair Rocks (n 4) 17, where age bias is termed the ‘last socially sanctioned prejudice’.
19 Leslie J Moran et al., ‘Introduction’ in Leslie J Moran et al. (eds), Law’s Moving Image (Cavendish Publishing 2004) xiv. The authors refer to films as a medium that can be utilised to challenge concepts constructed by law or embedded in it due to the alternative imagination they can offer of these concepts.
20 Doron and Hoffman, ‘Time for Law’ (n 5) 634, citing David B Wexler and Bruce J Winick, Law in a Therapeutic Key: Developments in Therapeutic Jurisprudence (Carolina Academic Press 1996) and Robert G Madden and Raymie H Wayne, ‘Social Work and the Law: A Therapeutic Jurisprudence Perspective’ (2003) 48(3) Social Work 338.
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Jindal Global Law Review
Jindal Global Law Review
0975-2498
2364-4869
Springer India New Delhi
185
10.1007/s41020-022-00185-6
Editorial
Age as a site of law’s meaning-making practices
http://orcid.org/0000-0001-8208-3548
Sanghi Sanskriti [email protected]
grid.449565.f OP Jindal Global University, Sonipat, India
5 12 2022
19
22 11 2022
© The Author(s), under exclusive licence to O.P. Jindal Global University (JGU) 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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pmcAge, ageing, and the law
Age, n.
Typically conceptualised as a fixed characteristic or objective unit signifying the length of time for which someone has lived or something has existed.1
Age, v. (ageing)
Commonly understood as a linear trajectory or process towards becoming older or more mature.2
Age is considered a universal phenomenon. Characteristic of an individual’s biological and social life, it is experienced by all, even though it may neither always be identifiable as such nor the only influential identity marker. Constitutive ideas about age—both, as a characteristic (n.) and process (v.)—shape the manner in which one experiences this phenomenon in society. These ideas often emerge out of or are legitimated by law, which constructs meanings out of and about age in its organisation of society. In doing so, law’s processes of construction are themselves also marked by the very passage of time that suffuses the motion of age through the lives of individuals and communities. The pervasiveness of age as a signifier of the human experience3 that law is interested in regulating renders scholarly inquiry into the relationship between law and age imperative.
The theme of this issue of Jindal Global Law Review (JGLR) is aimed at providing a forum for interdisciplinary reflections on this meaning-making capacity of law through its stated and unstated norms at the site of age. By interrogating whether law acts as a mediating force between the abstract concept of age and its conversion into a collectively held idea that is socially wielded and lived, this issue inaugurates a series of interconnected discourses that illumine, challenge, or subvert embedded notions about and boundaries around age.
These discourses traverse a wide expanse. Considering the universality of age to be punctuated by human variability can, for instance, demonstrate the contingency of seemingly objective units of measuring age utilised by law to draw boundaries.4 Such contemplation can also aid in the examination of the rationality and linearity of these boundaries.5 Similarly, attention to the distinctiveness of context can animate the assumptions and beliefs ingrained within a legal system from which biases, stereotypes, and prejudices founded on age may flow.6 By extension, age may emerge as an identity marker that can systemically be used to ‘other’ and which does not operate in isolation of intersecting identity markers.7 The law’s re/production of language that contains certain imaginations about age is another idea that merits exploration given the valence it carries in perpetuating perceptions about role, capacity, and pace among others. These perceptions can manifest through their superimposition upon identity—individual or collective.
By ruminating about several of these ideas—while by no means being limited by or to them—the contributions in this issue reveal the multifaceted nature of the relationship between law and age as well as the manner in which it is operationalised through legal discourse. From the contributions, age emerges as a plural, complex, and layered site at which law simultaneously constructs many meanings. That law’s processes of meaning-making are, in turn, shaped and altered by the passage of time that characterises the movement of age is also animated by several contributions. Demonstrating that the relationship between law and age is not unidirectional, these contributions urge that ideas about age entrenched in law be scrutinised as law ages.
The contributions
To demonstrate these claims, I discuss the contributions to this issue by organising them under select broad and intertwined constructions of age. These constructions—namely, age as a site for the creation of the ‘Other’, age as a site for demarcation of the inside/outside, and age as a site characterised by and communicative of time—are dwelled upon by each contribution in a distinctive fashion. Despite differences in subject-matter and methodology, the contributions are unified in their treatment of age as a site at which multiple meanings are constructed by law. The coming together of these processes—which work independently and in combination—results in a site at which law (repeatedly) draws meaning out of age. As several contributions showcase, law’s own processes of meaning-making are also concurrently shaped.
Age as a site for the creation of the ‘Other’
Law’s (age-old) influence in the organisation of social life has meant that it has hegemonic power in deciding the (relative) worth of individuals.8 This has ensued through law’s construction of an ‘ideal’ subject, deviation from the norms constituting which results in the creation of the ‘Other’.9 Though the ‘Other’ differs from one context to another, her failure to fit into the image of the idealised subject results in marginalisation. The gap between the ‘ideal’ and the ‘Other’ is characterised by—and may even widen due to—negative stereotypes against the ‘Other’, negation of the rights of the ‘Other’, pressure on the ‘Other’ to conform to the ‘ideal’ (the norm) and the like. Law helps sustain this gap between the ‘ideal’ and the ‘Other’ through its processes of meaning-making. That age is a site for law’s meaning-making regarding the ‘Other’ is demonstrated by the contributions authored by Mallika Ramachandran and Qian Liu.
In Ramachandran’s review of Tracey Gendron’s Ageism Unmasked: Exploring Age Bias and How to End It,10 age is conceptualised as a category undergirded by a complex infrastructure of notions that ‘other’. Though Ramachandran’s emphasis is on bias against older persons and their treatment as the ‘Other’, particularly through a systemic negation of the possible simultaneity of ‘decline, growth, and maintenance’, their review initiates a broader dialogue about the power of ageist narratives to ‘other’ individuals as un/productive and/or in/capable. Law is hardly immune to such ageist narratives. In fact, the infrastructure that ‘others’ often emanates out of and is sustained by law in its interaction with social, economic, political, and medical narratives that are prejudicial against or contain misinformation about age. Ramachandran’s critique of rights discourses in which such ageist narratives are unchallenged acts as an instantiation through its revelation of the danger of older persons being treated as objects instead of as subjects. Through her review, Ramachandran provokes the question of whether challenging these narratives can yield a community cognisant and accommodative of its differences instead of one that ‘others’.
With Liu’s article, our gaze shifts—from older persons to ‘leftover’ women, from ageist societies generally to an authoritarian state with a rapidly ageing population such as China, from systemic obscuration or belittlement to pressure to adhere to a heteronormative timeline in relation to marital and reproductive choices. Yet, much as in Ramachandran’s review, Liu’s article engages with law’s ‘othering’ force in its organisation of social life. Situating the pressure against a backdrop of state policies that have yielded a rapidly ageing population whose responsibility China wishes to shift from the state to the individual, Liu’s discussion reveals the oft-imperceptible role of law in perpetuating notions about age. These notions come alive in the daily negotiations engaged in by women in China as anxiety about not adhering to the heteronormative timeline and of consequently being ‘othered’. Equally, their embeddedness can foreclose alternative imaginations of social organisation. Through their arrangement of these seemingly disparate events and ideas into a complex web through which certain women are ‘othered’, Liu raises the crucial question of whether law has romanticised age-old traditional values that are unsuitable for present times.
Age as a site for demarcation of the inside/outside
Law’s creation of the ‘Other’ at the site of age results in the production of categories that are hierarchically situated vis-à-vis each other. As is evident from Ramachandran’s and Liu’s contributions, the demarcation results in ‘biased thoughts, feelings, and behaviors in relation to [one’s] own age and aging processes as well as in relation to the age and aging process of others.’11 Law’s ‘othering’ process need not, however, operate in isolation. Sometimes, through its treatment of certain individuals as the ‘Other’, it may create an ‘inside’ and an ‘outside’.12 This results in the creation of distinct classes whose segregation is marked by law’s line-drawing authority. This line-drawing authority of law inevitably ousts and is exercised by lawmakers on the basis of a range of reasons other than one’s identity too.13 The interview with Shohini Ghosh and the contributions authored by Khagesh Gautam, Rajashree K and Chetan Singai, Avantika Tiwari, and Sharmila HS and Sunitha Abhay Jain contemplate certain ‘insides’ and ‘outsides’ embedded within law and discuss how age is implicated in or ought to impact these discourses.
Gautam’s review of Linda A. Parker’s Cannabinoids and the Brain14 argues the need for Indian lawmakers to regulate rather than prohibit the consumption of cannabis due to its medicinal value. Citing increasing support for the regulation of cannabis consumption in the United States of America, particularly as a strategy for pain relief management among the elderly, Gautam juxtaposes scientific and experiential evidence against law’s presumption of cannabis as injurious to one’s body and mind. By exhorting lawmakers to regulate cannabis primarily due to its medicinal value for the elderly, Gautam positions age as an overlooked but pivotal consideration. They argue that the inclusion of age as a consideration in decision-making about the status law should accord to cannabis can help lawmakers understand the need to transition from prohibition to regulation, thus altering law’s demarcation of the ‘inside’ from the ‘outside’.
Similarly, Rajashree and Singai advocate that age be considered by the relevant authorities in determining the coverage of legal guarantees so as to create an inclusive society. Drawing on interviews conducted with senior citizens, civil society activists, advocates, district magistrates, and administrative officers, the authors weave a visceral, revelatory, and complex tale of the connections between the absence of legal aid for older persons and their faithlessness in a law insensitive to their vulnerabilities. By prompting a discussion about a much-needed systemic change, the authors raise difficult questions about the responsibility of the state towards older persons in particular and those disenfranchised due to certain identity markers more generally. It follows that inaccessibility of tools that empower and emancipate can relegate the elderly to the peripheries of society.
Tensions about law’s inside/outside are equally evident in instantiations of state paternalism. The interview conducted by Oishik Sircar with Ghosh and the case comment authored by Tiwari exhibit this. Contemplating whether age is treated as determinative in quantifying the harm that censorship is intended to provide protection from, Ghosh remarks that the state’s paternalism in its regulation of the public sphere through censorship is ‘compounded by protectionist impulses from a diversity of non-state players’ when it relates to minors. In the process, childhood—much like womanhood, historically—is considered a homogeneous experience without sufficient consideration for its graded character on the basis of factors such as class and gender. Law, thus, invisibilises children’s capacity to exercise moral judgement as political actors, even under conditions of paternal control exercised by guardians and the state alike.15 It, resultantly, ousts diverse experiences of childhood in favour of a ‘universal’ experience. Through censorship, law also ousts material considered ‘harmful’ for children. In doing so, it negates the unique relationship between the material and its spectator, negatively stereotyping children as ‘the vulnerable, suggestible and dangerous [who live] outside the stockade of maturity and reasonableness that the rest of “us” can take for granted’16 in the process.
These themes recur in Tiwari’s case comment on Anversinh v. State of Gujarat (2021).17 Tiwari frames the judgment as an instance of the Supreme Court of India’s negation of a young girl’s agency due to its paternalistic attitude towards her expression of desire. They argue that law rarely uses age as a carefully considered conceptual category; rather, it is often used as a bulwark against law’s erasure of the coercive social processes that shape an individual’s narrative—particularly when it encounters expressions of female desire. As law relegates the ‘desirous child’ to the realm of immaturity, age becomes a tool used to discipline and obfuscate the ‘complexity of a real human subject’ and the ‘messiness of sexuality’. The demarcation of maturity/immaturity results in an inside/outside that is only formally predicated upon age. In substance, it is an embodiment of law’s desire to discipline.
Tiwari also highlights law’s interest in presenting itself as pragmatic, objective, and neutral. Yet, though law may wish to oust affect from its realm—or, at least present itself as doing so—given that it is wielded and lived by individuals for whom the binary is not as stark implies that affect shapes at least some part of most legal processes. Sharmila and Jain’s contribution empirically analyses where age features in one such process, that of clients’ decision-making regarding their legal representation. Interestingly, given that the law tends to treat those trained in the discipline as being on the inside, the authors’ shift in gaze from lawyers to clients in their consideration of age as a criterion for lawyer-selection throws light on newer dimensions of the relationship that binds the two.
Age as a site characterised by and communicative of time
Law and age, individually and relationally, are never in stasis. Constructions of the ‘Other’ or demarcations of the inside/outside at the site of age are, thus, rarely exempt from the temporalising force of law or the movement of age. Several contributions animate this theme, by focusing on the COVID-19 pandemic as an event that reveals the vulnerabilities of age, standalone and in intersection with other identity markers as well as about states’ prolonged inattention to unique needs arising out of age.18 Deblina Dey’s contribution makes an intervention to discourses around this theme, particularly in the Indian context.
Dey’s article deliberates over the question of whether law metes out injustice or deals in violence with older prisoners through its production of ‘carceral time’. Showcasing law as neglectful and indifferent towards the unique needs of older persons, particularly during the COVID-19 pandemic, Dey critiques its implication about their disposability. In Dey’s analysis, law’s (convenient) omission to consider the age of a prisoner in its construction of time results in derogation of rights and normalisation of daily acts of violence. Law, thus, treats time as a march forward without sufficient regard for a parallel process of ageing in which that passage of time signals an impending end.
With Priyanka Tripathi and Debashrita Dey’s contribution, we shift our focus from law’s linear construction of time in negation of its implications for age to films as receptacles of ‘fictive microjurisprudences’19 that offer an alternative imagination—the non-linear experience of time passing through the body. Writing about the potential of films such as Mai and Maine Gandhi Ko Nahin Mara to shape perceptions, Tripathi and Dey explore the intersection between old age and disability (cognitive degeneration, more specifically) as marking a return to childhood. Intergenerational networks of caregiving are, by extension, implicated, with the adult daughter emerging as the primary caregiver. In contemplating these themes, Tripathi and Dey’s article presents ageing as a process in which the inversion of the parent-child relationship results in responsibilities that are rarely independent of gendered asymmetries. Through their treatment of films as texts that can subvert the prevalent ‘youth-centric, ableist gaze’, the authors position cinema as a medium through which our understanding of certain elderly subjects can be redefined.
It is therefore evident that age is characterised by the passage of time through the human body. Given that time inevitably moves, movement—regardless of its direction—is unavoidably bound with age. Tripathi and Dey analogise this process at the site of an individual’s body to bodies of thought foundational to a society. However, unlike the association of age with the mortality of life in its passage through the human body, the enduring quality of law necessitates engagement with the innumerable mutations law undergoes as it ages. The contribution by Shivangi Gangwar and Aishwarya Pagedar dwells upon law’s visibilisation of this quality through legal metaphors, despite its (frequent) invisibilisation of age as an identity marker meriting attention.
Tracing the ‘living’ metaphor in Indian constitutional discourse from the early 20th century into the present, Gangwar and Pagedar illustrate its frequent use by the Supreme Court to describe the evolutive capacity of the Constitution. In doing so, the authors offer an analysis of an idea that imbues meaning into the common understanding that law is alive and shapes our understanding of the realities we inhabit. The authors’ account is, however, not uncritical of the operationalisation of this metaphor in Indian constitutional discourse. Comparing its use in India with that in Canada, United States of America, and Australia, they attend to the inconsistency in the semantic reference to the metaphor across a set of judgments and its undertheorisation despite a ubiquitous presence. With the provocation that despite its repeated usage over a long span of time, the metaphor may yet be quite vacuous and foment illiberal results, the authors contemplate the maturation of the metaphor into a doctrine that can better guard against illiberal outcomes and yield greater certainty.
Unified by their treatment of age as a site for understanding law’s meaning-making practices, the contributions in this issue reveal the criticality of an engagement with the relationship between law and age. Though no one can definitively foresee the future, it is likely that (some) ‘therapeutic outcomes’20 will ensue through careful attention to the imbrication between law and age. This is highlighted in the interview conducted by Ankita Gandhi with Israel (Issi) Doron. Conceptualising age as a site ripe for social change achieved through law, Doron urges action arising out of and in response to constructions of age (n., v.). From their experience as an academic and activist in the field of ‘elder law’, Doron discusses the many forms such action can take. These include theorisation, human rights’ movements predicated on age, and strategic litigation. Through their interrogation of common conceptions associated with age (n., v.), implications for the development of discourses around the relationship between law and age, and demonstration of the intersection of age with other identity markers, such action can yield social change.
1 See, for instance, ‘age, n’ (Cambridge Dictionary). https://dictionary.cambridge.org/dictionary/english/age. Accessed 13 November 2022, which defines ‘age’ as ‘the period of time someone has been alive or something has existed’; ‘age, n’ (Collins Dictionary). https://www.collinsdictionary.com/dictionary/english/age. Accessed 13 November 2022, which defines ‘age’ as ‘the number of years that you have lived’; ‘age, n’ (Merriam-Webster). https://www.merriam-webster.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘the length of an existence extending from the beginning to any given time’, ‘the time of life at which some particular qualification, power, or capacity arises or rests’, and ‘an individual’s development measured in terms of the years requisite for like development of an average individual’; ‘age, n’ (Macmillan Dictionary). https://www.macmillandictionary.com/dictionary/british/age_1. Accessed 13 November 2022, which defines ‘age’ as ‘the number of years that someone has lived’; ‘age, n’ (Britannica Dictionary). https://www.britannica.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘the amount of time during which a person or animal has lived [or] the amount of time during which a thing has existed’ and ‘the time of life when a person does something or becomes legally able to do something’.
2 See, for instance, ‘age, v’ (Merriam-Webster). https://www.merriam-webster.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘to become old: show the effects or the characteristics of increasing age’ and ‘to bring to a state fit for use or to maturity’; ‘age, v’ (Britannica Dictionary). https://www.britannica.com/dictionary/age. Accessed 13 November 2022, which defines ‘age’ as ‘to become old or older’; ‘age, v’ (Cambridge Dictionary). https://dictionary.cambridge.org/dictionary/english/ageing. Accessed 13 November 2022, which defines ‘age’ as ‘relating to getting older’ and ‘used to describe a person or thing that is getting old’.
3 This is captured well in Jeff Hearn and Wendy Parkin, Age at Work: Ambiguous Boundaries of Organizations, Organizing and Ageing (SAGE 2021) 31, ‘age [is] something that (potentially) affects all people, whether in terms of time and/or biography, and is a profound social and societal relation and social division.’ At 36-37, Hearn and Parkin discuss the many ‘meanings’ of age. These are particularly telling about the pervasiveness of age as a signifier of the human experience and include ‘calendar age, apparent age, social age, emotional age, perceived age or felt age and [] working, organizational, occupational, professional and even academic age.’
4 See, for instance, Israel Issi Doron, ‘Chronological? Functional? or Subjective? The Legal Search for the Definition of Age’ in Yuval Palgi, Amit Shrira, and Manfred Diehl (eds), Subjective Views of Aging: Theory, Research, and Practice (Springer 2022) 365, 365: ‘Age can be defined “objectively,” through objective units of measurement (e.g., “chronological age,” using time units; “functional age,” using the ability to execute certain daily activities; or “biological time,” using biological and clinical indicators), or “subjectively,” through personal feelings or social norms and cultures...’; Ashton Applewhite, This Chair Rocks: A Manifesto Against Ageism (Celadon Books 2016) 62-63: ‘Human variability makes chronological age an increasingly unreliable benchmark of pretty much anything about a person...Age is real, but it is not a fixed characteristic...Age is an observation used to place ourselves relative to others.’
5 See, for instance, Israel Doron and Asaf Hoffman, ‘Time for Law: Legal Literacy and Gerontological Education’ (2006) 31(8) Educational Gerontology 627, 630-631: ‘From the sociological point of view, law is not only a mirror, passively reflecting social reality. It is also an active tool which takes a dynamic part in the definition of social borders and the structuring of fundamental values. In this context, “old age” and “the elderly” may be seen as artificial constructs of social structuring rooted in the laws.’; RC Morgan, ‘The Future of Elder Law’ in Israel Doron (ed), Theories on Law and Ageing: The Jurisprudence of Elder Law (Springer 2009) 145, 153: ‘Aging is a great universal—everyone does it—every day, but everyone does it differently.’
6 See, for instance, Liat Ayalon and Clemens Tesch-Römer, ‘Introduction to the Section: Ageism—Concept and Origins’ in Liat Ayalon and Clemens Tesch-Römer (eds), Contemporary Perspectives on Ageism (Springer 2018) 1, 1: ‘Human ageing is not solely the biological process of senescence... Human ageing is embedded in social contexts...’.
7 See, for instance, Applewhite, This Chair Rocks (n 4) 15-16: ‘Like all discrimination, ageism legitimizes and sustains inequalities between groups...Different kinds of discrimination—including racism, sexism, ageism, ableism, and homophobia—interact, creating layers of oppression in the lives of individuals and groups. The oppression is reflected in and reinforced by society through the economic, legal, medical, commercial, and other systems that each of us navigates in daily life...Like racism and sexism, ageism is not about how we look. It’s about what people in power want our appearance to mean.’
8 See, generally, Henrique Carvalho, ‘Concept: Hegemony’ in Illan rua Wall et al. (eds), The Critical Legal Pocketbook (Counterpress 2021) 72. Law’s hegemonic power in deciding the relative worth of individuals on the basis of certain identity markers has been discussed by numerous scholars. See, for instance, Fiona Kumari Campbell, Contours of Ableism: The Production of Disability and Abledness (Palgrave Macmillan 2009) 34; Carol Smart, Feminism and the Power of Law (Routledge 1989). It often extends to ‘deviant’ choices made by individuals too. See, for instance, Cheshire Calhoun, Feminism, The Family, and The Politics of the Closet: Lesbian and Gay Displacement (Oxford University Press 2000) 153.
9 See, for instance, Ratna Kapur, Erotic Justice: Postcolonialism, Subjects and Rights (Glasshouse Press 2005); Dipika Jain and Kavya Kartik, ‘Unjust Citizenship: The Law that Isn’t’ (2020) 13(2) NUJS Law Review 3; Corey Rayburn, ‘To Catch a Sex Thief: The Burden of Performance in Rape and Sexual Assault Trials’ (2006) 15(2) Columbia Journal of Gender and Law 436; Bill Hughes, ‘Invalidating Emotions in the Non-disabled Imaginary: Fear, Pity and Disgust’ in Nick Watson and Simo Vehmas (eds), Routledge Handbook of Disability Studies (2nd edn, Routledge 2020) 89. In the context of age, discourses about ‘othering’ are prominent in research pertaining to prejudices against older persons. Though these are not legal discourses, they represent narratives law interacts with. See, for instance, Ateret Gewirtz-Meydan et al., ‘Ageism and Sexuality’ in Ayalon and Tesch-Römer (eds), Contemporary Perspectives on Ageism (n 6) 149, 151: ‘The dominant, idealized notion of remaining young-looking, physically attractive and sexually active was highlighted [by an analysis of how Canadian newspapers and magazines portray and construct older people’s sexuality], which marginalized older people who chose not to conform to that ideal or were unable to do so’ and at 152: ‘The gaps between the idealized images of ageing and the subjective experience can harm older people’s self-image’; Martha C Nussbaum and Paul Levmore, Aging Thoughtfully: Conversations about Retirement, Romance, Wrinkles, and Regret (Oxford University Press 2017) 101: ‘We know of societies that glorify age, but ours has a strong preference for youth and therefore, individually, for bodily interventions that preserve the appearance of youth.’
10 Tracey Gendron, Ageism Unmasked: Exploring Age Bias and How to End It (Penguin Random House 2022).
11 Liat Ayalon, ‘Ageism Towards Oneself vs. Ageism Towards Others in the Context of Views of Aging’ in Palgi, Shrira, and Diehl (eds), Subjective Views of Aging (n 4) 41, 41.
12 See, for instance, Cathryn Costello, ‘Migrants and Forced Labour: A Labour Law Response’ in Alan Bogg et al., The Autonomy of Labour Law (Hart Publishing 2015) 189, 227: ‘The increasingly punitive and carceral aspects of migration control focused on “outsiders” are politically coherent with the insecurity of economic life for “insiders”’; Donna J Haraway, Modest_Witness@Second_Millennium. FemaleMan©_Meets_OncoMouseTM (Routledge 1997) 269: ‘Valid witness depends not only on modesty but also on nurturing and acknowledging alliances with a lively array of others, who are like and unlike, human and not, inside and outside what have been the defended boundaries of hegemonic selves and powerful places.’
13 Campbell, Contours of Ableism (n 8) 11: ‘For every outside there is an inside that demands differentiation...’.
14 Linda A Parker, Cannabinoids and the Brain (MIT Press 2018).
15 See, generally, Oishik Sircar and Debolina Dutta, ‘Beyond Compassion: Children of Sex Workers in Kolkata’s Sonagachi’ (2011) 18(3) Childhood 333 and Debolina Dutta and Oishik Sircar, ‘Notes on Unlearning: Our Feminisms, Their Childhoods’ in Rachel Rosen and Katherine Twamley (eds), Feminism and the Politics of Childhood: Friends or Foes? (UCL Press 2018) 83 for an account of how state and non-state actors instrumentalise the law to create and sustain the essentialist image of the vulnerable child—in this case, children of sex workers—in the name of compassion, to effectively depoliticise and flatten diverse forms of childhoods.
16 Graham Murdoch, ‘Reservoirs of Dogma: An Archaeology of Popular Anxieties’ in Martin Baker and Julian Petley (eds), Ill Effects: The Media Violence Debate (Routledge 1997) 83. Ghosh cites Murdoch in their interview with Sircar.
17 Anversinh v State of Gujarat AIR 2021 SC 477.
18 See, Applewhite, This Chair Rocks (n 4) 17, where age bias is termed the ‘last socially sanctioned prejudice’.
19 Leslie J Moran et al., ‘Introduction’ in Leslie J Moran et al. (eds), Law’s Moving Image (Cavendish Publishing 2004) xiv. The authors refer to films as a medium that can be utilised to challenge concepts constructed by law or embedded in it due to the alternative imagination they can offer of these concepts.
20 Doron and Hoffman, ‘Time for Law’ (n 5) 634, citing David B Wexler and Bruce J Winick, Law in a Therapeutic Key: Developments in Therapeutic Jurisprudence (Carolina Academic Press 1996) and Robert G Madden and Raymie H Wayne, ‘Social Work and the Law: A Therapeutic Jurisprudence Perspective’ (2003) 48(3) Social Work 338.
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| 0 | PMC9734839 | NO-CC CODE | 2022-12-14 23:28:31 | no | psychopraxis. neuropraxis. 2022 Dec 8; 25(6):298-299 | latin-1 | null | null | null | oa_other |
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Indian J Otolaryngol Head Neck Surg
Indian J Otolaryngol Head Neck Surg
Indian Journal of Otolaryngology and Head & Neck Surgery
2231-3796
0973-7707
Springer India New Delhi
3218
10.1007/s12070-022-03218-7
Original Article
Decreased Speech Comprehension and Increased Vocal Efforts Among Healthcare Providers Using N95 Mask
http://orcid.org/0000-0003-4580-8188
Wadia Jehaan A [email protected]
1
Joshi Anagha A [email protected]
2
1 grid.415652.1 0000 0004 1767 1265 Clinical Fellow in Laryngology, MS ENT, Department of ENT, Lokmanya Tilak Municipal General Hospital, Sion, Mumbai, India
2 grid.415652.1 0000 0004 1767 1265 Professor, MS ENT, Department of ENT, Lokmanya Tilak Municipal General Hospital, Sion, Mumbai, India
8 12 2022
16
22 5 2022
24 9 2022
© Association of Otolaryngologists of India 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Aim: N95 masks are recommended for the healthcare providers (HCPs) taking care of patients with coronavirus disease 2019. However, the use of these masks hampers communication. We aimed to evaluate the effect of N95 masks on speech comprehension among listeners and vocal efforts (VEs) of the HCPs.
Materials and Methods: This prospective study involved 50 HCPs. We used a single observer with normal hearing to assess the difficulty in comprehension, while VE was estimated in HCPs. The speech reception threshold (SRT), speech discrimination score (SDS), and VEs were evaluated initially without using N95 mask and then repeated with HCPs wearing N95 mask.
Results: The use of masks resulted in a statistically significant increase in mean SRT [4.25 (1.65) dB] and VE [2.6 (0.69)], with simultaneous decrease in mean SDS [19.2 (8.77)] (all p-values < 0.0001). Moreover, demographic parameters including age, sex, and profession were not associated with change in SRT, SDS, and VE (all p-values > 0.05).
Conclusion: Though use of N95 masks protects the HCPs against the viral infection, it results in decreased speech comprehension and increased VEs. Moreover, these issues are universal among the HCPs and are applicable to the general public as well.
Keywords
Audiometry
N95 masks
Speech comprehension
Speech discrimination scores
Speech reception thresholds
Vocal efforts
==== Body
pmcIntroduction
Declared as a pandemic by World Health Organization in March 2020, coronavirus disease 2019 (COVID-19) has resulted in more than 521 million confirmed cases and more than 6 million deaths globally, till date. 1,2 Severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) has been identified as an etiologic agent of COVID-19. Though various routes of transmission have been postulated, aerosol transmission is regarded as the main route. 3.
In the initial part of 1900s, surgical face masks were introduced to avoid the infection of surgical wounds due to bacteria originating from the mouth and nose of healthcare providers (HCPs). 4 In the current COVID-19 pandemic, use of masks has been mandated by various countries to halt the transmission of SARS-CoV-2. Face masks together with various other non-pharmacological approaches including social distancing, eye protection, maintaining hand hygiene, and isolation have been universally used and have been proved to curb the spread of COVID-19. 5,6.
To provide complete protection, face masks need to snugly cover the mouth and nose. However, this leads to substantially diminished visual cues as lip reading is not possible and view of facial expressions is hampered. Patients may fail to completely comprehend the instructions of HCPs. Moreover, communication among the HCPs may compel several repetitions and higher strain on both vocal effort (VE) and listening. During a surgical procedure, assisting HCPs may not accurately follow the instructions of the operating surgeon. This is likely to result in communication errors which can have serious consequences. 7.
During the COVID-19 pandemic, as in every healthcare set-up, HCPs in our hospital are required to regularly wear N95 masks to curb the spread to infection. In this study, we aimed to quantify the impact of N95 masks on speech comprehension and VE among the HCPs with normal vocal function by evaluating its impact on speech reception thresholds (SRTs), speech discrimination scores (SDSs), and vocal efforts (VEs).
Materials and Methods
This was a prospective, observational study conducted in the out-patient department of ENT of a tertiary care teaching hospital located in the western-part of India. The study was performed over a period of 2 months (from January to February 2021) and commenced after approval of the protocol by the institutional ethics committee and obtaining informed consent of the HCPs.
HCPs with normal vocal function, belonging to age group of 20–50 years, and working in the out-patient department of ENT were enrolled in the study. The HCPs enrolled in the study included resident doctors, interns, and nurses.
To ensure normal uniform hearing, we had a single observer who was subjected to pure tone audiometry (Elkon EDA 3N3 Multi, Mumbai, India), defined as a pure tone average of less than 25 dB at 500, 1000, and 2000 Hz. Normal vocal cord functioning of HCPs was ensured with GRBAS scale (Grade, Roughness, Breathiness, Asthenia, and Strain Scale). 8 HCPs with any hoarseness or change in voice, any proven vocal cord pathology, or change in voice due to old age were excluded.
To determine SRT and SDS, HCPs and observer sat at a distance of 0.6 m, so as to simulate standard conversational distance, and a decibel meter (Mextech SL36 sound level meter, Mumbai, India) was used. The same procedures for speech comprehension and VEs were performed initially with HCPs not wearing the mask and then repeated with the mask. The Venus V-4400 N95 masks were procured from Venus Safety & Health, Navi Mumbai, India.
To test SRT, we used a validated list of 50 spondee words recommended by the American Speech–Language–Hearing Association. 9 These were two-syllable words with same amount of stress on both syllables (e.g., ‘birthday’, ‘play ball’, and ‘tooth brush’). A volume unit meter was employed to get same amount of syllabic stress. Initially, without wearing the mask, HCPs were asked to read the words with uniform intensity and SRT was estimated as the lowest hearing level (intensity) at which the observer could correctly comprehend and repeat the speech stimuli 50% of the time. The same procedure was repeated with the HCPs wearing mask and SRT with mask was estimated.
To determine SDS, we used a set of monosyllabic phonetically balanced words. Standard word lists included those issued by the Psycho-Acoustic Laboratory and the Central Institute for the Deaf W-22 word list for auditory testing. 10,11 To suit the Indian population, we used an adapted and validated version of this list comprising of phonetically balanced words. Initially, without wearing the mask, HCPs were instructed to read a list of 20 words and observer was asked to hear the words. The number of words that could be correctly heard by the observer were expressed as percentage. The same procedure was repeated with HCPs wearing the mask and SDS was estimated.
To estimate the VE, we used the validated Rainbow Passage. 12 Initially, the HCPs were asked to read the passage at a uniform intensity without mask and rate the effort required with the adapted BORG CR-10 scale. 13 They were asked to repeat the same procedure with mask and read the passage with same intensity as that without the mask, and rate their efforts. BORG CR-10 is a Likert’s scale ranging from 0 to 10, with 0 suggesting no VE and 10 suggesting maximum VE.
These procedures were performed to determine the amount of hearing difficulty faced by listeners and the increased VEs that is faced by the HCPs when they wear the mask, thus, mimicking the real-world scenario.
Statistical Analysis
The categorical and continuous data was expressed in terms of frequency (percentage) and mean (standard deviation), respectively. The SRTs, SDSs, and VE with and without mask were compared with paired t-test. While, the change in SRTs, SDSs, and VE with and without mask for the categorical demographic variables were compared with independent sample t-tests. Statistical analysis was performed with SPSS (IBM, Armonk, NY, USA) version 23.0 for Windows. A two-tailed probability value (p-value) of < 0.05 was considered as statistically significant.
Results
Among 50 HCPs, 36 were resident doctors and medical interns, while the remaining were nurses. The age of HCPs ranged from 23 to 50 years, with a mean age of 29.6 (6.33) years. Moreover, 32 HCPs were male.
Without mask, the SRT ranged from 60 dB to 85.5 dB. With mask, the SRT increased and ranged from 64.5 dB to 89 dB. The mean increase in SRT with mask was 4.25 (1.65) dB and was found to be statistically significant (p-value < 0.0001) (Table 1).
Table 1 Speech reception thresholds, speech discrimination scores, and vocal efforts with and without N95 masks
Parameters With or without mask Mean (SD) p-value
SRT (dB) Without mask 74.51 (5.09) < 0.0001
Mask 78.76 ( 4.98)
SDS (%) Without mask 100 (0) < 0.0001
Mask 80.8 (8.77)
VE Without mask 0 (0) < 0.0001
Mask 2.6 (0.69)
SRT: Speech reception threshold; SDS: Speech discrimination score; VE: Vocal efforts; SD: standard deviation
We observed that, without mask, the SDS of the observer was 100% for all the HCPs. However, with mask, the SDS of the observer decreased and ranged from 70 to 100%. The mean decrease in SDS was 19.2 (8.77) and this decrease was found to be statistically significant (p-value < 0.0001) (Table 1).
Similarly, without mask, all the HCPs had zero VE. However, with mask, an increase in VE was observed and ranged from 1 to 4. The mean increase in VE was 2.6 (0.69) and this increase was found to be statistically significant (p-value < 0.0001) (Table 1).
Finally, the change in SRT, SDS, and VE with and without masks were analysed in terms of age, sex, and profession. We observed no statistically significant difference (all p-value > 0.05) in the change in SRT, SDS, and VE when comparison was made between different age groups (20–35 years versus 36–50 years), sex (male versus female), and profession (doctors versus nurses) (Table 2).
Table 2 Comparison of changes in speech reception thresholds, speech discrimination scores, and vocal efforts in terms of age, sex, and profession
Outcome measures Demographic parameters
Age (Years) Sex Profession
20–35 (N = 44) 36–50
(N = 6) Male
(N = 32) Female
(N = 18) Doctor
(N = 36) Nurse
(N = 14)
Change in SRT 4.22 (1.68) 4.50 (1.52) 4.41 (1.91) 3.97 (1.06) 4.08 (0.94) 4.68 (2.76)
p-value 0.697 0.379 0.258
Change in SDS 19.77 (8.48) 15.08 (10.49) 19.38 (9.14) 18.89 (8.32) 20.56 (8.60) 15.71 (8.52)
p-value 0.214 0.853 0.079
Change in VE 2.59 (0.69) 2.67 (0.82) 2.63 (0.79) 2.56 (0.51) 2.58 (0.69) 2.64 (0.74)
p-value 0.806 0.740 0.790
Data expressed as mean (standard deviation); SRT: Speech reception threshold; SDS: Speech discrimination score; VE: Vocal efforts
Discussion
Though the masks have been instrumental in curbing the spread of viral infections including SARS-CoV-2, 5,6 their use hinders the propagation of the sound waves because sound energy of some spectral component may be filtered out or attenuated. 14–16 The sound absorbing quality of the material used for making the mask determines the amount of attenuation during transmission. 16 Masks substantially compromises the comprehension of consonants and discrimination of unfamiliar talkers, 14 as well as the intensity and spectral features of the voiceless fricatives. 15.
N95 and surgical masks can attenuate higher-frequency sounds by around 3–12 dB. 17 With N95 masks, the word comprehension decreases by 1–17%.18 In the presence of background noise, their use is associated with a significant decrease in accuracy of speech perception. 19 At longer distances, compared to speaking without a mask, speaking with mask leads to a greater decline in accuracy of speech perception. 20 Moreover, the visual cues that contribute to speech comprehension are obstructed. 15.
The principal findings of our study suggest that use of mask leads to a significant increase in the SRT and VEs, with simultaneous decrease in SDS. The impaired speech comprehension and increased VEs were evident despite the fact that HCPs were evaluated in ideal conditions and with the probability of getting accustomed to words related with repeated testing.
Findings similar to our study were demonstrated by Bandaru et al. 21 They observed that use of N95 mask and face shield results in significantly increased SRT and decreased SDS. Though ideal for HCPs involved in management of patients with COVID-19, their findings cannot be extrapolated to the general public, as both N95 mask and face shield are not used universally. N95 mask alone provides superior protection against micro-organisms; thus, making our findings more pertinent to the public. Hampton et al. 22 reported that use of personal protective equipments, including masks, shields, and gowns, result in significantly impaired speech discrimination in the settings of intensive care units and operating rooms. Thus, use of protective equipments can adversely affect the communication among the HCPs and this has grave implications for patient safety.
To standardize the environment for quantitative assessment, we used acoustically treated room. However, in real world scenario, conversations in the healthcare setup mostly take place in the presence of substantial ambient noise and this could impair speech comprehension. Bottalico et al. 23 studied the effect of masks on speech comprehension in an acoustically treated room and observed that words were recognized to a significantly better extent in acoustically treated room than the room that was not acoustically treated (34% versus 21%). Moreover, the use of N95 mask was associated with significantly decreased probability of correct recognition of the words, around 47% less than without the mask. In another study, Mendel et al. 24 reported that use of surgical masks was associated with significant difference in the spectral analysis of speech stimuli than without mask. They further reported that use of surgical mask did not result in a significant difference in speech comprehension between individuals with normal hearing and those with impaired hearing; however, the presence of background noise led to reduced comprehension in both groups. Ideally, such studies should be performed in the out-patient setting. However, in such settings, it is not possible to maintain standard ambient noise and presentation level, and obtain reliable results. Thus, we evaluated the HCPs in acoustically treated room.
The relative position of speaker and listener affects the speech comprehension. When a person with mask speaks, the sound transmitted to the sides and behind him are affected to a significantly less extent than that in front. Moreover, if the person is using an additional face shield, then the sound is amplified for the listener behind. Rather than absorbing the sound energy, the mask deflects it to the sides and the maximum attenuation of the sound takes place for the listener in front. 25 Thus, the relative position of HCPs and observer, in our study, could have affected the findings. Alternatively, Llamas et al. 15 evaluated a variety of face coverings and reported that the loss of sound during transmission is negligible except with surgical masks. They suggested that reduced comprehension of sound with the use of mask is primarily due to the auditory consequences of disturbance in speech articulation and/or result of decreased visual characteristics that are accessible to listeners. Thus, with surgical and N95 masks, decreased speech comprehension is a due to both loss of sound energy during transmission and absence of visual cues.
Attenuation of voice by mask results in increased vocal intensity. Moreover, it can affect other aspects of voice generation, produce pneumo-phono-articulatory incoordination, and hampers visualization of articulation. Misuse and abuse of voice is linked to poor vocal adjustments and exaggerated muscle tension may heighten the perception of symptoms, discomfort, and even initiate behavioral dysphonia. 26–29 Similar to our study, Ribeiro et al. 30 reported that mask used for both professional and essential activities was associated with significantly increased VEs. These activities were linked to significantly increased scores of vocal fatigue symptoms, and higher frequency and intensity of vocal tract discomfort. Moreover, when compared to conditions without masks, use of masks was associated with increase in VEs; hardship in speech comprehension, speech coordination, and breathing; and reduced auditory feedback.
We observed that demographic parameters such as age, sex, and profession were not associated with change in SRT, SDS, and VEs. Similar findings are reported by Bandaru et al. 21 Thereby, suggesting that these findings can be generalized across the HCPs.
Our study had certain limitations. First, when determining SRT and SDS, the observer sat in front of the HCPs with mask and maximum attenuation of speech is reported in this setting. Studies needs to be performed with observer sitting at equal distance, on either side of participants with mask. Second, we used a single observer with normal hearing and thus, further research needs to involve multiple observers and analyze the inter-observer difference. Moreover, hearing impaired individuals should be enrolled in the study. Finally, we used single and two-syllable words without considering their effect on the meaning of the whole sentence. It is reported that the use of sentences contributes to the linguistic context, which may permit listeners to correctly comprehend the words that would otherwise be incomprehensible. 31 It is further reported that in fair or poor acoustics conditions, comprehension of sentences can outperform the comprehension of words by around 30%.32 Thus, future studies evaluating the effect of mask on speech comprehension should use sentences rather than the words.
Conclusion
Though the use of N95 masks protects the HCPs against the viral infection, it results in decreased speech comprehension and increased VEs. Although, these issues are universal among the HCPs, they can be applicable to the general public as well. To avoid miscommunication among the HCPs, use of supplementary methods of communication should be encouraged, especially in intensive care units and operating rooms.
Acknowledgements
The authors would like to thank Dr. Vikas S. Sharma (MD), Principal Consultant, Maverick Medicorum® (India), for statistical analysis and medical writing assistance in the preparation of this article.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Compliance with Ethical Standards
Conflict of Interest
There is no conflicts of interest among the authors.
Human and Animal Rights
No Animals or human experiments are done during the study.
Ethical Approval
Institutional ethical approval and consent for publication were obtained.
Informed Consent
Informed consent was taken from all the participants during the study to include their findings in the study not revealing their identity.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References
1. World Health Organization (WHO). Archived: WHO Timeline - COVID-19. Updated April 27 (2020) https://www.who.int/news/item/27-04-2020-who-timeline---covid-19. (Accessed on May 29, 2021)
2. World Health Organization (WHO) (2022) WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/table.
3. Karia R, Gupta I, Khandait H, Yadav A, Yadav A (2020) COVID-19 and its Modes of Transmission. SN Compr Clin Med 1–4. 10.1007/s42399-020-00498-4
4. Belkin NL A century after their introduction, are surgical masks necessary? AORN J 1996 64 4 602 607 10.1016/s0001-2092(06)63628-4 8893967
5. Rader B, White LF, Burns MR, Chen J, Brilliant J, Cohen J et al. Mask-wearing and control of SARS-CoV-2 transmission in the USA: a cross-sectional study.Lancet Digit Health. 2021Mar; 3(3):e148-e157. 10.1016/S2589-7500(20)30293-4
6. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ(2020) ; study authors. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet. ;395(10242):1973–1987. 10.1016/S0140-6736(20)31142-9
7. Bakhit M Krzyzaniak N Scott AM Clark J Glasziou P Del Mar C Downsides of face masks and possible mitigation strategies: a systematic review and meta-analysis BMJ Open 2021 11 2 e044364 10.1136/bmjopen-2020-044364
8. De Bodt MS Wuyts FL Van de Heyning PH Croux C Test-retest study of the GRBAS scale: influence of experience and professional background on perceptual rating of voice quality J Voice 1997 11 1 74 80 10.1016/s0892-1997(97)80026-4 9075179
9. ASHA Guidelines for determining threshold level for speech ASHA 1988 30 85 89 3155355
10. Hirsh IJ Davis H Silverman SR Reynolds EG Eldert E Benson RW Development of materials for speech audiometry J Speech Hear Disord 1952 17 321 337 10.1044/jshd.1703.321 13053556
11. Egan JP Articulation testing methods Laryngoscope 1948 58 955 991 10.1288/00005537-194809000-00002 18887435
12. The Rainbow Passage. 2nd edition, Grant Fairbanks’ Voice and Articulation Drillbook. New York: Harper & Row. pp. 127
13. Ford Baldner E Doll E van Mersbergen MR A review of measures of vocal effort with a preliminary study on the establishment of a vocal effort measure J Voice 2015 29 5 530 541 10.1016/j.jvoice.2014.08.017 26186811
14. Owren MJ Cardillo GC The relative roles of vowels and consonants in discriminating talker identity versus word meaning J Acoust Soc Am 2006 119 1727 1739 10.1121/1.2161431 16583915
15. Llamas C Harrison P Donnelly D Effects of different types of face coverings on speech acoustics and intelligibility York Papers on Linguistics 2009 9 80 104
16. Nute ME Slater K The effect of fabric parameters on sound-transmission loss J Text Inst 1973 64 652 658 10.1080/00405007308630315
17. Goldin A Weinstein BE Shiman N How do medical masks degrade speech perception? Hear rev 2020 27 5 8 9
18. Radonovich LJ Jr Yanke R Cheng J Bender B Diminished speech intelligibility associated with certain types of respirators worn by healthcare workers J Occup Environ Hyg 2010 7 63 70 10.1080/15459620903404803 19904661
19. Thomas F Allen C Butts W Rhoades C Brandon C Handrahanet DL Does wearing a surgical facemask or N95-respirator impair radio communication? Air Med J 2011 30 97 102 10.1016/j.amj.2010.12.007 21382570
20. Coyne KM Johnson AT Yeni-Komshian GH Dooly CR Respirator performance ratings for speech intelligibility Am Ind Hyg Assoc J 1998 59 257 260 10.1080/15428119891010523 9586201
21. Bandaru SV, Augustine AM, Lepcha A, Sebastian S, Gowri M, Philip A, Mammen MD (2020) The effects of N95 mask and face shield on speech perception among healthcare workers in the coronavirus disease 2019 pandemic scenario. J Laryngol Otol 1–4. 10.1017/S0022215120002108
22. Hampton T Crunkhorn R Lowe N Bhat J Hogg E Afifi W The negative impact of wearing personal protective equipment on communication during coronavirus disease 2019 J Laryngol Otol 2020 134 7 577 581 10.1017/S0022215120001437 32641175
23. Bottalico P, Murgia S, Puglisi GE, Astolfi A, Kirk KI (2020 Nov) Effect of masks on speech intelligibility in auralized classrooms. J Acoust Soc Am 148(5):2878. 10.1121/10.0002450
24. Mendel LL Gardino JA Atcherson SR Speech understanding using surgical masks: a problem in health care? J Am Acad Audiol 2008 19 686 695 10.3766/jaaa.19.9.4 19418708
25. Corey RM Jones U Singer AC Acoustic effects of medical, cloth, and transparent face masks on speech signals J Acoust Soc Am 2020 148 4 2371 10.1121/10.0002279 33138498
26. Balata PMM Silva HJ Pernambuco LA Amorim GO Maior Braga RS Fernandes da Silva EG Electrical activity of extrinsic laryngeal muscles in subjects with and without dysphonia J Voice 2015 29 1 129e9 12917 10.1016/j.jvoice.2014.03.012.e9-129.e17
27. Redenbaugh MA Reich AR Surface EMG and related measures in normal and vocally hiperfunctional speakers J Speech Hear Disord 1989 54 68 73 10.1044/jshd.5401.68 2915528
28. Hocevar-Boltezar I Janko M Zargi M Role of surface EMG in diagnostics and treatment of muscle tension dysphonia Acta Otolaryngol 1998 118 739 743 10.1080/00016489850183287 9840515
29. Behlau M, Zambon F, Moreti F, Oliveira G, de Barros Couto E Jr (2017) Voice self-assessment protocols: different trends among organic and behavioral dysphonias. J Voice 31 :112.e13-112.e27. 10.1016/j.jvoice.2016.03.014
30. Ribeiro VV, Dassie-Leite AP, Pereira EC, Santos ADN, Martins P, Irineu RA(2020) Effect of Wearing a Face Mask on Vocal Self-Perception during a Pandemic. J Voice. ;S0892-1997(20)30356-8. 10.1016/j.jvoice.2020.09.006
31. Allison KM Yunusova Y Green JR Shorter sentence length maximizes intelligibility and speech motor performance in persons with dysarthria due to amyotrophic lateral sclerosis Am J Speech Lang Pat 2019 28 1 96 107 10.1044/2018_AJSLP-18-0049
32. IEC 60268-16-2003: Sound System Equipment—Part 16: Objective Rating of Speech Intelligibility by Speech Transmission Index (2003) https://standards.iteh.ai/catalog/standards/clc/b1be26cf-af1f-42d9-a1fa-b187ff9b0239/en-60268-16-2003. (Accessed on August 12, 2021)
| 0 | PMC9734841 | NO-CC CODE | 2022-12-14 23:28:31 | no | Indian J Otolaryngol Head Neck Surg. 2022 Dec 8;:1-6 | utf-8 | Indian J Otolaryngol Head Neck Surg | 2,022 | 10.1007/s12070-022-03218-7 | oa_other |
==== Front
Nat Rev Microbiol
Nat Rev Microbiol
Nature Reviews. Microbiology
1740-1526
1740-1534
Nature Publishing Group UK London
36470999
835
10.1038/s41579-022-00835-5
Comment
Sewage surveillance of antibiotic resistance holds both opportunities and challenges
http://orcid.org/0000-0002-5496-0328
Larsson D. G. Joakim [email protected]
12
http://orcid.org/0000-0002-4101-5095
Flach Carl-Fredrik 12
Laxminarayan Ramanan 3
1 grid.8761.8 0000 0000 9919 9582 Department of Infectious Diseases, Institute for Biomedicine, University of Gothenburg, Gothenburg, Sweden
2 grid.8761.8 0000 0000 9919 9582 Centre for Antibiotic Resistance Research at University of Gothenburg, Gothenburg, Sweden
3 One Health Trust, Washington, DC USA
5 12 2022
12
21 11 2022
© Springer Nature Limited 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
A proposed European Union-directive requests that member states monitor antibiotic resistance at all sewage treatment plants serving >100,000 people. Sewage surveillance could provide information on the resistance situation in the underlying population and on environmental transmission risks. There are opportunities to make such surveillance data more informative and actionable, but there are also challenges.
Sewage surveillance could provide information on the resistance situation in the underlying population and on environmental transmission risks. There are opportunities to make such surveillance data more informative and actionable, but there are also challenges.
Subject terms
Bacterial infection
Microbial ecology
==== Body
pmcThe environment has several roles in the global antibiotic resistance crisis. The diverse ecological niches in the environment provide a vast reservoir for new antibiotic resistance genes that over time accumulate in pathogens. Polluted waters and soils are important transmission routes for several pathogens, including antibiotic-resistant enteric bacteria. From a more backward-looking perspective, studying resistance in the environment can provide a reflection of the resistance situation in the regional human (or domestic animal) population. Environmental surveillance of antibiotic resistance could therefore serve multiple purposes1,2.
Although sewage surveillance for poliovirus has been in place for decades, the COVID-19 pandemic gave this approach a new lease of life as a resource-efficient tool for monitoring the spread and evolution of SARS-CoV-2. The view on sewage as a resource for health care is likely to have had a role for the European Commission in their proposed revision of the Urban Waste Water Treatment Directive (UWWTD)3. The proposal emphasizes the role of sewage surveillance for preventive or early warning purposes, exemplified by the detection of specific viruses as a signal of the emergence of epidemics or pandemics. It also recognizes emissions from sewage treatment plants as a major transmission pathway for antimicrobial agents and resistant bacteria. However, the specific motivation for sewage surveillance of antimicrobial resistance (AMR) is primarily to increase the knowledge on main sources of antimicrobial resistance to the environment. We think that it would be a lost opportunity if such a surveillance effort would not aim to both address environmental transmission risks from sewage treatment plants and inform about the resistance situation in the primary source for many of these bacteria — the regional human population. The draft UWWTD requests sampling of both influents (untreated urban sewage) and treated effluent. This would perfectly match such dual objectives, as carriage in the population is best reflected by samples taken as close to the source as possible (influents), whereas environmental transmission risks are determined by what is released (effluents).
In parallel to the UWWTD, the US Centers for Disease Control and Prevention (CDC) is planning or already building capacity for AMR surveillance in wastewater treatment plants and health-care institutions across the USA. In some contrast to the UWWTD draft, the CDC initiative includes the explicit objective of reflecting AMR in the contributing human population, particularly silent outbreak detection4. Sewage surveillance has benefits compared with, and complements, traditional clinical surveillance as it is exceptionally resource efficient; that is, one sample can represent bacteria from hundreds of thousands of people. For this reason, it also enables early outbreak detection of rare or even novel forms of resistance using, for example, selective culture techniques, targeted PCR, tailored functional metagenomics or shotgun metagenomics combined with modelling5,6. Furthermore, it comes without the (often) strong bias resulting from different practices for collecting samples from patients in different regions, thus making data more directly comparable. However, it differs, for good and bad, in that sewage bacteria come from both the healthy and sick part of the population, even if taken from hospital sewers. Depending on the endpoint measured, the large contribution of bacteria in sewage that cannot be attributed to the human microbiota7 could also make interpretations challenging5.
Although some regions of the world, including Europe and the USA, have reasonably well-developed clinical surveillance systems, many countries lack systematic generation and collection of resistance data. The Global Antimicrobial Resistance and Use Surveillance System (GLASS) initiative by the World Health Organization is an important step in creating a foundation for harmonized data collection, but lack of resources will probably still be a limiting factor for a considerable time. Without surveillance data, physicians rely on their own experience of which antibiotics do or do not work. In such situations, a resource-efficient sewage surveillance system, based on isolates, would have the potential to directly inform empirical treatment and thus save lives. Such use, however, requires extensive benchmarking against clinical surveillance data8. Generating quantitative sewage surveillance data on a broad scale in Europe and the USA could therefore contribute to such an evaluation. This could, in turn, facilitate implementation of quantitative sewage surveillance as one additional means for combating bacterial infections and resistance in low-resource regions. Given how easily resistance spreads across the globe, it matters for every region how resistance is managed in each part of the world.
Before designing any surveillance action, the knowledge gaps that need to be filled (and why) should be specified, the type (or types) of data that could be collected and that would efficiently close those gaps should be identified, and feasible actions as a response to the new knowledge should be envisioned9. Surveillance data that do not fill an important knowledge gap or are not actionable are not very useful. It should be said that directing further research is a valid action, because it may request more than surveillance data to direct effective mitigations. For example, even if we know the exact level of discharged resistant bacteria from urban sewage, assessing risk of transmission to humans or animals would still require more knowledge on exposure levels and to what extent the exposure leads to colonization or disease. Depending on the objective (or objectives) of sewage surveillance, different endpoints (such as antibiotic residues, resistance genes or (absolute or relative) abundances of certain resistant bacteria) carry vastly different information value1. We therefore recommend a thorough exercise defining objectives, specifying knowledge gaps, selecting informative endpoints and envisioning potential actions to get the most value out of the effort. In contrast to viral pandemics, the silent pandemic of antibiotic resistance is slow, although it is continuously escalating in severity. Hence, sampling less frequently than twice a year, as indicated in the UWWTD, might be sufficient and instead allow analysis of a wider panel of endpoints that address the different objectives within a limited budget.
The Global Sewage Project has pioneered the field using metagenomic analyses, demonstrating feasibility in more than 100 countries10. Lessons learned include that centralized sample processing, sequencing and bioinformatic analyses strongly reduce total workload and increase comparability. Collected data on resistance in sewage can be either gene-based from communities (metagenomes) or phenotypic (cultivation-based). We have recently elaborated on the pros and cons with these strategies with regard to quantitative assessments of the regional resistance situation6. There are similar pros and cons with regard to transmission risks; analyses of resistance genes (for example, from PCR or short-read metagenomics) in environmental matrices without reliable host information are challenging to translate into any quantifiable transmission risk. In large parts, this is because most resistance genes occur in a range of different contexts and hosts, many of which do not pose any direct clinical threat (without involving horizontal gene transfer). Long-read sequencing may overcome some, but not all, of these limitations. Translation into transmission risks is considerably more straightforward from cultivation-based data, although such data collection may come with somewhat higher costs and is restricted to the cultured organism. Given the distinct strengths and weaknesses, we would currently recommend a combination of cultivation and cultivation-independent approaches. Highly specific methods for selective isolation of species other than Escherichia coli in complex sewage currently limit some of the expansions of a cultivation-based approach.
The recent initiative by the European Commission to include surveillance of antibiotic resistance is good and could prove to be important for addressing a critical health issue. Still, without paying careful attention to both possibilities and challenges, opportunities may be lost and/or many resources could be spent on collecting data that contributes little to actions.
Competing interests
The authors declare no competing interests.
==== Refs
References
1. Huijbers PMC Flach C-F Larsson DGJ A conceptual framework for the environmental surveillance of antibiotics and antibiotic resistance Environ. Int. 2019 130 104880 10.1016/j.envint.2019.05.074 31220750
2. Aarestrup FM Woolhouse MEJ Using sewage for surveillance of antimicrobial resistance Science 2020 367 630 632 10.1126/science.aba3432 32029617
3. European Commission. Proposal for a revised Urban Wastewater Treatment Directive. European Commission https://environment.ec.europa.eu/publications/proposal-revised-urban-wastewater-treatment-directive_en (2022).
4. US Centres for Disease Control and Prevention. COVID-19 impacts on environment (e.g., water, soil) and sanitation: addressing antimicrobials and antimicrobial resistant threats in the environment. US Centres for Disease Control and Prevention https://www.cdc.gov/drugresistance/pdf/covid19/COVID19-Impacts-AR-Environment-Sanitation-508.pdf (2021).
5. Flach C-F Hutinel M Razavi M Åhrén C Larsson DGJ Monitoring of hospital sewage shows both promise and limitations as an early-warning system for carbapenemase-producing Enterobacterales in a low-prevalence setting Water Res. 2021 200 117261 10.1016/j.watres.2021.117261 34082263
6. Larsson DGJ Flach C-F Antibiotic resistance in the environment Nat. Rev. Microbiol. 2022 20 257 269 10.1038/s41579-021-00649-x 34737424
7. Newton RJ Sewage reflects the microbiomes of human populations mBio 2015 6 e02574 10.1128/mBio.02574-14 25714718
8. Huijbers PMC Larsson DGJ Flach CF Surveillance of antibiotic resistant Escherichia coli in human populations through urban wastewater in ten European countries Environ. Pollut. 2020 261 114200 10.1016/j.envpol.2020.114200 32220750
9. Laxminarayan, R. & Macauley, M. K. The Value of Infromation: Methodological Frontiers and New Applications in Environment and Health 1st edn (Springer Dordrecht, 2012).
10. Munk P Genomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance Nat. Commun. 2022 13 7251 10.1038/s41467-022-34312-7 36456547
| 36470999 | PMC9734844 | NO-CC CODE | 2022-12-14 23:28:31 | no | Nat Rev Microbiol. 2022 Dec 5;:1-2 | utf-8 | Nat Rev Microbiol | 2,022 | 10.1038/s41579-022-00835-5 | oa_other |
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Acta Neurol Belg
Acta Neurol Belg
Acta Neurologica Belgica
0300-9009
2240-2993
Springer International Publishing Cham
36478544
2159
10.1007/s13760-022-02159-w
Letter to the Editor
Bilateral fornix infarction as a cause of acute amnesia
http://orcid.org/0000-0002-0357-5577
Thapa Kshitij [email protected]
1
Setyapranata Stella [email protected]
1
Choi Philip M. C. [email protected]
23
Clare Ian [email protected]
4
1 Department of Medicine, Echuca Regional Health, 226 Service St, Echuca, VIC 3564 Australia
2 grid.414366.2 0000 0004 0379 3501 Department of Neuroscience, Eastern Health, Melbourne, Australia
3 grid.1002.3 0000 0004 1936 7857 Eastern Health Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia
4 I-MED Radiology Network, Victoria, Australia
7 12 2022
12
2 9 2022
28 11 2022
© The Author(s) under exclusive licence to Belgian Neurological Society 2022
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
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pmcA 37-year-old male courier driver presented to the emergency department of a regional hospital with 2 days history of sudden onset memory deterioration complaints. His past medical history included ulcerative colitis for which he was on balsalazide 750 mg twice a day. His wife noted the patient was unable to recall places, events and was confused regarding his daily travel itinerary on the day before his presentation to hospital. He had received a mRNA coronavirus booster vaccine 4 days prior to onset of his symptoms. On examination, his vital signs were normal. He was able to recall personal information, oriented to year and month but not day of the week with a Mini-Mental State Examination score of 22/30. His general physical exam is otherwise unremarkable. Full blood counts, other biochemistries and cerebrospinal fluid examination were normal. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain, neck and cerebral vessels were normal apart from bilateral symmetrical foci of diffusion restriction and fluid attenuated inversion recover (FLAIR) hyperintensity lateral to the foramina of Munro. The cause and significance of this was uncertain.
Patient was then transferred to a tertiary center for further work-up. The initial MRI brain imaging was reviewed only 3 days later due to logistical issues. The non-specific diffusion-weighted imaging (DWI) lesions in the bilateral fornix is thought to be in keeping with acute ischemic infarctions causing the patient’s clinical symptoms. Transcranial Doppler with bubble study performed was strongly suggestive of patent foramen ovale and the patient was referred for further cardiac investigations.
Imaging findings
CT scan on admission showed no abnormality. Non-contrast MRI brain obtained 2 days after symptoms onset showed symmetrical diffusion restriction with corresponding low apparent diffusion coefficient (ADC) signal and FLAIR hyperintensity of the anterior body of the right and left fornix (Fig. 1A, B and C). No other abnormality was identified.Fig. 1 MRI brain two days post symptom onset. (A) DWI, (B) ADC and (C) T2 FLAIR
Discussion
The clinical differential diagnosis of acute memory loss is wide and most commonly include delirium, posterior circulation strokes, encephalitis, and metabolic disorders such as Wernicke encephalopathy. Small bilateral fornix infarction is a rare but recognised cause of acute memory impairment with the first case described in 2000 by Shyam et al. [1]. The fornix is the major white-matter efferent and afferent tract of the hippocampus which has a significant role in cognitive and memory function [2, 3]. The bilateral columns of the fornix, the genu of the corpus callosum and other basal forebrain structures are supplied by the unpaired subcallosal artery that mostly originates from the anterior communicating artery (ACoA). The unpaired nature of the artery most likely explains the bilateral infarctions seen in some patients with amnesia after surgical repairs of ACoA aneurysms [4]. Along with bilateral fornix infarctions, small bilateral thalamic infarcts due to occlusion of the artery of Percheron, and bilateral reversible DWI lesions in the hippocampi in transient global amnesia, have also been associated with acute amnesia.
Previous case series suggest iatrogenic injury after clipping ACoA aneurysm and microangiopathy are the two main causes of bilateral fornix infarctions [5]. The aetiology of the stroke remains uncertain in our patient at the time of discharge. He does not have any conventional vascular risk factors, such as diabetes, hypertension, smoking or dyslipidemia. Despite the topography of his stroke, in the absence of other risk factors, apart from the likely presence of a patent foramen ovale, cardioembolism seems the most likely aetiology. Regardless of the aetiology, it is important for recognize isolated infarctions in the bilateral fornix can cause acute amnesia. For our patient, a lumbar puncture, electroencephalography, and inter-hospital transfer may have been avoided if more attention was paid to the significance of initial MRI findings.
Declarations
Conflict of interest
None.
Data availability statement
All relevant data on this case report is available from the corresponding author upon reasonable request.
The patient and his next-of-kin have consented to this publication.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
1. Moudgil SS Azzouz M Al-Azzaz A Haut M Gutmann L Amnesia due to fornix infarction Stroke 2000 31 6 1418 1419 10.1161/01.STR.31.6.1418 10835465
2. Senova S Fomenko A Gondard E Lozano AM Anatomy and function of the fornix in the context of its potential as a therapeutic target J Neurol Neurosurg Psychiatry 2020 91 5 547 559 10.1136/jnnp-2019-322375 32132227
3. Karri M Ramasamy B Perumal S Ischemic amnesia caused by bilateral fornix infarction: a rare entity Ann Indian Acad Neurol 2019 10.4103/aian.AIAN_303_18
4. Mugikura S Kikuchi H Fujii T Murata T Takase K Mori E Marinković S Takahashi S MR imaging of subcallosal artery infarct causing amnesia after surgery for anterior communicating artery aneurysm AJNR Am J Neuroradiol 2014 35 12 2293 2301 10.3174/ajnr.A4057 25082820
5. Meila D Saliou G Krings T Subcallosal artery stroke: infarction of the fornix and the genu of the corpus callosum. The importance of the anterior communicating artery complex. Case series and review of the literature Neuroradiology 2015 57 1 41 47 10.1007/s00234-014-1438-8 25280444
| 36478544 | PMC9734847 | NO-CC CODE | 2022-12-14 23:28:31 | no | Acta Neurol Belg. 2022 Dec 7;:1-2 | utf-8 | Acta Neurol Belg | 2,022 | 10.1007/s13760-022-02159-w | oa_other |
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Stat Methods Appt
Stat Methods Appt
Statistical Methods & Applications
1618-2510
1613-981X
Springer Berlin Heidelberg Berlin/Heidelberg
677
10.1007/s10260-022-00677-8
Original Paper
The relative importance of ability, luck and motivation in team sports: a Bayesian model of performance in the English Rugby Premiership
http://orcid.org/0000-0002-7154-1192
Fioravanti Federico [email protected]
12
Delbianco Fernando [email protected]
13
Tohmé Fernando [email protected]
13
1 Instituto de Matemática de Bahía Blanca, CONICET - UNS, Bahía Blanca, Argentina
2 grid.412236.0 0000 0001 2167 9444 Departamento de Matemática, Universidad Nacional del Sur, Bahía Blanca, Argentina
3 grid.412236.0 0000 0001 2167 9444 Departamento de Economía, Universidad Nacional del Sur, Bahía Blanca, Argentina
8 12 2022
117
30 11 2022
© Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Results in contact sports like Rugby are mainly interpreted in terms of the ability and/or luck of teams. But this neglects the important role of the motivation of players, reflected in the effort exerted in the game. Here we present a Bayesian hierarchical model to infer the main features that explain score differences in rugby matches of the English Premiership Rugby 2020/2021 season. The main result is that, indeed, effort (seen as a ratio between the number of tries and the scoring kick attempts) is highly relevant to explain outcomes in those matches.
Keywords
Motivation
Effort
Bayesian
Luck
Ability
Rugby
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pmcIntroduction
The development of mathematical models of sports faces many obstacles. Assessing the potential impact of unobservable variables and establishing the right relations among the observable ones are the main sources of hardships for this task. Even so, the study of team sports data has become increasingly popular in the last years. Several models have been proposed for the estimation of the parameters (characteristics) that may lead to successful results for a team, ranging from machine learning methods to predict outcomes Štrumbelj and Vračar (2012); Asif and McHale (2016); Baboota and Kaur (2019), fuzzy set representations Hassanniakalager et al. (2020), statistical models Dyte and Clarke (2000); Goddard (2005); Boshnakov et al. (2017) and Bayesian models Baio and Blangiardo (2010); Constantinou et al. (2012); Wetzels et al. (2016); Santos-Fernandez et al. (2019).
One of the main issues in the study of sports is to disentangle the relative relevance of the possible determinants of outcomes. While ability and luck constitute, at least for both the press and the fan base, the main explanatory factors of the degree of success in competitions, the motivation of players is usually invoked only to explain epic outcomes or catastrophic failures. One possible reason for the neglect of motivation is that, unlike ability and luck, it is hard to assess. In this paper we define a particular notion of effort in Rugby games as a proxy for motivation and develop a Bayesian model of the final scores of teams in the English Rugby Premiership 2020/2021. These outcomes will be explained by several variables, among which we distinguish the ability of the teams and the effort exerted by them. We also include as explanatory variables other possible sources of psychological stimuli, as to capture a pure motivation to win, separated from those other factors.
One of the main advantages of using Bayesian techniques to model sports are that beliefs or expert information can be incorporated as priors, to obtain posterior distributions of the parameters of interest, easily updated when new data becomes available, dealing more effectively with small data sets. In our case, we propose a Bayesian hierarchical model to explain score differences on a rugby match, i.e, the difference between home team points and away team ones. The main parameters of the model are the ability of teams, the effort exerted by them and the advantage (or disadvantage) of home teams.
There are many papers that use Bayesian methods to model the score of a rugby game. Stefani (2009) finds that the past performance is better predictor of score difference than of the score total, and suggest that teams should focus strategy on score differences (to win or draw) rather than in score total. Pledger and Morton (2011) use Bayesian methods to model the 2004 Super Rugby competition and explore how home advantage impacts the outcomes. Finally, Fry et al. (2021) propose a Variance Gamma model where analytical results are obtained for match outcomes, total scores and the awarding of bonus points. The main difference between these works and ours, is that their primary goal is to predict outcomes, while ours is to explain them.
The ability of a team can be conceived as its “raw material”. The skills of its players, the expertise of its coaches and its human resources in general (medical staff, managers, etc.) constitute the team’s basic assets. Their value can vary during a season due to injuries, temporary loss of skilled players called to play for the national team, players leaving the team, etc. In this model we assume that the capabilities of teams do not change much from a season to the next. Accordingly, the ability of a team at the start of the season is assumed to be at a bounded distance from the performance in the previous season.
Luck in games and sports has been largely studied, from philosophical perspectives Simon (2007); Morris (2015) to statistical ones Denrell and Liu (2012); Pluchino et al. (2018). Mauboussin (2012) define that games that are high in luck are the ones that are highly unpredictable, it is not able to achieve great advantages through repetition and the ‘reversion to the mean’ effect in performance is high. Elias et al. (2012) and Gilbert and Wells (2019) define many types of luck, that we will later introduce. In this model, following the line from the later authors, we consider that luck is when the unexplained part differs markedly from the mean value in the noise distribution. That is, a series of unobserved variables have a huge impact on the outcome.
Effort, in turn, can be conceived as the cost of performing at the same level over time and staying steadily engaged on a determinate task Herlambang et al. (2021). Different measures of effort can be defined. In the context of decision making, effort can be the total number of elementary information processing operations involved Payne et al. (1995) or the use of cognitive resources required to complete a task Russo and Dosher (1983); Johnson and Payne (1985). Another measure of effort (or lack of it) can be defined in terms of the extent of anchoring in a self-reported rating scales, that is, the tendency to select categories in close proximity to the rating category used for the immediately preceding item Lyu and Bolt (2022). From a sports science perspective, the effort exerted by a team can be seen as the sum of all the players loads, that Quarrie et al. (2017) define as ‘the total stressors and demands applied to the players’. These loads can include the physical motions of the players, the preparation for future matches, the food intakes, the intensity of interpersonal relationships, etc. Our formal definition of effort is intended as a proxy for the amount of some of these loads. Although a commonly accepted definition of effort is lacking, according to Massin (2017) effort is understood as the force exerted in order to reach a goal. Our definition of effort is indeed intended to capture this notion, in the understanding that one of the main goals (and the hardest to achieve) in a rugby game is to score tries. We consider that deviating from the goal of scoring tries, that is, exerting forces in order to reach a different goal, implies a reduction of the effort.
In order to define a rough measure of the effort exerted by a rugby team, we follow the lead of Lenten and Winchester (2015), Butler et al. (2020) and Fioravanti et al. (2021). These works analyze the effort exerted by rugby teams under the idiosyncratic incentives induced in this game. Besides gaining points for winning or drawing in a game, teams may earn “bonus” points depending on the number of times they score tries on a game. Accordingly, any appropriate effort measure should also be defined taking into account the number of tries. In our model the effort is measured as the ratio between the number of tries scored and the sum of tries and scoring kicks attempts.1 In other words, following the same ideas of the literature discussed above, we intend to measure the effort of a team using observable variables such as tries and kicks. Attempts to increase the score with tries instead than with kicks can be seen, following the definition of Massin (2017), as indicating that the team is exerting more effort. Our idea is to emphasize on the identification of effort with the result of an offensive spirit, according to which a team maximizes this effort by seeking to get more tries, no matter what the final score is. But if we simply identify effort with the number of tries we run into a problem since the difference in scores (the dependent variable in our model) is highly correlated with the difference in tries. Considering instead the proportion of tries we do not run into that problem. Despite this, our formulation is not uncontroversial. It is easy to conceive a situation in which a team gets a lower value of our effort index by scoring more tries and kicks than a team that just scores one try with only one kick attempt. Again, our effort index intends to capture that tries involve an attacking, positive mindset, while penalties are a defensive, risk averse route to winning.2 We understand that this proxy of effort has its limitations, since it tends to disregard the defensive skills of the teams. Still, we can justify this choice by our goal of remaining close to the literature while keeping the model simple with minimal information requirements. It is worth to mention that asking teams to concentrate their efforts on scoring more tries is very intuitive albeit somewhat detrimental to the sport, as the uncertainty in results becomes highly reduced Scarf et al. (2019). Similar counter-intuitive ideas have been also discussed for soccer in Fry et al. (2021).
Several studies detected the relevance of home advantage, i.e. the benefit over the away team of being the home team. Schwartz and Barsky (1977) suggested that crowds exert an invigorating motivational influence, encouraging the home side to perform well. Still, a full explanation of this phenomenon requires taking into account the familiarity with the field of the home team, the travel fatigue of the away team, the social pressure exerted by the local fans over the referees, among other factors. Many other researchers investigated this advantage from different points of view, such as the physiological Neave and Wolfson (2003), the psychological Agnew and Carron (1994); Legaz-Arrese et al. (2013), the economic one Carmichael and Thomas (2005); Boudreaux et al. (2017); Ponzo and Scoppa (2018) and even exploring the possibility that referees may be favorably biased towards home teams Downward and Jones (2007); Page et al. (2010). Home advantage in Rugby Union and Rugby League has been studied and confirmed by Kerr and van Schaik (1995), Jones (2007), Page and Page (2010), García et al. (2013) and even during the Covid-19 pandemic by Fioravanti et al. (2021). In our model, home advantage is explored depending on if there is public allowed to attend the game, and in what day it is played.3 An extra parameter intends to capture the influence of factors other than public attendance inducing home advantage.
The plan of the paper is as follows. In Sect. 2 we present the data of the English Premiership Rugby Championship, played in 2020/2021. Section 3 presents a Bayesian hierarchical model of the variables that explain the difference of scores in that championship. Section 4 runs a statistical descriptive analysis of the matches of the Premiership Championship in the light of the variables defined in the Bayesian model. Section 5 presents the results of estimating our model with the data of the Rugby Union competition. Section 6 considers the outliers found in the previous section, treating them as the result of luck in those games. We assess the aspects that justify considering them as instances of luck. Finally, Sect. 7 concludes and discusses the opportunities for further research.
Data
The Premiership Rugby Championship is the top English professional Rugby Union competition. The 2020/2021 edition was played by 12 teams. The league season comprises 22 rounds of matches, with each club playing each other home and away. The top 4 teams qualify for the playoffs. Four points are awarded for the winning team, two to each team in case of a draw, and zero points to the loser team. However, a bonus point is given to the losing team in case the score difference is less than eight points. Teams also receive a bonus point in case they score four or more tries. In a game, a try is worth five points, a conversion two points and both penalty and drop kicks are worth three points each.4 During this season, if a game was canceled due to Covid-19, two points were awarded to the team responsible, and four to the other, while the match result was deemed to be 0–0. The 2020/2021 season was won by the Harlequins, who claimed their second title after ending in the fourth league position.
The total score, number of tries, converted tries, converted penalties, attempted penalties, converted drops, attempted drops and attendance at each of the 122 games of the 2020/21 Premiership season have been taken from the corresponding Wikipedia entry.5 We generate the priors of our Bayesian model based on the final ranking from the 2019/20 season as follows. An attack and defense ranking is built using the number of points scored and received by each team: the team with most tries scored and less points received is ranked first in both rankings. These rankings are then normalized, and their corresponding means are computed.
Model
We base our model on a previous work of Kharratzadeh (2017) that models the difference in scores for the soccer English Premier League. The score difference in game g, is denoted as yg, and is assumed to follow a tstudent distribution,yg∼tν(adiff(g)+effdiff(g)+ha(g),σy),
where adiff(g) is the difference in the ability of the teams, effdiff(g) is the difference in the effort exerted and ha(g) the home advantage at game g. We give it a N(0.5, 1) prior. In turn, we assign a prior Gamma(9, 0.5) to the distribution of degrees of freedom ν.6
We model the difference in abilities as follows:adiff(g)=ahw(g),ht(g)-aaw(g),at(g)
where ahw(g),ht(g) is the ability of the home team in the week where the game g is played (analogously for the away team). We assume that the ability may vary during the season. More precisely, we assume that the ability at a period t is the ability at t-1 plus a term representing the factors that may affect the ability at t:ahw(g),ht(g)=ahw(g)-1,ht(g)+σ·ηhw(g),ht(g)forhw≥2
where σ and η have weak informative priors N(0, 0.1) and N(0, 0.5), respectively. The model is analogous for the away team. The abilities for the first week depend on the previous performance of the teams, again assuming that ability has some sort of “inertia”:a1,ht(g)=βprev·prevperf(ht(g))+η1,ht(g)
where βprev is given the weakly informative prior N(0.5, 1) and prevperf(j) is the previous performance of team j. This value is obtained as follows: we build two rankings of tries scored and received during the last season, where a team is at the top of both rankings if it has scored the most and received the least tries in the last season. Then, the two rankings are normalized and averaged.
The variable that captures the relative motivations of the teams in the game is the difference in efforts:effdiff(g)=βeffort·(effH(g)-effA(g))
where βeffort has a N(0.5, 1) prior and the effort of the home team is given an observational approximation (analogously for the away team):effH(g)=numberofhometriesingamegnumberofhometriesingameg+attemptedhomescoringkicksingameg.
Notice that the variable attempted home scoring kicks in game g has, in turn, three components. The number of conversions allowed after scoring tries, the number of penalty kicks attempted and the number of drop kicks attempted by the home team.
Our intention with this definition is to capture the idea that scoring tries demands more effort than other means of scoring points, and motivated teams try to maximize this value.
Finally, to capture home advantage, we consider both the attendance and non-attendance (such as the weather, long trips to play the game, etc.) effects .ha(g)=βhome+βatten·atten(g),
where βhome and βatten have N(0.5, 1) priors and atten(g) is 0 if no fans were allowed and 1 otherwise. A graphical representation of the model is depicted in Fig. 1.
To ensure robustness in our results we work with four different models. Model I does not include attendance as a variable of home advantage. Model II includes the attendance variable, while Model III, incorporates a day variable day(g), with a N(0.5, 1) prior, which has value 1 if the game was played on Saturday or Sunday and 0 otherwise. This day variable allows to find out whether playing on a day in which almost all the fans can attend the game benefits either the home or the away team. Finally, Model IV includes a variation of prevperf(j), where instead of the tries, we use total points scored and received by each team. There is no crucial difference between the four models. The reason for including different specifications is to evaluate whether the coefficients corresponding to the variables of interest, common to the four models, are sensitive to the inclusion of other variables.Fig. 1 Graph corresponding to Model II
Descriptive statistics
On Tables 1 and 2 we can see the descriptive statistics for home and away teams respectively where Score, T, C, P, D, AC, AP, AD and eff indicate, respectively, total points, tries scored, conversions scored, penalty kicks scored, drop kicks scored, attempted conversions, attempted penalty kicks, attempted drop kicks and effort exerted.Table 1 Home team
ScoreH TH CH PH DH ACH APH ADH effH
Min. 3.00 0.00 0.00 0.00 0 0.00 0.00 0 0.00
1st Qu 17.00 2.00 1.00 1.00 0 2.00 1.00 0 0.28
Median 23.00 3.00 2.00 2.00 0 3.00 2.00 0 0.40
Mean 26.22 3.248 2.407 1.708 0 3.186 2.027 0 0.37
3rd Qu 34.00 4.00 3.00 3.00 0 4.00 3.00 0 0.46
Max. 74.00 12.00 7.00 6.00 0 12.00 7.00 0 0.55
H home team; T tries; C conversions; P penalties; D drops, A prefix for attempted actions; eff effort ratio
Table 2 Away team
ScoreA TA CA PA DA ACA APA ADA effA
Min 3.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
1st Qu. 15.00 2.00 1.00 0.00 0.00 0.00 0.00 0.00 0.28
Median 22.00 3.00 2.00 1.00 0.00 3.00 1.00 0.00 0.37
Mean 22.35 2.796 1.929 1.434 0.017 2.717 1.655 0.026 0.36
3rd Qu. 28.00 4.00 3.00 2.00 0.00 4.00 3.00 0.00 0.5
Max. 62.00 9.00 6.00 5.00 1.00 8.00 5.00 2.00 0.66
A away team; T tries; C conversions; P penalties; D drops, A prefix for attempted actions; eff effort ratio
Figure 2 shows that most of the score differences are around zero (even though there are very few draws obtained in the championship). This indicates that games usually end with little difference. Figures 3a and b depict the effort histograms. We can see great number of cases of effort=12. This is because teams almost always have the chance to go for a conversion after scoring a try, except when a penalty-try is awarded; and in many games the teams did not attempt to kick a penalty (maybe because they have no kickable penalties available).Fig. 2 Score difference histogram
Fig. 3 Effort histograms
Results
We estimate the model with the R package rstanTeam (2020). We use 4 cores, each one to run 2500 iterations and 1500 warm-up ones. The Stan code of the estimated model can be found in the Appendix.
The results obtained appear to hold a degree of robustness:The Rhat (or Gelman-Rubin) statistic measures the discrepancies between the chains generated in simulations of Bayesian models. The further its value is from 1, the worse. But we can see in all our results that Rhat is very close to 1.
neff is an estimate of the effective sample (of parameters) size. A large value indicates a low degree of error in the expected value of the parameter. We can see that, indeed, this is the case for all the parameters of interest.
Tables 3 and 4 show the results of Model I and II, respectively. The difference between them is the presence of βatten in the latter one. The posteriors of model II, and the corresponding histograms, shown in Figs. 4 and 5 , indicate that βprev and βeffort are the parameters distributed above zero. On the other hand, βhome has a wider credible interval that includes zero value if βatten is included, as in the comparison between Model I and Model II.Table 3 Posterior summary statistics, model I
Parameter Rhat n_eff Mean SD 2.5% 50% 97.5%
b_home 1.000 7792 0.366 0.168 0.036 0.362 0.704
b_prev 1.001 3919 1.760 0.722 0.360 1.757 3.194
b_effort 1.000 7228 3.147 0.767 1.641 3.139 4.686
nu 1.000 3048 12.375 5.036 5.057 11.566 24.360
sigma_y 1.000 4263 1.664 0.159 1.359 1.661 1.985
Table 4 Posterior summary statistics, model II
Parameter Rhat n_eff Mean SD 2.5% 50% 97.5%
b_home 1.000 7025 0.324 0.175 −0.028 0.327 0.657
b_prev 1.000 4516 1.758 0.729 0.297 1.768 3.185
b_atten 1.000 8830 0.376 0.496 −0.588 0.370 1.354
b_effort 1.000 9014 3.114 0.799 1.574 3.118 4.639
nu 1.000 3788 13.011 5.206 5.445 12.153 25.335
sigma_y 1.000 5291 1.683 0.158 1.380 1.680 2.012
Table 5 shows the difference of estimations when adding the βday parameter. The results seem to be stable, in the sense that the estimated values of βprev and βeffort remain in similar intervals. We also show the result of changing the mean of the prior of ν to 1.
Finally, Table 6 presents the results of Model IV. The ranking score is here based on the points (not the tries) of the previous season. We find in this case that the βeffort parameter is similar as that found in the other models, while βprev has a lower mean.Table 5 Posterior summary statistics, model III
Parameter Rhat n_eff Mean SD 2.5% 50% 97.5%
b_home 1.001 4146 0.322 0.320 −0.302 0.321 0.944
b_prev 1.000 3782 1.721 0.727 0.295 1.717 3.147
b_atten 1.000 5355 0.279 0.480 −0.670 0.276 1.249
b_effort 1.000 6561 3.064 0.770 1.571 3.066 4.538
b_day 1.001 3683 −0.003 0.365 −0.732 −0.004 0.715
nu 1.001 3424 6.876 2.301 3.355 6.498 12.389
sigma_y 1.000 3915 1.556 0.165 1.242 1.551 1.896
Table 6 Posterior summary statistics, model IV
Parameter Rhat n_eff Mean SD 2.5% 50% 97.5%
b_home 1.000 3328 0.321 0.311 −0.300 0.358 0.923
b_prev 1.000 3071 1.187 0.705 −0.307 1.112 2.518
b_effort 1.000 5604 3.168 0.802 1.654 3.189 4.657
b_atten 1.000 5391 0.215 0.575 −0.782 0.201 1.294
b_day 1.000 3382 0.001 0.422 −0.749 0.002 0.747
nu 1.000 2681 5.254 1.451 2.922 5.133 8.439
sigma_y 1.000 2996 1.591 0.208 1.244 1.572 1.818
Fig. 4 Posteriors for model II
Fig. 5 Posteriors for model II (Cont.)
Fig. 6 Bivariate relations between parameters
Besides the histograms corresponding to the values of the parameters , we can see in Figs. 6, 7, 8, and 9, further results of our model. Figure 6 illustrates the lack of relation between βprev and βhome and βeffort (for instance, the slope of the line that best fits in (a) is 0.008703 with p-value 0.27 and R2=0.008653). This is a strong suggestion that effort captures an effect that differs from both the ability of the team and the potential support (or antagonism) received in the field.
Figure 7, shows one of the 10,000 simulated histograms of score differences. It can be compared to the original histogram corresponding to the actual championship. This is further detailed in Fig. 8, where the histograms of the distributions of means and standard deviations, obtained in the replications, is depicted with gray bars, while the blue ones correspond to the values of the statistics computed from the observed data.
Notice that σ and η appear in the model only in a product and since both have Gaussian priors, it could be thought that they cannot be distinguished by likelihood. This would mean that only their product is identifiable but not the individual parameters. To check this we generate the trace-plots and histograms of these parameters. They are shown in Figs. 9 and 10, indicating that this concern can be discarded since σ and η are identifiable.
Fioravanti et al. (2021) indicate that score differences in favor of the home team could vary under different prior distributions . To explore this potential variability, we consider other prior distributions of βhome, with means 2, 4 and 6. In all these cases, the results are similar to those obtained with mean 0.5: the posterior converge to values close to 0.3.Fig. 7 Simulated score difference histogram
Fig. 8 Histogram of replicated score differences
Fig. 9 Trace and histogram of nu
Fig. 10 Trace and histogram of sigma
Luck in games
We assume that luck plays a significant role in games. According to the definition of Tango et al. (2007), luck in a game can be understood as the difference between the actual performance observed and the ability of a team. In our case, we could identify it with the difference between the performance and both the effort and ability of a team.
For Tango and coauthors, the variability of luck is p(1-p)g, where p=0.5 and g=22 is the number of games.7 Then Var(Luck)=0.0114. On the other hand, performance variability is the deviation in the number of games won by the teams in the league, yielding 0.0379. Finally, effort variability can be captured by the variance of the effort ratio, 0.0156. Then:Var(Performance)=Var(Luck)+Var(Effort)+Var(Ability)0.0379=0.0114+0.0156+Var(Ability)
then, we find that:Var(Ability)=0.0109
Then we can see that the variabilities in effort, ability and luck have slightly the same weight in the composition of the variability of performance.
An alternative definition of luck is that it arises when the residual in the regression of yg on the explanatory variables defined in Sect. 3 differs markedly from the mean value in the distribution of noises. That is, the presence of luck is revealed by a large impact of unobserved variables Mauboussin (2012). Elias et al. (2012) and Gilbert and Wells (2019) consider four types of luck. The first one arises from physical randomization, by the use of dice, cards, etc. (I). The second kind of luck is due to simultaneous decision making (II). The third one is due to human performance fluctuating unpredictably (III), while the last one arises from matchmaking (IV).8
The underlying theoretical framework is very rich. In the sequel we give a simple example of the kinds of analysis that may be ultimately possible. To start, consider the types of luck that may have affected the outcomes:Round 5 - London Wasps 34 versus 5 Exeter Chiefs: contrary to what happened in the previous week, the Wasps regained its captain and 3 players from the English national team, while Exeter missed 8 of its players who, after playing for the national team, were either injured or where forced to rest (type IV). Also, the Chiefs conceded 15 penalties (a high number for this level of competition) and were shown a yellow card, letting the Wasps score a try during the sin bin time (types II and III).9
Round 15 - Worcester Warriors 14 versus 62 Northampton Saints: the Warriors changed 10 players from the previous week’s game, and had three injured players (the fullback and two tighthead props), while the Saints recovered two players from the national team. A victory would close the gap for the Saints on the top four (type II and IV). A Warriors player was shown a red card at the 49th minute, allowing 6 tries after that (type III).
Round 20: Exeter Chiefs 74 versus 3 Newcastle Falcons: the Chiefs, already classified for the semifinals, needed a win to gain the home advantage during the playoffs. It was also the first game after more than 5 months that fans were allowed again to attend the play (type IV). Besides that, it was a record performance of Exeter, since it scored the largest difference in a top competition (type III). For the Falcons it was the longest trip of the tournament (type IV) and were shown a yellow card at minute 26, allowing two tries during the sin bin time (type II and III).
Discussion
In our analysis we found that while the results of rugby matches in the English Premiership can be explained by the ability of the teams, another highly significant variable is the motivation of players, reflected by the effort exerted by them. Luck, instead, seems to have had an impact only in games where the residuals are larger.
We have followed here Lenten and Winchester (2015), Butler et al. (2020) and Fioravanti et al. (2021), assuming that the number of tries is an important component of any measure of effort. While the results obtained in our Bayesian analysis are sound, there exist many other ways of defining a proxy of motivation in Rugby. We can argue that a large number of tackles reveals that a team has exerted a lot of effort, indicating that it is highly motivated. But this also indicates that team has not exerted a large effort aimed to keep the ball. One could also, with the help of GPS, track the physical effort of the players, and identify it with their motivation. In any case, selecting a certain measure of effort as a proxy of motivation is a rather arbitrary choice. But this also true for any proposed proxies for ability or luck.
Future lines of research involve exploring and comparing the impact of our proxy for motivation in other tournaments, and even postulate alternative definitions of ‘effort’ in different sports. Another topic that it is worth studying is the evolution of our measure of effort along time. The results of such investigation could be useful to assess how the incentives to the players may have changed, affecting the motivation for scoring tries rather than scoring kicks.
Appendix: STAN code
Acknowledgements
We would like to thank two anonymous reviewers and the Associate Editor for their comments, that were really helpful and constructive for the improvement of this work.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declarations
Conflict of interest
The authors declare that they have no conflict of interest.
1 By scoring kicks we refer to conversions, penalty and drop kicks; and by kick attempt we mean every time the team decided to do a scoring kick, no matter the outcome.
2 We are thankful to the Editor and two anonymous referees for pointing out that our definition of effort seems to be a strong proxy for attack mindedness or risk seeking behavior.
3 The tournament under consideration took place during the Covid-19 pandemic. Several games were played without attendance.
4 After a try, the scoring team has the chance to kick for a conversion, except when a penalty-try is awarded. In the latter case seven points are automatically awarded to the team.
5 Ten games were canceled because some players tested positive for COVID 19. We do not consider the playoff games as we assume that the incentives are not the same at the elimination stage as in the qualification games.
6 Kharratzadeh (2017) uses a prior of Gamma(2, 0.5) based on the work of Juárez and Steel (2010), where the shape parameter 2 corresponds to a more positive skewed distribution with a smaller average difference in goals in the Premier League in soccer. Here we use a higher shape parameter corresponding to the less skewed distribution with a larger mean difference in scores of the Premiership Rubgy Championship.
7 The theoretical standard deviation of the distribution of luck over a season, using a binomial approximation to the normal distribution can be expressed as p(1-p)g, where p=0.500 (since in average a team wins by chance half of the games), and g= number of games.
8 A yellow card shown to a player (type II and III) can be seen as bad luck for that player’s team and good luck for the rival. Although receiving a yellow or red card is somewhat under the control of a player, there are many situations where a lot of (bad) luck may be involved. Consider a player that it is in a perfect position for a tackle, but the player in front slips and end up receiving a hard hit in the head and get unconscious. While the slip mitigates the infraction, the tackler will be shown, at the very least, a yellow card. Having to play a game in the 15th round of the tournament between the top team and the bottom team means good luck for the top one and bad luck for the bottom team (Type IV).
9 A yellow card shown to a player means that he must leave the field for ten minutes (or is in the sin bin) while a red card means that he is expelled from the game.
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References
Agnew GA Carron AV Crowd effects and the home advantage Int J Sport Psychol 1994 25 1 53 62
Asif M McHale IG In-play forecasting of win probability in One-Day international cricket: a dynamic logistic regression model Int J Forecast 2016 32 1 34 43 10.1016/j.ijforecast.2015.02.005
Baboota R Kaur H Predictive analysis and modelling football results using machine learning approach for English Premier League Int J Forecast 2019 35 2 741 755 10.1016/j.ijforecast.2018.01.003
Baio G Blangiardo M Bayesian hierarchical model for the prediction of football results J Appl Stat 2010 37 2 253 264 10.1080/02664760802684177
Boshnakov G Kharrat T McHale IG A bivariate Weibull count model for forecasting association football scores Int J Forecast 2017 33 2 458 466 10.1016/j.ijforecast.2016.11.006
Boudreaux CJ Sanders SD Walia B A natural experiment to determine the crowd effect upon home court advantage J Sports Econ 2017 18 7 737 749 10.1177/1527002515595842
Butler R Lenten LJ Massey P Bonus incentives and team effort levels: evidence from the ”field” Scott J Polit Econ 2020 67 5 539 550 10.1111/sjpe.12249
Carmichael F Thomas D Home-field effect and team performance: evidence from English premiership football J Sports Econ 2005 6 3 264 281 10.1177/1527002504266154
Constantinou AC Fenton NE Neil M pi-Football: a Bayesian network model for forecasting association football match outcomes Knowl Based Syst 2012 36 322 339 10.1016/j.knosys.2012.07.008
Denrell J Liu C Top performers are not the most impressive when extreme performance indicates unreliability Proc Natl Acad Sci 2012 109 24 9331 9336 10.1073/pnas.1116048109 22645350
Downward P Jones M Effects of crowd size on referee decisions: analysis of the FA cup J Sports Sci 2007 25 14 1541 1545 10.1080/02640410701275193 17852675
Dyte D Clarke SR A ratings based Poisson model for World Cup soccer simulation J Oper Res Soc 2000 51 8 993 998 10.1057/palgrave.jors.2600997
Elias GS Garfield R Gutschera KR Characteristics of games 2012 Cambridge MIT Press
Fioravanti F, Delbianco F, Tohmé F (2021) Home advantage and crowd attendance: evidence from rugby during the Covid 19 pandemic. arXiv preprint arXiv:2105.01446
Fioravanti F Tohmé F Delbianco F Neme A Effort of rugby teams according to the bonus point system: a theoretical and empirical analysis Int J Game Theory 2021 50 2 447 474 10.1007/s00182-021-00756-2
Fry J Serbera J-P Wilson R Managing performance expectations in association football J Bus Res 2021 135 445 453 10.1016/j.jbusres.2021.06.052
Fry J Smart O Serbera J-P Klar B A variance Gamma model for rugby union matches J Quant Anal Sports 2021 17 1 67 75 10.1515/jqas-2019-0088
García MS Aguilar ÓG Vázquez Lazo CJ Marques PS Fernández Romero JJ Home advantage in home nations, five nations and six nations rugby tournaments (1883–2011) Int J Perform Anal Sport 2013 13 1 51 63 10.1080/24748668.2013.11868631
Gilbert DE Wells MT Ludometrics: luck, and how to measure it J Quant Anal Sports 2019 15 3 225 237 10.1515/jqas-2018-0103
Goddard J Regression models for forecasting goals and match results in association football Int J Forecast 2005 21 2 331 340 10.1016/j.ijforecast.2004.08.002
Hassanniakalager A Sermpinis G Stasinakis C Verousis T A conditional fuzzy inference approach in forecasting Eur J Oper Res 2020 283 1 196 216 10.1016/j.ejor.2019.11.006
Herlambang MB Taatgen NA Cnossen F Modeling motivation using goal competition in mental fatigue studies J Math Psychol 2021 102 102540 10.1016/j.jmp.2021.102540
Johnson EJ Payne JW Effort and accuracy in choice Manag Sci 1985 31 4 395 414 10.1287/mnsc.31.4.395
Jones MB (2007) Home advantage in the NBA as a game-long process. J Quant Anal Sports, 3(4)
Juárez MA Steel MF Model-based clustering of non-Gaussian panel data based on skew-t distributions J Bus Econ Stat 2010 28 1 52 66 10.1198/jbes.2009.07145
Kerr JH van Schaik P Effects of game venue and outcome on psychological mood states in rugby Personal Individ Differ 1995 19 3 407 410 10.1016/0191-8869(95)00044-7
Kharratzadeh M (2017) Hierarchical Bayesian modeling of the English Premier League. In Proceedings of the First Stan Conference, StanCon
Legaz-Arrese A Moliner-Urdiales D Munguía-Izquierdo D Home advantage and sports performance: evidence, causes and psychological implications Univ Psychol 2013 12 3 933 943 10.11144/Javeriana.upsy12-3.hasp
Lenten LJ Winchester N Secondary behavioural incentives: bonus points and rugby professionals Econ Rec 2015 91 294 386 398 10.1111/1475-4932.12185
Lyu W Bolt DM A psychometric model for respondent-level anchoring on self-report rating scale instruments Br J Math Stat Psychol 2022 75 1 116 135 10.1111/bmsp.12251 34350978
Massin O Towards a definition of efforts Motiv Sci 2017 3 3 230 10.1037/mot0000066
Mauboussin MJ The success equation: untangling skill and luck in business, sports, and investing 2012 Harvard Business Review Press
Morris SP Moral luck and the talent problem Sport Ethics Philos 2015 9 4 363 374 10.1080/17511321.2015.1121287
Neave N Wolfson S Testosterone, territoriality, and the ‘home advantage’ Physiol Behav 2003 78 2 269 275 10.1016/S0031-9384(02)00969-1 12576125
Page K Page L Alone against the crowd: individual differences in referees’ ability to cope under pressure J Econ Psychol 2010 31 2 192 199 10.1016/j.joep.2009.08.007
Page L, Page K et al (2010) Evidence of referees’ national favouritism in rugby. Paper provided by National Centre for Econometric Research in its series NCER Working Paper Series with, (62)
Payne J Bettman J Johnson E Kushniruk A Trading off accuracy for effort in decision making. Review of the adaptive decision maker J Math Psychol 1995 39 3 315 317 10.1006/jmps.1995.1030
Pledger MJ Morton RH Modelling the 2004 super 12 rugby union competition Aust N Z J Stat 2011 53 1 109 121 10.1111/j.1467-842X.2011.00599.x
Pluchino A Biondo AE Rapisarda A Talent versus luck: the role of randomness in success and failure Adv Complex Syst 2018 21 1850014 10.1142/S0219525918500145
Ponzo M Scoppa V Does the home advantage depend on crowd support? Evidence from same-stadium derbies J Sports Econ 2018 19 4 562 582 10.1177/1527002516665794
Quarrie KL Raftery M Blackie J Cook CJ Fuller CW Gabbett TJ Gray AJ Gill N Hennessy L Kemp S Managing player load in professional rugby union: a review of current knowledge and practices Br J Sports Med 2017 51 5 421 427 10.1136/bjsports-2016-096191 27506436
Russo JE Dosher BA Strategies for multiattribute binary choice J Exp Psychol Learn Mem Cogn 1983 9 4 676 10.1037/0278-7393.9.4.676 6227682
Santos-Fernandez E Wu P Mengersen KL Bayesian statistics meets sports: a comprehensive review J Quant Anal Sports 2019 15 4 289 312 10.1515/jqas-2018-0106
Scarf P Parma R McHale I On outcome uncertainty and scoring rates in sport: the case of international rugby union Eur J Oper Res 2019 273 2 721 730 10.1016/j.ejor.2018.08.021
Schwartz B Barsky SF The home advantage Soc Forces 1977 55 3 641 661 10.2307/2577461
Simon R Deserving to be lucky: reflections on the role of luck and desert in sports J Philos Sport 2007 34 1 13 25 10.1080/00948705.2007.9714706
Stefani RT Predicting score difference versus score total in rugby and soccer IMA J Manag Math 2009 20 2 147 158 10.1093/imaman/dpn021
Štrumbelj E Vračar P Simulating a basketball match with a homogeneous Markov model and forecasting the outcome Int J Forecast 2012 28 2 532 542 10.1016/j.ijforecast.2011.01.004
Tango TM Lichtman MG Dolphin AE The book: playing the percentages in baseball 2007 Potomac Books Inc
Team SD (2020) Rstan: the R interface to Stan. r package version 2.21. 2
Wetzels R Tutschkow D Dolan C Van der Sluis S Dutilh G Wagenmakers E-J A Bayesian test for the hot hand phenomenon J Math Psychol 2016 72 200 209 10.1016/j.jmp.2015.12.003
| 0 | PMC9734849 | NO-CC CODE | 2022-12-14 23:28:31 | no | Stat Methods Appt. 2022 Dec 8;:1-17 | utf-8 | Stat Methods Appt | 2,022 | 10.1007/s10260-022-00677-8 | oa_other |
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Jindal Global Law Review
Jindal Global Law Review
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10.1007/s41020-022-00175-8
Article
Law’s temporality and the construction of death-worlds: Custodial neglect of older prisoners in India
http://orcid.org/0000-0003-1594-0655
Dey Deblina [email protected]
grid.449565.f OP Jindal Global University, Sonipat, India
6 12 2022
121
26 10 2022
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The vexed relation between law and age/ageing is most apparent in the context of older prisoners. Late life may be accompanied by disabilities and dependencies. So, access to appropriate forms of care including medical care becomes even more crucial in custodial institutions like prisons where older prisoners live isolated from society. Since the spread of COVID-19, there have been attempts to decongest Indian prisons. However, older political prisoners charged (not convicted) for anti-state, terrorist activities continue to suffer in prison due to denial of bail. I argue that elderliness and the condition of health ought to be factors on which bail should be given irrespective of the nature of the charges. By using the framework of ‘law as temporality’, I elucidate how the politics around the denial of bail by courts in India and the treatment of older political prisoners by prison authorities lead to the production of a ‘carceral time’. This article discusses how carceral time structures the embodied experiences of ageing in ways that defy the human rights of prisoners. Time not only disciplines but also determines the expendability of ageing bodies, particularly when time is an insidious form of waiting, as in the case of older political prisoners in the Bhima Koregaon case in India. This article highlights the need for the criminal justice system in India to consider elderliness as a ground for compassionate treatment towards older prisoners, and to uphold their rights to healthcare and to live with dignity.
Keywords
Ageing
Carceral time
Prison
Disposability
Disability
Medical care
Judiciary
COVID-19 pandemic
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pmcIntroduction
Older prisoners are one of the most neglected categories of senior citizens.1 The criminal justice system in the country does not consider elderliness as a standalone criterion for more just and humane treatment of older prisoners when in custody or at the time of formulating judgments. Due to age and associated health challenges, older incarcerated individuals might be in a vulnerable position in custodial institutions where they do not have access to basic amenities related to care. Custodial life in prisons complicates the experiences of ageing, and certain medical conditions are fully incompatible with custody unless appropriate care is ensured. Chronic physical ailments, Alzheimer’s disease, and all those ailments which necessitate constant care in late life are conditions which make life in prisons challenging.2 There is a significant dearth of research on older prisoners in India, but those available demonstrate the heightened health risks and reduced life expectancy of the incarcerated.3 Thus, care, both social and medical care, becomes even more imperative for older prisoners whose suffering may be compounded owing to age, ailments, and incarceration.
The state cleverly thrusts responsibilities of care and maintenance of older people upon the family, especially on adult children. Even though laws such as the Maintenance and Welfare of Parents and Senior Citizens Act 2007 (MW Act) make it obligatory for state governments to establish old age homes and provide affordable medical support, this is poorly implemented.4 Among senior citizens, the older prisoner is a particularly vulnerable category. The state cannot sideline its duty to care for older prisoners as the rights of prisoners are internationally recognised. Rules regarding the treatment of prisoners have been codified in the International Covenant on Economic, Social and Cultural Rights, the International Convention on Civil and Political Rights, and the Nelson Mandela Rules, which will be discussed later.5
However, the political arrests and treatment thereof of several human rights activists in the Bhima Koregaon–Elgaar Parishad case,6 many of whom are senior citizens, reveal the failure of the Indian legal system to safeguard the human rights of prisoners. Elgaar Parishad is an event held at Bhima Koregaon in Pune, Maharashtra, to commemorate the historic defeat in 1818 of an upper-caste Maratha ruler by the British forces. A significant proportion of the British contingent was made up of Dalits (oppressed, lower-caste groups). Every year, Dalit groups, activists, and organisations co-organise this event. In the convention held in 2017, violence broke out between Dalits and upper-caste Hindus, after which several human rights activists were arrested. Accusations against them ranged from having Maoist links to planning the assassination of the prime minister to mobilising for a war against India.
The alleged criminals (all of them human rights activists) were arrested from 2018 onwards and have struggled to get bail ever since. The political prisoners whose experiences I discuss in this article are also among the more renowned figures, thereby having the support of their networks as well as attracting more media attention. Yet, their experiences remain relevant for a critical analysis of the carceral and juridical treatment of older prisoners. In this article, I have examined the role of law in structuring experiences of ageing among older prisoners (a) who are not yet convicted (but are pre-trial or undertrial prisoners); (b) who have co-morbidities or multiple health complications; (c) against the backdrop of a raging COVID-19 pandemic. By law, I refer to the draconian legislations such as the Unlawful Activities (Prevention) Amendment Act 2019, as well as to those who apply the law, namely the executive (police and prison authorities) and the judiciary. They all are implicated in the infringement of human rights of older political prisoners and must be held accountable.
I have analysed secondary data such as newspaper reports, bail orders, international guidelines, government data like Prisons Statistics reports of the National Crime Records Bureau (NCRB), Supreme Court and High Court orders mainly during the pandemic, as well as interviews of older political prisoners and their well-wishers available on the internet. In the second section, I provide a sketch of the condition of Indian prisons during the pandemic and explain the reasons for compounded suffering of older political prisoners. In the third section, I discuss the way the law frames dissenters as ‘disposable’ bodies. Here, I argue that in the spectrum of disposability, older dissenters are the worst off. In the fourth section, I discuss how the law produces ‘carceral time’ by crafting an insidious form of waiting that adversely impacts older prisoners who are dependent on care. In the fifth section, I analyse the narratives of a few older political prisoners. It is not my argument that the law is discriminatory towards older prisoners because of their age, but by neglecting their unique needs, the law’s insensitivity becomes apparent. The last two sections discuss the adverse implications of deliberate non-care on the part of the state and the creation of death-worlds for older political prisoners. I conclude by arguing that in a democratic society, we ought to also question the role of courts, which repeatedly denied medical bail to older political prisoners in ways that excluded them from appropriate healthcare during the pandemic and beyond,7 jeopardising their lives.8 Such treatment by the law compounds the suffering of older political prisoners, as they are afflicted with multiple forms of crises including:ailments related to late life;
health (physical and mental) risks arising out of a lack of timely and appropriate medical care in custody;
lack of social care from kin-group and friends as liberty is curbed;
the nature of allegation (which prolongs the trial due to the crime being designated as a non-bailable offence) and the dishonourable reputation associated with the allegation;
the threat of the spread of a contagion (like the COVID-19 pandemic) within prison premises.
The Indian state’s treatment of older political prisoners during the pandemic
Human rights activists in many parts of the world have rallied for decarceration during the pandemic. Some advocates of prison reform have stressed the need for releasing undertrial prisoners due to the increased chances of the virus spreading within institutional premises.9 Prisons in India are spaces in urgent need of reform due to the abysmal standard of life for the inmates.10 The high risks of contracting the virus in confined spaces are obvious, especially in light of poor medical care arrangements.11 Several human rights activists and advocates had brought this to the notice of the higher judiciary and the state and had urged them to release prisoners, especially older prisoners and women.12
In this article, I analyse the experiences of older activists13 arrested in connection with the Bhima Koregaon case. In 2018 and 2019, human rights activists Sudha Bharadwaj, Anand Teltumbde, Stan Swamy, Varavara Rao, and Gautam Navlakha (among others) were arrested from across the country. All of them were denied bail several times. Most of them already suffered from health issues such as high blood pressure, diabetes, and other co-morbidities. At the start of the pandemic, the scientific evidence demonstrated that the COVID-19 virus had an affinity towards people with co-morbid health conditions. Under such circumstances, the refusal to grant bail to these pre-trial older prisoners is inhumane.
In March 2020, the Supreme Court of India issued directives to the state governments to decongest the prisons.14 It asked states to constitute high-powered committees to consider the release of prisoners who were subject to seven years or more of incarceration. A year later, the Supreme Court passed another order in which it instructed states to expedite the process of decongesting prisons. In this order, the Supreme Court reiterated its guideline formulated in 2020 whereby:It was left open to the High Powered Committees to determine the category of prisoners who should be released depending upon the nature of offence, the number of years to which he/she has been sentenced, the severity of offences which he/she is charged with and the stage of trial or any other relevant factor which the Committee thinks appropriate.15
However, those charged under the UAPA or the Public Safety Act 1978 for plotting terrorist activities against the state were not to be granted bail despite their families pleading for their release owing to the spread of COVID-19 inside prisons.16 Recently, The Wire reported the death of older Kashmiri detainees due to COVID-19 in the jails and pointed to the lack of access to proper medical care in jails.17 The Kashmir High Court Bar Association also pleaded with the Government of India and the state to release prisoners. However, that has not happened. Until May 2021, the Bihar prison department was the only one to amend the conditions for the premature release of older prisoners.18 Thus, convicts who were above 65 years of age, and had completed seven years of incarceration that included release on parole, were deemed eligible for premature release.19 Further, those convicts who had been given life imprisonment and were suffering from incurable critical or transmissible diseases and who had completed at least five continuous years of imprisonment could be released prematurely. However, such a provision remains inadequate as there is no consideration for pre-trial or undertrial prisoners in police or judicial custody. Barring Sudha Bharadwaj, who has been granted default bail,20 and Varavara Rao, who has been given a three-month extension upon six months of initial medical bail, the rest continue to suffer in the prisons.
The spectre of disposability
All waste is potentially poisonous –– or at least, being defined as waste, it is deemed to be contaminating and disturbing to the proper order of things. If recycling is no longer profitable and its chances (at any rate in the present-day setting) are no longer realistic, the right way to deal with waste is to speed up its ‘biodegradation’ and decomposition while isolating it as securely as possible from ordinary human habitat.21
The politico-juridical apparatus often segregates some humans as ‘disposable’ through its policies and legal actions, either actively or inadvertently and unpremeditatedly. To be rendered disposable by the state implies that a particular individual or community is deemed useless to the state and therefore can be legitimately discarded. Throughout history, certain social groups have been classified as expendable, systematically excommunicated (foreigners and those from another ethnonationality considered as ‘suitable enemies’22) and even disposed of through the most inhumane techniques. The people thrown into labour camps in Nazi Germany and, among them, the human guinea pigs (Versuchspersonen) chosen for scientific experimentations,23 international refugees from war-torn zones, ‘victims of torture’, the dispossessed, and political prisoners are some examples.24 Ethnicity, race, religion, caste, and class have been grounds on which specific communities continue to face harassment, torture, expulsion, and even genocidal attacks under legal regimes. Many of these communities are often targets of heightened state surveillance. In India, Muslim detainees in Assam who were denationalised under the exercises of the National Register of Citizens, followed by the Citizenship Amendment Act 2019, could be viewed as disposable.25 The move to denationalise was made with a view to consolidating a Hindu nation by excluding more Muslims. Migrant labourers (mostly the non-contractual labourers in the informal economy), whose lives were wrecked by the sudden declaration of a nation-wide lockdown by the Indian state during the first wave of the pandemic, are another example of lives rendered disposable. Their harrowing experiences of loss of jobs and shelter and acute starvation beg the question, ‘When means are strained, who becomes dispensable?’26 Further, the urban poor have often been subject to a spectrum of violence by the state. ‘Modalities of uncaring’ such as indifference to and normalisation of poverty as well as arbitrary implementation of welfare schemes produce structural violence at the very scene of care.27 They are subjected to not only subtle, unintended forms of violence but even outright illegalisation of their existence and livelihoods.28 Farmers, tribals, and villagers too from time to time have been treated by the state as though they were dispensable. Forceful displacements due to industrial, developmental projects, overlooking the health hazards caused due to the establishment of nuclear power plants and unleashing physical brutalities upon protestors, are not unheard of.29
The older political prisoners whose experiences within the legal system I have analysed in this article, are/were advocates of human rights, particularly of the marginalised communities in India. They were arrested for opposing the state’s neoliberal agendas. This antipathy towards ‘dissenters’, however, is not a new phenomenon. Jawaharlal Nehru in post-colonial India also identified the Communist Party of India and labour organisations as ‘enemies’ of the nation.30 Once there is an enemy, a hegemonic discourse (or a ‘homogenous script’31) emerges in the name of security that claims to ‘save the nation’ from terror and threat to social order by ‘anti-national’ elements. Regrettably, ‘the first casualty of terror is human rights and diversity of opinion.’32 The older political prisoners, whose experiences I recount later, were arrested under the stringent anti-terror law, viz., the Unlawful Activities (Prevention) Amendment Act 2019 (UAPA) (the original act was enacted in 1967). Serious allegations were made against them that disqualified them from getting medical bail even during the pandemic when other prisoners were being (conditionally) released. The disposability in the context of older prisoners can be plotted in the bail denials and the subsequent sidelining of needs of care especially during the public health crisis of the COVID-19 pandemic. Such acts of non-care reveal the oppressive side of the legal system that jeopardises the safety and dignity of older prisoners and exacerbates their disposability. It is inhumane to keep prisoners incarcerated despite deteriorating health conditions, notwithstanding the Supreme Court’s order in 2020 to release prisoners during the pandemic.33 Even as judicial orders are being called out by several scholars and activists for endorsing or aligning with state policies,34 the consistent denial of bail highlights the perverseness of the legal system towards older people charged with crimes against the state.
Law, temporality, and resistance
Time is a crucial reference point for older people as well as those under trial in India. Ageing brings with it worries associated with ill-health and mortality. Trials in India are a time-consuming process, more so in the case of those convicted of serious crimes such as anti-state activities, terrorism, and murder. Thus, time is a significant aspect of the lives of older prisoners who have been charged with ‘serious offences’. In this section, I illustrate how law produces time and the implications of the same for prisoners and their loved ones. Renissa Mawani argues that time as a conceptual category has been mostly peripheral to law’s imagination. It is viewed as ‘external’ and ‘insignificant’ to the law.35 In this article, I assert the centrality of time to the debate on the rights of older prisoners and argue that ‘law is fundamentally about time.’36
Law crafts temporalities, as is seen, for example, in the case of Kashmiri Muslim older women,37 mostly mothers whose sons have been subjected to ‘enforced disappearances’ under laws like the Armed Forces (Special Powers) Act 1958. Ather Zia elucidates how the legal regime perpetuates a ‘state of waiting’ and a period of mourning for the disappeared among their families.38 The state produces and determines time by performing the law in the form of legal excesses. However, the womenfolk have used (continue to use) strategic ways of resisting the law’s temporalising forces that subject them to an endless wait for their beloved kin. An affective politics is at play wherein the women resist the forced invisibilisation of Muslim men from Kashmir (and the state’s denial of any role in it) by their hypervisible activist presence. Thus, the question ‘How does lived and experiential time escape, exceed, and reconfigure law’s temporalising force?’ becomes important in this context.39
Zia poignantly explains the significance of leaving the door of their house ajar for the older women from families with disappeared men. The door becomes a symbol of creating a counter-memory, a struggle for visibility and a vehement articulation of continual mourning of the loss; thereby also a site of resistance and hope (for the return). Simultaneously it becomes a way to seek what Zia calls a ‘private mode of justice’ when formal institutions of justice remain far-fetched.40 The open door is a manifestation of an affective law (‘subaltern power’) that these women have created to combat the sovereign law, which aims at the annihilation of Muslim Kashmiri men.41 In the context of incarceration, however, such strategic resistances are more subtle if not impossible. For example, one of the detainees in the Bhima Koregaon case, Sudha Bharadwaj, in a recent interview, spoke about how she attempted to help other prisoners with legal advice. She remarked that upon being rebuked for doing so she managed to ‘get her way around’ and got help from her lawyer for the fellow prisoners.42 This is how she subverted the prison gaze.43 Those she helped remarked, ‘Aunty, aap toh humaare ghar ke lawyer ho’ (Aunty, you are our in-house lawyer).44 The community feeling, the camaraderie and solidarity, that gets established is a source of strength for the incarcerated and becomes a shield against the prison’s unfair, arbitrary rules and especially recrafts time to make it more (socially) useful.
Resistance against law’s temporalities cannot, however, trivialise the pain and suffering of older prisoners.45 Laws like the UAPA produce carceral time that has unique consequences for an older prisoner. The carceral time crystallises into an insidious form of waiting that could create ‘death-worlds’ and finally dispose of life (as was seen in the case of one of the activists, Stan Swamy). The law’s necropolitics is thus exposed. Necropolitics, a term that I borrow from Mbembe, refers to the ways of ‘subjugating life to the power of death’ that produce ‘death-worlds’ or ‘forms of social existence’ in which people are ‘subjected to living conditions that confer upon them the status of the living dead’.46 In the next sections, I discuss the techniques by which carceral time is produced and which also reveal the necropolitical face of law.
Custodial neglect and illness narratives from prisons
‘Law traffics in violence every day’47 through the denial of basic rights, which directly affects the health of the older prisoners. The legal machinery is violent towards these prisoners as it has continually failed to reckon with the impact of the pandemic in prisons. The violence towards older prisoners pulsates through the law’s disregard for the needs of care and in its silence ‘that lies at the limits of legal texts and language’.48
Experiences of disability and negligence in prisons
Father Stan Swamy vociferously opposed the exploitation of marginalised communities in India, particularly the tribal population in Jharkhand, by political and corporate elites and was viewed suspiciously by the state. He was accused of terrorist activities against the state. In October 2020, he was arrested from Ranchi, Jharkhand, where he lived and worked. Initially, Swamy had refused to be taken away to a Mumbai prison from Ranchi on account of his age, health, and the pandemic, and agreed to attend court proceedings via videoconferencing. He was aware that his ordeal was not unique and that he was one among many to be implicated for challenging state policies and was also ‘ready to pay the price’.49 However, the prison conditions and the lack of appropriate and timely care cost him his life.
Eighty-four years old, Swamy suffered from Parkinson’s disease, most common among older people. Due to muscular tremors, he was dependent on a straw and sipper. He had urged the court to give him the straw and sipper from his bag, which he claimed had been seized by the National Investigation Agency (NIA) during the raid in his house. The court asked the NIA, the ‘chosen agent of the state’,50 for a response. The agency took 20 days to respond and clarified that it had never seized Swamy’s bag. The unnecessary delay in providing Swamy with a straw and a sipper marks the most poignant scene of non-care and neglect of an older individual in prison. The lack of promptness in addressing his need prolonged his suffering. Such forms of custodial neglect of the needs of an older, ailing prisoner can be interpreted as violent, especially because the object in question (a sipper) is a basic amenity that could have been immediately provided. As rightly pointed out by political analyst Akash Banerjee, providing a sipper ‘is not a question about jurisprudence’.51
While he was in judicial custody, Swamy’s health deteriorated significantly. A few months before his death in July 2021, Swamy told the Bombay High Court judge during video conferencing that at the time he was arrested,I would eat by myself, do some writing, walk, I could take bath by myself, but all these are disappearing one after another. So Taloja Jail has brought me to a situation where I can neither write nor go for a walk by myself. Someone has to feed me. In other words, I am requesting you to consider why and how this deterioration of myself happened.… My deterioration is more powerful than the small tablets that they give.52
However, bail was not granted to him on medical grounds. The court had ‘asked’ Swamy if he would like to be admitted to a certain government hospital in Mumbai on account of his ill-health, but he had refused. He was sceptical that admission to the government hospital would improve his condition and believed that staying in prison was better than being admitted to that hospital, where he had already stayed briefly earlier. This is also telling of the abysmal healthcare facilities for prisoners in India.
Swamy’s pleas highlighted his decreasing capacity to undertake what gerontologists call the Basic Activities of Daily Living (BADL), which include activities of self-care such as bathing, eating, and toileting, which in his case had become difficult. Under such health conditions, Swamy was entitled to individualised healthcare in a conducive environment. During a court hearing in May 2021, he expressed his desire to be amidst his people, and this could be read as his dying wish since soon afterwards he passed away.53 In his case, age and disability produced difficult experiences of neglect and isolation from his community when he was dying. The court, the prosecution, and the police were mute spectators to the violation of rights. This situation could have been prevented if his needs for health and social care had been addressed promptly. The law colonised his (ageing) body and denied him his bodily autonomy. Swamy passed away in a private hospital battling for life on a ventilator. The immediate cause of his death may have been the COVID-19 virus;54 however, the lack of care in the prison was responsible for the deterioration of his health even before he contracted COVID-19.
There ought to have been an acknowledgement of his complex medical needs, and accordingly a ‘multimorbidity model of care’ should have been adopted upon his admission into judicial custody.55 This model, used by geriatric medicine, has been recommended by the World Health Organization for prisoners in European countries.56 This model acknowledges the co-existence of multiple ailments among older persons and aims to provide patient-centred care wherein decisions about healthcare arrangements are based on a consultative process. However, the condition of healthcare facilities, and particularly geriatric medical care in India’s overcrowded prisons, is despairing. On the contrary, in India, the course of medical treatment for older prisoners like Swamy remains a matter of determination by the court and not an entitlement as it should be irrespective of his legal status. The UN General Assembly (of which India has been a member since 1945) in 1990–1991 added a resolution entitled ‘Basic Principles for the Treatment of Prisoners’, which states, ‘Prisoners shall have access to the health services available in the country without discrimination on the grounds of their legal situation.’57 In respect of this international standard, our legal system failed Swamy who had even declared to the court that he anticipated his death if the request for bail was not granted. Thus, the law had already produced a ‘future carceral time’ in the present in which the body was in the state of becoming disposable. The corporeality of the body is thus predicated upon law’s temporality. Swamy’s pleas were disregarded due to strict adherence to the law, sidelining other constitutional principles that exist to safeguard the human life of prisoners. The tardiness with which Swamy’s bail pleas were responded to signals a deep institutional crisis and unmasks the necropolitical face of the law.
Of dementia and (loss of) dignity
In what discourse
Can we converse
With the heartless?58
These words of Varavara Rao, an 82-year-old Telegu poet and activist, ring true in his own case. He was also arrested in 2018 in the Bhima Koregaon case. While in prison, his health condition deteriorated substantially. In May 2020, he was admitted to the hospital and discharged without proper communication with his family members, including his wife, P Hemlatha. In July 2020, he contracted COVID-19 and was sent to another hospital. The Nanavati Hospital authorities in Mumbai, where he was receiving his treatment, handed over their report in a sealed envelope, usually a practice followed in matters of grave security threats to the nation. The report was also incomplete as it did not contain medical test results and other details. Soon after, he was sent back to prison.59 The alarming conditions in which he continued to live and his deteriorating health were sufficient for granting him medical bail. Senior Advocate Indira Jaising, Rao’s counsel, argued, ‘His soul is not being kept intact with his body,’ and ‘Death is inevitable but everyone looks for a dignified exit from this world.’60 These statements highlighted the vulnerability that Rao continued to face in prison amidst the pandemic.
In November 2020, petitions were heard virtually by the Bombay HC to release Rao. In the virtual hearing, Jaising highlighted the lack of specialised medical attention for him, especially the need for a neurologist and a urologist that had been disregarded by the state prison authorities. Based on this, the court ordered a video examination by doctors.61 Pointing out the ridiculousness of the situation, Jaising remarked, ‘He is bed-ridden. He is in diapers. He can’t control urination. He is with a urine bag. His catheter has not been removed. Is this man going to flee away from justice?’62 At one point during the proceeding, the discussion revolved around whether Rao had dementia or not, as had been documented in a previous governmental hospital report. As an advocate of the rights of senior citizens, one can ask if dementia is a relevant ground to grant medical bail to an older prisoner.63 A later report by a different hospital provided inconclusive evidence about Rao’s dementia and suggested further tests for him. Providing proof that Rao’s neurological state of mind was in a critical condition after his arrest, Jaising informed the court: ‘He once wrote a letter to his wife, saying his wife passed away 15 years ago. Now he is interacting with her. This is the condition of people with dementia…. What is dementia? It’s not having awareness of time-space and people.’64 How frail should the prisoner be to be provided with a medically safe environment and care? As per the judgment, the respondents (NIA and the State of Maharashtra) believed that Rao should be sent back to the prison since his medical reports did not mention dementia (though it had not been ruled out either), and also that he was being provided with the treatment required (which was a half-baked truth).
Jaising made an age-sensitive observation. She argued, ‘No person above the age of 80 should ever be kept in prison. What life imprisonment means for a person at 80 is vastly different from what it means for a 25-year-old.’65 But the judge argued, ‘We don’t know if what you are arguing has ever been argued in any country before.’66 This legal uncertainty about the way to treat alleged older criminals must not persist at the cost of the fundamental rights of prisoners such as the right to life and healthcare. In late life, especially when health fails, it is a right to be looked after and cared for and be amidst loved ones. To disallow the company of loved ones/kin during illness is dehumanising as it tears apart the ‘social’ from human lives, as will be elaborated later.
After a prolonged process of adjudication, finally, the Bombay High Court in February 2021 granted Rao medical bail for six months. Keeping in mind the history of his health condition, including his contraction of COVID-19 while in prison, the bench argued that sending him back to prison would mean ‘endangering his life’.67 His medical bail was extended till 20 December 2021, and he was advised to stay in Mumbai and prohibited from travelling to his hometown, Hyderabad.
Once booked under UAPA and sedition laws in India, the state’s suspicion and surveillance over the accused is extreme. Getting medical bail is close to impossible; however, it is important to acknowledge the crucial role that courts can play in granting bail.68 Section 437 of the Code of Criminal Procedure 1973 (CrPC) mentions that ordinarily, an accused cannot be given bail if prima facie the allegation is true and if the person has been given life imprisonment or the death penalty. However, the court can, under specific circumstances, like for medical reasons, grant medical bail.69 It is here that the right to life under Article 21 may become the overriding principle. Rao has not been convicted yet, and this should have made it easier for courts to grant him bail. Rao’s ordeal highlights the need to reimagine the criminal justice system based on gerontological knowledge about care needs in late life.
Prison roles, social roles, and the time lag between
The violence of law threatens to expose the façade of law’s dispassionate reason, of its necessity and restraint, as just that –– a façade –– and to destabilise law by forcing choices between the normative aspirations of law and the need to maintain social order through force. Violence threatens to swallow up law and leave nothing but a social world of forces arrayed in aggressive opposition. Where violence is present, can there be anything other than violence?70
Austin Sarat makes this pertinent observation about capital punishment (as a form of law’s violence). In the case of dissenting citizens such as Swamy and Rao, national security was given a higher value at the cost of their rights as prisoners notwithstanding that the trial had not even begun. The custodial neglect they experienced is violent when age-based needs are disregarded. This, despite the trial not even having begun. The law is also violent in a different way. It severs the social from an individual’s life, and while modern prisons have always functioned on the principle of denial of liberty and isolation from family, during the pandemic, this severance of the social assumed a critical form.
Sudha Bharadwaj, a sexagenarian lawyer and an activist, was also arrested in 2018 by Pune police over the Bhima Koregaon issue. The courts refused to grant her bail four times.71 She has diabetes, hypertension, and suffers from pulmonary tuberculosis, and while residing in jail, she also developed a heart disease. She had also developed symptoms of COVID-19, such as loss of taste. At one point, she was living with a COVID-positive prisoner. Her daughter had pleaded with the high court to grant her interim bail on medical grounds.72 In an interview, her daughter (in her mid-20s) recounted the horror and trauma of having to deal with her mother’s incarceration amidst a pandemic on her own.The day I got to know about Father Stan’s death, I cried my heart out. I am very scared for my mother. When our lawyers tell us about how her health is deteriorating, it kills me on the inside. Father Stan could have been saved. But the state left him to die. I am scared they might do the same to my mother, she says.73
For a girl in her mid-20s, having to deal with this situation during the pandemic was horrifying. Such circumstances can significantly impact the mental health of both the prisoner and their dependents and/or significant others.
Gautam Navlakha, another accused in the same case, was shifted to the anda cell in October 2021. This move was perhaps, as Jinee Lokaneeta reminds us, ‘just another reminder that imprisonment itself appears inadequate for the state. Instead, there is a constant need to continually break the body and soul of a person by making the conditions more challenging.’74 Lokaneeta alerts us to the rampant and discretionary use of anda cells by prison authorities and highlights the ambiguity of its functioning as per state law. Navlakha’s partner Sahba Husain, herself an activist, in an interview revealed that the raid by the police was the most dreadful for her and that she was ‘shaken’ when he was taken away to Mumbai.75 ‘How do you deal with lockdown and his arrest at the same time?’ she pondered. It left her with ‘deep sorrow’ and affected her profoundly. Subsequently, the inability to get information about his health from time to time worried her. Meanwhile, he had also become a grandfather but could not visit his daughter abroad as he had had to surrender his passport.
The life course perspective in gerontology highlights the importance of historical, structural forces and social conditions that impact an individual’s role changes and role enactment, which has significant consequences for ageing in late life.76 According to the life course perspective, time and temporality are crucial determining factors to understand individual experiences of ageing and care related needs.77 In the context of Navlakha, his incarceration and the juridical gaze crafted his ageing experiences by excluding him from the familial role that he was expected to take on by thrusting him into a ‘new regime of prison roles’.78 Such an exclusion produces a time lag between his prison role and expected social role by stretching time of trial to an uncertain period.
In prison, Navlakha’s spectacles were stolen, and he was not allowed to contact his family members for a few days. Husain remarked that it was an ‘unbelievable’ and ‘inhuman’ act, especially because Navlakha was heavily dependent on his glasses. Husain had couriered another pair of glasses to him, but she said they were ‘received, refused and returned’ by the prison officials, suggesting a deliberate act of denial of a basic right by prison authorities. Thus, ‘The symbolic function of the prison reaffirms the lack of autonomy and choice of how the disciplinary and medical gaze constructs the aging body transforming the older inmate (the subject) into an object/commodity of need which others deal with.’79 The prison authorities, however, mentioned that the courier was not accepted due to security concerns.80 This argument appears rather insubstantial.
The state, in collusion with ‘petty sovereigns’ within state institutions like the prison administration, carries on its discretionary acts to suppress the basic rights of prisoners. Judith Butler defines the role of ‘petty sovereigns’ in the following manner:Petty sovereigns abound, reigning in the midst of bureaucratic army institutions mobilized by aims and tactics of power they do not inaugurate or fully control. And yet such figures are delegated with the power to render unilateral decisions, accountable to no law and without any legitimate authority. The resurrected sovereignty is thus not the sovereignty of unified power under the conditions of legitimacy, the form of power that guarantees the representative status of political institutions. It is, rather, a lawless and prerogatory power, a ‘rogue’ power par excellence.81
The overuse of power by the prison authorities goes against the rights of these prisoners and survival is contingent upon negotiating skills within prisons.82 Ethnographic studies have also highlighted that prisons continue to be spaces of negotiations between prisoners and the authorities.83 The type of life inside, specifically the ‘privileges’ prisoners can enjoy, albeit temporarily, depends on negotiations the prisoners can make with the wardens such as obtaining material goods or favours by bribing and then returning the favours.
Care crisis in the prisons and implications
The prison is a kind of a ‘quarantine zone’ where allegedly dangerous individuals are segregated in the name of public safety.84 There have been attempts to ensure that ‘[i]nstitutional power reaches into the very grain of older individuals, touches their bodies and inserts itself into their actions and attitudes, their discourses, learning processes and everyday lives.’85 The above cases of activists being booked for anti-state stances and the treatment being meted out to them are a ‘spectacular form of cruelty’.86 The pathetic living conditions, especially healthcare provisions for prisoners, have been exposed yet again during the pandemic. Also, when we speak of the rights of older persons, why must they be limited only to the discourse around the right to be cared for properly by one’s children? Denial of bail during the pandemic and under conditions of failing health prevented these older prisoners from meeting their loved ones, and is therefore dehumanising and cruel.87
The courts could have played a more proactive role in reinterpreting the constitutional rights granted to a prisoner. By not doing so, the Indian legal establishment is guilty of abandoning the rights guaranteed under the International Covenant on Civil and Political Rights 1976 which India ratified in 1979. The treatment meted out by courts and prisons flouted the following principles: Article 7 of the Covenant states, ‘No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment.’ Article 9(3) highlights the need for speedy trials by declaring, ‘Anyone arrested or detained on a criminal charge shall be brought promptly before a judge or other officer authorized by law to exercise judicial power and shall be entitled to trial within a reasonable time or to release. It shall not be the general rule that persons awaiting trial shall be detained in custody, but release may be subject to guarantees to appear for trial.’ As specified by Article 10(1), ‘All persons deprived of their liberty shall be treated with humanity and with respect for the inherent dignity of the human person.’ According to Article 10(3), ‘The penitentiary system shall comprise treatment of prisoners the essential aim of which shall be their reformation and social rehabilitation.’ Article 14(2) stipulates, ‘Everyone charged with a criminal offence shall have the right to be presumed innocent until proved guilty according to law,’ and according to Article 14(3)(c), anyone charged of a criminal offence has the right ‘to be tried without undue delay’. The trial in the case of these older prisoners is yet to start. It is worth examining how the disregard towards the above principles affects the survival of older prisoners.
Robert Cover once argued that ‘Legal interpretation takes place in the field of pain and death.… Interpretations in law also constitute justifications for violence which has already occurred or which is about to occur.’88 According to Cover, violence that is unleashed by the legal machinery, the judges being at its helm, is legitimised in modern states. Sarat and Kearns further argue that ‘constitutional violence … crushes and kills with a steadfastness equal to a violence undisciplined by legitimacy.’89 Though this is particularly argued in the case of capital sentences,90 I argue that this is true in the case of bail denial to older prisoners and their treatment in prisons during the pandemic. Judge Patricia Wald makes a very pertinent observation, that judges should take personal responsibility for their judgments, and that ‘[j]udges and others should be held accountable for the painful impositions they authorise or condone, and that such personal accountability would ensure that law’s violence would be dealt with more reasonably and responsibly.’91
The way the courts, both the appellate courts and NIA courts, the police, and prison authorities have responded to the persons named above generates a spectre of disposability of older alleged criminals. This violence of the law is both temporal and performative. It is not just the extraordinary delay in starting the trial92 that is violent, but law’s violence is performed on the bodies and minds of these incarcerated individuals in the way they are denied access to basic amenities, including medical facilities. The experience of violence, I argue, is magnified due to age and the pandemic. With the passing away of Stan Swamy in judicial custody, lessons need to be learnt, because such a ‘violence of indignity in death’ reinforces a culture of impunity and legitimises the violence against individuals.93
Conclusion
The carceral time produced by the legal apparatus jeopardises the lives of older prisoners. This has been demonstrated through the experiences of the accused in the Bhima Koregaon case. In the case of political prisoners, there is a different dynamic at work compared to other criminal offenders. The law and the accusations against political prisoners are generally aimed at prolonging the period of imprisonment.94 The nature of the UAPA law is such that the allegation (of anti-state activities) itself sets the pitch of the trial. The First Information Report (FIR) against the accused persons is like an ‘omnibus FIR’ which contains only general allegations without any specific details of the act of crime committed, those who are involved, and in what ways. The omnibus FIR is a legal tool through which the sovereign state produces time in a certain way. It arrests, manoeuvres, and prolongs time, and produces an insidious waiting for trial and justice. The wait is a way of silencing and exacerbates the disposability of older prisoners. The wait in prison, however, has a different meaning for an older prisoner who may have different care needs, as compared to a younger prisoner.
Even though the law may not be particularly harsh on older political prisoners because of their age, the ‘neglect and indifference are active modes of “letting die” some populations to “make live” others.’95 Older activists are perceived as a threat by the state and the legal apparatus is mobilised to repress them in total disregard of their human rights. The age of an older prisoner must be considered as a ground for bail even when the charges are grave. Prisoners with health conditions such as dementia and other disabilities in late life must be treated with more compassion and provided appropriate care. While the CrPC takes into cognisance sickness or infirmity as possible conditions for allowing bail, it does not regard age as a ground on which compassionate release can be made. A right to die at home, house arrest, assisted living facilities, and access to palliative and geriatric medical care are some of the provisions that must be available to older prisoners. These are concomitant with the fundamental right to life and death in dignity as enshrined in the Indian Constitution.
Acknowledgment
I am deeply grateful to the Institute for Global Law & Policy (IGLP) based at the Harvard Law School for the giving me the opportunity to present some of my ideas on ageing and incarceration. The inputs that I received from Professor Lucie E. White (Harvard Law School), Dr. Zinaida Miller (Seton Hall University) were particularly helpful. I also thank Dr. Nadia Lambek, Dr. Zeina Jallad Charpentier, Dr. Sarbani Sharma, Dr. Sapna Raheem, Dr. Chung Nguyen and Sabeen for their critical and detailed feedback on the paper. Professor Arun Sagar's suggestions were also very useful as they helped me refine some of my key arguments.
Declarations
Conflict of interest
The author has no conflicts of interest to declare that are relevant to the contents of this article.
1 In India, a senior citizen is officially recognised as an individual above 60 years of age.
2 Eva Steiner, ‘Early Release for Seriously Ill and Elderly Prisoners: Should French Practice Be Followed?’ (2003) 50(3) Journal of Community and Criminal Justice 270.
3 Tata Trusts, India Justice Report: Ranking States on Police, Judiciary, Prisons and Legal Aid (2019). https://www.tatatrusts.org/upload/pdf/overall-report-single.pdf. Accessed 18 September 2022.
4 The Maintenance and Welfare of Parents and Senior Citizens Act 2007, Act No. 56 of 2007; ‘SC Asks Centre to File Report on Old Age Homes, Relook at Schemes for Elderly’ (Indian Express, 14 December 2018). https://indianexpress.com/article/india/sc-asks-centre-to-file-report-on-old-age-homes-relook-at-schemes-for-elderly-5492829/. Accessed 15 September 2022.
5 United Nations Office on Drugs and Crime, ‘The United Nations Standard Minimum Rules for the Treatment of Prisoners (The Nelson Mandela Rules)’. https://www.unodc.org/documents/justice-and-prison-reform/Nelson_Mandela_Rules-E-ebook.pdf. Accessed 18 September 2022.
6 Christophe Jaffrelot, ‘Arrests in Bhima Koregaon Case Frame a Transformation in India’s Polity and Police Force’ (Indian Express, 29 October 2020). https://indianexpress.com/article/opinion/columns/bhima-koregaon-case-stan-swamy-nia-chargesheet-naxals-6907744/. Accessed 02 April 2022. Also see Somnath Waghmare, The Battle of Bhima Koregaon: An Unending Journey [documentary film]. https://www.youtube.com/watch?v=il8Yz-ywuZA. Accessed 19 September 2022.
7 Harsh Jain, ‘Bail under the UAPA’ (Law and Other Things, 05 November 2021). https://lawandotherthings.com/2021/11/bail-under-the-uapa/. Accessed 12 May 2022.
8 It is not my intention to tar courts and prisons with the same brush with regard to the afflictions caused by their actions to older prisoners. Judges in the past have upheld the rights of prisoners. For example, in Sunil Batra v Delhi Administration and Ors (1978) 4 SCC 494 [52], the judges argued that the right to equality (Article 14), the right to freedom (Article 19), and the right to life and liberty (Article 21) can be limited for a prisoner but cannot be ‘puffed out altogether’.
Another example from recent times which shows the thoughtful approach of courts was in April 2022, during the hearing of Gautam Navlakha’s plea for being moved from jail to house arrest. It became known that Navlakha had not been provided a book written by PG Wodehouse that he wished to read. Taking a jibe at the state’s prosecutor, the Bombay High Court judges reflected: ‘Is humor banished from jail?… Also, this is quite less. Even a secondary school would have more books. If there aren’t enough of books, something can be done by the bar or by the court. Because access to books is very important. It is an important step towards reformation of prison inmates.’ See Sharmeen Hakim, ‘Is Humour Banished from Jail? Even Secondary School Will Have More Books: Bombay High Court on Scanty Book Collection in Prison Library’ (LiveLaw.in, 05 April 2022). https://www.livelaw.in/news-updates/bombay-high-court-even-secondary-school-more-books-taloja-prison-librar-gautam-navlakha-195886?infinitescroll=1. Accessed 10 May 2022.
This was not the first instance where courts have upheld the reading and writing rights of prisoners. Kaur discusses salient judgments where the courts have highlighted the importance of critical pieces written by prisoners as key to ushering in prison reforms. See Baljeet Kaur, ‘Prisoners’ Right to Write: Why SC Rulings Should Be Taken Seriously by Prison Authorities’ (2019) 54(30) Economic and Political Weekly Engage.
9 The move to decongest prisons is not specific to the pandemic. Owing to the huge numbers of undertrial prisoners, efforts have been made by the state to decongest prisons, for example, by setting up fast-track courts and digitisation of court records. See Vijay Raghavan, ‘Undertrial Prisoners in India: Long Wait for Justice’ (2016) LI (4) Economic and Political Weekly 17. Yet the total number of undertrial prisoners has only risen over the years. The Prison Statistics India report informs us that the number increased from 67.6 per cent in 2013 to 76.12 per cent in December 2020. See more at NCRB, Prison Statistics India 2020. https://ncrb.gov.in/sites/default/files/PSI_2020_as_on_27-12-2021_0.pdf. Accessed 05 May 2022.
10 The ambience inside prisons is conducive to producing mental health issues among the inmates. The National Human Rights Commission (NHRC) in its 2014 report lists the following as reasons that induce suicidal tendencies among inmates: ‘fear of the unknown, distrust of the authoritarian environment, lack of apparent control over the future, isolation from family and significant others, shame of incarceration and the dehumanizing aspects of incarceration’. NHRC, Suicide in Prison: Prevention Strategy and Implication from Human Rights and Legal Points of View (10 December 2014). https://nhrc.nic.in/sites/default/files/SUICIDE%20IN%20PRISON%202014.pdf. Accessed 01 November 2021.
On a slightly different but related note, Vikram Patel (Professor of Global Heath, Harvard Medical School) stresses the need for humanising the criminal legal system from a mental health perspective. Quoting the results from the Deathworthy report published in 2021 by Project 39A anchored at National Law University, Delhi, Patel highlights the futility of a legal system which addresses only the crime/harm done but overlooks causal factors such as a history of deprivation of several kinds and also the oppressive conditions of life inside prison and depressive states of mind of criminals while awaiting death. Vikram Patel, ‘Why the Link between Mental Health and Death Penalty Deserves Greater Attention’ (Indian Express, 27 November 2021). https://indianexpress.com/article/opinion/columns/link-mental-health-death-penalty-deserves-more-attention-7641723/. Accessed 15 September 2022. See also National Law University, Delhi, Deathworthy: A Mental Health Perspective of the Death Penalty, Project 39A (2021). https://static1.squarespace.com/static/5a843a9a9f07f5ccd61685f3/t/616fd7988256c93ab9735618/1634719720928/Deathworthy_MainReport_19Oct_2021.pdf. Accessed 02 December 2021.
11 ‘350 Inmates in Six Rooms: Activist Gautam Navlakha Kept in Deplorable Conditions, Says Partner’ (Scroll.in, 22 June 2020). https://scroll.in/latest/965327/350-inmates-in-six-rooms-no-fresh-air-activist-gautam-navlakha-details-temporary-jail-condition. Accessed 15 September 2021.
12 Pratiksha Baxi and Navsharan Singh, ‘Gendering the Pandemic in the Prison’ (India Forum, 09 July 2020). https://www.theindiaforum.in/article/gendering-pandemic-prison. Accessed 05 December 2021; Yashraj Sharma, ‘India’s Political Prisoners in Bad Health, Lose Family amid COVID’ (Al Jazeera, 14 May 2021). https://www.aljazeera.com/news/2021/5/14/indias-political-prisoners-encounter-deaths-as-covid-rages. Accessed 15 September 2022.
13 Hartman de Souza, ‘Riffs of an Ageing Urban Naxal’ (Raiot, 16 September 2018). https://raiot.in/urban-naxals-surely-know-how-to-love/. Accessed 09 December 2021. Hartman de Souza calls the arrested activists ‘ageing Urban Naxals’ and mocks the rampant usage of the term by an anxious state.
14 In Re: Contagion of COVID 19 Virus in Prisons, Suo Motu Writ Petition (C) No. 1/2020 dt 08 May 2021.
15 Ibid.
16 According to Mihir Desai, a senior advocate, anti-terror laws such as UAPA are those that ‘allow the state to carve out exception for its own lawlessness’. It is a paradox wherein the state’s adherence to the rule of law is embedded in the violation of the rule of law through such legislations. In other words, these anti-terror laws restrain constitutional freedoms, equality, and the right to life. Through these laws, the state reserves exceptional power over its citizens. ‘Advocate Mihir Desai –– The Problem of Preventive Detention in India’ (KG Kannabiran Lectures, 23 November 2020). https://www.youtube.com/watch?v=30wFBnZWEQY. Accessed 12 May 2022.
17 Umer Maqbool, ‘Kashmir: Elderly, Ailing People Detained under Public Safety Act Don’t Get Proper Medical Care’ (Wire, 11 May 2021). https://thewire.in/health/public-safety-act-kashmir-detention-healthcare. Accessed 06 December 2021.
18 V Venkatesan, ‘COVID-19 in Prisons: SC Intervention Must Ensure the Centre Exercises Its Responsibility’ (Wire, 09 May 2021). https://thewire.in/law/covid-19-in-prisons-sc-intervention-must-ensure-the-centre-exercises-its-responsibility. Accessed 13 November 2021.
19 Ibid.
20 Default bail is a safeguard guaranteed to an arrested person under Section 167 of the Code of Criminal Procedure 1973, according to which the person can be granted bail after a maximum of 180 days from the time of appearance before a magistrate. The bail can be granted irrespective of whether the chargesheet had been filed by the police by then or not. However, the person must file an application within a specific time to be eligible for default bail. While Bharadwaj was able to file the application in time, the others were not. Also see Advait Tamhankar, ‘Default Bail: An Explainer’ (Leaflet, 23 February 2022). https://theleaflet.in/default-bail-an-explainer/. Accessed 15 September 2022.
21 Zygmunt Bauman, Wasted Lives: Modernity and Its Outcasts (Polity Press 2004) 117–118. Bauman is talking about certain categories of human beings, e.g., refugees, as ‘outcasts’ or ‘wasted lives’ produced by modernity.
22 Lois Wacquant, ‘Suitable Enemies: Foreigners and Immigrants in the Prisons of Europe’ (1999) 1(2) Punishment & Society 215.
23 Georgio Agamben, Homo Sacer: Sovereign Power and Bare Life (Stanford University Press 1998) 154.
24 Anthony Downey, ‘Zones of Indistinction: Giorgio Agamben’s “Bare Life” and the Politics of Aesthetics’ (2009) 23(2) Third Text 109.
25 Bishnupriya Ghosh, ‘The Refugee Within: Becoming Disposable in Modern India’ (2020) 29–30 The Large Glass: Journal of Contemporary Art, Culture and Theory 104.
26 Ibid. 105.
27 Akhil Gupta, ‘On Structural Violence’ in Kalpana Kannabiran (ed), Violence Studies: Oxford India Studies in Contemporary Societies (Oxford University Press 2016) 350.
28 D Asher Ghertner, ‘The Nuisance of Slums: Environmental Law and the Production of Slum Illegality in India’ in Jonathan Shapiro Anjaria and Colin McFarlane (eds), Urban Navigations: Politics, Space and the City in South Asia (Routledge 2011) 23; Usha Ramanathan, ‘Illegality and the Urban Poor’ (2006) 41(29) Economic and Political Weekly 3193; Jean Drèze, Sense and Solidarity: Jholawala Economics for Everyone (Permanent Black 2017).
29 Raminder Kaur, ‘Nuclear Necropower: The Engineering of Death Conditions around a Nuclear Power Plant in South India’ (2021) 85 Political Geography.
30 Ujjwal Kumar Singh, Political Prisoners in India (Oxford University Press 1998) 209.
31 Shiv Visvanathan, ‘In the Name of Terror’ in Chandan Gowda (ed), Theatres of Democracy (HarperCollins 2016) 14.
32 Ibid.
33 In Re: Contagion of COVID 19 Virus in Prisons (n 14).
34 ‘Modi’s Made India Communal & Authoritarian; Courts Caving-In; India May Fracture: Pratap Bhanu Mehta’ (Wire, 17 December 2021). https://www.youtube.com/watch?v=PcWYmM_7rw8. Accessed 08 May 2022.
35 Renissa Mawani, ‘Law as Temporality: Colonial Politics and Indian Settlers’ (2014) 4(65) UC Irvine Law Review 71.
36 Ibid.
37 Due to heavy militarisation, Kashmir has been compared to an everyday prison. See Haley Duschinski, ‘Destiny Effects: Militarization, State Power, and Punitive Containment in Kashmir Valley’ (2009) 82(3) Anthropological Quarterly 691.
38 Ather Zia, Resisting Disappearance: Military Occupation and Women’s Activism in Kashmir (University of Washington Press 2019) 31.
39 Mawani, ‘Law as Temporality’ (n 35) 73.
40 Zia, Resisting Disappearance (n 38) 36.
41 Ibid. 35.
42 ‘AILAJ Webinar: Conditions of Prisoners in Indian Prisons by Adv Sudha Bharadwaj’ (AILAJ HQ, 26 March 2022). https://www.youtube.com/watch?v=a5CSeFJgKyU. Accessed 11 May 2022.
43 Ethnographic studies have revealed how prisoners have managed to engage in reversing the disciplinary gaze. For example, in a study among female prisoners in North Ireland, Azrini Wahidin records how one respondent speaks about her ‘bravado’ in stripping fully when asked to strip parts of the body in turn. Fully stripping during strip searches by prison authorities was a technique to ‘control’ the disciplinary gaze by embarrassing the authorities who had come to strip the prisoners’ dignity. See Azrini Wahidin, ‘Reconfiguring Older Bodies in the Prison Time Machine’ (2002) 7(3) Journal of Aging and Identity 177.
44 Sadaf Modak, ‘Sudha Bharadwaj: “When Inside, You See How Cut Off a Prisoner Is from Legal Remedies”’ (Indian Express, 21 January 2022). https://indianexpress.com/article/cities/mumbai/sudha-bharadwaj-when-inside-you-see-how-cut-off-a-prisoner-is-from-legal-remedies-7734345/. Accessed 30 May 2022.
45 ‘Jailed to Die? India’s Incarcerated Human Rights Defenders and the Covid Emergency’ (InSAF India, 21 June 2021). https://www.youtube.com/watch?v=wBDl0ay253g&t=2319s. Accessed 01 April 2022.
46 Achille Mbembe, Necropolitics (Steven Corcoran tr, Duke University Press 2019) 92.
47 Austin Sarat, ‘Speaking of Death: Narrative Violence in Capital Trials’ in Austin Sarat and Thomas R Kearns (eds), The Rhetoric of Law (University of Michigan Press 1996) 136.
48 Marianne Constable, ‘The Silence of the Law: Justice in Cover’s “Field of Pain and Death”’ in Austin Sarat (ed), Law, Violence and the Possibility of Justice (Princeton University Press 2001) 85, 93.
49 Harsh Mander, ‘The Song of a Caged Bird: A Tribute to Fr Stan Swamy’ (Scroll.in, 07 July 2021). https://scroll.in/article/999486/the-song-of-a-caged-bird-a-tribute-to-fr-stan-swamy. Accessed 01 September 2021.
50 Arvind Narrain observes that the NIA is a chosen policy instrument of the state as through it the state can exercise unbridled control over citizens, especially the critics of the state. See Arvind Narrain, India’s Undeclared Emergency: Constitutionalism and the Politics of Resistance (Context 2022).
51 ‘No Sipper for Stan Swamy: Justice or Cruelty?’ (We the People, NDTV, 29 November 2020). https://www.youtube.com/watch?v=lkwm4Uk3eKA. Accessed 15 September 2021.
52 Sharmeen Hakim, ‘“I Would Rather Suffer, Possibly Die Very Shortly If This Were to Go On”: Stan Swamy Pleads for Interim Bail in Bombay HC’ (LiveLaw.in, 21 May 2021). https://www.livelaw.in/top-stories/stan-swamy-interacts-with-bombay-hc-for-interim-bail-bhima-koregaon-case-174477. Accessed 15 October 2021.
53 Ibid.
54 ‘Stan Swamy Passes Away after Contracting COVID-19 in Jail, Lawyer Demands Judicial Inquiry’ (Wire, 05 July 2021). https://thewire.in/rights/stan-swamy-death-covid-19-judicial-inquiry. Accessed 16 September 2022.
55 Brie Williams, Cyrus Ahalt, and Robert Greifinger, ‘The Older Prisoner and Complex Chronic Medical Care’ in Stefan Enggist, Lars Møller, Gauden Galea, et al. (eds), Prisons and Health (World Health Organization 2014) 165. https://www.euro.who.int/__data/assets/pdf_file/0005/249188/Prisons-and-Health.pdf. Accessed 20 November 2021.
56 Ibid. The World Health Organization and the United Nations Office on Drugs and Crime recognise the state’s duty to care for prisoners who are dependent on the state.
57 United Nations, ‘Basic Principles for the Treatment of Prisoners’, no. 9. https://www.ohchr.org/Documents/ProfessionalInterest/basicprinciples.pdf. Accessed 20 November 2021.
58 Varavara Rao, ‘The Other Day’. https://www.poetryinternational.com/en/poets-poems/poems/poem/103-15352_THE-OTHER-DAY. Accessed 01 May 2022.
59 Megha Katheria, ‘Why Did Varavara Rao Petition Courts for Access to Basic Healthcare in Prison?’ (Leaflet, 19 November 2020). https://www.theleaflet.in/why-did-varavara-rao-petition-courts-for-access-to-basic-healthcare-in-prison/. Accessed 30 November 2021.
60 Ibid.
61 Ibid.
62 ‘“He Is Almost on Deathbed”: Bombay HC Issues Order to Move Varavara Rao to Nanavati Hospital’ (Scroll.in, 18 November 2020). https://scroll.in/latest/978826/varavara-rao-to-be-moved-to-nanavati-hospital-for-15-days-orders-bombay-hc. Accessed 17 September 2022.
63 As a sociologist, I am wary of the objective usage of the term ‘dementia’, which has been shown to have different socio-cultural meanings and implications for interpersonal behaviour. The term ‘dementia’ was replaced with ‘major neurocognitive disorder’ by the American Psychiatric Association in 2013. See Bianca R Brijnath, ‘The Legislative and Political Contexts Surrounding Dementia Care in India’ (2008) 28 Ageing & Society 913.
64 Sharmeen Hakim, ‘“When You Are Selectively Charging People, You Are Undermining Rule of Law”: Jaising in Varavara Rao’s Bail Plea’ (LiveLaw.in, 22 January 2021). https://www.livelaw.in/news-updates/when-you-are-selectively-charging-people-you-are-undermining-rule-of-law-jaising-in-varavara-raos-bail-plea-168732. Accessed 12 September 2021.
65 Ibid.
66 Ibid.
67 Dr PV Varavara Rao v NIA and Ors, Criminal Appeal No. 52/2020 (Bombay HC, Judgment dt 22 February 2021).
68 Vakasha Sachdev, ‘When Can an Accused in Jail Get Medical Bail? Is It Possible in UAPA Cases?’ (Quint, 13 October 2021). https://www.thequint.com/news/law/when-can-an-accused-get-medical-bail-from-courts-uapa-bhima-koregaon#read-more. Accessed 30 October 2021.
69 Section 437 of the Indian Code of Criminal Procedure 1973, regarding ‘when bail may be taken in case of non-bailable offence’, contains the following clauses which are relevant here: ‘When any person accused of, or suspected of, the commission of any non-bailable offence is arrested or detained without warrant by an officer in charge of a police station or appears or is brought before a Court other than the High Court or Court of Session, he may be released on bail, but … (ii) such person shall not be so released if such offence is a cognizable offence and he had been previously convicted of an offence punishable with death, imprisonment for life or imprisonment for seven years or more, or he had been previously convicted on two or more occasions of a non-bailable and cognizable offence: Provided that the Court may direct that a person referred to in clause (i) or clause (ii) be released on bail if such person is under the age of sixteen years or is a woman or is sick or infirm.’
70 Sarat, ‘Speaking of Death’ (n 47) 181.
71 Chitrangada Choudhury, ‘The Sudha Bharadwaj the Govt Doesn’t Want You to Know’ (Article14, 28 August 2020). https://www.article-14.com/post/the-sudha-bharadwaj-the-govt-doesn-t-want-you-to-know. Accessed 20 September 2021.
72 Vidya, ‘Elgar Parishad Case: Bombay HC Asks Govt to Submit Sudha Bharadwaj’s Medical Reports’ (India Today, 14 May 2021). https://www.indiatoday.in/cities/mumbai/story/elgar-parishad-case-bombay-hc-asks-govt-to-submit-sudha-bharadwaj-medical-reports-1802392-2021-05-14. Accessed 19 November 2021.
73 Astha Savyasachi, ‘“The State Has Left My Mother to Die,” Says Sudha Bharadwaj’s Daughter’ (Outlook, 25 July 2021). https://www.outlookindia.com/website/story/india-news-the-state-has-left-my-mother-to-die-says-sudha-bharadwajs-daughter/389317. Accessed 08 December 2021.
74 Jinee Lokaneeta, ‘How the “Anda Cell” Is Used to Discipline Prison Inmates’ (Indian Express, 29 October 2021). https://indianexpress.com/article/opinion/columns/how-the-anda-cell-is-used-to-discipline-prison-inmates/. Accessed 01 November 2021.
75 Sahba Husain, ‘Keeping Hope, an Everyday Challenge: Imprisoned Human Rights Activist Gautam Navlakha’s Partner’ (Wire, 23 January 2021). https://www.youtube.com/watch?v=18YKVC4z2jg. Accessed 23 March 2021.
76 James A Holstein and Jaber F Gubrium, ‘Constructionist Perspectives on the Life Course’ (2007) 1(1) Sociology Compass 335.
77 Vern L Bengtson, Glen H Elder, and Norella M Putney, ‘The Lifecourse Perspective on Ageing: Linked Lives, Timing, and History’ in Malcolm L Johnson (ed), The Cambridge Handbook of Age and Ageing (Cambridge University Press 2005).
78 Azrini Wahidin and Jason L Powell, ‘The Loss of Aging Identity: Social Theory, Old Age, and the Power of Special Hospitals’ (2001) 6(1) Journal of Aging and Identity 42.
79 Ibid.
80 Kanchan Chaudhari, ‘Bombay HC Pulls Up Jail Officials for Denying Eyeglasses to Gautam Navlakha’ (Hindustan Times, 09 December 2020). https://www.hindustantimes.com/mumbai-news/bombay-hc-pulls-up-jail-officials-for-denying-eyeglasses-to-gautam-navlakha/story-pkcVDCqcw7k7QHyPpt3clL.html. Accessed 04 December 2021.
81 Judith Butler, Precarious Lives: The Powers of Mourning and Violence (Verso 2004) 56.
82 Nitya Ramakrishnan, In Custody: Law, Impunity and Prisoner Abuse in South Asia (SAGE 2013). In chapter 9 of this book, the author discusses cases of custodial torture inflicted on various kinds of people, such as political prisoners like SAR Geelani, a shop owner, sexual minorities, and a Bangladeshi refugee, to list a few.
83 Mahuya Bandopadhyay, ‘Reform and Everyday Practice: Some Issues of Prison Governance’ (2007) 41(3) Contributions to Indian Sociology 387.
84 Bauman, Wasted Lives (n 21).
85 Wahidin and Powell, ‘The Loss of Aging Identity’ (n 78) 44.
86 Pratiksha Baxi, ‘Delhi Court Granting Bail to Infant’s Mother Is a Welcome Change during the Pandemic’ (Indian Express, 21 April 2021). https://indianexpress.com/article/opinion/columns/bail-jurisprudence-womens-prisons-judiciary-7282034/. Accessed 02 December 2021.
87 Ibid.
88 Robert Cover, ‘Violence and the Word’ in Martha Minow, Michael Ryan, and Austin Sarat (eds), Narrative, Violence, and the Law (University of Michigan Press 1995) 203.
89 Austin Sarat and Thomas R Kearns, ‘Introduction’ in Austin Sarat and Thomas R Kearns (eds), Law’s Violence (University of Michigan Press 1995) 5.
90 Ibid. 4.
91 Ibid. 14 (citing Patricia M Wald).
92 Rajshree Chandra, ‘Bhima Koregaon Case: Trying without a Trial Is the Intent of Draconian UAPA Law’ (Wire, 09 July 2021). https://thewire.in/rights/bhima-koregaon-case-trying-without-a-trial-is-the-intent-of-draconian-uapa-law. Accessed 10 December 2021.
93 Kalpana Kannabiran, ‘Introduction’ in Kalpana Kannabiran (ed), Violence Studies: Oxford India Studies in Contemporary Society (Oxford University Press 2016) 43.
94 Mayur Suresh, ‘The Slow Erosion of Fundamental Rights: How Romila Thapar v Union of India Highlights What Is Wrong with the UAPA’ (2019) Indian Law Review 212.
95 Ghosh, ‘The Refugee Within’ (n 25) 105.
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J Autism Dev Disord
J Autism Dev Disord
Journal of Autism and Developmental Disorders
0162-3257
1573-3432
Springer US New York
36484961
5828
10.1007/s10803-022-05828-0
Original Paper
A Qualitative Study of Adults’ and Support Persons’ Experiences of Support After Autism Diagnosis
https://orcid.org/0000-0003-0961-8475
Huang Yunhe 13
https://orcid.org/0000-0003-2900-223X
Arnold Samuel R. C. [email protected]
13
Foley Kitty-Rose 12
Trollor Julian N. 13
1 grid.1005.4 0000 0004 4902 0432 Department of Developmental Disability Neuropsychiatry (3DN), Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW Australia
2 grid.1031.3 0000000121532610 Faculty of Health, Southern Cross University, Gold Coast, QLD Australia
3 grid.478764.e The Cooperative Research Centre for Living with Autism (Autism CRC), Brisbane, QLD Australia
9 12 2022
114
11 11 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Adulthood autism diagnosis has become increasingly common, but little is known about post-diagnosis support experiences and needs. We interviewed 19 autistic adults and 4 support persons on experiences of formal and informal post-diagnosis support. Reflexive thematic analysis was used to identify themes. Participants reported difficulties accessing suitable formal support, especially regarding education and employment. Informal support was helpful but created challenges in the relationships between autistic adults and support persons. For autistic adults, support from autistic peers fostered belonging and self-acceptance. We also identified complex interactions between adults’ post-diagnosis identity development and support experiences as they resolved the dilemma between self-acceptance and a desire to change. Findings have important implications for services working with autistic adults and their families.
Keywords
Autism
Adults
Qualitative research
Families
Support needs
Interventions
http://dx.doi.org/10.13039/100010433 Cooperative Research Centre for Living with Autism 3.013 Australian Government Department of Education, Skills and EmploymentResearch Training Program Huang Yunhe
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pmcIn recent years, a small number of mostly qualitative studies have explored the experiences of receiving an autism diagnosis in adulthood. Adults in these studies reported long histories of unexplained interpersonal difficulties and a sense of being different from others (Bargiela et al., 2016; Hickey et al., 2018; Punshon et al., 2009). For these adults, receiving the diagnosis led to re-interpretation of their strengths and difficulties (Hickey et al., 2018; Leedham et al., 2019; Lewis, 2016), accompanied by intense emotional reactions (Huang et al., 2021; Lewis, 2016; Powell & Acker, 2016). Despite having been diagnosed with a disorder, some adults embrace autism as a positive part of their identity (e.g. Lewis, 2016; Tan, 2018). Concerningly, adults often reported significant difficulties accessing support after diagnosis (Crane et al., 2018; Lewis, 2016). Most research into late diagnosis was focused on adults without intellectual disability, where delayed diagnosis was assumed to be due to more subtle autistic traits and fewer functional difficulties (Huang et al., 2020). Although several studies identified cases of previously-undiagnosed autism in adults with intellectual disability (Roy & Balaratnasingam, 2010; Saemundsen et al., 2010), relatively little is known about their subjective experiences or specific support needs. More research is needed to understand adults’ support needs and experiences in the context of broader discourse on the dual status of autism as both a disability and social identity.
Views of Autism and Disability
Autism’s complexity as a condition involving both strengths and vulnerabilities gave rise to disparate understandings with differing implications. Autism has traditionally been defined in terms of social and behavioural deficits in need of remediation (Baker, 2011; Kapp et al., 2013). These views are aligned with the medical model of disability, which regards disability to be the result of individual-level deficiencies that must be corrected to improve functioning (Chapman, 2019; Kapp et al., 2013). In contrast, the neurodiversity movement defines autism as a natural human variation and minority group identity deserving acceptance (Bagatell, 2010; Kapp et al., 2013). Neurodiversity proponents endorse the social model of disability, where disability is attributed to an unaccommodating society and should be remediated by efforts to reduce stigma and remove barriers to participation (Kapp et al., 2013; Shakespeare, 2017). However, neither medical nor social models fully account for the complex interaction between individual impairment and social barriers in autistic people’s experiences. Studies found that many autistic adults endorse a combination of medical model and neurodiversity beliefs, where appreciation of autistic identity and strengths coexist with a desire to reduce deficits through interventions (Bagatell, 2010; Kapp et al., 2013). These disparate perspectives have important implications for the understanding of autistic adults’ support needs and priorities.
Support for Autistic Adults
A key issue identified in studies of adulthood autism diagnosis is inadequate formal support (Arnold et al., 2020; Crane et al., 2018; Griffith et al., 2012). Adults reported receiving little to no guidance on navigating the gap between diagnostic and support services (Crane et al., 2018; Jones et al., 2014; Lewis, 2016). They were disappointed that autism services tend to focus on children or adults with higher support needs (Crane et al., 2018; Lewis, 2016), while mainstream mental health professionals are inadequate at addressing autism-related concerns (Griffith et al., 2012). Adults also described the dilemma of being considered too capable for disability services while still having significant support needs (Griffith et al., 2012). Studies reported a variety of desired supports including social skills, education/employment, self-care, and mental health, which are often unmet (Baldwin & Costley, 2016; Crane et al., 2018; Griffith et al., 2012; Jones et al., 2014). Studies of autistic adults with intellectual disability found them to have poorer adaptive functioning skills, more co-occurring psychiatric conditions, and more behaviours of concern compared to their non-autistic peers, suggesting greater support needs (Maguire et al., 2022; McCarthy et al., 2010; Totsika et al., 2010). Most research into supports and interventions for autistic adults with and without intellectual disability was focused on social skills (Lorenc et al., 2017; Walton & Ingersoll, 2013). There has also been a number of studies examining employment interventions for autistic adults with a range of intellectual abilities (Hedley et al., 2016).
Few studies have explored informal support from family, friends, and online communities. Autistic adults described varying responses from family and friends after their diagnosis, including acceptance, dismissiveness, and rejection (Crane et al., 2018; Lewis, 2016; Punshon et al., 2009). In these studies, support from other autistic people in real life and online allowed autistic adults to share experiences, feel accepted, and develop more positive views of autism (Hickey et al., 2018; Tan, 2018). Mothers and partners of late-diagnosed adults described significant difficulties coordinating formal support for their loved ones (Lewis, 2017; Raymond-Barker et al., 2018). Additionally, partners described a sometimes painful process of adjusting expectations and communication techniques (Lewis, 2017). These support persons reported wanting professional help to process their own feelings and learn to support their loved ones after diagnosis (Lewis, 2017; Raymond-Barker et al., 2018). Existing knowledge showed that while informal support can be highly valuable, the need to compensate for inadequate formal support may place undue burden on support persons.
Existing research on post-diagnosis support for adults are limited in both breadth and depth. With the exception of Griffith et al. (2012), most studies on adulthood autism diagnosis only involved cursory discussions of post-diagnosis support. Only a few studies addressed experiences of informal support. Additionally, most of these studies excluded adults with intellectual disability, with several older studies specifically focusing on the now-outdated diagnosis of Asperger’s syndrome. While autistic people without intellectual disability do not necessarily have low support needs (Alvares et al., 2019), it is still likely that these studies have overlooked support needs and services specific to autistic adults with intellectual disability.
The present study aims to comprehensively explore adults’ and support persons’ experiences of formal and informal support after autism diagnosis in adulthood. To achieve this, we interviewed a diverse sample of adults and support persons to understand their perspectives on support needs, roles of formal and informal support, influence of support on identity development, and improving support experiences in the future.
Method
This study formed part of a larger mixed-methods project on experiences of autism diagnosis in adulthood, approved by the UNSW Human Research Ethics Committee, project number HC190582. The research design for this study was mostly guided by pragmatism, a theoretical paradigm which values usefulness of resultant knowledge over adherence to specific philosophical positions (Feilzer, 2009). Our methodological approach was also informed by phenomenology, which aims to understand the essence of a phenomenon by studying individual experiences (Patton, 1990). Combining these theoretical orientations allowed this study to explore individual experiences and perspectives while situating them within the broader social context.
Participants
Advertisement for this study was distributed alongside a survey component via participant newsletters of existing research studies and various autism and disability organisations and service providers in Australia (see Huang et al., 2021 for details). The survey also contained an option for expressing interest in being interviewed. Additionally, we asked participants to distribute study information to any interested parties. Participants were required to be 18 or over, have received an autism spectrum diagnosis in adulthood (age ≥ 18), or have supported someone diagnosed in adulthood during and after their diagnosis.
To capture a variety of support experiences, we purposively sampled for maximum demographic variation (Sandelowski, 1995) in age, gender, intellectual disability, geographical location, and interview format. To achieve this, we initially prioritized emailing/phoning participants from less represented or unrepresented demographics from the list of all potential participants who expressed interest.
Nineteen autistic adults (7 male, 9 female, 3 non-binary) and four support persons (all female) were interviewed. Autistic adults had a mean age of 44.37 years (SD = 17.84) and were diagnosed between 2000 and 2019. Four adults self-reported mild to moderate intellectual disability. Support persons were mothers (n = 2) or wives (n = 2) of autistic adults who also participated in the study. Several other autistic adults had support persons who did not respond to invitation or chose not to participate in this study. There was at least one participant from each state/territory of Australia except South Australia and Northern Territory. See Table 1 for detailed participant information.
Table 1 Participant Information
Number Participant group Age Gender Intellectual disability State Interview mode Notes
1 Autistic adult 65+ Male No Victoria Email
2 Autistic adult 25–34 Non-binary No New South Wales Email
3 Autistic adult 25–34 Female No Queensland Video
4 Autistic adult 65+ Male No Victoria Phone
5 Autistic adult 55–64 Male No New South Wales Face-to-face
6 Autistic adult 25–34 Female No New South Wales Phone
7 Autistic adult 35–44 Female No Australian Capital Territory Instant message
8 Autistic adult 55–64 Male No Australian Capital Territory Video
9 Autistic adult 55–64 Female No New South Wales Video
10 Autistic adult 35–44 Female No Western Australia Instant message
11 Autistic adult 25–34 Female Yes Victoria Email
12 Autistic adult 45–54 Female Yes Queensland Email
13 Autistic adult 35–44 Non-binary Yes New South Wales Email
14 Autistic adult 25–34 Female No Queensland Video
15 Support person 45–54 Female No Queensland Video Mother of Participant 14
16 Autistic adult 25–34 Male Yes New South Wales Video
17 Support person 55–64 Female No New South Wales Video Mother of Participant 16
18 Autistic adult 18–24 Non-binary No Western Australia Video
19 Autistic adult 25–34 Male No Queensland Video
20 Support person 55–64 Female No Australian Capital Territory Video Wife of Participant 8
21 Autistic adult 55–64 Female No New South Wales Phone
22 Autistic adult 35–44 Male No Tasmania Phone
23 Support person 35–44 Female No Tasmania Phone Wife of Participant 22
Data Collection and Procedure
An online expression of interest form asked participants to provide informed consent, demographic information (date of birth, gender, intellectual disability, state/territory) and interview preferences. Participants who expressed interest via other means (such as contacting the researcher via telephone) completed the consent form via email or post. Participant information and consent documents were provided in both standard and easy-read formats. YH then contacted suitable participants and arranged interview times.
The first author developed a semi-structured interview guide (Supplementary material 1) involving seven questions on initial diagnosis, supports received/ wanted, meaning of diagnosis, and future suggestions in consultation with co-authors and autistic research advisors. Interview questions were piloted with several colleagues and associates including an advisor with intellectual disability. Prior to the interview, participants were provided with an accessible document with plain language and supporting images explaining the interview process and a copy of interview questions.
The interview was offered via online video conferencing (n = 10), email (n = 5), telephone (n = 5), instant messaging (n = 2), and face-to-face (n = 1) to accommodate participants’ locations and preferences, as recommended by Nicolaidis et al. (2019). Using a variety of data collection approaches helped reduce barriers to participation and recruit a more diverse sample, though not all methods resulted in the same level of richness and detail. The face-to-face interview was conducted at a university meeting room. Only one interview occurred face-to-face as these were discontinued following the outbreak of COVID-19 in 2020. Autistic adults and their support persons were given the option to be interviewed together or in separate sessions. All pairs chose to be interviewed separately. Participants were reimbursed with a $60 AUD gift card for remote interviews and $80 for the face-to-face interview to account for travel expenses and time. Participants who participated in member checking (see Data Analysis) received an additional $35.
The first author conducted all interviews between October 2019 and June 2020 and kept a journal of reflections and possible directions for analysis. The length of spoken interviews ranged from 34 to 148 min (M = 75.23), while typed interviews ranged from 693 to 4,636 words (M = 2,327). Recordings were transcribed verbatim by the first author and a professional transcriber, then checked for accuracy by the first and second authors. All transcripts were edited to remove identifying information.
Data Analysis
We used reflexive thematic analysis (Braun & Clarke, 2006, 2019), where the researcher develops patterns of meaning from active engagement with the data. Although our analytic approach was primarily data-driven and semantic, analysis of participants’ beliefs about autism and the self was conducted at a more latent level, informed by discourse on models of disability and neurodiversity. Analysis commenced shortly after the first interview and was conducted concurrently with data collection. Using NVivo 12 to manage data, YH read the transcripts repeatedly and generated initial codes. YH then developed themes from connections between frequent and/or thematically important codes, revisiting the initial codes and reorganising them as necessary. Throughout this process, YH used a reflexive journal to document the rationales for decisions and process of refining themes. All of the authors then met to discuss the proposed themes, correspondence between themes and codes, and relevance to the research question. To enhance authenticity of research findings, participants were given an opportunity to comment on a summary of themes with selected quotes, as recommended by Birt et al. (2016). Quotes were edited for clarity and the participant was given an opportunity to make changes before inclusion. We incorporated participants’ feedback into the final list of themes and discussion of their implications for practice.
Reflexivity and Position of the Researcher
YH is a doctoral student with personal connections to autism via family and social relationships, bringing aspects of both academic and real-life understandings to the project. Having conducted a literature review and other studies in the larger project, YH began this study with knowledge of autistic adults’ difficulties accessing formal post-diagnosis support and concerns around disclosing their diagnosis to others. YH also had pre-existing knowledge of the popularity of autistic self-advocacy and neurodiversity movements in autistic communities. While YH expected these ideas to emerge in participants’ interviews, she also paid attention to participants’ varied opinions on these topics and new or unexpected ideas. YH kept a reflexive journal throughout interview and analysis to maintain awareness of her own perspectives and influence on the research process. YH mainly presented herself as an outsider to participants while mentioning that she has some relevant personal experiences. This allowed her to connect with participants more closely while encouraging participants to elaborate on ideas that might be assumed or taken for granted within their communities. However, her outsider status may have motivated some participants to present themselves and their communities in a more socially desirable manner (Bergen & Labonté, 2019). While being a researcher naturally gave YH authority over participants, her young age and outsider status resulted in more fluid power dynamics as participants could educate the researcher on insider issues and life experiences.
SA, KF, and JT are experienced in the dual roles of researcher and clinician in the field of autism and developmental disabilities, who gave guidance based on academic expertise and reflections from clinical experience.
Community Involvement
Consultation with autistic people during the project helped promote authentic portrayal of the community and its interests. Autistic research advisors provided feedback on interview questions at the start of the project. Additionally, two non-autistic research advisors with intellectual disability reviewed Easy-read documents for accessibility. Preliminary themes were shared with interview participants for feedback. Autistic research advisors then provided feedback on the interpretations and implications of the findings. Financial reimbursement was offered to all participants and research advisors who gave feedback.
Results
Seven themes were developed from participants’ interview data. These themes captured autistic adults’ and support persons’ perspectives on professional support, informal support including autistic peer support, and identity formation as an autistic person.
Theme 1: Difficulty Accessing Support
Autistic adults and support persons found the system of formal support services confusing to navigate as they received little information at the time of diagnosis. Not knowing what services would be suitable or where to find them caused adults to miss out on support: “I really don’t know what to ask for. I’m unsure what’s available, especially for adults, and what will help me” (Participant 7, autistic adult).
Adults and support persons encountered numerous obstacles in the process of finding and organising formal support. Few autism services accepted adult clients, and those that did often came with prohibitive fees. This made them inaccessible to many participants:“[Diagnosis provider] would like me to come back to see them, to get my health services there, but I live about an hour out of the city and again, they’re very expensive. So unless I’m really, really desperate for mental health services, I’m not going there” (Participant 3, autistic adult).
Although avenues of government funding such as the National Disability Insurance Scheme helped ease financial burdens, not all participants were eligible to receive such assistance. Many autistic adults and support persons who applied for government funding found the steps required to demonstrate eligibility and provide ongoing documentation to be stressful. Both mothers interviewed were heavily involved in managing funding and services for their adult children. One mother said:“I have to tell them how to do their work like that. Like the speech therapist and the occupational therapist... I have to ring them like several times, send emails… that is their job” (Participant 17, support person).
The contrast between autistic adults’ apparent capabilities and significant support needs meant they were seen as both too disabled and not disabled enough. Some adults were reluctant to seek formal support for fear that others would underestimate their capabilities, while others struggled to have their support needs taken seriously. Although this was most apparent in the experiences of autistic adults without intellectual disability, the mother of a participant with mild intellectual disability also described the dilemma of being stuck between mainstream and disability-specific services: “He’s not there as a mainstream, he’s not totally disabled, so the gap’s there… They see what he can do, but there are some hidden things which they are not aware” (Participant 17, support person).
Personal factors also impacted autistic adults’ ability to seek and receive formal support. Adults found the process of searching for and contacting services difficult and stressful, which discouraged them from pursuing support. This was especially the case for adults with co-occurring physical or mental health conditions: “Between autism, depression and chronic fatigue, the few times I have the energy to ring up, cause ringing people up in the first place is challenging… every time you ring up, you get told ‘we’re not taking new patients’” (Participant 22, autistic adult).
Another factor raised mainly by support persons was their perception that adults were uncomfortable with aspects of formal support that require change. This was sometimes due to a fear of unfamiliar people, places, or ideas: “For him, anything new would be quite anxiety-producing” (Participant 20, support person). Other times, autistic adults and support persons had different views on whether certain characteristics or behaviours should be changed or accepted as part of the autism. An autistic adult, who did not have a support person participating in the study, was concerned that learning ways to mitigate negative aspects of autism would mean losing the positive aspects: “I was offered by [diagnosis provider] to work through some of my behavioural problems… I think I do need it… but I just don’t want to give up what gives me good sensations” (Participant 9, autistic adult).
In light of these barriers, both autistic adults and support persons wanted more information, advice and professional assistance on finding formal support after diagnosis: “I think somebody who could walk you through some of the processes… Somebody to give you a starting point to go, ‘You know what? I’ve been there’” (Participant 15, support person).
Theme 2: Support to Empower Growth
Most autistic adults’ experiences of professional support consisted of counselling and psychotherapy from mental health professionals, often during treatment for co-occurring mental illnesses. Both adults and support persons desired a greater variety of services to address adults’ individual needs.
Adults and support persons emphasised the importance of having autism-informed professional support. These professionals helped adults understand their strengths and difficulties, taught practical coping strategies, and adapted their treatment of co-occurring mental health conditions with autism in mind. For support persons, autism-informed professionals gave them greater insight into the adult’s behaviour and helped them respond more effectively. Unsurprisingly, both adults and support persons considered autism-informed professionals an indispensable part of good post-diagnosis support:“I would strongly recommend go to psychologists who specialise in treating autism spectrum disorders and get some strategies, because you might find stuff that you didn’t even know before” (Participant 19, autistic adult)
Although a few autistic adults were uninterested in social connections, most adults wanted to learn to connect with others more easily. Adults’ experiences of social skills advice from professionals included both simple rules such as “don’t speak for more than thirty seconds” (Participant 8, autistic adult) and more in-depth explanations of other people’s behaviours in social situations. Both were regarded as helpful, though one participant emphasised the latter helped them break away from superficial imitation of socially acceptable behaviour and respond more naturally:“I feel like there’s a difference between basing for example, body language on ‘this is what people do in this situation’ and basing body language on ‘this situation’s happening, what’s going on?’. I’m gonna react how I’m gonna react, but I’m going to know that my reaction isn’t gonna hurt anyone” (Participant 18, autistic adult)
Both adults and support persons expressed a need for more holistic support services addressing independence and community participation, including managing everyday tasks, attending events and activities, education, and employment. This was especially important for adults with intellectual disability who received professional assistance to manage their finances and participate in recreational activities, though other adults also desired support in these areas. A participant with intellectual disability described the benefits of having a support worker: “Accessing the community… like just have an outing in the park and do roller skating. It was quite easy together side by side” (Participant 16, autistic adult).
Younger autistic adults and their support persons were particularly concerned about the transition to adult life. Although young adults expressed a strong desire to become more independent, they found social isolation and lack of stable income to be major barriers to achieving their goals. Participant 14 reported wanting to move out of the parental home, though her mother feared that not having enough family support would worsen the daughter’s mental health. The mother said:“My fear was if she moves out without support that she would be at risk… Ideally I would like her to be able to move out into almost like a halfway house type program, but I don’t know of any” (Participant 15, support person).
On a deeper level, adults wanted to be accepted as they are, while being supported to work towards individualised goals. Adults believed it was important for professionals to embrace a positive understanding of autism and treat them as an equal partner. They also wanted to choose the goals of support based on their own values and needs, which may be different from what mainstream society would expect: “It is essential for support services to be directed by my values and my priorities. Not what my spouse wants, or my parents, or my doctor. It’s not even about what my peers, or community, or culture wants. It’s about what I want” (Participant 21, autistic adult).
Theme 3: Supporting Learning and Vocation
Although working-age autistic adults generally wanted to learn new skills and financially support themselves through paid work, they often needed support to cope with the demands of education and employment. Adults reported that social challenges of job interviews and workplace communication hindered their job prospects: “I’ve never been good at an interview… The only reason I’ve always had a job is because doctors were scarce in my time” (Participant 9, autistic adult). Autistic adults also found themselves confused and frustrated by vague instructions, unclear expectations and others’ unwillingness to follow rules in universities and workplaces. Additionally, some adults with co-occurring physical and/or mental health conditions desired greater flexibility in hours and tasks to help maintain wellbeing while studying or working.
Two adults with intellectual disability had received disability-specific employment support services, including disability job agencies, supported open employment and sheltered employment. Although both expressed a strong desire to work in open employment, the support offered by mainstream workplaces was often inadequate: “I have faced a lot of struggles because workplaces in Australia and New Zealand were not yet fully equipped for this kind of support… many corporate companies do all talk and no action which didn’t help me at all to stay on in the role” (Participant 11, autistic adult). Participant 16 found working at a disability enterprise to be mentally unstimulating and preferred an “office job” where he could use his skills more.
Despite challenges, adults found that certain aspects of autism gave them unique advantages in the workplace, such as being detail-oriented, focused, and rule-abiding: “I suspect being an Aspie actually makes me better at my job rather than worse, because of my ability to remember lots of information and stay task-focused” (Participant 5, autistic adult). Both adults and support persons hoped for more opportunities where autistic adults’ skills would be recognised and valued, “Because when they do something, they do it 110%” (Participant 23, support person).
Theme 4: Wanting to be Understood
After diagnosis, autistic adults wanted to share their newfound knowledge with friends and family, hoping others would understand them better. Adults explained that having an official label helped them communicate their experiences and needs to others. In many instances, disclosing the diagnosis resulted in improved understanding, acceptance, and informal support. One adult explained how disclosing the diagnosis allowed her to avoid eye contact, which made communication feel easier:“I just look away and I listen. I’m much better now at taking things in and remembering them… But to do that, I have to tell people I’m autistic, so they don’t ask me… and I can really concentrate on what they’re saying” (Participant 9, autistic adult).
In other instances, disclosing the autism diagnosis resulted in negative reactions, which added to adults’ sense of social isolation. Others often doubted whether the adult was really autistic due to their apparent lack of visible difficulties. Sometimes, the dismissiveness was coupled with a general lack of awareness of psychiatric conditions, which made it difficult for adults to communicate their needs. One adult described how she felt when a friend questioned her diagnosis: “It was frustrating and invalidating, and it did make me question it a bit, you know. I mean, it is also a bit of an abstract thing. It’s not like a blood test. It’s not something definitive like that.” (Participant 14, autistic adult).
Adults and support persons reported that some relatives and acquaintances would avoid the subject of autism after learning of the adult’s diagnosis. This reaction left adults wondering whether these people lacked autism knowledge, did not know how to respond, or simply did not care: “They sort of heard the news and then went ‘oh’ and then sort of didn’t visit it any further. So I don’t know if it’s because it doesn’t really matter to them or that they don’t want to ‘pry’ or what” (Participant 7, autistic adult).
Both adults and support persons believed the wider community needed to adopt more positive understandings of autism in adulthood and reject stigmatizing stereotypes, so that others would be more likely to respond positively to the diagnosis and offer informal support. They were pleased that public attitudes appeared to be improving: “It’s educating the public, so people don’t go up and say, “You don’t look autistic’, ‘You don’t act autistic’. And I think that must be happening, cause the young people are so much better” (Participant 9, autistic adult).
Theme 5: To Care and be Cared for
Following diagnosis, adults and support persons underwent a mutual process of understanding and adjustment. While some support persons quickly accepted the diagnosis, others were initially resistant due to not wanting to view their loved one as impaired. One adult described his mother’s reluctance and eventual acceptance:
“Well, I spoke to her about it, probably more of a defence mechanism to say, ‘no, my son doesn’t have this’, you know, ‘my son is not defective’… maybe just the feeling of shame that ‘I put that in the world and that’s not possible’… But then when my dad and I gave her more information. She then realized, ‘oh yeah, actually that made sense, and this is what it is’” (Participant 19, autistic adult).
Diagnosis and subsequent support alerted support persons to previously hidden support needs such as sensory sensitivities and a need for predictability. Improved understanding also helped support persons interpret the adult’s behaviours differently, reframing them as autism-related difficulties rather than personality flaws:“Since his diagnosis, the first thing that came to my mind was: I can’t leave, here’s somebody with something that he can’t help doing, I’ve got to stay and work it out with him” (Participant 20, support person).
An important aspect of mutual understanding was adapting to each other’s communication styles. Some autistic adults’ direct communication style was sometimes perceived as offensive, while support persons’ attempts at subtle communication resulted in misunderstandings. One support person described how using direct communication helped her husband understand her better:“Just tell him what’s not acceptable to you and that’ll help him… He’s very good with clear, one-sentence requests, whereas I talk around the block and try and make it really sweet and soft, and then he says, ‘What are you talking about? I don’t understand’” (Participant 20, support person).
Support persons helped adults navigate many aspects of life after diagnosis. Autistic adults appreciated having someone who could help them understand social situations in real time: “If I’m wondering why somebody said this or why somebody acted in that way, she can translate for me in a way that I’ll understand, which is such a unique skill” (Participant 3, autistic adult). Support persons also helped link autistic adults with professional services. Several younger adults reported that their parents took on the responsibility of managing professional support for them:“My parents, especially my mother; helped me to get into these support groups to meet other people. I was not mature enough to care about doing these activities at the time, but looking back, I realise I should have made the effort myself” (Participant 11, autistic adult).
The autistic adult’s needs resulted in additional responsibilities for the support person, which led to a deviation from expected relationship dynamics. While this was less of a problem for adults supported by their parents, receiving informal support from siblings, partners, or children created discomfort for both the adult and the support person. Participant 9 was deeply embarrassed at the realization that her daughter had been helping her interpret social situations for years: “My daughter is so emotionally intelligent and she’s also very bright. I’m almost a child to her now. And it’s embarrassing cause she’s right. She’s interpreted for me, and I never listen” (Participant 9, autistic adult). Support persons also found it stressful to manage the autistic adult’s needs in addition to other responsibilities. This was particularly difficult in intimate relationships where both partners were expected to support each other. Participant 20 described the responsibility of helping her husband in social settings:“As a communication person, I feel a very, very heavy burden that I’m the only person who can notice and say things, because I’m the one who sees him every day, 24 hours, one-on-one as well as in social settings” (Participant 20, support person).
Despite challenges, support persons valued their relationship with the autistic adult. Both autistic adults and support persons wanted more resources and services for loved ones of newly diagnosed autistic adults, such as information packs, one-on-one consultations, and support groups. One participant commented on the lack of existing services: “It does leave a lot of adults struggling and their families struggling too, because they have to support people on the spectrum… They don’t have any resources any more than we do, and they need support too” (Participant 3, autistic adult).
Theme 6: Being Different Together
Autistic adults valued connections with other autistic people both in-person and online, through friendships and autism-specific support groups. Adults described feeling more understood and accepted by autistic people who shared their experiences. They also found interactions less stressful due to similar thinking and communication styles. An autistic adult with intellectual disability described her friendship with two other autistic people: “We are just nice to each other and don’t need to deal with small chat and useless talk” (Participant 12, autistic adult).
These similarities made other autistic people a good source of knowledge and advice for newly diagnosed adults. Adults reported that suggestions from autistic peers helped them understand themselves and develop coping strategies. Adults also offered advice to people who were struggling with various issues. The exchange of informal support helped strengthen adults’ sense of belonging in an autistic community. Participant 21 considered connections with the autistic community or “tribe” to be an essential aspect of post-diagnosis support:“The most helpful thing to do after diagnosis is to find an Autistic community to help orientate your identity. It is important to get validation from shared idiosyncrasies and experiences, but also vital for personal growth to have opportunities to discover unique differences, be it within one’s own tribe or not” (Participant 21, autistic adult).
Meeting other autistic people with a variety of autistic traits, interests, personalities and support needs helped broaden participants’ understandings of autism. However, some adults found it difficult to relate to autistic people who were very different from them, and preferred those who matched their gender, interests, and support needs. Some women who had attended autistic adult support groups reported difficulties connecting with other group attendees who were mostly young men. An autistic adult with intellectual disability was disappointed by online autism communities’ tendency to overlook people with intellectual disability and higher support needs:“We are people just like any autistic. We grow up. We’re not children forever. We have different experiences but we want to make friends and connect to others too. Just because we may not understand or we take longer to learn or we can’t learn something doesn’t make our value less. Our voice matters too” (Participant 13, autistic adult).
Some autistic adults found it unhelpful when people in online autism groups became fixated on pessimistic complaints without offering solutions. They also wanted to avoid the emotionally charged and argumentative discussions that often occur in these groups. One participant described an online forum she was a part of:“People post every day about their difficulties to see who else experiences the same thing. I used to read but I stopped responding because I would get some negative feedback… I don’t dare to be a positive voice or to defend neurotypical people” (Participant 3, autistic adult).
While only a few autistic adults had attended organised support groups, many were interested in attending one. Participants differed greatly on the preferred format and goals of their ideal support group. Some adults were primarily interested in making social connections at their own pace, while others wanted to focus on problem-solving strategies in a more structured setting. Adults also had different opinions on the level of involvement from non-autistic professionals and community members. While some participants preferred an autistic-only group free from external authority and mainstream social expectations, others saw an opportunity to bridge the gap between autistic and non-autistic people. One participant explained that although his ideal group would include neurotypical people, “the neurotypical would need to be in a position where they understand the autism, and not ram their own ideas of healing down your throat” (Participant 4, autistic adult).
Theme 7: Negotiating Autistic Identity
For many adults, diagnosis and subsequent support led them onto a pathway of self-discovery as they sought to learn more about autism in relation to their lives and relationships, resulting in deeper changes in how they perceived their identity and relationship with the world.
An important aspect of post-diagnosis self-reflection is self-acceptance. Letting go of the expectation to act neurotypical helped adults reduce self-blame and view themselves more positively: “It meant that things weren’t all my fault… I wasn’t just a problem, there were things that I couldn’t actually control” (Participant 14, autistic adult). They remarked that autism not only explained their difficulties, but also their strengths such as honesty, intense focus, and rational thinking. Thus, many adults accepted autism as a permanent and positive part of themselves that should not be erased: “It’s not an impediment. It’s just a different way of doing things” (Participant 8, autistic adult).
Acceptance of autism also included accepting autism-related difficulties, which led to feelings of self-doubt and inadequacy in some participants. However, adults found ways to reconcile their difficulties with a positive view of autism. Some had adapted their interests and activities to minimise the effects of difficulties, while others considered certain difficulties not central to their identity as an autistic person. In general, adults considered it more helpful to focus on special interests and strengths rather than dwelling on deficits. An adult with intellectual disability said, “Don’t feel bad about yourself. And autism makes you special, I mean, you could have special skills” (Participant 16, autistic adult).
For many adults, autism acceptance coexisted with a desire to change certain aspects of themselves through professional support. Participants’ perspectives on balancing acceptance and change were deeply personal and varied. Some believed in primarily adapting the environment to the person, favouring minor adjustments that allow them to be themselves as much as possible. Others were highly motivated to learn new skills and sought constant self-improvement. Although adults’ opinions varied, most agreed that self-acceptance can co-exist with a desire to change: “I feel less pressured to change how I approach things, but at the same time I recognise that maybe I can approach things in a different way, recognising that I can be overly direct and overly blunt” (Participant 5, autistic adult).
For many adults, the importance of autism as part of their identity changed over time. Several adults experienced a strengthening of autistic identification as their self-understanding and involvement with the autistic community increased. However, others described that autism became less prominent as they integrated the diagnosis into their identities over time: “For a while, when I thought about myself, there would be this ‘and I’m autistic’ along with other things… but as I’ve come to terms with them more, they’ve become just part of the landscape” (Participant 18, autistic adult).
Autism diagnosis also changed how adults viewed their place in society. The sense of kinship with other autistic people was accompanied by feelings of being out of place in the wider neurotypical world. It was common for participants to depict autistic and non-autistic people as two tribes or communities with complementary abilities and preferences, where the dominance of non-autistic norms led to autistic people’s alienation from mainstream society: “Three-quarters of the problem that people who are on the spectrum have with other people is that we’re not them. And they don’t like it. They can’t accept it” (Participant 21, autistic adult). However, adults also expressed a desire for mutual understanding and connection: “I wanted to find more ways to come together with people, to help other people understand me and to understand them better, because it’s a two-way street” (Participant 3, autistic adult).
Discussion
Our qualitative study aimed to understand experiences of support after adulthood autism diagnosis. Findings revealed significant unmet need for formal support after adulthood autism diagnosis. By interviewing autistic adults and support persons, we were able to identify key benefits and challenges of informal support from both perspectives. Additionally, our study uncovered interesting interactions between adults’ experiences of support and development of autistic identity. These findings have important implications for improving post-diagnosis experiences of autistic adults and support persons.
Adults and support persons in our study reported a shortage of available formal support and significant barriers to access, consistent with previous research (e.g., Crane et al., 2018; Jones et al., 2014). Navigating the gap between diagnosis and support required significant knowledge, time, finances and personal resources, which was especially challenging considering adults’ reported difficulties with social communication, mental health, and employment. Support persons who helped their loved ones find services encountered many of the same barriers. Our findings indicate a need for diagnosing clinicians to provide comprehensive information, advice, and personalised guidance to help bridge the path to post-diagnosis support for adults. It is also important to increase the availability and range of services for autistic adults, including those who may not qualify for more intensive disability support. Services that offer information, general support, and links to external providers such as described in Southby and Robinson (2018) may be a candidate for broader implementation. Autism training for mainstream health professionals would also help them to either directly support autistic adults or refer them to appropriate services more effectively. Furthermore, it may be necessary for providers to explore additional formal supports or links to existing services to ensure that specific populations such as transition-age youth or people with co-occurring mental health conditions are adequately supported.
The theme Supporting Learning and Vocation was originally conceptualised as part of Support to Empower Growth but was separated after participants’ feedback highlighted its importance to working-age autistic adults and their support persons. A major concern for autistic adults was how to make use of their abilities in paid employment without being held back by social challenges. Our findings are consistent with previous research highlighting social difficulties and unaccommodating workplaces as major barriers to positive employment experiences in autistic adults (Anderson et al., 2021; Baldwin et al., 2014; Harvery et al., 2021). Additionally, adults with intellectual disability in our study faced a unique challenge, where they found sheltered employment unfulfilling but did not have enough support to transition to open employment. This was in line with past research showing supported open employment to be superior to sheltered employment in terms of job satisfaction and income for people with intellectual disability (Cimera, 2011; Jiranek & Kirby, 1990). Our research supports the call for more diverse employment opportunities that meet the social and financial needs of people with intellectual disability, with examples including non-segregated social enterprises and a combination of open and sheltered employment (Meltzer et al., 2018; Rustad & Kassah, 2021)., Formal supports including autism and disability-specific employment programs (Brooke et al., 2018), career planning (Hatfield et al., 2017), and training for employees and employers (Wehman et al., 2016) have shown promise for improving autistic adults’ workplace experiences and independence as well as lessening the economic impact of autism on society (Hedley et al., 2016; Scott et al., 2018).
The apparent dilemma between acceptance and change was developed from the interweaving of positive feelings about autism diagnosis with the desire to remediate certain aspects in autistic adults’ interviews. We then applied the dynamics of acceptance and change to interpret individual variations in autistic identity development and support preferences. The coexistence of acceptance and change is reminiscent of Kapp et al.’s (2013) deficit-as-difference view, which reflect the complexity of autism as both a disability and identity. Most of our participants endorsed the neurodiversity movement’s view of autism as a positive neurological difference, which encouraged self-acceptance and positive self-esteem. Contrary to the assertions of Jaarsma and Welin (2012, p. 27), neurodiversity-aligned views were not limited to “high-functioning” individuals but were also shared by participants with intellectual disability. However, this acceptance did not hinder participants’ recognition of their difficulties or their practical desire to improve the lives of themselves and those around them through change. Autistic adults’ highly varied perspectives on whether certain aspects of the autistic experience should be accepted or changed shaped their preferences and goals for formal support, which are sometimes incongruent with support persons’ expectations. Considering the diversity of autistic people’s beliefs and support needs, it is important for formal support to respect each individual’s balance between acceptance and change, fostering positive self-esteem through autism acceptance while empowering the individual to make necessary changes to achieve their goals. It is also important for professionals to explore possible differences in autistic adults and support persons’ expectations when devising support goals, and ensure that needs for autonomy, wellbeing, and healthy relationships are accounted for.
Our findings on informal support mostly confirmed existing research on support person experiences (Lewis, 2017; Raymond-Barker et al., 2018). Additionally, exploration of autistic adults’ perspectives allowed us to gain a fuller understanding of the benefits of and barriers to informal support, especially in cases where loved ones are unable or unwilling to provide much assistance. Although informal support persons played a valuable role in autistic adults’ lives after diagnosis, our data highlighted a number of challenges including support persons’ inadequate autism knowledge, mutual miscommunication, and changes in relationship dynamics. If left unaddressed, these challenges may have a significant negative impact on both parties’ wellbeing and relationship quality. Newly diagnosed adults may benefit from advice on disclosing their diagnosis and take-home resources to help loved ones understand their diagnosis and support needs. For support persons, autism-informed individual counselling, family and relationship counselling, and support groups may help them improve wellbeing, maintain healthy relationships, and better support their loved ones.
Informal support from other autistic people helped fulfill adults’ need for social connection and belonging, consistent with Tan (2018). Autistic peers also provided knowledge and advice that helped fill the gap in autism-informed formal support. Somewhat unexpectedly, our participants reported some dissatisfactory experiences with informal autistic peer support, where people’s tendency to commiserate over negative experiences shifted the focus away from problem-solving. This has seldom been mentioned in previous research involving late-diagnosed adults, which tended to emphasize positive aspects of community and identity formation (Bargiela et al., 2016; Tan, 2018). Research in the general population suggested that while sharing negative emotions with others produced immediate relief and facilitated interpersonal bonding, it had little benefit for emotional recovery and may even promote negative emotions through rumination (Choi & Toma, 2014; Rimé, 2009). Anonymity has also been found to contribute to verbal aggression in online settings (Zimmerman & Ybarra, 2016). As support groups were highly desired by our participants, formal, structured group-based support co-led by professionals and autistic adults may help combine the benefits of autistic peer support with professional knowledge, while minimising unhelpful venting and conflict. Considering the variation in participants’ preferences and goals for attending a group, group facilitators need to work closely with members to ensure their needs are met, with the option of starting subgroups for people with specific needs or preferences if required.
Although the interview did not specifically mention societal attitudes, participants’ experiences of formal and informal support were often shaped by other people’s level of autism knowledge and acceptance. A common thread across both autistic adults’ and support persons’ responses was the need for positive autism awareness in society, which may have wide-reaching benefits for adults’ social relationships, formal and informal support, and employment. Misconceptions and overly narrow understandings of autism contributed to adults’ experiences of not having their needs taken seriously by professionals and social connections, preventing them from receiving support. As late diagnosis may be a result of having subtle or atypical autistic traits (Lai & Baron-Cohen, 2015), increasing community awareness of diverse presentations of autism may be especially important for individuals diagnosed in adulthood. Our data also highlighted consequences of autism stigma, where associating autism with incompetence made support persons reluctant to accept the diagnosis and adults less willing to seek support. As knowledge alone may have limited effectiveness at improving attitudes towards autistic people (Mac Cárthaigh & López, 2020), interventions incorporating components such as increased contact with autistic people (Shand et al., 2020) may be more effective at promoting positive understandings of autism in the wider community.
Our study highlighted several key differences in the experiences of autistic adults with and without intellectual disability. Adults with intellectual disability accessed a greater variety of formal support compared to adults without intellectual disability. This is consistent with quantitative research indicating that autistic individuals with intellectual disability had greater access to services than those without (Lai & Weiss, 2017; Zablotsky et al., 2015). Our participants with intellectual disability also received more informal assistance from family members, which often included managing formal support services. Although participants with intellectual disability enjoyed friendships with other autistic people, they were not always included or comfortable in autistic communities dominated by people without intellectual disability. This is consistent with research showing few social connections between people with intellectual disability and people without intellectual disability who were not staff or family members (Verdonschot et al., 2009). Our findings highlight the need for further research on the social needs and experiences of autistic adults with intellectual disability, with the goal of supporting their social participation and inclusion in a range of autism-specific and general settings.
Our study had several limitations. Although we reached out to intellectual disability organisations during recruitment, we were only able to interview a small number of adults with intellectual disability. The small sample size limited our ability to explore the support needs and experiences of late-diagnosed adults with intellectual disability in detail and compare them to adults without intellectual disability. Considering the under-representation of people with intellectual disability in autism research, further exploration of these adults’ experiences of autism diagnosis and subsequent support would help ensure their needs are addressed by diagnosticians and support services. Our sample of support persons was also small and only involved women. Some autistic adults in this study received no informal support, while others received low-level support from several individuals, meaning there was no designated support person role. In the case of autistic adults receiving significant informal support, it may have been difficult for support persons to find the time and energy to take part in an interview-based study. Less intensive data collection methods such as brief online surveys may be more suitable for this population.
The use of text-based and asynchronous modes of data collection in addition to traditional spoken interviews had both benefits and drawbacks. This was most evident in email interviews, where the letter format and time gaps between replies limited rapport-building and amount of detail in the data. However, the asynchronous nature gave participants more time to produce considered responses that conveyed their ideas more succinctly. It also allowed us to reach participants who may not have time or feel comfortable enough for a traditional interview. To compensate for the reduced amount of detail, future researchers may wish to expand sample sizes accordingly when using email-based interviews.
The small number of support persons in our study meant we were unable to explore relationship dynamics between autistic adults and support persons in detail. Future researchers examining informal support may wish to use autistic adult-support person dyads rather than individuals as the unit of analysis. Dyadic analysis would allow the researcher to triangulate both parties’ perspectives in relation to the same event or phenomenon (Eisikovits & Koren, 2010). Researchers will need to consider the choice of joint versus separate interviews carefully with regards to participant comfort, richness of data, and equal opportunities to contribute. This is especially important in autism research considering the historical dominance of parental narratives over autistic self-advocacy (Ward & Meyer, 1999).
Our study highlighted autistic adults’ and their loved ones’ difficulties finding suitable formal support after adulthood autism diagnosis. We also uncovered unique rewards and challenges of informal support from family, friends, and autistic peers. We look forward to future developments in research and practice that help address the diverse needs of late-diagnosed adults and their support persons.
Acknowledgements
This work was supported by the Cooperative Research Centre for Living with Autism (Autism CRC), established and supported under the Australian Government’s Cooperative Research Centres Program. The authors also acknowledge the financial support of the Australian Government Research Training Program. We thank Dr Ye In (Jane) Hwang for assistance with developing participant information documents, and Michael and Sharon Bartels, Matthew Bennett, Jen Harland, Julianne Higgins, Michael Knight, Joanne Mahony, and Chris Tanner for their advisory input into this project.
Author Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yunhe Huang. The first draft of the manuscript was written by Yunhe Huang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Ethics Approval
This study was approved by the UNSW Human Research Ethics Committee, number HC190582.
Consent to Participate/Publish
All participants provided informed consent to participate in the study and for the results to be published in a journal.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Alvares GA Bebbington K Cleary D Evans K Glasson EJ Maybery MT Pillar S Uljarević M Varcin K Wray J Whitehouse AJ The misnomer of ‘high functioning autism’: intelligence is an imprecise predictor of functional abilities at diagnosis Autism 2019 24 1 221 232 10.1177/1362361319852831 31215791
Anderson C Butt C Sarsony C Young adults on the autism spectrum and early employment-related experiences: aspirations and obstacles Journal of Autism and Developmental Disorders 2021 51 1 88 105 10.1007/s10803-020-04513-4 32356082
Arnold SRC Huang Y Hwang YI Trollor JN Richdale AL Lawson LP The single most important thing that has happened to me in my life”: Development of the impact of diagnosis scale—preliminary revision Autism in Adulthood 2020 2 1 34 41 10.1089/aut.2019.0059
Bagatell N From cure to community: transforming notions of autism Ethos 2010 38 1 33 55 10.1111/j.1548-1352.2009.01080.x
Baker, D. L. (2011). The politics of neurodiversity: why public policy matters. Lynn Rienner Publishers.
Baldwin S Costley D The experiences and needs of female adults with high-functioning autism spectrum disorder Autism 2016 20 4 483 495 10.1177/1362361315590805 26111537
Baldwin S Costley D Warren A Employment activities and experiences of adults with high-functioning autism and Asperger’s disorder Journal of Autism and Developmental Disorders 2014 44 10 2440 2449 10.1007/s10803-014-2112-z 24715257
Bargiela S Steward R Mandy W The experiences of late-diagnosed women with autism spectrum conditions: an investigation of the female autism phenotype Journal of Autism & Developmental Disorders 2016 46 10 3281 3294 10.1007/s10803-016-2872-8 27457364
Bergen N Labonté R “Everything is perfect, and we have no problems”: detecting and limiting social desirability bias in qualitative research Qualitative Health Research 2019 30 5 783 792 10.1177/1049732319889354 31830860
Birt L Scott S Cavers D Campbell C Walter F Member checking: a tool to enhance trustworthiness or merely a nod to validation? Qualitative Health Research 2016 26 13 1802 1811 10.1177/1049732316654870 27340178
Braun V Clarke V Using thematic analysis in psychology Qualitative Research in Psychology 2006 3 2 77 101 10.1191/1478088706qp063oa
Braun V Clarke V Reflecting on reflexive thematic analysis Qualitative Research in Sport Exercise and Health 2019 11 4 589 597 10.1080/2159676X.2019.1628806
Brooke V Brooke AM Schall C Wehman P McDonough J Thompson K Smith J Employees with autism spectrum disorder achieving long-term employment success: a retrospective review of employment retention and intervention Research and Practice for Persons with Severe Disabilities 2018 43 3 181 193 10.1177/1540796918783202
Chapman, R. (2019). Neurodiversity theory and its discontents: Autism, schizophrenia, and the social model of disability. In S. Tekin, & R. Bluhm (Eds.), The Bloomsbury companion to philosophy of psychiatry (pp. 371–389). Bloomsbury Academic.
Choi M Toma CL Social sharing through interpersonal media: patterns and effects on emotional well-being Computers in Human Behavior 2014 36 530 541 10.1016/j.chb.2014.04.026
Cimera RE Does being in sheltered workshops improve the employment outcomes of supported employees with intellectual disabilities? Journal of Vocational Rehabilitation 2011 35 21 27 10.3233/JVR-2011-0550
Crane L Batty R Adeyinka H Goddard L Henry LA Hill EL Autism diagnosis in the United Kingdom: perspectives of autistic adults, parents and professionals Journal of Autism and Developmental Disorders 2018 48 11 3761 3772 10.1007/s10803-018-3639-1 29948530
Eisikovits Z Koren C Approaches to and outcomes of dyadic interview analysis Qualitative Health Research 2010 20 12 1642 1655 10.1177/1049732310376520 20663940
Feilzer MY Doing mixed methods research pragmatically: implications for the rediscovery of pragmatism as a research paradigm Journal of Mixed Methods Research 2009 4 1 6 16 10.1177/1558689809349691
Griffith GM Totsika V Nash S Hastings RP ‘I just don’t fit anywhere’: support experiences and future support needs of individuals with Asperger syndrome in middle adulthood Autism 2012 16 5 532 546 10.1177/1362361311405223 21610188
Harvery M Froude EH Foley KR Trollor JN Arnold SRC Employment profiles of autistic adults in Australia Autism Research 2021 14 10 2061 2077 10.1002/aur.2588 34374491
Hatfield M Falkmer M Falkmer T Ciccarelli M Effectiveness of the BOOST-A™ online transition planning program for adolescents on the autism spectrum: a quasi-randomized controlled trial Child and Adolescent Psychiatry and Mental Health 2017 11 1 54 10.1186/s13034-017-0191-2 29051774
Hedley D Uljarević M Cameron L Halder S Richdale A Dissanayake C Employment programmes and interventions targeting adults with autism spectrum disorder: a systematic review of the literature Autism 2016 21 8 929 941 10.1177/1362361316661855 27542395
Hickey A Crabtree J Stott J ’suddenly the first fifty years of my life made sense’: experiences of older people with autism Autism 2018 22 3 357 367 10.1177/1362361316680914 29153003
Huang Y Arnold SRC Foley KR Trollor JN Diagnosis of autism in adulthood: a scoping review Autism 2020 24 6 1311 1327 10.1177/1362361320903128 32106698
Huang Y Arnold SRC Foley KR Trollor JN Choose your own adventure: pathways to adulthood autism diagnosis in Australia Journal of Autism & Developmental Disorders 2021 10.1007/s10803-021-05169-4
Jaarsma P Welin S Autism as a natural human variation: reflections on the claims of the neurodiversity movement Health Care Analysis 2012 20 1 20 30 10.1007/s10728-011-0169-9 21311979
Jiranek D Kirby N The job satisfaction and/or psychological well being of young adults with an intellectual disability and nondisabled young adults in either sheltered employment, competitive employment or unemployment Australia and New Zealand Journal of Developmental Disabilities 1990 16 2 133 148 10.1080/07263869000033951
Jones L Goddard L Hill EL Henry LA Crane L Experiences of receiving a diagnosis of autism spectrum disorder: a survey of adults in the United kingdom Journal of Autism & Developmental Disorders 2014 44 12 3033 3044 10.1007/s10803-014-2161-3 24915932
Kapp SK Gillespie-Lynch K Sherman LE Hutman T Deficit, difference, or both? Autism and neurodiversity Developmental Psychology 2013 49 1 59 71 10.1037/a0028353 22545843
Lai JKY Weiss JA Priority service needs and receipt across the lifespan for individuals with autism spectrum disorder Autism Research 2017 10 8 1436 1447 10.1002/aur.1786 28383156
Lai MC Baron-Cohen S Identifying the lost generation of adults with autism spectrum conditions Lancet Psychiatry 2015 2 11 1013 1027 10.1016/S2215-0366(15)00277-1 26544750
Leedham A Thompson AR Smith R Freeth M ‘I was exhausted trying to figure it out’: the experiences of females receiving an autism diagnosis in middle to late adulthood Autism 2019 24 1 135 146 10.1177/1362361319853442 31144507
Lewis LF Realizing a diagnosis of autism spectrum disorder as an adult International Journal of Mental Health Nursing 2016 25 4 346 354 10.1111/inm.12200 26940281
Lewis LF We will never be normal”: the experience of discovering a partner has autism spectrum disorder Journal of Marital and Family Therapy 2017 43 4 631 643 10.1111/jmft.12231 28394020
Lorenc T Rodgers M Marshall D Melton H Rees R Wright K Sowden A Support for adults with autism spectrum disorder without intellectual impairment: systematic review Autism 2017 22 6 654 668 10.1177/1362361317698939 28683565
Mac Cárthaigh S López B Factually based autism awareness campaigns may not always be effective in changing attitudes towards autism: evidence from british and south korean nursing students Autism 2020 24 5 1177 1190 10.1177/1362361319898362 31957462
Maguire E Mulryan N Sheerin F McCallion P McCarron M Autism spectrum disorder in older adults with intellectual disability: a scoping review Irish Journal of Psychological Medicine 2022 39 3 287 300 10.1017/ipm.2021.65 34612183
McCarthy J Hemmings C Kravariti E Dworzynski K Holt G Bouras N Tsakanikos E Challenging behavior and co-morbid psychopathology in adults with intellectual disability and autism spectrum disorders Research in Developmental Disabilities 2010 31 2 362 366 10.1016/j.ridd.2009.10.009 19954927
Meltzer A Kayess R Bates S Perspectives of people with intellectual disability about open, sheltered and social enterprise employment Social Enterprise Journal 2018 14 2 225 244 10.1108/SEJ-06-2017-0034
Nicolaidis C Raymaker D Kapp SK Baggs A Ashkenazy E McDonald K Weiner M Maslak J Hunter M Joyce A The AASPIRE practice-based guidelines for the inclusion of autistic adults in research as co-researchers and study participants Autism 2019 23 8 2007 2019 10.1177/1362361319830523 30939892
Patton, M. Q. (1990). Qualitative evaluation and research methods (2nd ed.). SAGE Publications.
Powell T Acker L Adults’ experience of an Asperger syndrome diagnosis: analysis of its emotional meaning and effect on participants’ lives Focus on Autism and Other Developmental Disabilities 2016 31 1 72 80 10.1177/1088357615588516
Punshon C Skirrow P Murphy G The not guilty verdict: psychological reactions to a diagnosis of Asperger syndrome in adulthood Autism 2009 13 3 265 283 10.1177/1362361309103795 19369388
Raymond-Barker P Griffith GM Hastings RP Biographical disruption: experiences of mothers of adults assessed for autism spectrum disorder Journal of Intellectual & Developmental Disability 2018 43 1 83 92 10.3109/13668250.2016.1262011
Rimé B Emotion elicits the social sharing of emotion: theory and empirical review Emotion Review 2009 1 1 60 85 10.1177/1754073908097189
Roy M Balaratnasingam S Missed diagnosis of autism in an australian indigenous psychiatric population Australasian Psychiatry 2010 18 6 534 537 10.3109/10398562.2010.498048 21117839
Rustad M Kassah KA Learning disability and work inclusion: on the experiences, aspirations and empowerment of sheltered employment workers in Norway Disability & Society 2021 36 3 399 419 10.1080/09687599.2020.1749564
Saemundsen E Juliusson H Hjaltested S Gunnarsdottir T Halldorsdottir T Hreidarsson S Magnusson P Prevalence of autism in an urban population of adults with severe intellectual disabilities - a preliminary study Journal of Intellectual Disability Research 2010 54 8 727 735 10.1111/j.1365-2788.2010.01300.x 20633201
Sandelowski M Sample size in qualitative research Research in Nursing & Health 1995 18 2 179 183 10.1002/nur.4770180211 7899572
Scott M Milbourn B Falkmer M Black M BÓ§lte S Halladay A Lerner M Taylor JL Girdler S Factors impacting employment for people with autism spectrum disorder: a scoping review Autism 2018 23 4 869 901 10.1177/1362361318787789 30073870
Shakespeare, T. (2017). The social model of disability. In L. J. Davis (Ed.), The disability studies reader (pp. 195–203). Routledge.
Shand, A. J., Close, S. A. D., & Shah, P. (2020). Greater autism knowledge and contact with autistic people are independently associated with favourable attitudes towards autistic people. Experimental Results, 1, 10.1017/exp.2020.46. e46, Article e46.
Southby K Robinson O Information, advocacy and signposting as a low-level support for adults with high-functioning autism spectrum disorder: an example from the UK Journal of Autism and Developmental Disorders 2018 48 2 511 519 10.1007/s10803-017-3331-x 29063482
Tan CD "I’m a normal autistic person, not an abnormal neurotypical”: Autism Spectrum Disorder diagnosis as biographical illumination Social Science & Medicine 2018 197 161 167 10.1016/j.socscimed.2017.12.008 29247898
Totsika V Felce D Kerr M Hastings RP Behavior problems, psychiatric symptoms, and quality of life for older adults with intellectual disability with and without autism Journal of Autism and Developmental Disorders 2010 40 10 1171 1178 10.1007/s10803-010-0975-1 20182784
Verdonschot MML De Witte LP Reichrath E Buntinx WHE Curfs LMG Community participation of people with an intellectual disability: a review of empirical findings Journal of Intellectual Disability Research 2009 53 4 303 318 10.1111/j.1365-2788.2008.01144.x 19087215
Walton KM Ingersoll BR Improving Social Skills in adolescents and adults with autism and severe to Profound Intellectual disability: a review of the literature Journal of Autism and Developmental Disorders 2013 43 3 594 615 10.1007/s10803-012-1601-1 22790427
Ward MJ Meyer RN Self-determination for people with developmental disabilities and autism: two self-advocates’ perspectives Focus on Autism and Other Developmental Disabilities 1999 14 3 133 139 10.1177/108835769901400302
Wehman P Schall CM McDonough J Graham C Brooke V Riehle JE Brooke A Ham W Lau S Allen J Avellone L Effects of an employer-based intervention on employment outcomes for youth with significant support needs due to autism Autism 2016 21 3 276 290 10.1177/1362361316635826 27154907
Zablotsky B Pringle BA Colpe LJ Kogan MD Rice C Blumberg SJ Service and treatment use among children diagnosed with autism spectrum disorders Journal of Developmental & Behavioral Pediatrics 2015 36 2 98 105 10.1097/dbp.0000000000000127 25650952
Zimmerman AG Ybarra GJ Online aggression: the influences of anonymity and social modeling Psychology of Popular Media Culture 2016 5 2 181 193 10.1037/ppm0000038
| 36484961 | PMC9734854 | NO-CC CODE | 2022-12-14 23:28:31 | no | J Autism Dev Disord. 2022 Dec 9;:1-14 | utf-8 | J Autism Dev Disord | 2,022 | 10.1007/s10803-022-05828-0 | oa_other |
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Global Surg Educ
Global Surgical Education - Journal of the Association for Surgical Education
2731-4588
Springer US New York
75
10.1007/s44186-022-00075-4
Original Article
How to say “I don’t know”: development and evaluation of workshops for medical students and surgical residents on communicating uncertainty using the ADAPT framework
Duval Margaret [email protected]
1
Zewdie Monica 2
Kapadia Muneera R. 3
Liu Chang 4
Mohess Denise 5
Bachman Sharon L. 4
Dort Jonathan 4
Newcomb Anna B. 6
1 grid.253615.6 0000 0004 1936 9510 George Washington University School of Medicine and Health Sciences, Washington, D.C. 20007 USA
2 grid.27755.32 0000 0000 9136 933X University of Virginia School of Medicine, Charlottesville, VA USA
3 grid.10698.36 0000000122483208 Department of Colorectal Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
4 grid.417781.c 0000 0000 9825 3727 Department of Surgery, Inova Fairfax Medical Campus, Fairfax, VA USA
5 grid.417781.c 0000 0000 9825 3727 Department of Medicine, Inova Fairfax Medical Campus, Fairfax, VA USA
6 grid.417781.c 0000 0000 9825 3727 Division of Trauma, Department of Surgery, Inova Fairfax Medical Campus, Falls Church, VA USA
3 12 2022
2023
2 1 126 5 2022
12 10 2022
8 11 2022
© The Author(s), under exclusive licence to Association for Surgical Education 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Purpose
Uncertainty, or the conscious awareness of having doubts, is pervasive in medicine, from differential diagnoses and the sensitivity of diagnostic tests, to the absence of a single known recovery path. While openness about uncertainty is necessary for shared decision-making and is a pillar of patient-centered care, it is a challenge to do so while preserving patient confidence. The authors’ aim was to develop, pilot, and evaluate an uncertainty communication curriculum to prepare medical students and residents to confidently navigate such conversations.
Methods
The authors developed ADAPT, a mnemonic framework to improve student comprehension and recall of the important steps in uncertainty disclosure: assess the patient’s knowledge, disclose uncertainty directly, acknowledge patient emotions, plan next steps, and temper expectations. Using this framework, the authors developed, piloted, and evaluated an uncertainty communications course as part of an ongoing communication curriculum for second year medical students in 2020 and with surgical residents in 2021.
Results
Learner confidence in uncertainty communication skills significantly increased post-class. Resident confidence in disclosing uncertainty was significantly correlated with observer ratings of their related communication skills during simulation. Students expressed positive experiences of the class, noting particular appreciation for the outline of steps included in the ADAPT framework, and the ability to observe a demonstration prior to practice.
Conclusions
The ADAPT communication curriculum was effective at increasing learner confidence and performance in communicating uncertainty. More rigorous evaluation of the ADAPT protocol will be important in confirming its generalizability.
Supplementary Information
The online version contains supplementary material available at 10.1007/s44186-022-00075-4.
Keywords
Communication training
Simulation
Uncertainty disclosure
Virtual education
issue-copyright-statement© The Author(s), under exclusive licence to Association for Surgical Education 2023
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pmcBackground
Uncertainty is defined as the conscious awareness of having doubts; it is pervasive in medicine, from differential diagnoses and the sensitivity of diagnostic tests, to the lack of a single known recovery path [1]. Given variability in patient responses to disease processes and interventions, virtually every decision in medical practice is made with a level of uncertainty [2]. However, clinicians often fail to communicate their uncertainty to patients: in one analysis of over 1000 encounters, PCPs and surgeons discussed the uncertainty surrounding their treatment plan in 1% of encounters for basic decisions, 6% for intermediate decisions, and 17% for complex decisions [3]. The hesitancy to discuss uncertainty may stem from a host of factors: the medical field culture to strive for perfection, fear of losing patient trust, or the lack of skills to have the complex conversation about uncertainty [4].
The ability to discuss uncertainty is critical to ensuring patient autonomy: shared decision-making necessitates transparency and is a pillar of patient-centered care. Moreover, discomfort expressing uncertainty within medical teams may lead to premature decision-making [5]. It is thus important to train students to accept and confidently navigate conversations surrounding uncertainty in a way that maintains, or even improves, the doctor-patient relationship, and facilitates shared decision-making [2]. Though previous studies have yielded inconsistent results on the effect of communicating uncertainty to patients [6], a 2017 systematic review concluded that studies unanimously found patient satisfaction and trust after physician disclosure of uncertainty to be dependent on how the uncertainty was communicated [7]. Such variability in patient response based on physician communication technique further indicates a need for standardized, evidence-based training on this important form of communication.
While the past decade has seen calls to increase inclusion of uncertainty topics in medical curricula, we were unable to identify established curricula in the literature regarding the communication of uncertainty. Given the growing importance of this communication topic noted in recent literature, and with suggestions from several surgical faculty—including a colorectal surgeon, acute care surgeon, and surgical residency program director, all in practice for over 10 years—we chose to introduce a module on discussing uncertainty in ongoing communication courses for medical students and surgical residents. Mnemonics and simulated patient practice have both been shown to enhance learners’ medical communication performance [8, 9]. Thus, we believed development of a mnemonic framework, coupled with simulated practice of our framework, would offer an effective method to teach communicating uncertainty. As the COVID-19 pandemic necessitated a move to online learning to comply with social distancing protocols, our aim was to design, pilot, and evaluate a framework for conversations about uncertainty in a virtual class for medical students, and to then implement a refined curriculum with surgical residents.
Methods
ADAPT framework development (Fig. 1)
Fig. 1 Adapting to uncertainty in medicine: a framework to tell patients “I don’t know”
We developed a mnemonic framework to assist students in approaching uncertainty conversations: a 20 min focus group workshop including surgeons, physicians, social workers, and patients created a list of steps they identified as necessary for physicians to take in uncertainty conversations and yielded a list of key teaching points. Four themes derived from the focus group were similar to the four broad domains listed in Simpkin and Armstrong’s narrative review on uncertainty communication strategies [2]; our focus group identified a fifth domain of tempering patient expectations. The final set of steps were worked into a mnemonic (ADAPT) for improved recall. Adaptability is an important skill to employ in situations without a known outcome, and the letters of ADAPT stand for the key uncertainty discussion steps: assess the patient’s current knowledge, disclose uncertainty directly, acknowledge patient emotions, plan next steps with patient, and temper expectations. These steps are both easy to recall and conform to important uncertainty discussion categories denoted in the existing literature [2].
Setting and communication program
The Inova Fairfax Medical Campus includes a level I trauma center and 900-bed tertiary care referral center. The hospital’s academic affiliation with the University of Virginia (UVA) School of Medicine enables students to engage in research and other educational opportunities at the hospital during the summer following their 1st year. As COVID-related restrictions limited medical student access to the campus, we invited second-year medical students (M2s) from the UVA and George Washington University (GWU) Schools of Medicine to participate in a virtual communication course in 2020. The Human Subjects Protection Program at Inova Health System approved this research as an exempt study of standard educational practices. Given positive feedback from the course pilot in July 2020, the course—including the module on uncertainty communication—was tested with the Inova surgical residents during their ongoing quarterly communication training program in April 2021.
Communication training for M2s included a five-session simulation-based curriculum using Zoom technology (San Jose, CA). The overarching skills focus for the course was “fostering a connection” with the patient and family in telemedicine appointments using empathic communication. Each class featured a unique communication task: bad news discussions, explaining complications, managing bias, apologizing for a mistake, and communicating uncertainty. Communication tasks were presented by a different specialist each class, including geriatrics, surgery, family medicine, pediatrics, and emergency medicine. The “Communicating Uncertainty” module was the final class presented over the summer. Faculty and students found that the 1 h allotted to the first four classes did not leave enough time for reflection and discussion; thus, this final class was elongated to 1.5 h.
This 1.5 h session began with a dual demonstration: an attending surgeon demonstrated communicating uncertainty to a patient and illustrated a few common errors; students then discussed what the surgeon did well and what improvements could be made. The surgeon followed with a demonstration of an ideal disclosure of uncertainty. A 10 min didactic discussion ensued, including explanation of the ADAPT framework for disclosing uncertainty (Fig. 1). Following this didactic discussion, students practiced communicating uncertainty with actors in small groups of 4–6 learners using Zoom breakout rooms; the scenario featured a recently admitted concussion patient’s parent calling the Emergency Department for information on their son’s prognosis. The student was instructed to answer their questions using the techniques described in the didactic session.
Each room was facilitated by one faculty member and featured two simulated patients (SPs). SPs were drawn from our pool of former-patient volunteers from the Trauma Survivors Network (TSN) [10] as well as staff members trained as actors for communication simulation. Prior to class, students were provided the scenario and “cheat sheet” of medical and communication tips (Supplemental Appendix 1). In breakout practice sessions, two students worked with an SP in a simulated video-consult for 5 min, then participated in a 10 min facilitated debriefing including time for self-reflection and feedback from peers, SPs, and the faculty member present. In a second round of simulated practice, a second set of students worked with an SP on a voice call (without video). All groups then returned to the main room for a large group discussion and facilitated reflection (Supplemental Appendix 2).
The surgical residency in-person “Uncertainty” module was implemented as part of an ongoing communication curriculum, the structure of which has been fully described previously [11, 12]. Updates in educational content for the resident module included: residents were not provided with a “cheat sheet” prior to class; practice scenarios were conducted by one resident at a time; all practice scenarios were conducted as an in-person conversation; time was increased to 2 h to allow increased time for feedback of student performance and reflective discussion. All other educational elements remained the same as in the medical student pilot, including the didactic portion with demonstration, breakout rooms with actors and facilitators, and a final debriefing session.
Learner confidence and curriculum feedback
Learners rated their confidence levels on four module-specific skill objectives before and after the session using Likert-type items rated from 1, “no confidence/can’t do it,” to 5, “completely confident/can do it without a problem.” These included skills related to the ADAPT framework, including assessing understanding before sharing new information, directly communicating uncertainty, helping patients develop realistic expectations, and exploring the patient’s story when they are upset or distressed. Upon completion of the module, learners rated the session for its contribution to their skill set, graded the course from A + to F, and provided open-ended feedback. The post-session M2 reflection discussion in 2020 was also captured and transcribed for analysis.
We calculated medians and interquartile ranges (IQRs) for the pre- and post-module skill confidence assessment scores for both the medical students and residents, and further compared these data using Wilcoxon signed rank test. P values of less than 0.05 were considered statistically significant. We report M2 feedback on the curriculum using descriptive statistics and summaries of qualitative open-ended comments. All statistical analyses were conducted in R 3.3.2 [13].
Resident skill assessment
At the in-person residency module, we measured learner communication skill using the 14-item Communication Assessment Tool (CAT), a previously validated instrument developed as a patient assessment of physician interpersonal communication skills [14]. The CAT has been validated for use in simulation [11, 14, 15] and recommended for inclusion in the ACGME toolbox by the ACGME Advisory Committee on Educational Outcome Assessment [16]. Simulation observers and SPs completed the CAT following the student’s interview with the SP.
Residents’ pre-module skill confidence was compared to each CAT item to identify how pre-module confidence influenced specific behaviors during their interview, as rated using the CAT. To identify more granular changes in resident confidence, we compared pre and post-module top box scores (those self-rating as “completely confident” in the skill), using McNemar’s test to calculate P values. Of note, this analysis was inappropriate for the M2 class, as none of the M2 learners were “completely confident” before class. Generalized linear mixed models were used to assess the impact of the individual pre-module confidence on each CAT item, where the outcomes variables were the CAT item assessments (dichotomized as 5 vs 1–4). Pre-module confidence was included as a fix effect (dichotomized as 5 vs 1–4) and random effects were included to account for the intra-subject correlations among the assessments contributed by the same subject. Odds ratios for obtaining a CAT assessment equal to 5 for subjects with a pre-module confidence score equal to 5 compared with subjects with pre-module confidence score ranging from 1 to 4 were reported, along with 95% confidence intervals (CI).
Results
Learner confidence and course grade
In our M2 pilot course, 28 students attended class. As this was the final class of 5 weekly modules, only six students (21%) completed the optional pre- and post-module surveys. While student comfort and engagement appeared to increase during class over time, survey response rate decreased over the summer. Prior to the class, students’ median confidence in communicating uncertainty was 2 (where 1 was “no confidence” and 5 was “complete confidence”) with an IQR of 2–2.75. After class, student median confidence increased to 4 [IQR 3.25–4] (P = 0.053). We also assessed student confidence in other communication skills included in the ADAPT framework, including: assessing patient understanding (pre-module median confidence was 3 [IQR 3–3]; post-module median confidence was 4 [4–4]; P = 0.089), providing realistic expectations (2 [2–2] pre; 3 [3–3.75] post; P = 0.053), and exploring emotions (3 [2.25–3] pre; 3.5 [3–4] post; P = 0.037). All students rated the class an “A” or “A+” and noted that the course exposed them to new skills.
In our surgical residency module, 24 learners attended class and 15 (63%) completed the pre- and post-module confidence surveys. Not surprisingly, resident pre-module confidence was higher than that for M2 learners; resident median confidence in communicating uncertainty increased from 4 [4–4] pre-module to 5 [4–5] after (P = 0.008). Confidence in other communication skills also significantly increased, including assessing understanding (4 [4–4.5] pre to 5 [4.5–5] post; P value 0.018), developing realistic expectations (4 [3–4] to 5[4–5]; P = 0.007), and exploring emotions (4 [4–4] to 5 [4–5]; P = 0.009). Eleven residents (73%) rated the class an A or A+, three (20%) a B or C. Figure 2 displays the combined scores of both groups’ pre- and post-module confidence scores.Fig. 2 Combined M2, resident self-reported confidence scores in uncertainty communication skills before and after class
Resident pre-confidence vs. CAT skills assessment (Table 1)
Table 1 Resident “Uncertainty” module results: Communication Assessment Tool vs. Pre-Class Confidence Scores
CAT Item Pre-confidence items
Assess p/f understanding before sharing new information Directly communicate uncertainty to p/f Explore p/f story when they are upset or distressed
OR 95% CI P OR 95% CI P OR 95% CI P
Greeted me in a way that made me feel comfortable 3.44 0.11, 103.76 0.477 1.41 0.06, 33.28 0.83 3.44 0.11, 103.7 0.477
Treated me with respect 2.18 0.06, 78.815 0.67 3.14 3.11, 3.17 < 0.001 2.18 0.06, 78.82 0.67
Showed interest in my ideas about my health 2.97 0.11, 77.66 0.513 0.73 0.03,16.59 0.846 2.97 0.11, 77.6 0.513
Understood my main health concerns 1.92 0.04, 83.1 0.734 1.13 0.03,43.81 0.947 0.43 0.01, 19.9 0.669
Paid attention to me (looked at me, listened carefully) 1.63 1.62, 1.65 < 0.001 2.26 0.08,60.48 0.628 1.63 1.62, 1.65 < 0.001
Let me talk without interruptions NA NA NA NA NA NA 0.17 0.00, 21.39 0.475
Gave me as much information as I wanted NA NA NA 3.13 0.05,211.9 0.596 1.13 0.01, 101.6 0.957
Talked in terms I could understand NA NA NA NA NA NA NA NA NA
Checked to be sure I understood everything 3.53 0.24, 51.05 0.355 2.22 0.17,29.55 0.546 0.93 0.05, 17.41 0.96
Encouraged me to ask questions 2.37 0.24, 23.80 0.463 1.5 0.17, 13.41 0.716 0.67 0.05, 98.69 0.756
Involved me in decisions as much as I wanted 0.7 0.038, 12.77 0.806 0.49 0.03, 8.07 0.618 2.68 0.18, 39.78 0.474
Discussed next steps, including any follow-up plans 0.72 0.037, 13.79 0.825 4.51 0.37,54.51 0.237 NA NA NA
Showed care and concern NA NA NA NA NA NA 1.1 0.03, 41.02 0.957
Spent the right amount of time with me 1.86 0.06, 54.89 0.719 NA NA NA 0.45 0.02, 10.87 0.622
Statistically significant P values in bold
Residents self-identifying as “completely confident” at “assessing the patient/family understanding before sharing new information” were 60% more likely to be rated “excellent” at “paying attention (looking, and listening carefully)” by their SP and observers on the CAT (CI 1.62, 1.65; P < 0.001). Those “completely confident” at “exploring the patient/family story when they are upset or distressed” were also 60% more likely to be rated “excellent” at paying attention (CI 1.62, 1.65; P < 0.001). Those “completely confident” at “directly communicating uncertainty” were three times as likely to be rated “excellent” at “treating me with respect” by their SP and observers (CI 3.11, 3.17; P < 0.001). None of the residents self-rated as “completely confident” regarding their ability to “Help the patient/family develop realistic expectations” before the class.
Student experience and lessons learned
Open-ended feedback from the post-session M2 debrief and survey provided further insight on participant experiences (additional illustrative quotes in Table 2). Overall, students expressed a positive experience:This session was great… It is important for us to be open and honest with our patients and their families.
Table 2 Additional medical student and medical faculty uncertainty communications class feedback from post-class discussion and written evaluations collected in July, 2020
Important teaching points emphasized by faculty Use your open-ended questions to explore what is the most worrisome about the situation
It is telling people that you do not know either, but that whatever happens, we will have a plan for that contingency
What patients really notice, even if you are rushed, if you pay attention to them and the words you use when you talk to them… this was aiming to give you skills to make people feel comfortable, even if you are uncomfortable—because you will be uncomfortable for the next several years!
I think people forgive you for uncertainty. What people do not forgive you for is poor communication
I have to assess surgeons on 19 competencies, and of those 19, 1 involves technical skills… several of them involve communications… These skills are so critical and vital and you cannot start learning them early enough in your training
Student experiences I really like the interviews—that definitely should stay
I… like when we had a list right before we went into interviews with…the points we should hit
I loved having the cheat sheets… and scenarios…, but I think it would enhance our “to go” skills if there were surprise cases
I would not have thought to bring up patient privacy rights but it’s a really important topic to discuss when it comes to disclosure to family
Students noted that having access to the ADAPT framework was helpful in their practice:[The framework] helped me to come up with a strategy for different situations like uncertainty.
Students emphasized that seeing a demo scenario prior to practicing with SPs was particularly helpful:I really liked how… we had example cases… I really liked seeing… here’s what you might be inclined to do and here’s what would be ideal to do.
Students also appreciated having the opportunity to practice both with and without video:I really appreciated that… we had one practice scenario with video and one without… phone calls will always be a part of our practice.
Our surgery faculty reiterated the importance of communicating uncertainty, and emphasized key teaching points:I think people forgive you for uncertainty. What people don’t forgive you for is poor communication.
Discussion
Though levels of uncertainty guide virtually every medical decision, medical education has historically emphasized a black-and-white approach: classic clinical vignettes and multiple choice exams lead students to become used to the idea that there is a clear, correct answer for every problem [4]. Such paradigms encouraging the existence of certainty poorly prepare students for the reality of uncertainty they face upon engaging in patient care; this leads to student feelings of inadequacy and anxiety, and to a constant quest for unattainable perfection, which in turn leads to burnout [17].
We present a conceptual framework and class design to allow easier implementation of important uncertainty curricula in medical training programs. First, we recommend a class that is at least 1.5 h in length to ensure enough time for feedback and discussion. Second, we recommend opening the class with a demonstration of appropriate uncertainty communication from a faculty member; our students were overwhelmingly appreciative of seeing an example on which to guide their practice. We further recommend including a list of discussion steps, such as the ADAPT framework. The ADAPT framework is a literature-based mnemonic summary of the important steps in an uncertainty discussion and was helpful to our students in digesting the lesson and in retaining and implementing key points during their practice. Observed practice with SPs in small groups, followed by immediate faculty and SP feedback, is also widely accepted as an important communication course tool, allowing solidification of theoretical concepts [18]. While in-person simulation is a preferred learning environment for skills practice, communication skills can be effectively taught virtually when breakout rooms are used for small-group practice and a facilitator is assigned to each room.
Importantly, our results suggest a significant link between learner confidence prior to skills practice and observer/SP-assessment of their skills demonstration, validating the importance of assessing and addressing skills confidence. Overall, learner confidence in communicating uncertainty significantly increased after learning and practicing the ADAPT framework for both M2 and resident groups. Confidence in all other communication areas assessed also significantly increased. In addition, our results highlight the significant increase in students who reported feeling “completely confident” in the emphasized communication skills from pre- to post-class. As the ultimate goal of any curriculum is for students to leave feeling “completely confident” in implementing their newly learned skill, we believe this result further demonstrates the efficacy of our curriculum.
Our team presented an uncertainty communication module centered around the ADAPT framework to a second year of medical students; analysis of student confidence and feedback data is ongoing and will be presented in a future manuscript. We plan to incorporate ADAPT modules with tailored role play scenarios into continuing education of medical students, residents, attendings, and other healthcare workforce members; we anticipate this framework will similarly improve uncertainty communication in these groups, given that comparable curricular designs have increased communication knowledge and confidence in residents, nurses, and attending physicians alike [19, 20]. We believe ADAPT will prove to be a useful tool for educators as they present the myriad important uncertainty-related communication topics, including prognosis and end-of-life issues.
Overall, the course design presented requires limited time, materials, and faculty, and provides a feasible path to implement important uncertainty communication curricula in a virtual or in-person setting.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 Student Practice Scenario and Cheat Sheet from Medical Uncertainty Communications Class, July 2020. (DOCX 19 KB)
Supplementary file2 Managing Simulation Using Zoom Breakout Rooms. (DOCX 53 KB)
Acknowledgements
The authors would like to acknowledge the volunteer actors and patients who made this module possible, including Bob Baldassari, Melissa Blazic, Kelvin Centeno, Jane Harrison, Heather Hunn, Kelly Lang, John Opitz, Leon Ransome, and Richard Schiller.
Funding
None.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
The author declares that they have no conflict of interest.
Ethical approval
The Inova Institutional Review Board reviewed the study (IRB #U20-04-3993) and deemed the project exempt on July 9, 2020.
Data
No data were accessed from outside sources.
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References
1. Hatch S Uncertainty in medicine BMJ 2017 357 j2180 10.1136/bmj.j2180 28495912
2. Simpkin AL Armstrong KA Communicating uncertainty: a narrative review and framework for future research J Gen Intern Med 2019 34 11 2586 2591 10.1007/s11606-019-04860-8 31197729
3. Braddock CH Edwards KA Hasenberg NM Laidley TL Levinson W Informed decision making in outpatient practice: time to get back to basics JAMA 1999 282 24 2313 2320 10.1001/jama.282.24.2313 10612318
4. Simpkin AL Schwartzstein RM Tolerating uncertainty—the next medical revolution? N Engl J Med 2016 375 18 1713 1715 10.1056/NEJMp1606402 27806221
5. Simpkin AL Murphy Z Armstrong KA A randomized experimental study to assess the effect of language on medical students’ anxiety due to uncertainty Diagnosis 2019 6 3 269 276 10.1515/dx-2018-0050 30753157
6. Ogden J Fuks K Gardner M Doctors expressions of uncertainty and patient confidence Patient Educ Couns 2002 48 2 171 176 10.1016/s0738-3991(02)00020-4 12401420
7. McGovern R Harmon D Patient response to physician expressions of uncertainty: a systematic review Ir J Med Sci 2017 186 4 1061 1065 10.1007/s11845-017-1592-1 28271278
8. Marschollek P Bąkowska K Bąkowski W Marschollek K Tarkowski R Oncologists and breaking bad news-from the informed patients’ point of view. The evaluation of the SPIKES protocol implementation J Cancer Educ 2019 34 2 375 380 10.1007/s13187-017-1315-3 29399734
9. Kaplonyi J Bowles KA Nestel D Understanding the impact of simulated patients on health care learners’ communication skills: a systematic review Med Educ 2017 51 12 1209 1219 10.1111/medu.13387 28833360
10. Trauma Survivors Network. Home. 2021. https://www.traumasurvivorsnetwork.org/pages/home. Accessed 26 Jan 2021.
11. Trickey AW Newcomb AB Porrey M Wright J Bayless J Piscitani F Graling P Dort J Assessment of surgery residents’ interpersonal communication skills: validation evidence for the communication assessment tool in a simulation environment J Surg Educ 2016 73 6 e19 e27 10.1016/j.jsurg.2016.04.016 27216300
12. Newcomb AB Trickey AW Porrey M Wright J Piscitani F Graling P Dort J Talk the talk: implementing a communication curriculum for surgical residents J Surg Educ 2017 74 2 319 328 10.1016/j.jsurg.2016.09.009 27825662
13. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. 2014. https://stat.ethz.ch/pipermail/r-help/2014-October/422975.html. Accessed 26 Jan 2021.
14. Makoul G Krupat E Chang CH Measuring patient views of physician communication skills: development and testing of the communication assessment tool Patient Educ Couns 2007 67 3 333 342 10.1016/j.pec.2007.05.005 17574367
15. Stausmire JM Cashen CP Myerholtz L Buderer N Measuring general surgery residents’ communication skills from the patient’s perspective using the communication assessment tool(CAT) J Surg Educ 2015 72 1 108 116 10.1016/j.jsurg.2014.06.021 25139607
16. Swing SR Clyman SG Holmboe ES Williams RG Advancing resident assessment in graduate medical education J Grad Med Educ 2009 1 2 278 286 10.4300/JGME-D-09-00010.1 21975993
17. George RE Lowe WA Well-being and uncertainty in health care practice Clin Teach 2019 16 4 298 305 10.1111/tct.13051 31295790
18. Passiment M Sacks H Huang G Medical simulation in medical education results of an AAMC survey 2011 Washington, DC Association of American Medical Colleges
19. Allenbaugh J Spagnoletti CL Rack L Rubio D Corbelli J Health literacy and clear bedside communication a curricular intervention for internal medicine physicians and medicine nurses MedEdPORTAL. 2019 15 10795 10.15766/mep_2374-8265.10795 30800995
20. Allenbaugh J Corbelli J Rack L Rubio D Spagnoletti C A brief communication curriculum improves resident and nurse communication skills and patient satisfaction J Gen Intern Med 2019 34 7 1167 1173 10.1007/s11606-019-04951-6 30997637
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==== Front
J Neurol
J Neurol
Journal of Neurology
0340-5354
1432-1459
Springer Berlin Heidelberg Berlin/Heidelberg
36477636
11499
10.1007/s00415-022-11499-9
Original Communication
Profile of precipitating factors and its implication in 160 Indian patients with Moyamoya angiopathy
http://orcid.org/0000-0001-9075-2000
Das Shambaditya [email protected]
1
http://orcid.org/0000-0003-2063-8370
Ray Biman Kanti [email protected]
1
http://orcid.org/0000-0003-3738-4741
Pandit Alak [email protected]
1
http://orcid.org/0000-0002-8192-0807
Ghosh Ritwik [email protected]
2
Diehl Rolf [email protected]
3
http://orcid.org/0000-0003-1733-3429
Dubey Souvik [email protected]
1
http://orcid.org/0000-0002-5667-3621
Kraemer Markus [email protected]
34
1 grid.414764.4 0000 0004 0507 4308 Department of Neurology, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal India
2 grid.413141.2 0000 0004 1792 3733 Department of General Medicine, Burdwan Medical College and Hospital, Burdwan, West Bengal India
3 Department of Neurology, Alfried Krupp von Bohlen und Halbach Hospital Essen, Alfried Krupp Strasse 21, 45130 Essen, Germany
4 grid.411327.2 0000 0001 2176 9917 Medical Faculty, Neurology, Heinrich Heine University of Duesseldorf, Düsseldorf, Germany
7 12 2022
18
12 6 2022
20 11 2022
21 11 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Introduction
Moyamoya angiopathy (MMA) has been known to manifest with myriad of neurological manifestations, often in association with various precipitating factors. This is the first study to systematically analyze the precipitating triggers to neurological symptoms done on the largest cohort of MMA in India.
Methods
A single-centered, cross-sectional observational study, recruiting 160 patients with consecutive angiographically proven MMA over a period of 5 years (2016–2021), was undertaken to evaluate the profile of immediate precipitating factors in temporal association to the neurological symptoms, along with their clinical and radiological characteristics. SPSS 25 was used for statistical analysis.
Results
Among the 160 patients (Adult-85, children-75), precipitating factors were seen in 41.3%, significantly higher in children (52%) than adults (31.8%) (p value: 0.011). The commonest triggers included fever (18.8%), emotional stress (8.1%), heavy exercise and diarrhea (6.3% each). Cold bath triggered MMA symptoms in 1.3%. Fever (p value: 0.008) and persistent crying (p value: 0.010) triggered neurological symptoms more commonly in children than in adults. Amongst MMA patients with precipitating factors, the commonest MMA presentation included cerebral infarction type (37.9%) and TIA (31.8%). The majority of precipitating factors that preceded an ischemic event were BP-lowing ones (54.7%).
Conclusion
Neurological symptoms of MMA are commonly associated with several precipitating factors, including the lesser known triggers like cold bath. The frequency and profile precipitating factors varies with the age of presentation and type of MMA. It can serve as an early clue to the diagnosis of MMA and its careful avoidance can be largely beneficial in limiting the distressing transient neurological symptoms.
Keywords
Moyamoya angiopathy
Precipitating factor
Moyamoya disease
Spicy food
Fever
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pmcIntroduction
Moyamoya angiopathy (MMA) is a chronic, progressive intracranial vasculopathy characterized by steno-occlusive lesions of intracranial anterior circulation large vessels with compensatory collateral formation [1–4]. Chronic cerebral hypoperfusion secondary to both occlusion and steal phenomenon leads to ischemic presentation in MMA, and is seen in both adults and children [5–7]. The neurological manifestations in MMA has been closely described in association with several precipitating factors like fever, diarrhea, heavy exercise, crying and hyperventilation, spicy food intake and hot bath [8, 9]. Recently, the precipitation of MMA following Covid-19 vaccination has also been described [10]. However, literature pertaining to the exact frequency of precipitating factors and its clinical implication is sparse. Ours is the first study to systematically analyze the specific triggers to neurological symptoms in MMA, done in the largest cohort of MMA patients in India. We also herein report cold bath as a trigger to neurological symptoms in MMA, which to the best of our knowledge has not been described previously.
Methodology
A descriptive, observational, cross-sectional study was undertaken from a single, tertiary-care-centre (Bangur Institute of Neurosciences, Kolkata) over a period of 5-years (2016–2021) recruiting 160 consecutive angiographically proven MMA patients with bilateral disease. Each patient was scrutinized for clinical and radiological characteristics. Perfusion study in the form of Single-photon emission computerized tomography (SPECT) was done for cerebral blood flow and cerebrovascular reserve index. All of them were systematically questioned regarding any precipitating factor which occurs in temporal association to the neurological symptoms in the patient (Table 1). The documentation was based on the history given by patient’s kin (for children with MMA) or self-recollection for adult patients. The precipitating factor was considered if it occurred within 15 min prior to onset of neurological symptoms. Exception was made for fever and diarrhea as precipitating factors, for which latency was considered as within hours. Fever was defined as oral temperature greater than 37.7 °C (> 99.9 °F). Diarrhea was defined as 3 or more loose stools per day. For rest of the precipitating factors, standardization was not possible due to cultural and social heterogeneity. Their mere presence or absence from a qualitative history was considered for the study. Thorough investigations were done to identify any secondary cause of MMA. All additional work-up was done depending on the clinical need case-to-case basis. All patient with history of precipitating factors were followed up for 6 months and reassessed in terms of frequency and duration of episodes of perfusion-dependent transient neurological symptoms (TIA, vascular type headache, transient EPS like chorea) in comparison to their status at diagnosis and any new onset fixed neurological symptom (fixed motor weakness, visual symptoms excluding amaurosis fugax, cognitive decline, fixed extra-pyramidal symptoms). SPSS 25 was used for statistical analysis. Data were summarized by routine descriptive statistics, namely mean and standard deviation for numerical variables that are normally distributed, median and inter-quartile range (IQR) for skewed numerical variables and counts and percentages for categorical variables. Numerical variables were compared between two groups by Student’s independent samples t test, if normally distributed, or by Mann–Whitney U test, if otherwise. For multiple group comparison of skewed variables, Kruskal–Wallis ANOVA was used followed by Dunn’s test for post hoc comparisons between two individual groups. Fischer’s exact test or Pearson’s Chi-square test were employed for intergroup comparisons of categorical variables. Analyses were two-tailed and statistical significance level was set at p < 0.05 for all comparisons. The study was undertaken following the consent of institutional ethical committee.Table 1 Questionnaire regarding the precipitating factor occurring in temporal association to the neurological symptoms
Did you have neurological symptoms (TIA, vascular type headache, transient or fixed EPS like chorea, fixed motor weakness or cognitive and behavioral symptoms) following occurrence of-
1. Fever Yes/no
2. Exercise Yes/no
3. Spicy food Yes/no
4. Hot bath Yes/no
5. Cold bath Yes/no
6. Crying Yes/no
7. Emotional stress Yes/no
8. Diarrhea Yes/no
Results
Among the 160 MMA patients, all the patients had bilateral disease, 85 had adult-onset MMA and 75 had childhood-onset MMA. The presence of immediate precipitating factor was seen in 66 (41.3%) out of the 160 MMA patients, significantly higher among children (52%) than adults (31.8%) (p value 0.011). The commonest triggers included fever (18.8%), emotional stress (8.1%), heavy exercise and diarrhea (6.3% each). The precipitation of MMA symptoms in temporal relation to fever and persistent crying was significantly higher in children than adults (p-value 0.008 and 0.010 respectively). Amongst the MMA cohort with presence of precipitating factor, mean age of onset of first neurological symptoms was 15.9 ± 15.9 years (median 9.0 years, range 3.5–24.3 years), followed by mean interval of 32.2 ± 58.6 months (median 12.0 months, range 0.0–36.0 months) and ultimately final diagnosis occurred at the mean age of 18.6 ± 16.3 years (median 12.0 years, range 4.8–31.5 years). The presence of one and two precipitating factors were seen in 72.7% and 19.7% patients with triggers respectively, while three or more triggers were seen in 7.6%, no significant differences in adult or child was noted. There was no instance of simultaneous occurrence of two or more trigger in any of our patient. The commonest MMA types associated with precipitating factors were cerebral infarction and TIA comprising of 37.9% and 31.8% of MMA cohort with triggers respectively. Baseline bihemispheric cerebral hypoperfusion was noted in 77.3%, while absence of hypoperfusion was noted in 4.5% of MMA patients with trigger. A presence of precipitating factor lowering blood pressure (BP) (fever, hot bath) was noted in 54.7% of ischemic events (p value 0.579), compared to presence of precipitating factor known to elevate blood BP (exercise, emotional stress) which was seen in of 28.3% of ischemic events (p value 0.080), amongst the MMA cohort with triggers. Hemorrhagic event was seen in only 2 out of the 66 patients with triggers. Results of base-line characteristics are summarized in Tables 2, 3, 4.Table 2 Frequency of precipitating factors in the whole cohort
Overall (n = 160) Adult (n = 85) Child (n = 75) p value
Precipitating factor
Present 66 (41.3%) 27 (31.8%) 39 (52.0%) 0.011
Absent 94 (58.7%) 58 (68.2%) 36 (48.0%)
Table 3 List and frequency of precipitating factors among children and adult:
Overall (n = 160) Children (n = 75) Adults (n = 85) p value
Precipitating factor history
1. Fever 30 (18.75) 21 (28.00) 9 (10.59) 0.008
2. Heavy exercise 10 (6.25) 5 (6.67) 5 (5.88) 1.000
3. Spicy food 12 (7.50) 9 (12.00) 3 (3.53) 0.068
4. Hot bath 8 (5.00) 5 (6.67) 3 (3.53) 0.476
5. Cold bath 2 (1.25) 2 (2.67) – 0.218
6. Crying 6 (3.75) 6 (8.00) – 0.010
7. Emotional stress 13 (8.13) 3 (4.00) 10 (11.76) 0.087
8. Diarrhea 10 (6.25) 5 (6.67) 5 (5.88) 1.000
Table 4 Baseline clinical characteristics, number of precipitating factor in each patient, distribution of precipitating factor in relation to the type of MMA presentation and perfusion status at base-line in the cohort of MMA patients with history of precipitating factor:
Overall (n = 66) Adult (n = 27) Child (n = 39) p value
1. Sex ratio (male:female) 1:2 1:2.9 1:1.6 0.288
2. Area of residence
Rural 69.7% 70.4% 69.2%
Urban 30.3% 29.6% 30.8%
3. Mean age at onset of first neurological symptoms (years) 15.9 ± 15.9
Median with range: 9.0 (3.5–24.3)
32.0 ± 12.8
Median with range: 32.0 (19.0–42.0)
4.8 ± 3.0
Median with range: 4.0 (2.5–6.5)
4. Mean age at diagnosis (years) 18.6 ± 16.3
Median with range: 12.0 (4.6–31.5)
34.0 ± 13.2
Median with range: 37.0 (21.0–45.0)
7.9 ± 7.1
Median with range: 6.0 (3.5–11.0)
5. Latency: First appearance of neurological symptoms to confirmed diagnosis (months) 32.2 ± 58.6
Median with range: 12.0 (0–36.0)
25.1 ± 48.8
Median with range: 12.0 (0–24.0)
37.2 ± 64.7
Median with range: 12.0 (0–36.0)
6. Number of precipitating factors
(a) One 48 (72.7%) 22(81.5%) 26(66.7%) 0.334
(b) Two 13 (19.7%) 3(11.1%) 10(25.6%)
(c) Three or more 5 (7.6%) 2(7.4%) 3(7.7%)
7. Presence of precipitating factor according disease presentation type
(a) TIA 21(31.8%) 8(29.6%) 13(33.3%) 0.751
(b) Cerebral infarction 32(48.5%) 9(33.3%) 23(59.0%) 0.040
(c) Hemorrhage 2(3.0%) 2(7.4%) 0 0.084
(d) Headache 11(16.7%) 8(29.6%) 3(7.7%) 0.019
8. Cerebral Perfusion status at baseline
(a) Bihemispherical hypoperfusion 51 (77.3%) 19(70.4%) 32(82.1%) 0.359
(b) Unihemispherical hypoperfusion 12 (18.2%) 7(25.9%) 5(12.8%)
(c) No hypoperfusion 3 (4.5%) 1(3.7%) 2(5.1%)
Reassessment at follow-up after 6 month period revealed, among the 66 MMA patients with history of precipitating factor, none of them had any new onset of fixed neurological symptom, while 28 (42.4%) of them had decrease (either in frequency or severity or both)in their perfusion-dependent transient neurological symptom (TIA or headache).
Case presentation: A 5-year-old boy from rural Bengal presented to us with five episodes of transient left hemiparesis with slurring of speech and one episode of right fixed hemiparesis in the last 10 months. On detailed history-taking, the mother revealed that all the episodes have occurred during or immediately following bath in cold water. Magnetic resonance imaging (MRI) brain revealed T2/FLAIR multiple foci of white matter signal changes in the right subcortical, periventricular region with cystic changes. Magnetic resonance angiography (MRA) showed occlusive changes involving bilateral distal ICA, proximal MCA and right ACA, with collateral formation, suggestive of MMA. Brain SPECT revealed reduced perfusion with significantly impaired cerebral vascular reserve in bilateral ACA and MCA territories. The patient’s kin was counseled in details regarding the avoidance of cold water bath. The patient had no further TIA or new-onset fixed neurological deficit at 6 month follow-up period.
Discussion
MMA can be considered as a model of hemodynamic insufficiency, wherein depending on the adequacy of collateral status, reduced cerebral perfusion pressure and ultimately decreased blood flow may occur distally. Despite autoregulatory vasodilation and increased oxygen extraction fraction acting as compensatory mechanisms, impaired hemodynamics lends a major risk of future cerebrovascular events in these patients [11]. Kraemer et al. observed evidence of syncope in 6.5% of its MMA patients hinting towards a heightened intolerance to orthostatic maneuvers in MMA [6]. MMA often manifests itself, in the face of transient changes in cerebral hypoperfusion caused by various triggering factors, with wide array of paroxysmal and fixed neurological symptoms, depending on the severity and duration of changes in the already compromised cerebral perfusion [7, 12–14]. A history of immediate precipitating factor was observed in 41.3% of MMA in our cohort, more frequently in children than adults (p-value 0.011). Thus, it is a frequent finding in MMA. But it is commonly over-looked, possibly due lack of awareness on the part of treating physician of its high incidence and its clinical implication in MMA [5]. Also, younger patients fail to appreciate these triggers themselves, only to be picked up by their vigilant guardians later in the course of the disease and it is also not infrequent for the patients to think that these triggers are unrelated.
Dynamic cerebral autoregulation (CA) normally maintain cerebral blood flow (CBF) homeostasis in normal population. However, it has been seen that dynamic CA is limited in MMA and dynamic, short (± 10–20% of mean arterial pressure) blood pressure (BP) changes can markedly affect CBF (± 10–15%), making them susceptible to hypoperfusion or hyperperfusion related cerebral insults. Thus, maintenance of a strict BP becomes imperative in this population to avoid neurological complications [15]. It may be interesting to note the triggers known to elevate BP like emotional stress and exercise preceded the hemorrhagic events among the two cases in our cohort. Similarly, BP lowering precipitating factors was commoner amongst patients with ischemic events in temporal association than BP elevating factors in our cohort, although statistical significance could not be reached. The development of the pathological collateral systems provides an alternate route for cerebral perfusion in MMA. But it is often insufficient to compensate reduced cerebral perfusion. This is more conspicuous in children than adult MMA, thus making them further vulnerable to changes in BP and precipitating factors known to alter the cerebral perfusion [15–17].
Fever and increased body temperature can potentiate symptoms of MMA related to hemodynamic stress. Our findings resonate with the observation by Das et al., wherein Covid-19 infections precipitated MMA symptoms [14, 18, 19]. It has been seen that there is a marked drop of central blood-pressure post bath in hot water that can persist for 45–60 min. This can further lead to decompensation of already compromised cerebral circulation and seems to be the major drive in precipitation of neurological symptoms following hot bath [20, 21]. Cold water bath related potentiation of MMA symptoms may be hypothesized to the fact that a abrupt fall in skin temperature can lead to powerful cardio-respiratory changes called as the “cold shock” response, this leads to hyperventilation and subsequent decrease in cerebral blood flow (CBF). Besides, corroborative evidence suggests that repeated cold exposure can modulate endothelial nitric oxide (NO) synthase and bioavailability of NO and impair endothelial vasodilatory function [22–24]. Chen et al. described a case of MMA precipitated following whole body cryotherapy and linked the events mechanistically as cryotherapy induced cerebral autonomic dysregulation and vasoconstriction, potentially through transient hyperventilation [25].
Crying as a precipitating factor was significantly commoner in children with MMA, conforming to previous reports. It may be presumed due to the essential differences in susceptibility to ischemia of brain of children and adults. Thus, even a moderate decrease in cerebral perfusion can potentiate ischemic symptoms in children, who have higher cerebral oxygen consumption in comparison to adults. Besides, a child is more prone to crying in response to uncomfortable situation due to its intellectual and emotional immaturity. Other less plausible explanations could be more severely compromised cerebral circulation and possibility of better vasoconstrictive response to hyperventilation in children compared to adults [26].
Hyperventilation-induced intracranial vasoconstriction subsequent decrease in cerebral perfusion is a result of hypocapnia. Crying and intake of spicy food causes precipitation of ischemic symptoms chiefly by the mechanism of hyperventilation. Besides, spicy food can lead to increased blood flow through external carotid artery (ECA) to oral glands and mucosa causing a “steal phenomenon” to the anterior cerebral circulation, previously being compensated by collaterals from ECA. Further, spicy food intake causes increased body temperature [9, 26–29]. Previous studies have shown exercise induced hyperthermia can lead to decrease in middle cerebral artery (MCA) velocity [30]. Its extrapolation may be reasonable in cases of spicy food intake as well. Exercise, on the other hand, also causes increased hemodynamic demand [9, 31, 32]. Diarrhea and dehydration can lead to decrease in systemic pressure and subsequently diminution of cerebral perfusion [33]. An already compromised cerebral circulation in MMA, is thus often decompensated by this mechanisms leading to manifestation of ischemic symptoms [5, 7, 8].
Acute emotional stress is proposed to enhance the risk of ischemic stroke by excessive sympathomimetic activity and complex interactions of altered coagulation and inflammatory states [34–37]. It has been speculated that stress can cause endothelial dysfunction with decreased NO production leading to loss of anti-coagulant and pro-fibrinolytic properties [34–36]. This becomes particularly important in individuals with pre-existing vessel lumen compromise. Besides, it can cause alteration of immune system by increasing IL-8, pro-inflammatory TNF- α and unaltered induction of anti-inflammatory cytokine IL-10, which is already known to be implicated in worsening of MMA [34, 38–42]. Also, several studies have shown that sympathetic activity can decrease CBF or attenuate CBF increases, but under normal physiological condition neurogenic control has lesser influence over cerebral autoregulation in comparison to vasomotor, metabolic and chemical mechanism. However, in chronic ischemic states, these dominant mechanisms are often overwhelmed and a dysautoregulation secondary to accentuation of neurogenic, sympathetic control of CBF occurs [43]. A similar pathophysiology might be underpinning the precipitation of transient symptoms in MMA secondary to emotional stress leading to sympathetic stimulation.
Certain symptoms in MMA like limb-shaking TIA (LS-TIA) and focal motor seizures are difficult to tell apart. A reliable clinical clue is the history of temporal association of symptom onset to triggers causing cerebral hypoperfusion which usually points towards the diagnosis of LS-TIA [8, 44–46].
It was noticed that 4.5% of the patient did not document any evidence of cerebral hypoperfusion on baseline imaging. They were only decompensated on exposure to precipitating factors leading to manifestation of transient neurological symptoms. Though a very minor fraction, these patients can greatly benefit from detailed elicitation and attribution of these triggers to an underlying occlusive vasculopathy, which can aid in early diagnosis and better prognostication. It was further observed that careful avoidance of the specific precipitating factors led to decrease of transient neurological symptoms, in either severity or frequency or both, among 42.4% patients with history of precipitating factors and none of them had new onset fixed motor neuro-deficit over a follow-up period of 6 months. This is likely due to reduction of transient worsening of the cerebral perfusion in the absence of triggers. Behavioral therapy promoting avoidance of preventable triggers can be useful. Physical measures aiding in blood pressure regulation, drinking adequate fluids and occasional use of compression hosiery can greatly aid in maintenance of blood volume and subsequently cerebral perfusion. This undermines the importance of meticulous elicitation of history of such triggering factors which can greatly aid in decreasing the distressing neurological symptoms while a definite therapy for MMA is awaited. This is especially important in countries like India, where the health-care system is not robust and MMA patients have to travel great distances to avail centers with facilities for revascularization surgery [5, 7, 8, 45].
This is the first study to explore the effects of triggering factors in MMA patients. The potential limitation includes a single-centered observational study. A perfusion study at follow-up period could have further strengthened the observations. However, the strength lies in the relatively large cohort of MMA patients included in the study.
Conclusion
MMA is frequently associated with triggers that can cause transient cerebral hypoperfusion, more common in children than adult-onset MMA. Certain precipitating factor can affect an age group more commonly, crying more commonly potentiated ischemic symptoms in children. It can be an early clue to diagnosis in MMA, even before the setting of cerebral hypoperfusion. A careful avoidance of these factors can help alleviate distressing transient neurological symptoms, which is especially beneficial in resource-limited setting.
Author contributions
SD: conceptualization-equal, data curation-lead, formal analysis-equal, investigation-equal, methodology-equal, resources-equal, supervision-equal, visualization-equal, writing-original draft-lead, writing-review & editing-equal. BR conceptualization-equal, formal analysis-equal, project administration-equal, supervision-equal, visualization-equal, writing-review & editing-equal. AP conceptualization-equal, formal analysis-equal, supervision-equal, visualization-equal, writing-review & editing-equal. RG writing-review & editing-equal. RD writing-review & editing-equal. SD conceptualization-equal, formal analysis-equal, methodology-equal, project administration-equal, supervision-equal, visualization-equal, writing-review & editing-lead. MK supervision-equal, visualization-equal, writing-review & editing-lead.
Funding
The authors have stated that there was no funding source in connection to this work and article.
Data availability
Data not provided in the article because of space limitations may be shared (anonymized) at the request of any qualified investigator for the purposes of replicating procedures and results.
Declarations
Conflicts of interest
The authors have stated explicitly that there are no conflicts of interest in connection with this article.
Informed consent
Written informed consent was obtained from all individual participants included in the study.
Role of medical writer or editor
No medical writer or editor help was taken during the preparation of this manuscript.
Research involving human participants and/or animals
Approval was obtained from the ethics committee of Institute of Post-graduate Medical Education & Research, Kolkata, India. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. (Ethics committee reference number- ECR/35/Inst/WB/2013/RR-16).
Authorship agreement
I, Dr Markus Kraemer take full responsibility for the data, the analyses and interpretation, and the conduct of the research. I have full access to all the data and have the right to publish any and all data, separate and apart from the guidance of any sponsor.
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References
1. Scott RM, Smith ER (2009) Moyamoya disease and moyamoya syndrome. N Engl J Med [Internet]. 360(12):1226–37. http://www.nejm.org/doi/abs/10.1056/NEJMra0804622. Cited 24 Nov 2018
2. Ihara M, Yamamoto Y, Hattori Y, Liu W, Kobayashi H, Ishiyama H et al. (2022) Moyamoya disease: diagnosis and interventions. Lancet Neurol [Internet]. 21(8):747–58. Available from: http://www.thelancet.com/article/S147444222200165X/fulltext. Cited 4 Oct 2022
3. Pilgram-Pastor S, Chapot R, Kraemer M (2022) The angiographic presentation of European Moyamoya angiopathy. J Neurol 269(2):997–1006. https://link.springer.com/article/10.1007/s00415-021-10684-6. Cited 23 Feb 2022
4. Das S, Dubey S, Acharya M, Chatterjee S, Lahiri D, Das G et al (2019) Thalassemia and Moyamoya syndrome: unfurling an intriguing association. J Neurol [Internet]. 266(11):2838–47. https://pubmed.ncbi.nlm.nih.gov/31422456/. Cited 30 Aug 2020
5. Das DS Dubey DS Acharya DM Ghosh DR Chatterjee DS Hazra PA The disease presentation of Moyamoya Angiopathy in Eastern India J Stroke Cerebrovasc Dis 2020 29 8 104957 10.1016/j.jstrokecerebrovasdis.2020.104957 32689603
6. Kraemer M, Schwitalla JC, Diesner F, Aktas O, Hartung HP, Berlit P (2019 ) Clinical presentation of Moyamoya angiopathy in Europeans: experiences from Germany with 200 patients. J Neurol 266(6):1421–8. Available from: https://link.springer.com/article/10.1007/s00415-019-09277-1. Cited 23 Feb 2022
7. Das S, Dubey S, Das S, Hazra A, Pandit A, Ghosh R et al (2022) Epidemiology of Moyamoya Angiopathy in Eastern India. Front Neurol [Internet]. 282. Available from: https://www.frontiersin.org/articles/10.3389/fneur.2022.837704/full. Cited 9 Mar 2022
8. Das S, Ghosh R, Dubey S, Pandit A, Ray BK, Kraemer M (2021) Limb-shaking TIA in Moyamoya angiopathy. Clin Neurol Neurosurg 207:106783. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0303846721003127. Cited 5 Jul 2021
9. Dubey S Ghosh R Chatterjee S Dubey MJ Ray BK Das S Spicy foods triggering clinical symptoms in Moyamoya angiopathy J Neurosurg Sci 2020 65 85 88 32550609
10. Das S, Kanti Ray B, Pandit A, Dutta A, Bhat S, Bhattacharyya D et al (2022) COVID-19 vaccine (Covishield) heralding Moyamoya angiopathy. Neuroimmunol Reports [Internet]. 2:100100. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2667257X2200047X. Cited 16 May 2022
11. Derdeyn CP (2018) Hemodynamics and oxygen extraction in chronic large artery steno-occlusive disease: clinical applications for predicting stroke risk. J Cereb Blood Flow Metab [Internet]. 38(9):1584–97. Available from: https://pubmed.ncbi.nlm.nih.gov/28925313/. Cited 1 Mar 2022
12. Vuignier S, Ito M, Kurisu K, Kazumata K, Nakayama N, Shichinohe H, et al (2013) Ivy sign, misery perfusion, and asymptomatic moyamoya disease: FLAIR imaging and 15O-gas positron emission tomography. Acta Neurochir (Wien) [Internet]. 155(11):2097–104. Available from: https://link.springer.com/article/10.1007/s00701-013-1860-4. Cited 5 Jul 2021
13. Kraemer M Heienbrok W Berlit P Moyamoya disease in Europeans Stroke 2008 39 12 3193 3200 10.1161/STROKEAHA.107.513408 18787200
14. Das S, Ray BK, Ghosh R, Sengupta S, Pandit A, Dubey S (2021) Impact of COVID-19 pandemic in natural course of Moyamoya Angiopathy: an experience from tertiary-care-center in India. Egypt J Neurol Psychiatry Neurosurg 571 [Internet]. 57(1):1–6. Available from: https://ejnpn.springeropen.com/articles/10.1186/s41983-021-00412-2. Cited 16 Dec 2021
15. Liming Z, Weiliang S, Jia J, Hao L, Yang L, Ludtka C et al (2021) Impact of blood pressure changes in cerebral blood perfusion of patients with ischemic Moyamoya disease evaluated by SPECT. J Cereb Blood Flow Metab [Internet]. 41(6):1472–80. Available from: https://pubmed.ncbi.nlm.nih.gov/33153375/. Cited 12 Mar 2022
16. Pilgram-Pastor S, Chapot R, Kraemer M (2022) The angiographic presentation of European Moyamoya angiopathy. J Neurol [Internet]. 269(2):997–1006. Available from: https://pubmed.ncbi.nlm.nih.gov/34240321/. Cited 12 Mar 2022
17. Kim JS (2016) Moyamoya disease: epidemiology, clinical features, and diagnosis. J Stroke [Internet]. 18(1):2–11. Available from: https://pubmed.ncbi.nlm.nih.gov/26846755/. Cited 16 Dec 2021
18. Ghosh R, Dubey S, Kanti Ray B, Chatterjee S, Benito-León J (2020) COVID-19 presenting with thalamic hemorrhage unmasking moyamoya angiopathy [Internet]. vol. 47, Canadian Journal of Neurological Sciences. Cambridge University Press; pp 849–51. Available from: /pmc/articles/PMC7327161/. Cited 18 Mar 2021
19. Das S, Dubey S, Pandit A, Ray BK (2021) Moyamoya angiopathy unmasking systemic lupus erythematosus. BMJ Case Rep [Internet]. 14(1):e239307. Available from: https://casereports.bmj.com/content/14/1/e239307. Cited 27 Feb 2021
20. Ishikawa J, Yoshino Y, Watanabe S, Harada K (2016) Reduction in central blood pressure after bathing in hot water. Blood Press Monit [Internet] 21(2):80–6. Available from: https://pubmed.ncbi.nlm.nih.gov/26657048/. Cited 11 Mar 2022
21. Kim J Bin, Yu S (2013) Transient ischemic attack after hot bath in a patient with Moyamoya disease. Neurol Sci [Internet]. 34(12):2231–3. Available from: https://koreauniv.pure.elsevier.com/en/publications/transient-ischemic-attack-after-hot-bath-in-a-patient-with-moyamo. Cited 23 Feb 2022
22. Barwood M, Burrows H, Cessford J, Fraser L, Goodall S, Griffiths S (2015) Brain blood flow and hyperventilation on cold water immersion: can treading water help control these symptoms of cold shock? Extrem Physiol Med 41 4(1):1–2. Available from: https://extremephysiolmed.biomedcentral.com/articles/10.1186/2046-7648-4-S1-A40. Cited 23 Feb 2022
23. Kjeld T, Pott FC, Secher NH (2009) Facial immersion in cold water enhances cerebral blood velocity during breath-hold exercise in humans. J Appl Physiol 106(4):1243–8. Available from: https://pubmed.ncbi.nlm.nih.gov/19179653/. Cited 23 Feb 2022
24. Benedict PS, Pandian JD (2014) Stroke after cold bath. CHRISMED J Heal Res [Internet]. 1(4):283. Available from: https://www.cjhr.org/article.asp?issn=2348-3334;year=2014;volume=1;issue=4;spage=283;epage=285;aulast=Benedict. Cited 23 Feb 2022
25. Chen PM, Chen MM, Chiang CC, Olson S, Bolar DS, Agrawal K (2020) Moyamoya presenting after whole body cryotherapy [Internet]. vol. 29, Acta Neurologica Taiwanica. p. 64–6. Available from: https://pubmed.ncbi.nlm.nih.gov/32436205/. Cited 11 Mar 2022
26. Tagawa T, Naritomi H, Mimaki T, Yabuuchi H, Sawada T (1987) Regional cerebral blood flow, clinical manifestations, and age in children with moyamoya disease. Stroke [Internet]. 18(5):906–10. Available from: https://www.ahajournals.org/doi/abs/10.1161/01.str.18.5.906. Cited 23 Feb 2022
27. Storozhuk MV Moroz OF Zholos AV Multifunctional TRPV1 ion channels in physiology and pathology with focus on the brain, vasculature, and some visceral systems Biomed Res Int 2019 10.1155/2019/5806321
28. Ma L, Lee BH, Mao R, Cai A, Jia Y, Clifton H et al (2014) Nicotinic acid activates the capsaicin receptor TRPV1—a potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol [Internet]. 34(6):1272. Available from: /pmc/articles/PMC4063526/. Cited 18 Apr 2022
29. Boudreau SA, Wang K, Svensson P, Sessle BJ, Arendt-Nielsen L (2009) Vascular and psychophysical effects of topical capsaicin application to orofacial tissues. J Orofac Pain [Internet]. 23(3):253. Available from: /pmc/articles/PMC3069052/. Cited 18 Apr 2022
30. Nybo L, Nielsen B (2001) Middle cerebral artery blood velocity is reduced with hyperthermia during prolonged exercise in humans. J Physiol [Internet] 534(Pt 1):279–86. Available from: https://pubmed.ncbi.nlm.nih.gov/11433008/. Cited 16 May 2022
31. Mustafa S, Thulesius O, Ismael HN (2004) Hyperthermia-induced vasoconstriction of the carotid artery, a possible causative factor of heatstroke. J Appl Physiol [Internet]. 96(5):1875–8. Available from: https://pubmed.ncbi.nlm.nih.gov/15075312/. Cited 23 Feb 2022
32. Shoukat S, Itrat A, Taqui AM, Zaidi M, Kamal AK (2009) Moyamoya disease: a clinical spectrum, literature review and case series from a tertiary care hospital in Pakistan. BMC Neurol [Internet]. 9. Available from: https://pubmed.ncbi.nlm.nih.gov/19368734/. Cited 23 Feb 2022
33. Trangmar SJ, Chiesa ST, Llodio I, Garcia B, Kalsi KK, Secher NH et al (2015) Dehydration accelerates reductions in cerebral blood flow during prolonged exercise in the heat without compromising brain metabolism. Am J Physiol - Hear Circ Physiol [Internet]. 309(9):H1598. Available from: /pmc/articles/PMC4670459/. Cited 16 May 2022
34. Kotlęga D, Gołąb-Janowska M, Masztalewicz M, Ciećwież S, Nowacki P (2016) The emotional stress and risk of ischemic stroke. Neurol Neurochir Pol [Internet]. 50(4):265–70. Available from: https://pubmed.ncbi.nlm.nih.gov/27375141/. Cited 23 Feb 2022
35. R Kanel PMCFJD (2001) Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis [Internet]. Psychosom Med. 63:531–44. Available from: https://journals.lww.com/psychosomaticmedicine/Abstract/2001/07000/Effects_of_Psychological_Stress_and_Psychiatric.3.aspx. Cited 16 May 2022
36. Von Känel R (2015) Acute mental stress and hemostasis: when physiology becomes vascular harm. Thromb Res [Internet]. 135(S1):S52–5. Available from: http://www.thrombosisresearch.com/article/S0049384815504441/fulltext. Cited 16 May 2022
37. Austin AW, Wissmann T, Von Kanel R (2013) Stress and hemostasis: an update. Semin Thromb Hemost [Internet]. 39(8):902–12. Available from: http://www.thieme-connect.de/products/ejournals/html/10.1055/s-0033-1357487. Cited 16 May 2022
38. Limb-shaking TIA related to moyamoya disease: diagnosis with magnetic resonance imaging and magnetic resonance angiography - PubMed [Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/21210328/. Cited 4 Jan 2021
39. Yashar VB, Barenholz Y, Hy‐Am E, Rachmilewitz EA, Eldor A (1993) Phosphatidylserine in the outer leaflet of red blood cells from β‐thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes. Am J Hematol [Internet]. 44(1):63–5. Available from: https://pubmed.ncbi.nlm.nih.gov/8342566/. Cited 8 Mar 2021
40. Bersano A, Guey S, Bedini G, Nava S, Hervé D, Vajkoczy P et al. (2016) Research progresses in understanding the pathophysiology of moyamoya disease. Cerebrovasc Dis [Internet]. 41(3–4):105–18. Available from: https://www.karger.com/Article/FullText/442298. Cited 8 Mar 2021
41. Lyoo CH, Oh SH, Joo JY, Chung TS, Lee MS (2000) Hemidystonia and hemichoreoathetosis as an initial manifestation of moyamoya disease. Arch Neurol [Internet]. 57(10):1510–2. Available from: https://jamanetwork.com/journals/jamaneurology/fullarticle/777669. Cited 23 Feb 2022
42. van Westerloo DJ, Choi G, Löwenberg EC, Truijen J, de Vos AF, Endert E et al (2011) Acute stress elicited by bungee jumping suppresses human innate immunity. Mol Med 17(3):180–8. Available from: https://molmed.biomedcentral.com/articles/10.2119/molmed.2010.00204. Cited 16 May 2022
43. Ter Laan M, Van Dijk JMC, Elting JWJ, Staal MJ, Absalom AR (2013) Sympathetic regulation of cerebral blood flow in humans: a review. Br J Anaesth [Internet]. 111(3):361–7. Available from: https://pubmed.ncbi.nlm.nih.gov/23616589/. Cited 12 Mar 2022
44. Kraemer M Trakolis L Platzen J Schwitalla JC Bersano A Albrecht P Movement symptoms in European Moyamoya angiopathy–first systematic questionnaire study Clin Neurol Neurosurg 2017 1 152 52 56 10.1016/j.clineuro.2016.11.017
45. Das S, Ray BK, Ghosh R, Dubey S (2022) “Asymptomatic” Moyamoya angiopathy: is it truly asymptomatic? J Stroke Cerebrovasc Dis [Internet] 31(6):106432. Available from: http://www.strokejournal.org/article/S105230572200129X/fulltext. Cited 9 Apr 2022
46. Das S, Ray BK, Dubey S (2021) Temporal lobe epilepsy with nocturnal wandering leading to discovery of Moyamoya Angiopathy. Acta Neurol Belgica [Internet]. 1–3. Available from: https://link.springer.com/article/10.1007/s13760-021-01830-y. Cited 2 Dec 2021
| 36477636 | PMC9734856 | NO-CC CODE | 2022-12-14 23:28:31 | no | J Neurol. 2022 Dec 7;:1-8 | utf-8 | J Neurol | 2,022 | 10.1007/s00415-022-11499-9 | oa_other |
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Int Adv Econ Res
International Advances in Economic Research
1083-0898
1573-966X
Springer US New York
9862
10.1007/s11294-022-09862-7
Article
The Puzzling Convergence of Intangible Investments
Antzoulatos Angelos A. [email protected]
Karanastasis Dimitris
Syrmos Thomas
grid.4463.5 0000 0001 0558 8585 Department of Banking & Financial Management, University of Piraeus, 80 Karaoli & Dimitriou Street, 18534 Piraeus, Greece
5 12 2022
2022
28 3-4 171182
22 11 2022
© International Atlantic Economic Society 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Motivated by the rising prominence of intangibles, this paper explores whether there are common forces that drive intangible investments in the U.S. and the Euro area, in tandem with firm-specific characteristics. If such forces exist, there should be groups of firms (convergent clubs) for which the time-varying cross-sectional variance of intangible investments (scaled by total assets) declines over time. The empirical results indicate that there is a big convergent club in both economic areas, the sectoral composition of which is similar to that of the entire sample, an indication that the common forces are economy-wide and not sector-specific. Moreover, the country composition of the big club in the Euro area is also similar to that of the entire sample, an indication that they are not country-specific either. More puzzling, the evidence of common forces is stronger for the Euro area countries, despite their differing overall economic and financial-market conditions, and that their bank-based financial systems are less likely to finance intangible assets than the U.S. market-based one. The paper also used probit analysis to identify the common forces; but this analysis did not yield any firm results. Nevertheless, the main finding of the paper, itself a novel contribution to the rapidly growing literature on intangibles, suggests another angle to re-examine the existing empirical literature and identifies potential misspecification problems of related microeconomic studies. As such, it should be of interest to researchers, market participants, and to standard-setters and policymakers who base their decisions on empirical studies.
Keywords
Intangible investments
Convergence
Phillips and Sul algorithm
JEL
E20
G30
G32
C33
issue-copyright-statement© International Atlantic Economic Society 2022
==== Body
pmcIntroduction
In today’s economy, most sectors (industrial ones notwithstanding) rely heavily on services and technologies, a development that highlights the importance of intangible assets, such as human capital, innovative products, brands, patents, software, customer and supplier relationships, database collection and processing, and distribution systems. Indicatively, Corrado and Hulten (2010) estimated that, during the period 1995–2007, intangible assets accounted for 34% of total corporate capital in the U.S. nonfarm business sector. Using a sample of U.S. firms involved in more than 1,500 acquisition events, Ewens et al. (2019), estimated that intangible assets increased from 37% of total assets in 1975 to 60% in 2016. Across sectors, this proportion in 2016 ranged from 40% in manufacturing to more than 80% in healthcare. At the macro level, Gu and Lev (2017) reported that investments in intangible assets in the U.S. increased from 9% of gross value-added in 1977 to 14% in 2014, while investments in tangible assets declined from 15% of gross value-added to 9% over the same period. As corroborating casual evidence, the combined stock-market capitalization of the six biggest tech companies, Facebook, Amazon, Apple, Netflix, Alphabet-Google and Microsoft (FAANGM), was $9.29 trillion in October 2021, more than 20% of the entire stock market capitalization.
Motivated by the rising prominence of intangibles, this paper uses the Phillips and Sul (2007) convergence algorithm to explore whether there are any common forces that drive intangible investments. This algorithm tests for convergence for a group of cross-sectional units (firms) either as a whole or in subgroups of one or more convergent clubs. Lack of convergent clubs would indicate that firm-specific characteristics dominate the relevant decisions of firms, here intangible investments (scaled by total capital). At the other end, convergence in levels would indicate that some, common to all club members, force(s) drive(s) intangible investments to the same value. In between, convergence in rates would indicate that both firm-specific and common forces work in tandem, the former sustaining the distance between the firms as time goes by, while the latter causes intangible investments to move in parallel. The common force(s) may be related to specific sectors or to the overall economic and financial-market conditions in a country.
The results, from a sample of 843 United States (U.S.) firms for which relevant data exist for the period 1990–2020, indicate that there is convergence in rates. Specifically, there are four convergent clubs, the biggest of which comprises 65% of the sample firms, while the share of the remaining three clubs ranges from 6 to 15%. For a sample of 251 European firms from eight Euro area countries over the same period, convergence is seemingly stronger. There are only two clubs with convergence in rates, the biggest of which comprises 87% of the sample firms. In both samples, the sectoral composition of the big convergent club is similar to that of the whole sample, an indication that sector-specific forces are not behind convergence. Additionally, in the Euro area sample, the country composition of the big club is similar to that of the whole sample, an indication that convergence is not driven by country-specific forces, but by forces operating across the Euro area.
The existence of the two big convergent clubs is puzzling, but even more so is the stronger convergence in the Euro area. For one thing, the economic and financial market conditions, such as financial development, competition in the banking sector, contract enforcement, bankruptcy rules and access to credit information (Demmou et al., 2019) differ across the Euro area countries. Thus, the forces that might lead to a big convergent club are likely to be weaker than in the U.S. In addition, the U.S. market-based financial system is more likely to finance intangible investments than Europe’s bank-based financial systems (Demmou et al., 2019). Hence, given convergence, one would reasonably expect it to be stronger in the U.S.
To shed some light on this puzzle, probit analysis was used to explore the measurable characteristics of the firms in the big clubs. The underlying expectation was that these characteristics might help identify the forces behind convergence. Unfortunately, no firm insights emerged from that analysis.
Literature Review
To the best of our knowledge, this is the first paper that identifies this puzzle. As such, the paper contributes to the rapidly growing literature on intangibles which, so far, has explored issues related to the rising importance of intangibles, productivity, measurement, information asymmetry, financing, and asset pricing.
The importance of intangible capital as a driver of productivity growth has been widely recognized both at the macroeconomic and microeconomic/firm levels. At the macroeconomic level, the positive effects of intangible capital are viewed as externalities that lead to regional concentration of economic activity (Corrado et al., 2009, 2012; Goodridge et al., 2017). In turn, this promotes economies of scale, workforce specialization and lower transaction costs, all of which improve efficiency at the firm and local-economy level (Duranton & Puga, 2004; Krugman, 1991, 1998). At the firm level, intangible capital has been recognized as an important determinant of innovation and growth (Ilmakunnas & Piekkola, 2014; Marrocu et al., 2012; Riley & Robinson, 2011). Related to this, Li et al. (2021), found evidence that the adoption by U.S. state governments of addback statutes, in order to constrain the use of intangible assets in tax-motivated state income shifting, impeded corporate innovation.
It has also been recognized that the measurement of intangible assets is difficult (Riley & Robinson, 2011) and further complicated by the lack of an accurate definition (Marrocu et al., 2012; Webster & Jensen, 2006). Intuitively, intangible assets are more firm-specific and, thus, less comparable across firms than tangible assets (e.g., fixed assets, real estate, factories, and equipment). Compounding the difficulty, the existing accounting and reporting rules have not kept pace with the rise of intangible investments (Dugar & Pozharny, 2021), potentially leading to significant mismeasurement of important firm characteristics, such as productivity (Bhandari & McGrattan, 2021; Corrado et al., 2009; Haskel & Westlake, 2017), book equity and earnings (Lev, 2019; Srivastava, 2014).
The preceding suggests that the increase in intangible assets may have been associated with an increase in information asymmetry. Consistent with this, Gu and Wang (2005) found that analysts’ earnings forecast errors were larger for more intangible-intensive firms, the hypothesis being that intangible assets are associated with information complexity. In addition, Palmon and Yezegel (2012) found that analysts’ recommendation revisions were more valuable for firms with high research & development (R&D) intensity, the hypothesis being that R&D intensity increases information asymmetry. Furthermore, Dugar and Pozharny (2021) found that the value relevance of book equity and earnings declined only in firms with high intangibles.
Turning to financing, Segol et al. (2021) showed that quantity rationing is a primary determinant of borrowers’ propensity to invest in intangible assets. Related to this, Montresor and Vezzani (2016) found that the lack of tangible collateral is one of the obstacles frequently identified by investing firms. In addition, Demmou et al. (2019) concluded that market-based systems are more likely to finance intangible assets, as equity investors are more willing to finance risky investments without collateral, a conclusion that neatly encompasses the findings and intuition of the papers mentioned previously.
Lastly, Gulen et al. (2022) showed that incorporating intangibles into the empirical factor models of Fama and French (1993, 2015) and Hou et al. (2015) significantly improved these models, especially over recent decades during which intangible investments became increasingly important. In addition, Peters and Taylor (2017) argued that there is a role for intangible capital in neoclassical investment theory. According to this theory, tangible capital plays a prominent role. They also proposed a new Tobin’s Q measure that incorporates intangible capital, with excellent empirical results.
Empirical Issues
Convergence Algorithm
The methodology to test for convergence was developed by Phillips and Sul (2007), hereafter referred to as PS. In essence, this methodology tests whether the dispersion of the variable of interest across cross-sectional units declines over time. Let Xit denote the variable of interest, with i=1,2,⋯,N and t=1,2,⋯,T denoting, respectively, the cross-sectional units and time periods. Xit is deconstructed into a common, git, and an idiosyncratic, ait, component. Convergence occurs when the idiosyncratic components across the cross-sectional units converge over time.1 Xit=git+ait
PS transform Eq. (1) such that Xit is decomposed into two time-varying components, one common, μt, and one idiosyncratic, δit.Xit=git+aitμtμt=δitμt,for alli,t
In this way, testing for convergence is equivalent to testing whether the idiosyncratic components δit converge. To this end, PS define the relative transition parameter,hit=Xit1N∑i=1NXit=δitμt1N∑i=1Nδitμt=δit1N∑i=1Nδit,
where hit measures the idiosyncratic component δit in relation to the panel average, 1N∑i=1Nδit. Note that its mean is equal to 1 for all t, and the time-varying cross-sectional variance, Ht, isHt=1N∑i=1Nhit-12.
Under convergence, Ht declines over time.
PS developed a formal econometric procedure to test for convergence. Briefly, the null hypothesis of convergence is rejected if the t-statistic of the estimated b^ coefficient in Eq. (2) is below the critical value of -1,65.2 logH1Ht-2loglogt=c+blogt+ut,
In the case of convergence, the absolute value of b^ determines whether convergence is in rates or in levels. |b^|<2 implies convergence in rates and b^≥2 implies convergence in levels. The standard errors are heteroskedasticity and autocorrelation consistent (HAC). The data for this regression start at T0=rT, where rT is the integer part of rT and r=1/3, as suggested by PS.
Furthermore, PS extend their algorithm to test for convergent clubs in case there is no convergence for the full sample. The cross-sectional units not belonging to any club are characterized as divergent.
Application to Intangible Investments
Regarding the variable of interest, the idiosyncratic component, δit, corresponds to firm-specific forces that affect the relevant decisions of firms, while the common component, μt, corresponds to sector-specific and/or economy-wide forces. The latter pertain to both economic and financial-market conditions. If, as previously mentioned, the firm-specific forces are significant, there cannot be convergence in levels, only in rates. In this case, if economy-wide forces are driving convergence, there will be a big convergent club whose sectoral composition will be similar to that of the whole sample. By the same logic, if the sector-specific forces are driving convergence, the composition of each convergent club will be dominated by firms in one or more sectors. ‘Dominated’ means that these clubs will have a higher proportion of firms from these sectors relative to the whole sample.
In the Euro area, country-specific forces may also drive convergence. In this case, the convergent clubs will be dominated by firms in one or more countries. However, if the common forces operate across the Euro area, there will be one big convergent club. Moreover, as stated in the introduction, when a big convergent club exists, one would expect stronger evidence of convergence in the U.S.
Data
The variable of interest, intangible investment, was calculated as in Peters and Taylor (2017):Research&Development(R&D)+0.3xSales,General&AdministrativeSG&Aexpense,
scaled by total capital. Total capital was also calculated as in Peters and Taylor (2017).
The sample includes all Refinitiv/Eikon listed firms except financials (TRBC Business Classification) (Refinitiv, 2022a), economic sector 55), utilities (59), real estate (60), institutions, associations & organizations (61), government activity (62) and academic & educational services (63). The sample period is 1990–2020. Firms with missing values were excluded, as the PS algorithm works with balanced panels.
Results
Main Results
Table 1 summarizes the results of the Phillips and Sul (2007) convergence tests. Column (1) shows the sample and number of firms. Columns (2) and (3) show the results of the tests for full-sample convergence, and column (4) displays the conclusion: when the t-statistic, tb, is less than the critical value of -1.65, there is no convergence. Column (5) shows the number of the convergent clubs. The next three columns present the results of the convergence tests for the big convergent club; when the estimated coefficient b^ is less than 2 in absolute value, it is convergent in rates. The next column shows the percentage and the number (in parentheses) of firms in the big convergent club. The last column displays the percentage and the number of firms in the remaining convergent clubs.Table 1 Convergence tests results for 1990–2020
Full sample # of clubs Big club % of firms in other clubs
Sample b^ tb Convergence b^ tb Convergence % of firms
U.S
(843 firms)
-3.31 -18.31 No 4 -0.14 -1.24 In rates 65.2%
(550)
5.8%-15.4%
(49–131)
Euro area
(251 firms)
-1.65 -4.47 No 2 -0.80 -1.61 In rates 87.2%
(219)
12.7%
(32)
Data Source: Worldscope (Refinitiv, 2022b)
As Table 1 indicates, there is no convergence for the full sample for either the U.S. or the Euro area samples. In both cases, tb is less than the critical value of -1.65. However, there are convergent clubs, with convergence in rates: 4 in the U.S. and 2 in the Euro area. For all convergent clubs, for both samples, tb is greater than -1.65 and b^ is between 0 and 2 in absolute value. In addition, there are no divergent firms.
Two things stand out in these results. First, the existence of a big club. For the U.S. sample, the biggest club comprises 65.2% of the sample firms. For the Euro area, this proportion rises to 87.2%. Notably, convergence is not likely driven by sector-specific forces for, as Table 2 documents, the sectoral composition of the whole sample and the big club are essentially the same. Table 2, column (1) displays the sector according to the TRBC Business Classification (Refinitiv, 2022a) system. Columns (2) and (3) show the sectoral composition: the number of firms and percentage of the whole sample. Columns (4) and (5) display the same information for the big convergent club for the U.S. sample. The remaining four columns show the same information for the Euro area sample. Furthermore, convergence in the Euro area sample is not likely driven by country-specific forces (Table 3). The country composition of the whole sample and of the big club are essentially the same.Table 2 Sectoral composition of the big clubs for 1990–2020
U.S. sample Euro area sample
Whole sample Big club Whole sample Big club
Sector # of firms % of total sample # of firms % of total sample # of firms % of total sample # of firms % of total sample
Basic Materials 34 4.0% 26 4.7% 30 11.9% 28 12.8%
Consumer Cyclicals 157 18.6% 121 22.0% 73 29.1% 59 26.9%
Consumer Non- Cyclicals 45 5.3% 33 6.0% 24 9.6% 19 8.7%
Energy 56 6.6% 36 6.6% 7 2.8% 7 3.2%
Healthcare 187 22.2% 108 19.6% 22 8.8% 19 8.7%
Industrials 137 16.3% 90 16.4% 47 18.7% 46 21.0%
Technology 227 26.9% 136 24.7% 48 19.1% 41 18.7%
Data Source: Worldscope (Refinitiv, 2022b)
Table 3 Country composition of the Euro area big club for 1990–2020
Whole sample Big club
Country # of firms % of the total sample # of firms % of the total sample
Austria 10 4.0% 10 4.6%
Belgium 7 2.8% 7 3.2%
Finland 13 5.2% 12 5.5%
France 35 13.9% 32 14.6%
Germany 87 34.7% 75 34.3%
Greece 27 10.8% 21 9.6%
Italy 60 23.9% 51 23.3%
Netherlands 12 4.8% 11 5.0%
Data Source: Worldscope (Refinitiv, 2022b)
Second, contrary to expectations, the evidence of convergence is stronger for the Euro area sample. Specifically, there are two convergent clubs, versus four for the U.S. sample, and the biggest club comprises a much bigger fraction of the sample firms, 87.2% vs. 65.2%.
Characteristics of the Firms in the Big Convergence Club
To shed some light on these results, probit analysis was used to explore the measurable characteristics of the firms in the big clubs. Probit was chosen because the dependent variable is dichotomous. It takes the value of one for the firms in the big club and zero otherwise. The underlying expectation was that the statistically significant explanatory variables might help identify the forces behind convergence.
The potential explanatory variables and their expected signs are from the literature review. Briefly, a positive coefficient of the ratio market value to book value, a proxy of growth prospects, would provide evidence that the common forces are related to the stock market. It would also be consistent with the assessment by Demmou et al. (2019) that a market-based system is more likely to finance intangible investments. Likewise for earnings before income taxes (EBIT), a proxy of profitability, the logic being that shareholders benefit more from the upside potential of firms than debt-holders.
Moreover, a positive coefficient of (log) total assets would be consistent with the expectation that lenders are more willing to finance big firms because these firms are, all else equal, less likely to default (Montresor & Vezzani, 2016; Segol et al., 2021), hence the common forces could be related to the banking sector and the debt markets. Likewise, a positive coefficient of total debt to total assets would be an indication that, due to the common forces, firms had the opportunity to borrow to finance intangible investments. Lastly, a positive coefficient of sales to total assets would be consistent with the need of firms to invest more in distribution channels, customer relationships and databases, all of which are part of intangible capital.
The values of these variables are from 2020, at the end of the sample period. As a robustness check, and to account for the dynamic nature of convergence, probit was also run using the average 2016–2020 values of the potential explanatory variables. In further robustness checks, the two probit models were run with country (for the Euro area sample) and sector dummies. Note, however, that the results of the Euro area sample should be viewed with caution, due to the very high percentage of the firms in the big club (more than 85%).
Again, the sample includes all Refinitiv/Eikon listed firms except financials, utilities, real estate, institutions, associations & organizations, government activity and academic & educational services. Firms with a missing or non-positive book value of assets or sales and firms with less than $5 million in physical capital were excluded, as is standard in the literature. Also, all variables were winsorized at the 0.5% level to remove outliers.
The results, similar in all specifications, do not provide any firm insights about the forces behind convergence. Briefly, for the U.S. sample, sales to total assets and (log) assets, both with positive signs, are significant at the 5% or higher level. However, the economic significance is low, as indicated by the less than 3% (pseudo) R2. For the Euro area sample, (log) assets, with a positive sign, is significant at the 5% or higher level, while the (pseudo) R2 is around 10%.
Further Research
Despite that the probit analysis did not provide any concrete evidence about the forces behind convergence, the main finding of the paper, the existence of a big convergent club, suggests several research questions that are worthy of further investigation. To begin with, it provides a new angle to re-examine existing empirical evidence, an angle that should be of interest to both researchers and market participants. Consider, for example, the studies that explored analyst forecasts and intangibles (Dugar & Pozharny, 2021; Gu & Wang, 2005; Palmon & Yezegel, 2012). Another way to split the sample, other than high vs. low intangibles as in the existing literature, is convergent club firms vs. all others. The researchers may not know what the common forces are, but the analysts, who examine a vast array of quantitative and qualitative information, may take these forces into consideration. Similarly for the papers that explore intangible assets and firm financing.
Moreover, the finding that there are common forces driving intangible investments, which operate at the economy-wide level, raises the possibility of potential misspecification problems in microeconomic studies of the determinants of intangible investments. These problems potentially apply to every variable for which there exist big convergent clubs, something researchers and policymakers who estimate and use empirical models must take into account.
Briefly, let Xi,t denote the variable of interest in the panel estimation Xi,t=ai+bZi,t+dYt+eCt+ui,t; Zi,t is a vector of firm-specific characteristics, Yt a vector of variables related to the common forces driving convergence, Ct a vector of country-specific variables, b, d and e are the respective coefficient vectors, ai the cross-sectional intercepts and ui,t the usual stochastic term. Not including Yt in the equation would result in biased estimates of the firm-specific and the country-specific variables that are correlated with the omitted Yt. Additionally, and related to the current paper, estimating this equation would result in lower significance of the variable(s) in Yt because they affect only the firms in the big convergent club. Even worse, some significant variable(s) might become insignificant. Hence, the estimated equation would not provide reliable indications of what the common forces might be.
Returning to the seemingly stronger convergence in the Euro area relative to the U.S., a possible explanation might be the strong intervention of the European Central Bank (ECB), starting with the European debt crisis in the early 2010s, to avert the then perceived as existential threat for the euro, and continuing with the unconventional monetary-policy measures in the middle of the decade, in an effort to combat the then looming deflation, and in 2020, to ameliorate the economic fallout from the Covid-19 pandemic. This prolonged intervention may have weakened the effect on intangible-investment decisions of the diverging economic and financial-market conditions across the Euro area countries and strengthened the effect of the common across the Euro area forces.
Looking forward, another interesting question is whether the forces behind convergence will continue operating in the future. Consider the case where these forces were related to the rise of global supply chains in the 1990s. These chains allowed U.S. and European firms to subcontract a bigger part of production to other firms all over the world, thus reducing their own need for investments in tangible assets. Could the unravelling of the global supply chains, in the wake of the Covid-19 crisis and the rising geopolitical risks, lead to higher tangible investments by firms and, thus, strengthen the firm-specific determinants of intangible investments and weaken convergence? In such a case, while intangible assets will continue to be crucial for competitiveness (Marrocu et al., 2012), tangible investments could become a necessary condition in the emerging new economic environment. As a result, the implied hollowing out of the productive capacity of U.S. and European firms, a side effect of the presumed subcontracting, may in the future be associated with higher stock-price volatility of firms with high intangibles.
Acknowledgements
This research was co-financed by Greece and the European Union (European Social Fund - ESF) through the Operational Programme “Human Resources Development, Education and Lifelong Learning 2014-2020” in the context of the project “Intangible capital, finance and banking institutions” (MIS 5050635). We thank an anonymous referee and Nicholas Apergis whose comments and suggests helped improve the paper substantially.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
Bhandari, A., & McGrattan, E.R. (2021). Sweat Equity in U.S. Private Business. The Quarterly Journal of Economics, 136(2), 727–781.
Corrado CA Hulten C How Do You Measure a "Technological Revolution"? American Economic Review 2010 100 2 99 104 10.1257/aer.100.2.99
Corrado, C.A., Haskel, J., Jona-Lasinio, C., & Iommi, M. (2012). Intangible capital and growth in advanced economies: measurement methods and comparative results. CEPR Discussion Paper No. DP9061, https://ssrn.com/abstract=2153512
Corrado, C.A., Hulten, C., & Sichel, D. (2009). Intangible capital and U.S. economic growth. Review of Income and Wealth, 55(3), 661–85.
Demmou, L., Stefanescu, I., & Arquie, A. (2019). Productivity growth and finance: The role of intangible assets – a sector level analysis. OECD Economic Department Working Papers No. 1547, 10.1787/e26cae57-en
Dugar A Pozharny J Equity Investing in the age of Intangibles Financial Analysts Journal 2021 77 2 21 42 10.1080/0015198X.2021.1874726
Duranton G Puga D Micro-foundations of urban agglomeration economies 2004 Amsterdam, The Netherlands Elsevier
Ewens, M., Peters, R.H., & Wang, S. (2019). Measuring intangible capital with market prices. NBER Working Paper No. w25960, https://ssrn.com/abstract=3406478
Fama EF French KR Common risk factors in the returns on stocks and bonds Journal of Financial Economics 1993 33 1 3 56 10.1016/0304-405X(93)90023-5
Fama EF French KR A five-factor asset pricing model Journal of Financial Economics 2015 116 1 1 22 10.1016/j.jfineco.2014.10.010
Goodridge P Haskel J Wallis G Spillovers from R&D and other intangible investment: Evidence from UK industries Review of Income and Wealth 2017 63 S22 S48 10.1111/roiw.12251
Gu F Lev B Time to change your investment model Financial Analysts Journal 2017 73 4 23 33 10.2469/faj.v73.n4.4
Gu F Wang W Intangible assets, information complexity, and analysts’ earnings forecasts Journal of Business Finance & Accounting 2005 32 9–10 1673 1702 10.1111/j.0306-686X.2005.00644.x
Gulen, H., Li, D., Peters, R.H., & Zekhnini, M. (2022). Intangible capital in factor models. Available at SSRN: https://ssrn.com/abstract=3725002
Haskel J Westlake S Capitalism without Capital: The rise of the intangible economy 2017 Princeton, NJ Princeton University Press
Hou K Xue C Zhang L Digesting anomalies: An investment approach The Review of Financial Studies 2015 28 3 650 705 10.1093/rfs/hhu068
Ilmakunnas P Piekkola H Intangible investment in people and productivity Journal of Productivity Analysis 2014 41 3 443 456 10.1007/s11123-013-0348-9
Krugman P Increasing returns and economic geography Journal of Political Economy 1991 99 3 483 499 10.1086/261763
Krugman P What's new about the new economic geography? Oxford Review of Economic Policy 1998 14 2 7 17 10.1093/oxrep/14.2.7
Lev B Ending the accounting-for-intangibles status Quo European Accounting Review 2019 28 4 713 736 10.1080/09638180.2018.1521614
Li, Q., Ma, M.S., & Shevlin, T. (2021). The effect of tax avoidance crackdown on corporate innovation. Journal of Accounting and Economics, 71(2–3), April-May, 101382.
Marrocu E Paci R Pontis M Intangible capital and firms’ productivity Industrial and Corporate Change 2012 21 2 377 402 10.1093/icc/dtr042
Montresor S Vezzani A Intangible investments and innovation propensity: Evidence from the innobarometer 2013 Industry and Innovation 2016 23 4 331 352 10.1080/13662716.2016.1151770
Palmon D Yezegel A R&D intensity and the value of analysts’ recommendations Contemporary Accounting Research 2012 29 2 621 654 10.1111/j.1911-3846.2011.01117.x
Peters RH Taylor LA Intangible capital and the investment-q relation Journal of Financial Economics 2017 123 2 251 272 10.1016/j.jfineco.2016.03.011
Phillips PC Sul D Transition modeling and econometric convergence tests Econometrica 2007 75 6 1771 1855 10.1111/j.1468-0262.2007.00811.x
Refinitiv (2022a). TRBC Business Classification. Available at: https://www.refinitiv.com/content/dam/marketing/en_us/documents/quick-reference-guides/trbc-business-classification-quick-guide.pdf. Accessed July 19, 2022a.
Refinitiv (2022b). Worldscope fundamentals. Available at: https://www.refinitiv.com/en/financial-data/company-data/fundamentals-data/worldscope-fundamentals. Accessed July 19, 2022b.
Riley, R., & Robinson, C. (2011). Agglomeration spillovers from intangible capital: An Analysis of UK City Regions. National Institute of Economic and Social Research Discussion Papers No. 3160, https://www.niesr.ac.uk/publications/agglomeration-spillovers-intangible-capital-analysis-uk-city-regions?type=report
Segol, M., Kolev, A., & Maurin, L. (2021). The Impact of Bank Loan Terms on Intangible Investment in Europe. EIB Working Papers No. 2021/05, https://www.eib.org/en/publications
Srivastava A Why have measures of earnings quality changed over time? Journal of Accounting and Economics 2014 57 2–3 196 217 10.1016/j.jacceco.2014.04.001
Webster E Jensen PH Investment in Intangible Capital: An enterprise Perspective Economic Record 2006 82 256 82 96 10.1111/j.1475-4932.2006.00296.x
| 0 | PMC9734857 | NO-CC CODE | 2022-12-14 23:45:33 | no | Int Adv Econ Res. 2022 Dec 5; 28(3-4):171-182 | utf-8 | null | null | null | oa_other |
==== Front
Appl Health Econ Health Policy
Appl Health Econ Health Policy
Applied Health Economics and Health Policy
1175-5652
1179-1896
Springer International Publishing Cham
36471226
776
10.1007/s40258-022-00776-3
Original Research Article
A Guideline-Implementation Intervention to Improve the Management of Low Back Pain in Primary Care: A Difference-in-Difference-in-Differences Analysis
http://orcid.org/0000-0001-8505-8081
Wilson Ross [email protected]
1
Pryymachenko Yana 1
Abbott J. Haxby 1
Dean Sarah 2
Stanley James 3
Garrett Sue 4
Mathieson Fiona 5
Dowell Anthony 4
Darlow Ben 4
1 grid.29980.3a 0000 0004 1936 7830 Department of Surgical Sciences, Centre for Musculoskeletal Outcomes Research, University of Otago, Dunedin, New Zealand
2 grid.8391.3 0000 0004 1936 8024 College of Medicine and Health, University of Exeter Medical School, University of Exeter, Exeter, UK
3 grid.29980.3a 0000 0004 1936 7830 Biostatistical Group, University of Otago, Wellington, New Zealand
4 grid.29980.3a 0000 0004 1936 7830 Department of Primary Health Care and General Practice, University of Otago, Wellington, New Zealand
5 grid.29980.3a 0000 0004 1936 7830 Department of Psychological Medicine, University of Otago, Wellington, New Zealand
6 12 2022
110
21 11 2022
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Background
Real-world adherence to clinical practice guidelines is often poor, resulting in sub-standard patient care and unnecessary healthcare costs. This study evaluates the effect of a guideline-implementation intervention for the management of low back pain (LBP) in general practice–the Fear Reduction Exercised Early (FREE) approach—on LBP-related injury insurance claims, healthcare utilisation, and costs of treatment.
Design
Data were extracted from comprehensive nationwide New Zealand injury insurance claims records. Data were analysed using a ‘triple-difference’ (difference-in-difference-in-differences) method to isolate the causal effect of FREE training on LBP claims activity, comparing the difference in general practitioner (GP) LBP claims and associated activity before and after training with their non-musculoskeletal injury claims for the same periods (assumed to be unaffected by training), relative to the same comparisons for GPs not trained in the FREE approach.
Results
Training GPs in the FREE approach resulted in significant reductions in the number of LBP injury claims lodged (− 19%, 95% CI −34 to −5), the use of physiotherapy (−30%, 95% CI − 42 to − 18) and imaging (− 27%, 95% CI − 46 to − 8%), and the healthcare costs (− 21%, 95% CI − 41 to − 1) of LBP injury. Changes in claims for earnings’ compensation (− 10%, 95% CI − 34 to 13) were not significant.
Conclusions
A brief guideline-implementation intervention following best-practice LBP management and guideline-implementation strategies achieved significant reductions, persisting over at least 6 to18 months, in healthcare utilisation consistent with improved delivery of guideline-concordant care.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40258-022-00776-3.
http://dx.doi.org/10.13039/100007598 Accident Compensation Corporation http://dx.doi.org/10.13039/501100019219 National Institute for Health Research Applied Research Collaboration South West Peninsula
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pmcKey Points for Decision Makers
Adherence to clinical guideline recommendations for the management of low back pain in primary care is poor, despite clear international consensus on optimal treatment.
We found that a brief training intervention developed to address known barriers to effective implementation reduced unnecessary healthcare use and healthcare costs of managing low back pain.
Tailored, context-specific implementation strategies should be used to improve the use of clinical practice guidelines.
Introduction
Low back pain (LBP) is the leading cause of disability and health loss worldwide, affecting more than 500 million people at any point in time and is responsible for more than 60 million years lived with disability in 2019 [1, 2]. It imposes considerable costs on individuals, health system funders, and societies, particularly through reduced productivity and absence from work and due in part to an over-reliance on medically intensive treatment approaches that deliver relatively low benefit [3–6]. There is a pressing need for evidence-based, cost-effective, and context-specific strategies to reduce the LBP burden.
There is clear international consensus on best-practice primary care treatment and management of LBP [7], but a substantial gap exists between guideline recommendations and actual practice [7, 8]. Guideline-recommended care emphasises a biopsychosocial view of back pain, recognising the association between behavioural, psychological, and social factors in the experience of, and recovery from, pain. Self-management, physical activity, and psychological therapies are recommended ahead of pharmacological or surgical interventions [7, 9, 10]; imaging is not recommended in the absence of specific ‘red flags’ indicating potential serious disease [7]. Despite these recommendations, current practice commonly involves an overuse of opioid medications for pain relief, inappropriate spinal imaging, and potentially harmful interventional procedures, including surgery [3, 7]. Key barriers to effective implementation of best-practice recommendations include clinicians’ beliefs about the causes and optimal treatment of LBP, inadequate knowledge of and confidence in best-practice management, patient expectation of interventional treatment, and inadequate time to provide high-value personalised care [7, 11–13].
The Fear Reduction Exercised Early (FREE) approach to LBP was designed to empower and support general practitioners (GPs) to provide effective guideline-concordant care for LBP in routine clinical practice [14]. It provides information, support, and guidance for GPs to implement evidence-based care in accordance with guideline recommendations, encouraging activity and work participation, integrating a biopsychosocial approach, and discouraging interventions with low beneficial value and potential risk of harms. It was designed to explain the rationale and evidence for current guideline recommendations and to overcome key barriers to their effective implementation [15]. The Fear Reduction Exercised Early includes brief (5 hours) GP education and training, resources to support patients with education, advice, and reassurance, and electronic consultation support to encourage adherence to guideline-recommended management [14].
The FREE approach was evaluated in a pragmatic cluster-randomised controlled trial (RCT), which found that training GPs in the FREE approach had a substantial positive impact on GPs’ knowledge, attitudes, and confidence to deliver best-practice care for LBP and improved alignment with guideline recommendations, over a 6-month follow-up [16]. Economic evaluation suggested reductions in unnecessary healthcare utilisation and healthcare costs, but results were uncertain due to the short follow-up period, inherent wide variability in healthcare costs, and the limited sample size of the RCT [16]. In this study, we evaluate the effect of training GPs in the FREE approach on injury insurance claims, healthcare utilisation, and costs over longer-term follow-up (33 months), using routinely collected insurance claims data for a larger cohort of GPs trained in both the RCT and a concurrent implementation study.
Methods
Data Sources
Both the RCT and the implementation study were conducted in the Greater Wellington region of New Zealand (NZ). General practitioners were recruited for the studies through practices or direct approach via primary healthcare organisations. All GPs working in practices in the primary study region (Hutt Valley) were invited to participate in either the RCT or the implementation study. Additional GPs from secondary implementation areas (Wellington City, Kāpiti, and Wairarapa) were invited to the sample for the implementation study to add diversity in the study population (e.g., rural practice, migrant health, indigenous Māori health, and older adult care). Training was conducted between July 2016 and April 2018.
Data used in this study were obtained from routine insurance claims records held by the Accident Compensation Corporation (ACC), NZ’s universal national no-fault insurance scheme for personal injury and the primary funder of LBP health care in NZ. Data were extracted from the ACC claims database by month (relative to date of training) for 36 months before and 33 months after training for all consenting FREE-trained GPs in both the RCT and the implementation study, and by calendar month between July 2013 (36 months before the first FREE training date) and December 2020 (33 months after the last training date) for all GPs nationwide not involved in FREE training during either study. Data from the FREE-trained GPs (collected by month relative to the specific training date) were mapped to the nearest calendar month to form the combined dataset for analysis: for training dates on or before the 15th of the month, the first month’s data were matched to the calendar month of training; for training dates on or after the 16th of the month, the first post-training month was matched to the following calendar month (e.g., for a GP trained on 25 August 2017, the first post-training month, representing claims lodged between 26 August and 25 September, was aligned with calendar month data for non-trained GPs for September 2017).
Outcome Measures
For each month, all LBP injury claims made during that month were identified (see Table C1 in Appendix C in Online Resource 1 for the list of codes used). For each claim, associated activity was calculated over a 6-month period following the index claim date (i.e., the most recent data cover activity up to June 2021, for claims lodged in December 2020). In the ACC system, all activity associated with a given injury event is recorded against the initial claim (and thus included in the data used in this study), regardless of the healthcare provider referring for or delivering the service. Outcome measures calculated were the total number of LBP injury claims per month, the number of healthcare visits paid on those claims (GP visits, imaging, physiotherapy, other allied and complementary health services, and specialist consultations), the cost of claims (total costs including healthcare costs, vocational rehabilitation, and earnings’ compensation payments; and healthcare costs only), the number of claims for which earnings compensation was paid and the total number of days of earnings compensation paid, the number of subsequent LBP insurance claims made by the same patients (lodged by either the original GP or any other healthcare provider), and the number of non-musculoskeletal injury claims (used as a control measure as described below). All costs are reported in 2018 NZ dollars (NZ$), adjusted using NZ Consumer Price Index inflation rates [17] (in 2018, 1 NZD ≈ 0.70 USD). All data were observed at the GP-month level of the original claim (i.e., all claims lodged by a given GP in a given month, and their associated outcomes).
Statistical Analysis
To identify causal effects of providing FREE training to GPs, we used a triple-difference design exploiting three sources of variation in exposure to the effects of training [18]. First, we used data from pre-training (over 36 months prior to each GP’s individual training date) and post-training periods (claims over 33 months after the training date, with subsequent activity for each claim recorded over the following 6 months). Second, we used the number of non-musculoskeletal injury claims for each GP to serve as a control for time-varying changes in GPs’ overall level of activity, contrasted with the LBP claims measures. Third, we used claims made by non-FREE-trained GPs as a control for variation in national practice patterns or activity unrelated to FREE training, contrasted with the data on claims made by FREE-trained GPs. Full details of the triple-difference model are provided in Appendix A (in Online Resource 1). Validation of the modelling assumptions of the triple-difference model, including event study figures to assess the plausibility of the parallel trends assumption (Figs B1 and B2), are provided in Appendix B (in Online Resource 1).
Our primary model provides estimates of the average effect of FREE training over the full 33-month follow-up period. To investigate the persistence of effects, we also calculated effect estimates for 6-month periods (1–6 months, 7–12 months, etc., post-training) and, for graphical presentation of results, for each month 1, …, 33 following training. We estimated effects using a generalised linear model (GLM), with a log link and quasi-Poisson (for count outcomes) or gamma (for cost outcomes) variance function. For interpretation, we report the average treatment effects (on the treated: the mean difference, per FREE-trained GP over the follow-up period, between observed LBP claims/healthcare visits/costs and predicted outcomes if they had not received FREE training) alongside the coefficient estimates.
Sensitivity Analyses
We conducted several robustness checks on our model specification and sample selection assumptions. First, we excluded GPs practising in the Greater Wellington region (the region in which FREE training was implemented) from the national GP cohort, to exclude possible ‘spill-over’ effects of training (for example, through local professional networking). Second, we re-ran the analyses using only data on claims lodged up to 18 months post-training (or prior to September 2019, 18 months after the last FREE training date, for the non-FREE-trained cohort). In March 2020 (i.e., within the 6-month follow-up period of claims lodged in September 2019), NZ entered a strict nationwide lockdown in response to the COVID-19 pandemic, resulting in a sharp discontinuity in ACC claims activity and other healthcare utilisation, which may impact our results for later periods. Third, we excluded observations (GP-months) with abnormally high numbers of either LBP or non-musculoskeletal claims (more than 10 LBP or 100 non-musculoskeletal injury claims in a month), as these outlying values may have a disproportionate impact on our estimated results (these high volumes were considered unlikely to represent routine general practice and may indicate practitioners working in acute care settings such as after-hours or urgent care clinics). Fourth, we excluded all claims lodged in the last 6 months before training for all FREE-trained GPs. Outcomes were recorded over the 6 months following the original index claim date; outcomes measured against these late pre-training claims may therefore have been affected by FREE training. Fifth, we aggregated the monthly data extracted from claims records to the quarterly level, to reduce the sparsity of the data for rare outcomes. Lastly, we estimated models allowing for linear time trends in each outcome and for each study cohort. Full details of the rationale and specification of each sensitivity analysis are reported in Appendix B in Online Resource 1.
Results
Descriptive Statistics
Sixty-three GPs (from 8 practices) took part in the RCT, of whom 58 were trained in the FREE approach (34 GPs in the intervention group; 24 of the 29 GPs in the control group received the intervention following completion of RCT data collection in their practices), and a further 123 GPs (43 practices) in the implementation study (all of whom received training). Of the 181 GPs trained in the FREE approach, 175 (97%) consented to the use of their insurance claims data in the study; 7 had no relevant claims over the study period or could not be linked with claims records, resulting in 168 FREE-trained GPs included in the analysis. Baseline descriptive statistics of GP characteristics and injury claims activity are reported in Table 1. The average age was 47 years, and slightly more than half were female. Comparable data were not available for the non-FREE-trained cohort used in this study; compared to the nationwide average for practising GPs (53 years and 50% female in 2017 [19]), the FREE-trained cohort was slightly younger and had a slightly higher proportion of women. The GPs had been in practice for an average of 16 years at the time of training.Table 1 Descriptive statistics of GP cohorts
Outcome FREE-trained cohort Non-trained cohort
N 168 6075
GP characteristics
Age, years 47.4 (11.2)
Gender, n (%) female 94 (56%)
Length in practice, years 15.9 (11.6)
Pre-training Post-training Pre-training Post-training
LBP claims
Number of LBP claims 30.7 (25.6) 27.4 (22.2) 42.6 (111.7) 39.2 (110.5)
Number of healthcare visits on LBP claims
GP 17.4 (19.5) 17.5 (18.8) 32.1 (87.8) 31.1 (88.8)
Physiotherapy 49.1 (47.0) 35.9 (34.4) 68.7 (171.3) 59.2 (162.5)
Imaging 6.8 (7.7) 5.8 (5.5) 10.5 (24.4) 10.4 (25.8)
Allied health 21.3 (26.5) 24.3 (29.5) 65.2 (307.1) 64.0 (295.6)
Specialist consultations 3.3 (4.5) 2.9 (5.1) 6.3 (17.2) 6.3 (18.5)
Cost of LBP claims
Total $19,946 ($25,108) $21,941 ($23,646) $33,730 ($93,669) $36,232 ($109,738)
Medical fees $6210 ($7677) $5843 ($6178) $13,126 ($36,211) $12,881 ($37,359)
Earnings’ compensation on LBP claims
Number of claims receiving earnings’ compensation 1.9 (2.4) 2.0 (2.4) 3.0 (8.9) 3.0 (10.0)
Total days earnings’ compensation 99 (146) 111 (136) 160 (476) 171 (561)
Claims subsequent to LBP claims
Number of subsequent claims 0.8 (5.0) 0.5 (1.0) 1.6 (6.0) 1.4 (6.0)
Number of non-MSK claims filed 169.0 (192.9) 172.0 (294.3) 333.6 (1647.3) 300.1 (1598.6)
Values are mean (standard deviation) unless otherwise stated. GP characteristics as at date of training. Injury claims data collected over 33 months before and after training date for FREE-trained GPs; 33 months before and after the median training date (November 2017) for non-trained GPs. Baseline GP characteristics were not available for the non-trained cohort
FREE Fear Reduction Exercised Early approach (intervention), GP general practitioner, LBP low back pain, MSK musculoskeletal injury
Over the 3 years prior to training, FREE-trained GPs lodged an average of 31 ACC claims for LBP, incurring total claims costs of $19,900 (per GP). The most common healthcare referrals on LBP claims were to physiotherapy (49 visits per GP) and other allied health providers (21 visits).
The national cohort of GPs not trained in the FREE approach (N = 6075) had higher claims numbers (LBP and non-musculoskeletal), healthcare utilisation, and costs, largely due to a small number of GPs with extremely high levels of activity (see the large standard deviations in Table 1, and Figs C1 and C2 in Appendix C in Online Resource 1). As noted above, these observations with abnormally high volumes were considered unlikely to represent routine general practice. Excluding these outlying observations (GP-months with more than 10 LBP claims or 100 non-musculoskeletal claims), the baseline numbers of claims, healthcare utilisation, and costs were much more similar in the FREE-trained and non-trained cohorts (Table B2 in Appendix B in Online Resource 1; excluding these months from our analyses did not meaningfully change any of our main results).
Primary Results
Our primary triple-difference estimates of the effects of FREE training are presented in Table 2. There was a large and statistically significant reduction in the number of LBP injury claims filed over 33 months post-training (− 8.1 claims per GP [equivalent to a 19% reduction]; 95% CI − 15.7 to − 0.4), and in the number of visits to physiotherapy (− 18.9 visits [− 30%]; 95% CI − 30.9 to − 6.9) and imaging (− 2.7 visits [− 27%]; 95% CI − 5.2 to − 0.1). Reductions were also seen in the number of specialist consultations (− 1.3 visits [− 27%]; 95% CI − 3.0 to 0.3), although these were statistically significant only in the first 6 months following training. There was no significant reduction in the number of LBP claim-funded visits to GPs (− 3.3 visits [− 13%]; 95% CI − 8.9 to 2.2) or allied health services other than physiotherapy (− 1.0 visits [− 3%]; 95% CI − 8.5 to 6.5).Table 2 Triple-difference estimates of change in LBP claims activity following FREE training
(1) (2) (3) (4) (5) (6) (7)
Outcome Regression coefficients Average treatment effect (per GP over 33 months)
Full 33-month follow-up period Months 1–6 Months 7–12 Months 13–18 Months 19–24 Months 25–30
Panel A. LBP claims
Number of LBP claims − 0.22 (0.09)** − 0.20 (0.06)*** − 0.27 (0.08)*** − 0.14 (0.08)* − 0.18 (0.09)* − 0.23 (0.13)* − 8.1 (− 15.7 to − 0.4)
Panel B. Number of healthcare visits
GP − 0.14 (0.11) − 0.16 (0.09)* − 0.12 (0.12) − 0.09 (0.12) − 0.05 (0.14) − 0.14 (0.16) − 3.3 (− 8.9 to 2.2)
Physiotherapy − 0.37 (0.09)*** − 0.56 (0.09)*** − 0.42 (0.11)*** − 0.39 (0.09)*** − 0.24 (0.12)** − 0.18 (0.15) − 18.9 (− 30.9 to − 6.9)
Imaging − 0.32 (0.13)** − 0.56 (0.12)*** − 0.39 (0.14)*** − 0.26 (0.15)* − 0.14 (0.17) − 0.23 (0.18) − 2.7 (− 5.2 to − 0.1)
Allied health − 0.04 (0.12) − 0.12 (0.16) − 0.22 (0.19) − 0.04 (0.13) 0.24 (0.17) − 0.08 (0.18) − 1.0 (− 8.5 to 6.5)
Specialist consultations − 0.32 (0.18)* − 0.59 (0.21)*** − 0.14 (0.24) − 0.25 (0.23) − 0.16 (0.28) − 0.35 (0.23) − 1.3 (− 3.0 to 0.3)
Panel C. Cost of claims
Total − 0.21 (0.13) − 0.37 (0.16)** − 0.15 (0.17) − 0.25 (0.20) − 0.01 (0.21) − 0.14 (0.20) − $5 583 (− $14 201 to $3 035)
Medical fees − 0.26 (0.12)** − 0.33 (0.19)* − 0.29 (0.15)* − 0.33 (0.14)** − 0.06 (0.18) − 0.22 (0.16) − $1 881 (− $4 126 to $364)
Panel D. Earnings compensation
Number of claims receiving earnings’ compensation − 0.11 (0.13) − 0.24 (0.14)* 0.07 (0.14) − 0.14 (0.21) − 0.09 (0.18) − 0.03 (0.21) − 0.3 (− 1.0 to 0.4)
Total days earnings’ compensation − 0.15 (0.15) − 0.28 (0.18) − 0.07 (0.20) − 0.33 (0.25) 0.08 (0.23) − 0.02 (0.24) − 21 (− 70 to 28)
Panel E. Subsequent claims
Number of subsequent claims − 0.64 (0.41) − 0.50 (0.39) − 0.74 (0.44)* − 0.33 (0.50) − 0.61 (0.50) − 1.05 (0.54)* − 0.5 (− 1.5 to 0.4)
Periods defined by the date of the index LBP claim; associated healthcare visits, costs, and subsequent claims calculated over 6 months from index claim date
All regressions include non-parametric controls for all two-way interactions (injury type-by-time period, cohort-by-time period, injury type-by-cohort)
Standard errors, clustered at the GP level, are shown in parentheses. p values: *** < 0.01 < ** < 0.05 < * < 0.1
Average treatment effects reported with 95% confidence intervals in parentheses
FREE Fear Reduction Exercised Early approach (intervention), GP general practitioner, LBP low back pain
There were also substantial reductions in both total claims costs (− $5 486 [− 18%]; 95% CI − 13,924 to 2951) and healthcare treatment costs (− $1852 [− 21%]; 95% CI − 4053 to 350). For total claims costs, this reduction was statistically significant only in the first 6 months after training, while reductions in medical fees costs were significant up to 18 months post-training. Effects on the number of claims receiving earnings’ compensation (− 0.3 claims [− 10%]; 95% CI − 1.0 to 0.4) and on the total days of earnings compensation paid (− 21 days [− 13%]; 95% CI − 70 to 28) were generally not significant, except for a marginally significant reduction in the number of claims for which the patient received earnings compensation in the first six months after training only. There was a very large proportional reduction in the number of subsequent LBP claims lodged (for the same patients, by any healthcare provider; − 0.5 claims [− 47%]; 95% CI − 1.5 to 0.4); however, as the number of subsequent claims over the 6-month follow-up period was small, these estimates were very imprecise.
Estimates of the intervention effect by time since training are shown graphically in Fig. 1 (for the outcomes with significant effects in Table 2; see Fig. C3 in Appendix C in Online Resource 1 for all other outcomes). Intervention effects generally decreased in magnitude over the 2 years following training; there was a later increase in effects on most outcomes starting from around 18–24 months post-training, but this was subject to wide uncertainty intervals.Fig. 1 Trajectory of triple difference estimates of effect of FREE training. Each dot represents the month-specific treatment effect estimate. Smoothed curve and confidence band (representing 95% confidence intervals) from cubic spline smoothing function. FREE Fear Reduction Exercised Early approach (intervention)
Sensitivity Analyses
Our primary results were robust to all sensitivity analyses considered. Full results from all sensitivity analyses are presented in Appendix B in Online Resource 1.
Discussion
Improving adherence to best-practice care for LBP in primary care has proven persistently challenging despite clear and consistent guideline recommendations [3, 7]. Key implementation barriers that need to be overcome to realise effective implementation of guideline-concordant care include clinicians’ and patients’ beliefs about the causes and treatment of LBP, lack of knowledge and confidence in managing LBP among GPs, and patient expectations for medical intervention [7, 11–13]. This study reports on the evaluation of a guideline-implementation intervention designed specifically to overcome these barriers and demonstrates large and sustained changes in GP behaviour and reductions in healthcare utilisation for LBP following a brief training intervention.
Our estimate of the reduction in LBP injury claims filed over 33 months (19%) is consistent with previously reported results (over 6 months) from the RCT (in the trial, 54% of consultations with FREE-trained GPs were linked to ACC claims compared to 69% of consultations with non-trained GPs, a 22% reduction). The FREE approach emphasises that LBP can occur without injury and that framing it as an injury risks unnecessarily medicalising LBP and may have negative consequences on the patient’s perception of fragility and willingness to return to physical activity. This result likely indicates that trained GPs became less willing to ascribe LBP to injury (as required to lodge an ACC claim), and more confident that patients would recover without additional treatment (and therefore saw less need to support patients with an ACC claim).
The primary mechanism through which the FREE approach is expected to impact patient care and costs of treatment is by changing GP behaviour with respect to referral of patients to other health services; much of this additional care is considered medically unnecessary, wasteful, and, especially in the case of imaging and some specialist referrals for surgical intervention, potentially harmful [7]. Consistent with this expectation, we found substantial and statistically significant reductions in the number of visits to physiotherapy, imaging, and specialist consultations, but no significant reduction in the number of funded visits to GPs for LBP. These results suggest that GPs have increased confidence in their own abilities to effectively manage LBP patients, and are consistent with qualitative and quantitative findings from the prior implementation study. There was no significant change in the use of allied health services other than physiotherapy; utilisation of these services is commonly driven by prior patient experience and beliefs rather than GP recommendation [20, 21], and may therefore be less amenable to GP-level intervention.
Repeated episodes of LBP are very common, although patients may or may not seek care for any given episode. Guideline recommendations and the FREE approach aim to help clinicians and patients to reduce the perceived need for medical intervention to manage LBP and to develop peoples’ skills and confidence to effectively self-manage their LBP, thereby reducing the demand for future healthcare for LBP. This is supported by the very large reductions found in this study in the number of subsequent claims lodged (although these were imprecisely estimated due to the small number of subsequent claims lodged over the 6-month follow-up period).
Given the high prevalence, burden, and costs of LBP globally, and ongoing use of ineffective and potentially harmful treatments, there is a clear need to improve LBP management from both an economic and health perspective. Evidence from the previous RCT of the FREE approach indicates that this training intervention was able to achieve changes in GP beliefs and behaviour, improvements in the delivery of guideline-concordant care, and patient outcomes comparable to those of usual care [16]. The results of the present study further suggest that FREE training resulted in measurable and meaningful impacts on healthcare use and costs over the medium-term in a real-world care setting. Although GPs were reimbursed for attending the training workshop and for the first three consultations undertaken during the training period, no subsequent incentives or encouragement were provided to achieve uptake and adherence in routine practice. Process evaluation undertaken in the RCT found that LBP consultations by FREE-trained GPs were longer than those by non-trained GPs; this does not appear to have prevented sustained behaviour change, suggesting that GPs saw benefits in delivering guideline-concordant care after training in the FREE approach and that the tools provided were able to support this activity. It is not known whether FREE consultations became shorter as GPs became more experienced with the approach, or whether they continued to allocate more time to these consultations despite not receiving any extra funding to do so.
This study is subject to several limitations. There was a relatively small number of GPs trained in the RCT and implementation study phases, resulting in wide uncertainty around our estimates, particularly for less common outcomes (such as earnings’ compensation or subsequent LBP claims). Despite being rare occurrences, these outcomes contribute a large share of the total costs of LBP. Further research with a larger sample size will be needed to assess possible effects on these outcomes.
Our findings are limited to LBP covered by ACC. The ACC system covers all work-related back pain, and non–work-related back pain attributable to injury, occurring within NZ, with universal no-fault coverage of the entire population; however, no data were available in this study on patients consulting their GP for non–work-related LBP that was not attributed to an injury event (i.e., not covered by ACC). Our results may not be generalisable to LBP not covered by ACC (or comparable compensation and insurance schemes in other health care systems), as ACC coverage may influence the way in which patients seek healthcare and how their LBP is managed (due to the increased resources available to fund investigations and treatment). We also have no data on any costs of care not covered by ACC. While most injury-related care is covered by ACC, there are additional out-of-pocket costs (co-payments and non-covered items) incurred by patients for some primary and community-provided care. For non–work-related injury, the first 5 days of absence from work is usually covered by the employee’s sick leave and is not represented in ACC data.
General practitioners who self-selected into study participation and completed training may be more open to change in their management of LBP than other GPs who did not select into training, questioning the generalisability of these results to the wider workforce. This possibility should be mitigated by two factors. First, uptake of training and study participation was high: 82% of GPs in the primary study area attended FREE training. Second, many GPs were recruited and trained within practices, so even GPs who may not have individually selected into training would likely complete the training if their practice was involved in the study. Nevertheless, these results should be viewed as applying to a cohort at least nominally willing to engage with changes in their clinical practice to deliver more guideline-concordant LBP care.
Implications for Policy and Practice
Our results, and the findings from the previous RCT and implementation study, suggest that a brief GP training intervention can effectively improve the management of LBP in primary care. These findings support previous studies suggesting a need for tailored guideline-implementation strategies to overcome known, context-specific barriers to effective guideline adherence in clinical practice [12, 15]. Key barriers to delivery of guideline-concordant care for LBP in the NZ primary care system were identified in development of the FREE approach through literature review, interviews with both GPs and people with LBP, a national survey, and pilot testing of the intervention. Achieving change in the behaviour of both GPs and patients was supported by evidence-based behaviour change techniques; education and training increased GPs’ knowledge of and confidence in applying LBP clinical practice guidelines; electronic consultation support was provided to facilitate use of the FREE approach in routine practice; and an information booklet and website for both patients and GPs provides clear, accessible, and easily understood evidence-based information on recommended LBP management and outcomes [16, 22].
The potential return on investment for healthcare funders of successful implementation of LBP clinical practice guidelines is substantial. The cost of providing the brief training intervention evaluated in this study was approximately $1025 per GP (Table C2 in Appendix C in Online Resource 1), compared with estimated healthcare cost savings of $1852 and total claims cost savings of $5486 over 33 months. There are potential additional implementation costs and considerations in adaptation of the approach for other countries and health systems. General practitioner consultations in NZ are generally about 15 minutes in duration, longer than in other comparable health systems; the feasibility and potential cost of the longer consultations required to deliver the FREE approach would need to be considered in other health systems. There is also a need for the (one-off) development of the electronic consultation support tool and its integration with existing practice management systems. There may be ongoing costs of printing and distributing the patient information booklets, although an electronic version is available.
Previous systematic reviews have found that implementation interventions need to be ongoing and regular to generate sustained changes in clinical practice [12]. In this study, we found a brief (half-day) training intervention was able to deliver sustained changes over a 33-month follow-up; however, effects on most outcomes were strongest over the first 6–18 months, suggesting a possible role for refresher sessions to reinforce long-term behaviour change and potentially further strengthen intervention cost effectiveness. We suggest future guideline implementation interventions consider the optimal use of refresher sessions or other strategies to enhance long-term adherence and cost effectiveness.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 883 KB)
Acknowledgements
The authors gratefully acknowledge the contribution of Auren Xu, Customer Insights Analyst, Accident Compensation Corporation, who extracted the data used in the analysis.
Author Contributions
Conceptualisation: BD, JS, SD, JHA, FM, AD conceptualised and developed the FREE approach; RW, YP, BD, JHA conceptualised the data collection and analysis reported in this article. Formal analysis: RW. Funding acquisition: BD, JS, SD, JHA, FM, AD. Methodology: BD, RW, YP, JHA. Project administration: BD, AD, SG. Visualisation: RW. Writing—original draft: RW. Writing—review & editing: YP, JHA, SD, JS, SG, FM, AD, BD.
Declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethics approval and trial registration
The RCT and implementation study providing data for this study were registered with the Australia New Zealand Clinical Trial Registry (Trial IDs ACTRN12616000888460 and ACTRN12616000896471, respectively) and approved by the New Zealand Central Region Health and Disability Ethics Committee (16/CEN/43 and 16/CEN/77).
Consent to participate
All FREE-trained GPs whose data were used in the study gave consent for their study data to be linked to ACC claims records for the purpose of this study. Claims data for GPs not trained in the FREE approach were extracted by ACC from their database, anonymised, and shared with the research team; GP consent was not required for this audit activity.
Consent for publication
Not applicable.
Funding
The RCT and the implementation study providing data for this study were funded by the Accident Compensation Corporation (https://www.acc.co.nz). BD, JS, SD, JHA, FM, and TD were named investigators on the funding application. For this study, the funder extracted the data from routine insurance claims records, but had no other role in study design, conduct, analysis, interpretation, reporting, or the decision to submit for publication. SD is partially supported by the National Institute for Health Research Applied Research Collaboration South West Peninsula, UK. The views expressed in this publication are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care, UK.
Data availability
The data used in this study are proprietary and are held by the Accident Compensation Corporation (ACC), but may be made available to interested researchers with the explicit permission of the ACC.
Code availability
All analysis code used in this study is available on request from the authors.
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References
1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22.
2. IHME. GBD Compare Data Visualization. Seattle, WA: Institute for Health Metrics and Evaluation (IHME), University of Washington; 2020.
3. Hartvigsen J Hancock MJ Kongsted A Louw Q Ferreira ML Genevay S What low back pain is and why we need to pay attention Lancet 2018 391 2356 2367 10.1016/S0140-6736(18)30480-X 29573870
4. Coombs DM Machado GC Richards B Wilson R Chan J Storey H Healthcare costs due to low back pain in the emergency department and inpatient setting in Sydney, Australia Lancet Region Health West Pac. 2021 7 100089 10.1016/j.lanwpc.2020.100089
5. Kamper SJ Logan G Copsey B Thompson J Machado GC Abdel-Shaheed C What is usual care for low back pain? A systematic review of health care provided to patients with low back pain in family practice and emergency departments Pain 2020 161 4 694 702 10.1097/j.pain.0000000000001751 31738226
6. Downie A Hancock M Jenkins H Buchbinder R Harris I Underwood M How common is imaging for low back pain in primary and emergency care? Systematic review and meta-analysis of over 4 million imaging requests across 21 years Br J Sports Med 2020 54 11 642 651 10.1136/bjsports-2018-100087 30760458
7. Foster NE Anema JR Cherkin D Chou R Cohen SP Gross DP Prevention and treatment of low back pain: evidence, challenges, and promising directions Lancet 2018 391 10137 2368 2383 10.1016/S0140-6736(18)30489-6 29573872
8. Williams CM Maher CG Hancock MJ McAuley JH McLachlan AJ Britt H Low back pain and best practice care: a survey of general practice physicians Arch Intern Med 2010 170 3 271 277 10.1001/archinternmed.2009.507 20142573
9. Qaseem A, Wilt TJ, McLean RM, Forciea MA, for the Clinical Guidelines Committee of the American College of Physicians. Noninvasive treatments for acute, subacute, and chronic low back pain: A clinical practice guideline from the American College of Physicians. Ann Rheumat Dis. 2017;166(7):514–30.
10. NICE. Low back pain and sciatica in over 16s: Assessment and management. National Institute for Health and Care Excellence (NICE); 2016 Nov.
11. Slade SC Kent P Patel S Bucknall T Buchbinder R Barriers to primary care clinician adherence to clinical guidelines for the management of low back pain Clin J Pain 2016 32 9 800 816 10.1097/AJP.0000000000000324 26710217
12. Mesner SA Foster NE French SD Implementation interventions to improve the management of non-specific low back pain: a systematic review BMC Musculoskelet Disord 2016 17 258 10.1186/s12891-016-1110-z 27286812
13. Morgan T Wu J Ovchinikova L Lindner R Blogg S Moorin R A national intervention to reduce imaging for low back pain by general practitioners: a retrospective economic program evaluation using Medicare Benefits Schedule data BMC Health Serv Res 2019 19 983 10.1186/s12913-019-4773-y 31864352
14. Darlow B. The development of a new approach to acute low back pain management in general practice [PhD thesis]. [Wellington, New Zealand]: University of Otago; 2014.
15. Damschroder LJ Aron DC Keith RE Kirsh SR Alexander JA Lowery JC Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science Implem Sci 2009 4 50 10.1186/1748-5908-4-50
16. Darlow B Stanley J Dean S Abbott JH Garrett S Wilson R The Fear Reduction Exercised Early (FREE) approach to management of low back pain in general practice: a pragmatic cluster-randomised controlled trial PLoS Med 2019 16 9 e1002897 10.1371/journal.pmed.1002897 31498799
17. Reserve Bank of New Zealand. Inflation calculator. 2022. https://www.rbnz.govt.nz/monetary-policy/about-monetary-policy/inflation-calculator. Accessed 23 Sep 2022.
18. Angrist JD Pischke J-S Mostly harmless econometrics: An empiricist’s companion 2009 Princeton Princeton University Press
19. Medical Council of New Zealand. The New Zealand medical workforce in 2019. MCNZ; 2020.
20. Busse JW Pallapothu S Vinh B Lee V Abril L Canga A Attitudes towards chiropractic: a repeated cross-sectional survey of Canadian family physicians BMC Fam Pract 2021 22 188 10.1186/s12875-021-01535-4 34525953
21. Wardle JL Sibbritt DW Adams J Primary care practitioner perceptions and attitudes of complementary medicine: a content analysis of free-text responses from a survey of non-metropolitan Australian general practitioners Primary Health Care Res Dev. 2018 19 246 255 10.1017/S1463423617000664
22. Darlow B Stanley J Dean S Abbott JH Garrett S Mathieson F The Fear Reduction Exercised Early (FREE) approach to low back pain: Study protocol for a randomised controlled trial Trials 2017 18 484 10.1186/s13063-017-2225-8 29041947
| 36471226 | PMC9734860 | NO-CC CODE | 2022-12-14 23:28:31 | no | Appl Health Econ Health Policy. 2022 Dec 6;:1-10 | utf-8 | Appl Health Econ Health Policy | 2,022 | 10.1007/s40258-022-00776-3 | oa_other |
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