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References | PMC10327391 |
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Background | malaria, MPE | MALARIA | School-aged children (SAC) have an increased risk to contract malaria and play a major role in its transmission dynamics. However, their malaria prevention experience is poor. Thus, the effect of malaria prevention education (MPE) on bed net utilization, treatment seeking from a health facility and cumulative incidence of malaria was evaluated in Southern Ethiopia. | PMC10360348 |
Methods | malaria | MALARIA, REGRESSION | A two arm cluster randomized controlled trial was conducted by recruiting 2038 SAC from 32 schools. Structured questionnaire was used to collect data on socio-demographic, economic, bed net ownership, bed net utilization, whether the participated child suffered from malaria and has got treatment from a health facility. Generalized mixed effect logistic regression using school as random variable was used to assess the effect of the intervention on the outcome variables. | PMC10360348 |
Results | malaria | MALARIA | The ownership of bed net in households of the control and intervention schools was similar respectively with 84.6 and 88.6% (Crude Odds Ratio (COR): 1.5; 95%CI: 0.5–4.8). The percentage of SAC slept under the bed net the night before the survey was also similar (55.1% versus 54.0%); COR:1.04; 95%CI: 0.5–2.4). Bed net utilization was affected by household size to the bed net ratio ≤ 2 (Adjusted Odds Ratio (AOR) = 1.6; 95%CI:1.3–2.1), bed net utilization at baseline of the study (AOR = 2.3; 95%CI:1.5–3.6), and history of malaria attack in the last twelve months (AOR = 1.3; 95%CI:1.01–1.8). Reported cumulative incidence of malaria and treatment seeking from a health facility by SAC was similar between intervention and control arms: -2.1% (COR = 0.8; 95%CI: 0.5–1.5) and 9.6% (COR = 1.4; 95%CI: 0.4–4.3) respectively. The reported incidence of malaria was affected by altitude (AOR = 0.5; 95%CI: 0.3–0.8), low and medium wealth index (AOR = 0.7; 95%CI: 0.5–0.96 and AOR = 0.7; 95%CI: 0.5–0.98), adequate bed net number for household members (AOR = 0.7; 95%CI:0.5–0.9) and bed net utilization (AOR = 1.3; 95%CI:1.1–1.8). | PMC10360348 |
Conclusions | malaria, MPE | MALARIA | MPE had no significant effect on the use of malaria prevention measures considered, treatment seeking from a health facility and reported cumulative incidence of malaria though bed net use was associated with malaria incidence. Before organizing any health education program, sustainable implementation efforts have to be warranted especially in SAC, a neglected but relevant vulnerable and reservoirs. | PMC10360348 |
Trial registration | Pan African Clinical Trials Registry PACTR202001837195738, registered 21/01/2020. | PMC10360348 |
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Keywords | PMC10360348 |
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Introduction | malaria, infections | DISEASE TRANSMISSION, MALARIA, DISEASE, INFECTIONS, MALARIA | Malaria remains the leading cause of morbidity and mortality in economically disadvantaged tropical and subtropical regions, particularly in Africa [As the transmission intensity reduces due to the widespread use of malaria prevention measures, there is change in age pattern of malaria. The proportion of clinical malaria among under-five children was above 60% in high endemic settings but the same age group account for below 20% in low transmission settings [Most of these infections among SAC are asymptomatic and not presented to a health facility for treatment to halt either progression to clinical or severe malaria and/or interrupt disease transmission [Unfortunately, SAC are the least likely to get proven malaria intervention measures such as LLINs and prompt diagnosis and effective treatment. Their care givers visit informal shops for the management of their clinical malaria and are less likely to sleep under insecticide-treated bed nets as compared to other population segments [Ethiopia is one of the malaria-endemic countries in the SSA, and both Prompt diagnosis and treatment of malaria and vector control measures are the major malaria prevention practices in Ethiopia. As a means of disease prevention, Ethiopia has deployed a huge workforce of health extension workers in the fight against malaria in 2004. At the same time, Ethiopia introduced LLINs (distributed free of charge) [To overcome the underutilization of malaria prevention measures and broader strategies to control and eliminate malaria, different researches suggest the use of targeted and well-tailored awareness creation to increase the utilization of malaria prevention measures [ | PMC10360348 |
Methods | PMC10360348 |
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Study area and participants | malaria | MALARIA | This study was conducted in Dara Mallo and Uba Debretsehay districts in Gamo and Gofa Zones respectively. These districts were selected as they harbor the highest burden of malaria in the former Gamo Gofa Zone in Southern Nations, Nationalities, and Peoples Regional (SNNPR) state. In line with the national malaria elimination program, the major malaria prevention measure in use in the two districts is LLINs. The study area was in the western part of Arba Minch town, the capital of the former Gamo Gofa zone (Fig.
Study area in Gamo Gofa Zone in South Nations, Nationalities and peoples regional state, 2019 | PMC10360348 |
Trial design and participants | malaria | MALARIA | A 1:1 two-arm parallel open cluster randomized controlled trial was conducted to address the trial objectives. The trial was registered in Pan African Clinical Trials Registry (PACTR202001837195738). Clusters are primary schools that are found in malaria transmission settings in the two districts and enrolled at least 72 children aged 5–14 years. There were a total of 32 eligible primary schools in the two districts. Half of these schools were allocated to the intervention and the other half in the control groups. From each of these schools, 72 children attending their education from grade one to three, mentally fit to respond questions directed to them and without any physical problem to measure their height were included in the study. The selected 72 children and one of their parents in the intervention schools and only the selected SAC from the control arm of the trial participated in the study. An equal number of children were approached to be enrolled in the study from each school. The cluster randomized trial was used to minimize the information contamination from the intervention schools to the people in the control schools. | PMC10360348 |
The intervention and its implementation | malaria, anaemia | MALARIA, ANAEMIA | The intervention was malaria prevention education. The content of the intervention package was developed after exploring the parent’s perception of the cause of malaria and their malaria prevention experience [Two science teachers and a school director from each intervention schools were trained by the research team from Arba Minch University. The trained teachers provided the intervention to the selected SAC and their parents separately. The intervention was planned to be delivered twice per annum, once each semester. However, due to the COVID-19 pandemic and associated prevention measures, the intervention was given once in December 2019. To minimize dropouts and increase adherence to the intervention, sensitization of the students as there is malaria prevention education was done about two days before the date of delivery of the intervention by the trained teachers. Nothing is done to students in the control arm except prevention measures underway by the national malaria control program.The intervention was hypothesized to reduce the prevalence of malaria and associated morbidities among SAC. As indicated in Fig.
Model on causal pathway of MPE on malaria, anaemia and cognitive development of SAC, 2019 | PMC10360348 |
Outcomes | malaria, anemia | MALARIA, SECONDARY, ANEMIA | The initial aim of the study was to assess the effect of MPE on incidence of malaria, anemia, and cognitive performance of SAC. However, because of the low prevalence of malaria than assumed, the outcomes of the intervention were changed to the proxy indicators of malaria. The primary and secondary outcomes used to evaluate the effectiveness of the intervention were described below. | PMC10360348 |
Primary outcome | The primary outcome of the trial was bed net utilization by SAC. It was defined as a percentage of SAC that slept under LLINs the night before the interview irrespective of bed net ownership. | PMC10360348 |
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Secondary outcomes | malaria | MALARIA, SECONDARY | The secondary outcomes of the trial were self-reported cumulative incidence of malaria, the percentage of children with symptoms of malaria who sought treatment from a health facility, and bed net ownership. Bed net ownership was defined as the presence of at least one bed net in the household. Reported cumulative incidence of malaria was defined as the percentage of SAC that self-reported suffering from malaria after the baseline data collection was completed. Percentage of SAC sought treatment from a health facility for malaria symptoms was defined as the percentage of SAC that sought treatment only from a health facility as the 1st choice to the total number of children reported as suffered from malaria during the follow-up period. | PMC10360348 |
Sample size | malaria, anemia | MALARIA, SECONDARY, ANEMIA | The bed net utilization among SAC in primary school was 30.7% in Uganda [The estimated sample size for malaria and anemia as outcome variables was 16 clusters with the minimum cluster size of 72 and 1152 children in each of the intervention and control arms. To assess the effect of the intervention on the bed net utilization as primary endpoint and other secondary outcomes mentioned above, all children enrolled in the 16 clusters per group were included in the final analysis [ | PMC10360348 |
Sampling techniques and data collection | malaria | MALARIA | A total of 3,204 children attending their primary education were approached at 32 primary schools. Seventy-two children from grades one to three were selected using systematic random sampling technique from eligible children in each section of the students with a class roster as the sampling frame. The number of participants from each grade level (grade 1 to 3) was determined by their relative contribution to the total enrolment of students in the school. Children aged 5–14 years and attending their education in the schools during the data collection period were included in the study, but those mentally not fit to respond to questions directed to them and with physical problems to measure their height were excluded from the study. The selected children were used to trace their households. Participants’ households were approached by trained data collectors for interview.A pretested, structured questionnaire was used to collect data on demographics, water source, toilet structure, household assets, and bed nets. The questions were adapted to the local context from the Demographic and Health Surveys (DHS) malaria indicator survey household questionnaire [After baseline data were collected, the 32 schools were stratified into districts (Dara Mallo or Uba Debretsehay) and residence places (rural or urban). From each of these strata, schools were randomly assigned to intervention and control arms by a statistician who was not aware of schools. The final interview was made with either the parents or adults in the household. The data collectors were supervised daily for completeness and correctness of the data by supervisors from Arba Minch University. | PMC10360348 |
Data analysis | malaria | REGRESSION, MALARIA | The data collection and analysis methods used were described elsewhere [Univariable mixed effect logistic regression using glmer function of R version 4.0.4 statistical software was used to assess the effect of MPE on outcome variables by taking schools as a random variable to account for the cluster effect. Odds ratio (OR) and corresponding 95% confidence interval (CI) were used to assess the strength of association between the outcome variables and the intervention. For bed net utilization and reported incidence of malaria, whether there is a confounding effect or not is analyzed by using multivariable mixed-effect logistic regression. Therefore, apart from the intervention, other factors predicting the bed net utilization and reported cumulative incidence were assessed. The fit of the model in predicting the outcome variables was checked by Akaike Information Criterion (AIC). The selection of variables for multivariable mixed-effect logistic regression was made through the backward stepwise variable selection method in which the variable with the largest P-value is removed from the model and checked for AIC. If the removal of a variable from the model improves the AIC value, it is removed from the model, otherwise, it is retained in the final model. For multivariable mixed-effects models, P-values less than 0.05 were considered statistically significant. | PMC10360348 |
Results | death, MPE | A total of 2304 SAC were approached for enrollment in the study. Of these, 2156 (93.6%) participants were consented and enrolled in the study. For evaluation of the intervention effectiveness, data from a total of 2138 (92.8% response rate) were analyzed and 118 were lost from the follow-up. Most common reasons for not enrolled in the study or lost from the follow-up were the mothers or caregivers being not available in repeated visits (two times), out-migration during the follow-up, refusal to participate due to underlying morbidity and death (Fig.
Flow diagram of clusters and participants in the MPE trial in Southern Ethiopia, 2019–2020The mean number of SAC involved per cluster in the analysis, was 67.1 in the control arm and 66.6 in the intervention group. The background characteristics of SAC and their household sociodemographic and economic characteristics in both the intervention and control arms were depicted in Table
Baseline and sociodemographic characteristics of study participants in control and MPE intervention group of in Southern Ethiopia, 2019–2020 | PMC10360348 |
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Effect of the intervention on outcome variables | malaria, MPE | MALARIA, REGRESSION | The mean number of parents and SAC attended the MPE in each school were 62.9 and 93.5% respectively. The difference in bed net ownership before the intervention and after intervention in the control arm was 65.4% (84.6–19.2%) while it was 70.4% in the intervention group. The corresponding numbers for bed net utilization among SAC were 47.0 and 47.2 respectively. However, the differences in the bed net ownership as well as the difference in bed net utilization by SAC in the intervention and control group was not statistically significant (Table The reported number of malaria cases was higher in the control schools as compared to children in the intervention group. The reported cumulative incidence of malaria within one year of follow-up among children in the control group was 18.3%, but it was 16.2% in the intervention group. This difference was also not statistically significant (COR = 0.8; 95%CI of 0.5–1.5). The reported malaria cases sought treatment for malaria from different sources: health facilities (76.4%), taking antimalarial treatment from the private pharmacies without health professionals prescription (13.0%), traditional medicine (1.1%), homemade remedies (5.4%), and religious leaders (1.1%). The number of children who visited a health facility as the 1st choice after noticing the symptoms of malaria was 81.5% in the intervention arm and 71.9% in the control group. However, the difference (9.6%) was not statistically significant (COR = 1.4; 95%CI of 0.5–4.3). The detailed effect size of the intervention on the outcome variables was described in Table
Analysis of the effect of malaria prevention education on study outcomes and its effect size taking control groups as a reference, 2020Apart from the intervention, other factors affecting the bed net utilization by the SAC were also assessed. In the univariable mixed effects logistic regression, several factors significantly affected bed net utilization by the SAC. Children from households where the household head is a civil servant were about 2 times more likely to slept under the bed net the previous night before the survey (95%CI of 1.2–3.2). The other factors significantly influenced bed net utilization by SAC were the educational status of the child’s mother/caretaker (COR = 1.3; 95%CI of 1.1–1.7), mothers/caretakers who were educated more than grade six (COR = 1.3; 95%CI of 1.3–1.7) as compared to those who did not reach to grade six among literates ones. Table
Univariate analysis of bed net utilization by SAC in a MPE intervention study Southern Ethiopia, 2019–2020*Statistically significant at univariable analysis
Predictors of bed net utilization by SAC in a MPE intervention study Southern Ethiopia, 2019–2020** statistically significant at multivariable analysisTables
Univariate analysis of reported malaria incidence among SAC in a MPE intervention study in Southern Ethiopia, 2019–2020
Multivariable analysis of reported malaria incidence among SAC in a MPE intervention study in Southern Ethiopia, 2019–2020**statistically significant at multivariable analysis | PMC10360348 |
Discussion | malaria, MPE | MALARIA | In our study, bed net utilization among children in the intervention arm increased substantially from 7.9–55.1%% due to a bed net distribution and this rise was similar in both arms (p value:0.92). The MPE did not significantly affected both bed net ownership and its utilization. However, bed net utilization by SAC was associated with adequate access to bed net in the household (i.e., household size to bed net ratio ≤ 2) and with a reported malaria attack in the last 12 months. Cumulative incidence of malaria by consequence was also similar, 16.2% and 18.2% in MPE and control groups respectively. Bed net use was affected by an altitude of the residence place, wealth of the household, adequate access to the bed nets and the use of bed net by the study SAC at baseline of the study. Seeking treatment from a health facility as the 1st choice for malaria in the MPE group was 81.5% compared to 71.9% in control group.Bed net utilization is one of the effective malaria prevention measures in SSA. SAC who slept under a bed net the previous night before data collection are 22% less likely to be infected by malaria in SSA [Apart from the MPE, bed net utilization among SAC was affected by using bed net at bassline survey, household size to bed net ratio equal or less than 2 and reported that the children suffered from malaria. It was also observed in Dar es Salaam [The MPE given by science teachers in the current study did not show significant effect on the cumulative incidence of reported malaria. This reported cumulative incidence of malaria could be overestimated and which may vary between intervention arms. Thus, future studies would consider ecological studies or analysis at cluster level to see the effect of such interventions on laboratory confirmed malaria. Unlike the finding of this study, teachers- lead participatory education given to schoolchildren in Mali significantly affected the point prevalence of malaria in the intervention arm as compared to those in the control arm [The percentage of children who sought treatment from a health facility as the 1st choice was not different between arms. The low number of parents attended MPE, health facility problem and poverty could be the reason for the insignificant effect of the intervention on treatment seeking from a health facility. MPE implementation research should be conducted after ensuring the problems hampering seeking treatment from a health facility are removed. In Indonesia, poor understanding of seeking medical care from a health facility was associated with economy and educational status [One of the limitations of our study was the MPE being given only once, a year before the evaluation of its effectiveness. This might be presumptive reason for the insignificant effect of the intervention on the outcome variables considered. The 2nd limitation of the study was failure to include SAC not enrolled to a school. These children may differ in certain aspects affecting the use of malaria prevention measures. The third limitation was low number of parents attended the MPE. The other limitation was that bed net coverage was very low in the study area at the baseline of the study which might underestimate the true effect on the reported cumulative incidence of malaria. The strength of this study was that it is a large study that involved children from both urban and rural areas of hard-to reach settings. | PMC10360348 |
Acknowledgements | malaria | MALARIA | We would like to thank Arba Minch University for funding for the data collection, Dara Mallo and Uba Debretsehay district health offices for informing lists of malaria endemic kebeles. Our sincere appreciation goes to school directors, other implementers and all participants involved in the study. | PMC10360348 |
Authors’ contributions | FM | ZZ, JP, HB, SA, GB, MS, AT, FM, YC & TY conceived the idea and designed the study; ZZ, MM, MS & YC participated in the acquisition of data; ZZ & JP analyzed and interpreted the data; ZZ, JP, HB, SA& FM drafted the manuscript. | PMC10360348 |
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Funding | Arba Minch University financed the data collection process. | PMC10360348 |
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Data Availability | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10360348 |
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Declarations | PMC10360348 |
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Ethical approval and consent to participate | The trial was approved with the written consent procedure to be followed by the Institutional Research Ethics review Board (IRB) in College of Medicine and Health Sciences, Arba Minch University with the reference number of IRB/154/12. The world medical association declaration of the Helsinki was followed in each step of the research. Official permission letter to conduct the research was submitted to district health offices and education offices in Dara Mallo and Uba Debretsehay districts. Support letters written by the respective education offices were given to each participating school and written consent was obtained from school head teachers. Written informed consent was obtained before data collection from the parents or guardian of children and it was documented in College of Medicine and Health Sciences, Arba Minch University. | PMC10360348 |
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Consent for publication | Not applicable. | PMC10360348 |
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Competing interests | The authors declare that we have no competing interests. | PMC10360348 |
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Abbreviations | DISEASE | artemisinin-based combination therapyAkaike Information CriterionAdjusted Odds Ratioconfidence intervalCrude odds ratioCoronavirus Disease 2019comma-separated valueDemographic and Health Surveysglobal positioning systemintracluster correlation coefficientInstitutional Research Ethics Review BoardResearch Ethics Review BoardInsecticide-treated bed netlong-lasting insecticide-treated netsMeters above sea levelMalaria prevention educationOpen Data KitParticipantPrompt diagnosis and treatmentSchool-aged childrenSouthern Nations, Nationalities, and Peoples Regionalsub-Saharan AfricaWorld Health organization | PMC10360348 |
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References | PMC10360348 |
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Abstract | PMC10364520 |
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Background | Diverticulitis | PERFORATED DIVERTICULITIS, DIVERTICULITIS | The Scandinavian Diverticulitis (SCANDIV) trial and the LOLA arm of the LADIES trial randomized patients with Hinchey III perforated diverticulitis to laparoscopic peritoneal lavage or sigmoid resection. The aim of this analysis was to identify risk factors for treatment failure in patients with Hinchey III perforated diverticulitis. | PMC10364520 |
Methods | This was a | PMC10364520 |
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Results | The pooled analysis included 222 patients randomized to laparoscopic lavage and primary resection (116 and 106 patients respectively). Univariable analysis found ASA grade to be associated with advanced morbidity in both groups, and the following factors in the laparoscopic lavage group: smoking, corticosteroid use, and BMI. Significant factors for laparoscopic lavage morbidity in multivariable analysis were smoking (OR 7.05, 95 per cent c.i. 2.07 to 23.98; | PMC10364520 |
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Conclusion | diverticulitis | PERFORATED DIVERTICULITIS, DIVERTICULITIS | Active smoking status and corticosteroid use were risk factors for laparoscopic lavage treatment failure (advanced morbidity) in patients with perforated diverticulitis.This study analysed a prospectively collected cohort of patients with Hinchey III diverticulitis from two large randomized trials (SCANDIV and LOLA), aiming to find risk factors for treatment failure. The results showed that only active smoking status and corticosteroid use in the laparoscopic lavage group were risk factors for treatment failure. | PMC10364520 |
Introduction | stenosis, diverticulitis, Hinchey III disease | STENOSIS, DIVERTICULITIS | Complicated diverticulitis is characterized by perforation, stenosis, fistulas, and obstructionThe role of laparoscopic lavage as means of treating Hinchey III disease has been debated and investigated. Recently, the results of three RCTSThe SCANDIV trial | PMC10364520 |
Methods | COMPLICATIONS | Both studies were approved by national ethics boards initially, and a supplement to the primary ethics approval was sent in and approved (2021-06755-02) in Sweden and Norway. In the Netherlands, additional approval was not considered necessary by the Medical Ethics Review Committee of the Academic Medical Centre.Individualized data were retrieved from SCANDIV and the LOLA arm of the LADIES trial. All data were collected prospectively. The SCANDIV trial was designed as a pragmatic, two-armed, open-labelled, multicentre, superiority randomized trial. Patients were enrolled in 21 surgical units (9 in Sweden and 12 in Norway)Patients were evaluated on an intention-to-treat basis. All factors that may predict treatment failure, defined as complications of at least Clavien–Dindo grade IIIb (requiring general anaesthesia), were analysed | PMC10364520 |
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Statistical analysis | REGRESSION | Logistic regression in a two-step approach was used to investigate risk factors for failure and compare potential risk factors between operation types. ORs with 95 per cent confidence intervals and | PMC10364520 |
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Results | stoma, GI, gastrointestinal. | REGRESSION, PERFORATED DIVERTICULITIS | A total of 222 patients with Hinchey III perforated diverticulitis were included in the pooled analysis, of whom 116 were randomized to the laparoscopic lavage group and 106 to the primary resection group (Study flow chartPRA, primary resection with anastomosis; ITT, intention to treat.Baseline characteristics of all patients with Hinchey III diverticulitisBaseline characteristics for all patients who had laparoscopic lavageBaseline characteristics of all patients who underwent resectionIn the resection group, patients had either Hartmann's operation (67), or sigmoid resection with (15) or without (18) a stoma. Two patients had an anastomosis that was later converted into Hartmann's operation, and four patients in the resection group underwent lavages. The median age of patients in the Hartmann's group was 69 (i.q.r 58–76) years and that of patients undergoing primary anastomosis was 58 (i.q.r 47–69) years.The treatment failure rate was 32.8 per cent (38 patients) in the laparoscopic lavage group and 18.9 per cent (20 patients) in the resection group (In univariable analysis, smoking was a risk factor for treatment failure in the laparoscopic lavage group (OR 3.24, 95 per cent c.i. 1.19 to 8.81; Univariable logistic regression analysis of risk factors for treatment failure with interaction model for adjustment for studyValues in parentheses are 95% confidence intervals. GI, gastrointestinal.In multivariable analysis, the only statistically significant risk factors for treatment failure were smoking (OR 7.05, 2.07 to 23.98; Multivariable logistic regression analysis of risk factors for treatment failure with interaction model for adjustment of studyValues in parentheses are 95% confidence intervals. | PMC10364520 |
Discussion | cancers, failure of laparoscopic lavage, carcinoma, perforated carcinoma, Peritonitis, diverticulitis, Hinchey III disease, sigmoid cancer, failure of laparoscopic peritoneal lavage | CANCERS, CARCINOMA, PERITONITIS, SECONDARY, PERFORATED DIVERTICULITIS, DIVERTICULITIS, SIGMOID CANCER, LIVER METASTASIS | By combining two of the largest randomized trials of treatment of perforated diverticulitis, a large prospectively collected data set within a trial setting of patients with Hinchey III disease could be assessed. Main risk factors for treatment failure in the laparoscopic lavage group were smoking and corticosteroid use. No other factors analysed were associated with treatment failure. Smoking is known to impair wound healing and is a well acknowledged risk factor for complicationsConcerns have been raised regarding patients who were diagnosed with cancers and misdiagnosed as having Hinchey III perforated diverticulitis initially. In the SCANDIV study, five patients were assessed as having Hinchey III perforated diverticulitis and three of these were randomized to the laparoscopic lavage arm. Two of these patients had failure of lavage, and both were diagnosed with sigmoid cancer and had surgery within 90 days of laparoscopic lavage (1 sigmoid resection and 1 transversostomy before neoadjuvant treatment for sigmoid cancer with liver metastasis). Of the nine patients who experienced treatment failure after lavage in the LADIES trial, one was diagnosed with an underlying carcinoma during pathological assessment. In both studies, these patients were included in the analysis, as this best reflects clinical practice with the inherent difficulty in differentiating correctly between perforated diverticulitis and perforated carcinoma.In recent years, trialsOther studies have examined risk factors for failure of laparoscopic lavage. In a study by Radé The strength of this study lies in the inclusion of the two largest randomized cohorts studying Hinchey III diverticulitis in a prospective manner. Nevertheless, there are several methodological differences between the SCANDIV and LOLA studies which limit interpretation of the results. For example, the set of baseline characteristics collected and secondary outcomes studied were different. Hence, not all baseline characteristics could be considered in the risk factor analyses. To correct for study heterogeneity in the statistical analyses, care was taken to adjust for study population. As exclusion criteria were different, many patients with high corticosteroid use were excluded from the LOLA study, but were included in the SCANDIV study, making the baseline populations different. Furthermore, both trials did not register Mannheim Peritonitis Index and it was therefore not possible to assess this as a risk factor in the present analysis. Although this is the largest cohort of patients with Hinchey III diverticulitis who underwent laparoscopic lavage in a trial setting, the total number of included patients and variables still limited the extent of multivariable analyses.In the largest assessment of risk factors for treatment failure of laparoscopic peritoneal lavage in a prospectively collected Hinchey III cohort, active smoking and corticosteroid use at index surgery were found to be statistically significant. Smoking and corticosteroid use are, therefore, factors that should be considered when assessing surgical options for patients with perforated Hinchey III diverticulitis. | PMC10364520 |
Collaborators | RA, Opmeer, MP, TG | DER | A Papp, U Ersson, T Zittel, N Fagerström, D Gustafsson, G Dafnis,: M Cornelius, M Egenvall, P O Nyström, I Syk, D Vilhjalmsson, C Wallon, G Arbman, J Folkesson, A Chabok, M Helgeland, J Bondi, A Husby, R Helander, A Kjos, H Gregussen, A J Talabani, G Tranø, I H Nygaard, G Wiedswang, O Helmer, K F Desserud, S Norderval, M Vikhammer Gran, T Pettersen, A Sæther, H Kørner; L Blesic, H M Forsmo, S Vennix, GD Musters, IM Mulder, HA Swank, EC Consten, EH Belgers, AA van Geloven, MF Gerhards, MJ Govaert, WM van Grevenstein, A Hoofwijk, PM Kruyt, SW Nienhuijs, MA Boermeester, J Vermeulen, S van Dieren, WC Hop, BC Opmeer, JB Reitsma, RA Scholte, EWH Waltmann, DA Legemate, JF Bartelsman, DW Meijer, M de Brouwer, J van Dalen, M Durbridge, M Geerdink, GJ Ilbrink, S Mehmedovic, P Middelhoek, M J Boom, ECJ Consten, JDW van der Bilt, GDJ van Olden, MAW Stam, MS Verweij, ORC Busch, CJ Buskens, Y El-Massoudi, AB Kluit, C van Rossem, MP Schijven, PJ Tanis, C Unlu, MF Gerhards, TM Karsten, LC de Nes, H Rijna B, A van Wagensveld, GI Koffeman, EP Steller, JB Tuynman, SC Bruin, DL van der Peet, CFJ M Blanken-Peeters, HA Cense, E Jutte, RMPH Crolla, GP van der Schelling, M van Zeeland, EJR de Graaf, RPR Groenendijk, TM Karsten, M Vermaas, O Schouten, MR de Vries, HA Prins, DJ Lips, RJI Bosker, JAB van der Hoeven, J Diks, PW Plaisier, PM Kruyt, C Sietses, MWJ Stommel, SW Nienhuijs, IHJT de Hingh, MDP Luyer, G van Montfort, EH Ponten, JF Smulders, EB van Duyn, JM Klaase, DJ Swank, RT Ottow, HBAC Stockmann, J Vermeulen, RJCLM Vuylsteke, HJ Belgers, S Fransen, EM von Meijenfeldt, MN Sosef, AA W van Geloven, ER Hendriks, B ter Horst, MMN Leeuwenburgh, O van Ruler, JM Vogten, EJ C Vriens, M Westerterp, QAJ Eijsbouts, A Bentohami, TS Bijlsma, N de Korte, D Nio, JJA Joosten, LPS Stassen, MJ Wiezer, EJ Hazebroek, AB Smits, HL van Westreenen, A Brandt, WN Nijboer, BR Toorenvliet, WF Weidema, PPL O Coene, GHH Mannaerts, D den Hartog, RJ de Vos, JF Zengerink, AGM Hoofwijk, KW E Hulsewé, J Melenhorst, JHMB Stoot, WH Steup, PJ Huijstee, JWS Merkus, JJ Wever, JK Maring, J Heisterkamp, WMU van Grevenstein, MR Vriens, MGH Besselink, IHM Borel Rinkes, AJ Witkamp, GD Slooter, JLM Konsten, AF Engel, EGJM Pierik, TG Frakking, D van Geldere, GA Patijn, AJL D’Hoore, A de Buck van Overstraeten, M Miserez, I Terrasson, A Wolthuis, S Di Saverio, MG De Blasiis. | PMC10364520 |
Acknowledgements | The authors thank T. Schyman and A. Åkesson at Forum South, Clinical Studies Sweden, for help with the statistical analysis. | PMC10364520 |
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Funding | The investigator-initiated LADIES trial was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw). The SCANDIV trial was funded by the South-Eastern Norway Regional Health Authority (PNR 2719011). | PMC10364520 |
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Author contributions | P. | SCHULTZ | Najia Azhar (Conceptualization, Data curation, Formal analysis, Methodology, Writing—original draft, Writing—review & editing), Daniël Lambrichts (CRediT contribution not specified), Sheraz Yaqub (Conceptualization, Methodology, Supervision, Writing—review & editing), Johan Lange (CRediT contribution not specified), Tom Oresland (Conceptualization, Methodology, Writing—review & editing), Willem Bemelman (Conceptualization, Data curation, Methodology, Supervision, Writing—review & editing), Johannes Schultz (Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Writing—original draft, Writing—review & editing), and P. Buchwald (Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Resources, Supervision, Writing—original draft, Writing—review & editing). | PMC10364520 |
Disclosure | The authors declare no conflict of interest. | PMC10364520 |
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Data availability | Original data will be available upon request. | PMC10364520 |
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References | PMC10364520 |
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Background | humerus fractures, fractures | The authors have declared that no competing interests exist.Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking. | PMC10683994 |
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Methods and findings | SE, fractures | RECRUITMENT, COMPLICATIONS | The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up.Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group.The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [−9.5,11.7]; At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely. | PMC10683994 |
Conclusions | COMPLICATIONS | In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments. | PMC10683994 |
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Author summary | PMC10683994 |
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Why was this study done? | osteoporotic, fractures | Proximal humerus fractures (PHFs) are among the most common fractures in older adults. The risks for suffering a PHF increase with age, especially after the age of 60 years.Nonoperative treatment of non-displaced PHF is uniformly approved, but the treatment of displaced 3- and 4-part PHF remains controversial. Recently, several studies have reported a significant increase in the surgical treatment of the PHF, mainly due to the introduction of locking plates (LPs) suitable for treating osteoporotic bone.In this study, we investigated whether surgery with an LP or hemiarthroplasty (HA) is superior to nonoperative treatment with a collar-cuff and early physiotherapy in the treatment of 3- or 4-part PHF involving the surgical neck. | PMC10683994 |
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What did the researchers do and find? | COMPLICATIONS | We randomly allocated 160 patients to either nonoperative treatment or operative treatment with HA or LP.We recorded the Disabilities of Arm, Shoulder, and Hand (DASH) score, other measures of shoulder function and quality of life, and complications at 2-year follow-up.We found no significant or clinically important between-group differences in any of the outcomes. | PMC10683994 |
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What do these findings mean? | fractures | This trial provides no evidence that surgery is superior to nonoperative treatment in the treatment of displaced 3- or 4-part PHF involving the surgical neck in older adults.These results suggest that the current practice of performing surgery on the majority of displaced 3- or 4-part proximal fractures of the humerus in older adults may not be beneficial.The limitation is the trial was ended before intended group sizes. | PMC10683994 |
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Data Availability | Data are available from the Tampere university hospital Institutional Data Access (contact via | PMC10683994 |
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Introduction | fracture, fractures | Proximal humerus fractures (PHFs) are one of the main fractures in the upper extremities sustained by older female patients [To date, several attempts have been made to describe the fracture using various current and updated classifications. However, none of these have shown acceptable potential for clinical decision-making, not to mention acceptable reproducibility [In a recent Cochrane review, insufficient evidence was found to support the use of any of the operative methods in the treatment of 3- and 4-part PHF [ | PMC10683994 |
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Methods | OSTEOPOROTIC FRACTURES | This study was a parallel group, superiority multicenter NITEP (Nordic Innovative Trial to Evaluate Osteoporotic Fractures; The original protocol consisted of 2 stratums [The protocol was signed by the principal investigator (PI) of each site, and the investigator site file (ISF) was held locally using good clinical practice as the gold standard in maintaining the trial. Local researchers and site PIs gathered and managed the data.The authors who signed the protocol confirmed the accuracy of the reported data, the analysis, and the fidelity of the study to the protocol, with exceptions noted separately. We, the authors, wrote this manuscript and made a joint decision to submit it for publication. The study is reported according to the recommendations of the Consolidated Standards of Reporting Trials (see | PMC10683994 |
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Patients | Patients aged 60 years and older with displaced 3- and 4-part low-energy PHF sustained within 2 weeks prior to allocation were eligible for inclusion. We used the Neer classification (displacement more than 1 centimeter and/or 45 degrees, with bony contact between all fragments) [Patients were randomly assigned in a 1:1:1 ratio to undergo nonoperative treatment or operative treatment with LP or HA ( | PMC10683994 |
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Participant flow diagram of the Nordic Innovative Trial to Evaluate osteoPorotic fractures (NITEP). | All patients analyzed according to ITT analysis. Definitions: “Lost to follow-up”–patient could not be reached for the follow-ups; “Not obtained”–Some of the patient data missing, but patient continued in the follow-ups; “Discontinued from the study”–patient wished to discontinue from the trial. | PMC10683994 |
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Surgical and postoperative procedures | The treatment in all groups was standardized. Patients receiving operative treatment had either Philos LP (Synthes, Solothurn, Swizerland) or HA (various brands; see | PMC10683994 |
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Outcome measures | PROM | COMPLICATIONS | The primary outcome in this trial was DASH score at 2-year follow-up. The DASH is a patient-reported outcome measure (PROM), which measures self-reported disability and symptoms with 36 questions regarding different daily tasks [The patient data acquired were stored in paper portfolios from where they were extracted after the final patient’s 2-year follow-up was completed in December 2021. The portfolios contained the patients’ baseline characteristics, questionnaires, and case report files in which the allocation, collected radiographs, crossovers, complications, AEs, and SAEs were recorded.In order to avoid the wide interobserver variation reported with the CS, we arranged pretraining sessions for the assessors to standardize the measurements [ | PMC10683994 |
Ethical approval | RECRUITMENT | The initial ethical approval was received from the Regional Ethics Committee of Tampere University Hospital (approval-code R10127). All sites gained local ethical committee approval before the recruitment. Only voluntary patients who gave their informed written consent were included. All data were deidentified. | PMC10683994 |
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Public and patient involvement | When designing the trial, we did not involve patients in trial planning. | PMC10683994 |
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Statistical analysis | The trial was designed to detect an MCID in the DASH score of at least 10 points with a standard seviation (SD) of 18 (effect size d = 0.67). Our pretrial assumption was that the operative treatment arms (LP and HA) would gain an average improvement of 10 points of difference compared to nonoperative treatment (arms 1:1:1), and we used ANOVA (alpha = 0.05, power = 0.8). We assumed a common SD of 18 points and a between-group variance as 25 points. That would have led to an estimated sample size of 66 patients per group, making a total of 198 patients, including an estimated 10% dropout rate. We conducted a preinterim analysis and found no significant differences between the groups. The nonoperative treatment became more common during the study period in the Nordic countries, and in the cases needed, the reverse prosthesis was used. These factors led to a higher-than-expected exclusion rate toward the end of the trial, followed by a premature termination of the trial.The baseline characteristics were analyzed with descriptive statistics. The primary analysis was carried out with 95% confidence intervals (CIs) after all patients had completed the 2-year follow-up after initial treatment.The difference between groups was estimated using a linear mixed model allowing for repeated measures. Study group and time of assessment (baseline, 3, 6, 12, 24 months) were included as fixed factors, patients as random factors. The model included interactions between study group and time of assessment. The model was used to estimate the treatment effect as the absolute difference between the groups in DASH score (mean and 95% CIs) and Continuous outcomes were compared using the Student | PMC10683994 |
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Results | Between February 2011 and December 2019, a total of 160 patients with 3- and 4-part PHFs were randomly assigned to undergo nonoperative treatment or operative treatment with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group ( | PMC10683994 |
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Characteristics of 160 patients with displaced 3–4-part PHF at baseline. | SE, humerus fracture | DASH, Disabilities of the Arm, Shoulder, and Hand; EQ-5D, EuroQol Group’s 5-dimension self-reported questionnaire; HA, hemiarthroplasty; LP, locking plate; OSS, Oxford Shoulder Score; PHF, proximal humerus fracture; SD, standard deviation; SE, standard error; 15D, 15-dimensional quality-of-life questionnaire. | PMC10683994 |
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Primary outcome | SE | The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 24 months, the between-group differences were 1.07 points (95% CI [−9.5, 11.7]; | PMC10683994 |
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Between-group differences in mean DASH score (0 representing the best, 100 the worst) from baseline to 24-month follow-up. | (Vertical lines represent 95% confidence intervals. DASH, Disabilities of the Arm, Shoulder and Hand). | PMC10683994 |
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Between-group differences in mean Constant–Murley Score (100 representing the best, 0 the worst) from 6- to 24-month follow-up. | (Vertical lines represent 95% confidence intervals). | PMC10683994 |
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Secondary outcomes | SECONDARY | There was no difference between the study groups in any of the secondary outcomes: CS, OSS, VAS, EQ-5D, or 15D ( | PMC10683994 |
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Adverse events | COMPLICATIONS | At 2-year follow-up, we found 30 complications (3/52, 5.8% in nonoperative group; 22/49, 45% in LP group; and 5/49, 10% in HA group, | PMC10683994 |
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AEs at 2-year follow-up by type and group of treatment. | stroke, pain, pneumonia, AVN | MYOCARDIAL INFARCTION, PNEUMONIA, STROKE, AVASCULAR NECROSIS, ADVERSE EVENT | AE, adverse event; AVN, avascular necrosis; HA, hemiarthroplasty; LP, locking plate.SAEs, other than severe pain, occurred in 4 patients. In the LP group, 1 patient had myocardial infarction. In the HA group, 1 patient had a stroke, 1 patient had myocardial infarction, and 1 patient had pneumonia. | PMC10683994 |
Discussion | fracture, fractures | RECRUITMENT, COMPLICATION, FRAGILITY, SECONDARY, COMPLICATIONS | This multicenter, assessor-blinded, randomized trial involving adult patients aged 60 years and older with 3- and 4-part PHF revealed that operative treatment with LP or HA was not superior to nonoperative treatment with regard to the primary outcome, DASH, assessed at 24-month follow-up. Moreover, the nonoperative group had significantly fewer complications and AEs leading to reoperations. Although all groups showed significant improvement in primary outcome until 12 months, there was no further improvement at 24 months, which is in contrast to the findings of previous smaller trials [In this study, we found no between-group differences based on the confidence intervals in any of the used outcome measures, including our primary outcome DASH and secondary outcomes CS, OSS, EQ-5D, 15D, VAS, or mortality.After completing our previous and present PHF studies, combined with the recent Cochrane review, we can acknowledge that the operative treatment of PHF does not provide added benefits in outcomes compared to nonoperative treatment [We detected a high rate of complications of up to 45% in the LP group. However, our complication rates were mainly higher than those reported in the current literature, where rates of up to 29% have been reported [In all 3 treatment methods, the shoulder function, measured with DASH, CS, or OSS, remained clinically worse at 1 and 2 years after the fracture when compared to the prefracture baseline level. Recovery after multipart fracture seems to differ from that of 2-part fractures. Indeed, the results of our previous study showed that patients with 2-part fractures regained the prefracture level of function at 1 year [Interestingly, the best DASH scores but at the same time the poorest CS scores (not exceeding the MCID) were observed in the HA group. The discrepancy between these 2 contradicting results might be explained by the assumption that patients slowly adapt to the poor postfracture function in their shoulder, as a portion of the raw points in CS is formed from muscle strength testing and range of motion [A recent study suggests that fracture is a sign not only of bone fragility but also of a frail patient, resembling patients with hip fractures [Some limitations in this trial warrant discussion. We ceased recruitment before the predefined power calculation. The results of the preplanned interim analysis after two-thirds of the recruitment was completed revealed no significant differences between treatment alternatives. The trial recruitment period was longer than expected due to a high number of exclusions after assessment of eligibility, since the nonoperative treatment grew more standard in the Nordic countries during the trial. A strength of the study is the multinational, multicenter nature of this NITEP group collaboration, which gives the results high external validity.It must be acknowledged that in the study, we only investigated nonoperative, HA, and LP treatment options for 3- and 4-part PHF. These were, however, the most relevant treatment options at the start of the trial. Reverse shoulder arthroplasty (RSA) has emerged as a treatment option but was not included in the present study. Furthermore, the number of RSA operations was not screened during the trial. Nevertheless, the NITEP group has already initiated a trial to investigate the outcomes of RSA in comparison to nonoperative treatment (The main conclusion of the present trial is that no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. When compared to the prefracture level, functional outcomes still remain at a lower level 1 and 2 years after the fracture. In addition, we observed a high rate of complications related to operative treatments. Further studies should focus on nonoperative methods of treatment, for example, the rehabilitation of these frail patients. | PMC10683994 |
Supporting information | PMC10683994 |
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Checklist of information to include when reporting a randomized trial assessing nonpharmacologic treatments (NPTs). | (DOCX)Click here for additional data file. | PMC10683994 |
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Checklist of information reporting RCTs assessing NPTs in Journal Abstract. | (DOCX)Click here for additional data file. | PMC10683994 |
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Hemiarthroplasty brands and their amounts/fractions used throughout the trial. | (DOCX)Click here for additional data file. | PMC10683994 |
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Rehabilitation programs used throughout the trial. | (DOCX)Click here for additional data file. | PMC10683994 |
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Sample size and analysis plan. | (DOCX)Click here for additional data file.Our group wishes to thank all the patients who participated in this trial. Moreover, this trial could not have been carried out without our oranizations and the personnel and residents of our clinics who participated treatment of the study patients. The group would like to offer our thanks to our research coordinators Seija Rautiainen and Meri Järvinen. Finally, we thank Peter Heath BA, MA for the excellent language editing. | PMC10683994 |
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Abbreviations | adverse eventavascular necrosisconfidence intervalConstant–Murley Scorecomputed tomographyDisabilities of the Arm, Shoulder, and HandEuroQol Group’s 5-dimension self-reported questionnairehemiarthroplastyinvestigator site fileintention-to-treatlocking plateminimal clinically important differenceNordic Innovative Trial to Evaluate Osteoporotic FracturesOxford Shoulder Scoreproximal humerus fractureprincipal investigatorpatient-reported outcome measurerandomized controlled trialreverse shoulder arthroplastyserious adverse eventstandard deviationstandard errorvisual analog scale | PMC10683994 |
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References | PMC10683994 |
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Introduction | anxiety | Edited by: Jiachao Zhang, Hainan University, ChinaReviewed by: Yingli Jing, China Rehabilitation Research Center, Capital Medical University, China; Wenwei Lu, Jiangan University, China; Lijun Wang, Xihua University, ChinaThis article was submitted to Microbial Immunology, a section of the journal Frontiers in ImmunologyTest anxiety is a common issue among college students, which can affect their physical and psychological health. However, effective interventions or therapeutic strategies are still lacking. This study aims to evaluate the potential effects of | PMC10077425 |
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Methods | depression, insomnia, anxiety | Sixty anxious students were enrolled and randomly allocated to the placebo group and the probiotic group. Both groups were instructed to take placebo and JYLP-326 products twice per day for three weeks, respectively. Thirty unanxious students with no treatments were assigned to a regular control group. The anxiety, depression, and insomnia questionnaires were used to measure students’ mental states at the baseline and the end of this study. 16S rRNA sequencing and untargeted metabolomics were performed to analyze the changes in the gut microbiota and fecal metabolism. | PMC10077425 |
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Results | depression, insomnia, anxiety | The questionnaire results suggested that JYLP-326 administration could relieve the symptoms of anxiety, depression, and insomnia in test anxious students. The gut microbiomes of the placebo group showed a significantly greater diversity index than the control group (p < 0.05). An increased abundance of | PMC10077425 |
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Conclusion | The results indicate that the intervention of | PMC10077425 |
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Introduction | anxiety | Test anxiety, characterized by feelings of failure, tension, and worrying when an individual faces a vital test for promoting, occurs prevalently among college students. We reported that about 20%-40% of college students suffer from test anxiety in our previous study (The issue of how anxious students process these exam stress-induced health threats is of great interest. Although many coping strategies have been suggested to address anxiety for students, including supplying proper nutrition (Recently, a variety of probiotics have been reported to possess effective stress-modulating and anxiolytic effects on stressed subjects
| PMC10077425 |
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Materials and methods | PMC10077425 |
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PMC10077425 |
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Participants and experimental design | Anxiety, anxiety, Insomnia, depression, Depression | RECRUITMENT | We conducted this study to evaluate the effects of 3-week supplementation of JYLP-326 on the exam stress-induced behaviors in senior college students. Students who were nervously studying for the UNGEE during September to December 2020, a critical period for students to prepare the exam, were recruited from Nanchang University. All procedures were approved and complied with by the Institutional Ethics Committee on medical research of the Second Affiliated Hospital of Nanchang University (Examination and approval No. is Review [2020] No. (038)). All participants signed and informed consent.Following that, a total of 230 students were enrolled to interview and completed the 14-item of Hamilton Anxiety Scale (HAMA-14), 8-item of the 8-item Athens Insomnia Scale (AIS-8) and the 17-item Hamilton Depression Rating Scale (HDRS-17); out of 230, 60 with baselines HAMA-14 for anxiety score of 8 or higher and HDRS-17 for depression score of 8 or higher were screened (Study flow chart showing recruitment and group assignment.Out of those 60 students with anxiety and depression facing UNGEE, 30 were selected randomly as the PB group to receive the probiotic product; another 30 received placebo product were regarded as the P group. The 30 un-anxious students were assigned as the healthy control group (HP group). The subjects in each group were of the same age and the ratio of male to female was 1:1. The subjects in PB and P groups were instructed to take probiotic and placebo product twice per day for 3 consecutive weeks with a 12-hour set time between two intakes, respectively. While students in HP group were asked to maintain their normal lifestyle and diet habits. All treatments were stopped 2 weeks before UNGEE commenced. The validated questionnaires (i.e., HAMA-14, HDRS-17, and AIS-8) were provided to determine their mental conditions at baseline (Week 0) and the end of intervention (Week 3). The subjects were instructed to collect fecal samples by themselves at home using a stool sampling tube according to the manufacture’s introduction. The first pooped fecal sample in a day were collected during 3 days after the indicated time points and stored at -80 °C immediately for further research. | PMC10077425 |
Questionnaires | insomnia | The severity of the insomnia symptoms was measured using the Chinese version of AIS-8 ( | PMC10077425 |
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DNA extraction and 16S rRNA sequencing | Total genomic DNA in students’ feces samples was extracted from the glass fiber filters using TIANamp Bacteria DNA Kit (QIAGEN) following the manufacturer’s instructions. The concentration and quality of the extracted genomic DNA were determined using spectrophotometer (NanoDrop, Thermo Fisher Scientific, Inc., USA). Extracted DNA was subjected to 16S sequencing at Shanghai Personal Biotechnology Cp. Ltd. The following universal 16S rRNA primers were used for the PCR reaction: 520F (5′-AYTGGGYDTAAAGNG-3′) and 802R (5′-TACNVGGGTATCTAATCC-3′) for the V4 region, and these PCR products were sequenced with an Illumina HiSeq 2000 platform. FLASH was applied to merge overlapped reads, and sequence analysis was performed using UPARSE software package. Reads with quality scores lower than 20, ambiguous bases, and improper primers were discarded prior to clustering. Simultaneously, chimaeras were checked and eliminated during clustering. The resulting high-quality sequences were clustered into operational taxonomic units (OTUs) at 97% similarity. According to the annotation of taxa, the relative abundance of total bacteria in each sample was categorized into different classification levels (Phylum, Class, Order, Family, and Genera). The alpha diversity index (Shannon index and Chao1 index) was calculated, and the beta diversity index (principal component analysis, PCoA) was mapped in QIIME2 software. The raw reads were deposited in the Sequence Read Archive (SRA) database of NCBI (PRJNA883039). | PMC10077425 |
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Fecal metabolites analysis | SEPARATION | Metabolomics in feces were analyzed at Shanghai Personal Biotechnology Cp. Ltd using an UHPLC (1290 Infinity LC, Agilent Technologies) coupled to a quadrupole time-of-flight (AB Sciex TripleTOF 6600). Stool weighing 100 mg was added with 400 ml extract of methanol-acetonitrile-water (2:2:1, vol/vol/vol), vortexed and centrifuged at 14,000 g for 20min, and the supernatant was collected for further measurement. For HILIC separation, samples were analyzed using a 2.1 mm × 100 mm ACQUIY UPLC BEH 1.7 µm column (waters, Ireland). In both ESI positive and negative modes, the mobile phase contained A=25 mM ammonium acetate and 25 mM ammonium hydroxide in water and B= acetonitrile. For RPLC separation, a 2.1 mm × 100 mm ACQUIY UPLC HSS T3 1.8 µm column (waters, Ireland) was used. In ESI positive mode, the mobile phase contained A= water with 0.1% formic acid and B= acetonitrile with 0.1% formic acid; and in ESI negative mode, the mobile phase contained A=0.5 mM ammonium fluoride in water and B= acetonitrile. The raw MS data (wiff.scan files) were converted to MzXML files using ProteoWizard MSConvert before imported into freely available XCMS software. For peak picking, the following parameters were used: centWave m/z = 10 ppm, peak width = c (10, 60), prefilter = c (10, 100). For peak grouping, bw = 5, mzwid = 0.025, minfrac = 0.5 were used. CAMERA (Collection of Algorithms of MEtabolite pRofile Annotation) was used for annotation of isotopes and adducts.After normalized to total peak intensity, the processed data were analyzed by R package, where it was subjected to multivariate data analysis, including Pareto-scaled principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA). The 7-fold cross-validation and response permutation testing were used to evaluate the robustness of the model. The variable importance in the projection (VIP) value of each variable in the OPLS-DA model was calculated to indicate its contribution to the classification. Metabolites with the VIP value > 1 were further applied to Student’s t-test at the univariate level to measure the significance of each metabolite. The | PMC10077425 |
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Statistical analysis | anxiety/depression | Spearman correlation analysis was performed by R package and used to determine the correlation between anxiety/depression scores and the main changed microbes, as well as the correlation between microbes and the differential metabolites ( | PMC10077425 |
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Results | PMC10077425 |
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JYLP-326 alleviates anxiety, depression, and insomnia symptoms in students | Anxiety, anxiety, depressive, insomnia, Insomnia, Depression | There were no significant differences in the background features of age and BMI among the enrolled students in these groups (Characteristics of subjects enrolled in this study and efficacy outcomes of tests as assessed Data was shown as mean ± SD; n refers to number; BMI, baseline body mass index.The 14-item Hamilton Anxiety Scale (HAMA-14) was used to assess the anxiety symptoms.The 17-item Hamilton Depression Rating Scale (HDRS-17) was used to evaluate the depressive symptoms.The 8-item Athens Insomnia Scale (AIS-8) was used to assess the insomnia symptoms.*Intragroup, compared to baseline (Week 0), *p < 0.05, **p < 0.001, ***p < 0.001, ****p < 0.0001. ns refers to no significance.Capital letters refer to Tukey’s multiple comparisons test at intergroup, p < 0.001. | PMC10077425 |
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JYLP-326 has impacts on the gut microbial diversity | anxiety | All subjects were invited to provide fecal samples voluntarily. But we finally collected 25 fecal samples from the HP group, 20 from P group and 20 from PB group to perform 16S rRNA high-throughput sequencing analysis. And 2 samples in P group and 1 sample in PB group failed to establish sequencing library. There was a difference in α-diversity indices of gut microbiota among these three groups as the Chao 1 and Shannon index presented, suggesting that test anxiety might disturb the balance of human gut microbiota (Effects of | PMC10077425 |
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Effects of JYLP-326 on the fecal microbial composition | At the phylum level, Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria were the most common populations in these groups, and they accounting for 99.76%,99.53%, and 99.30% of the total sequencing results in these three groups, respectively (Effects of JYLP-326 on the gut microbial composition. At the genus level ( | PMC10077425 |
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Identification of changed fecal metabolites among each group | The quality control (QC) samples were inserted into the sample cohorts to monitor and evaluate the stability of the test system and the reliability of experimental data. The response intensity and retention time of each chromatographic peak of all QC samples were almost overlapped in their total ion chromatograms (Fecal metabolome profiling among groups. | PMC10077425 |
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JYLP-326 promotes the fecal metabolic rearrangement in anxious students | To explore the differential metabolites among these groups, we used OPLS-DA models to compare the differential variables between groups, and the value of variable importance for the projection (VIP) obtained by OPLS-DA (VIP > 1) and p value (Pathway enrichment analysis of differential metabolites. Meanwhile, there were 13 variables in the intersection between P The detailed information of 13 significantly changed metabolites among HP, P, and PB groups
m/z means the mass-to-charge ratio of each metabolite.rt(s) refers to the retention time of metabolite on the chromatography, i.e., the peak time, which is expressed in second.VIP, the variable Importance for projection; the larger of the value, the more important.FC means fold changes of metabolite in the compared groups. | PMC10077425 |
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