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Introduction | PMC10131812 |
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Background | The COVID-19 “infodemic” [However, it is also important not to oversimplify such concepts (eg, “trust the science”) [Scientists often share cognitive claims (eg, the results of their work) In further support of investigating differences between cognitive and normative claims, and their impact on perceptions of science and scientists, we point to evidence that greater belief in science may be associated with moralization of COVID-19 mitigation measures (eg, endorsing statements such as “Overall, I believe that | PMC10131812 |
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Study Objectives and Hypotheses | This study is designed to better understand the degree to which the use of cognitive and normative language by scientists influences perceptions of trust and credibility. Specifically, this paper reports the results from a highly granular, causal assessment of the effect of a single exposure to normative language from a scientist. For transparency, we use much of the language from our study protocol verbatim [Our study will draw conclusions by randomizing a large, nationally representative sample of US adults to view a sample social media post that either (1) shares a cognitive claim from a 2020 study on face masks (control group), or (2) shares the same cognitive claim but also includes a normative claim about what people should do, given the cognitive claim, which is also from that study (intervention group; see the “Methods” section). We hypothesize the following:Hypothesis 1: Overall trust in science and scientists [Hypotheses 2-5: The Preregistered analyses (without hypotheses): We will study the interaction between the study arm and political orientation for each of the 5 preregistered hypotheses. We included these analyses because of complex and nuanced, but consistent evidence that trust in science and scientists is associated with political orientation [ | PMC10131812 |
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Methods | PMC10131812 |
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Study Design and Participants | Participants were a nationally representative US sample by cross sections of age, sex, and race/ethnicity obtained using the online research and data collection platform Prolific (Prolific Academic Ltd). Prolific maintains a panel of around 130,000 research participants and verifies the identity of all accounts using a 3-part procedure including email, phone number, and identity, such as US driver’s license or passport [Before randomization, we implemented 4 quality control questions to attempt to limit the impact of automated, dishonest, or inattentive respondents [All participants digitally provided informed consent prior to beginning the study (Indiana University Institutional Review Board, approval number 16141). Participants who successfully completed the study and submitted a compensation request to Prolific were paid US $1.50. Participants whose data were used took an average of 7.37 (SD 9.61) minutes to complete the study. This study was preregistered using the Open Science Framework and the protocol was published in full prior to any data collection [ | PMC10131812 |
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Randomization, Masking, and Enrollment | LGA | Participants who passed all quality control checks were randomized to 1 of the 2 study arms. The intervention arm (arm 1) contained an image of a social media post about face masks for reducing COVID-19 transmission that included both cognitive and normative claims. The control arm (arm 2) contained the same image except that it did not include the normative claim. Both images were otherwise identical.Prolific fully managed enrollment. Individuals who were enrolled accessed a link that we provided to our study in the online study platform Qualtrics XM (Qualtrics International Inc). Participants who were not rejected by quality control were randomized using the Qualtrics “randomizer” tool, hence no study personnel were involved in assignment to arms. To avoid enrollment by individuals specifically interested in the study topic, our invitation summary text was vague (“We are interested in understanding how people perceive and think about messages”). Initial analyses were completed by a statistician (LGA) who was blinded to the meaning of the arm variable. | PMC10131812 |
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Procedures | As previously described, participants who began the study in Qualtrics completed sociodemographic questions intermixed with quality control checks (see our rationale for the importance of such checks in [Intervention image.Control image.Once participants advanced, they were shown a smaller copy of the image they had just viewed along with 1 (control) or 2 (intervention) comprehension questions. Participants who responded correctly to all questions advanced in the study, and those who did not respond correctly were returned to the larger image and shown the message, “At least one of your answers was incorrect. Please re-read the post carefully and then answer the following (one/two) questions to verify your understanding of the post.” Such participants then moved forward to the comprehension question page again. The comprehension questions were prespecified in our protocol [Both arms: (true/false) “In the social media post you read about a scientific study from April 2020, the study authors found that face masks could reduce the spread of COVID-19 as well as lowering hospitalizations and deaths.”Intervention arm only: (true/false) “In the social media post you read about a scientific study from April 2020, the study authors recommended that everyone in the US should start wearing masks immediately.”Comprehension was generally good. For the intervention group, 38/778 (4.9%) responded incorrectly to 1 or both questions the first time, and only 5 participants did the second time (0.6%). In the control arm, 14/748 (1.9%) responded incorrectly to the question the first time, and none did the second time.Finally, participants completed all prespecified outcome measures and covariates (see the “Outcomes” section and the protocol [ | PMC10131812 |
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Outcomes | There were 5 primary outcome variables, each of which corresponded to a hypothesis as well as a prespecified reanalysis of that hypothesis (in which arm × political orientation was added as an interaction term). The variables were collected as prespecified, so we directly copied the text from our protocol here [The overall trust in science and scientists was measured by the 21-item scale developed and validated by Nadelson et al [Measures of credibility and trust that were specific to the hypothetical social media post and the scientist who conducted the study (from Song et al [“How credible is the scientist who conducted the study described in the post?” (1=not credible at all to 7=extremely credible); note that this language is slightly different from the original item to avoid ambiguity arising from the potential that a scientist authored the social media post;“How credible is this research?” (1=not credible at all to 7=extremely credible);“I would trust scientific information if I knew it came from this author.” (1=strongly disagree to 7=strongly agree);“I trust this scientific information.” (1=strongly disagree to 7=strongly agree). | PMC10131812 |
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Covariates | RTI | As with the outcome variables, the covariates were collected as prespecified, so we directly copy the text from our protocol here [Familiarity with science was measured by 1 item asking, “How often do you read science papers or science in the news?” (1=never to 5=always); this item was suggested in Song et al [Level of religious commitment (0=low to 10=high), as used in our previous studies [Political orientation (0=liberal to 10=conservative), as used in our previous studies [Political party (Republican, Democrat, or other), given recent research suggesting divergence between political orientation and party orientation pertaining to face masks [Race, ethnicity, gender, age (“About how old are you [in years]?”), and education level (“What is the highest grade or level of school you have completed, or the highest degree you have received?”) from the PhenX Toolkit (RTI International) [ | PMC10131812 |
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Statistical Analysis | We planned to recruit 1500 participants, which would allow the detection of small effects at α=.05 (Cohen For hypotheses 1 through 5, we used analysis of covariance, with the study arm (intervention or control) as the independent variable and each of the outcome variables set as the dependent variable (1 per hypothesis). Each analysis incorporated all measured covariates and was checked for violations of any statistical assumptions prior to being run (no violations were found; see | PMC10131812 |
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Ethics Approval and Consent to Participate | All participants digitally provided informed consent prior to beginning the study (Indiana University Institutional Review Board, approval number 16141). | PMC10131812 |
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Results | PMC10131812 |
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Overview | Additional details from the study, including raw data, data cleaning syntax, and analytic code, are available in | PMC10131812 |
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Sample Characteristics | A total of 1635 unique individuals accepted the survey in their Prolific account and accessed the study between September 4, 2022, and September 6, 2022, when 1500 surveys were verified for payment. Prior to randomization, cases were removed from the data set and resampled if they declined to participate after reading the study information sheet (n=2) or agreed to the study information sheet but exited the survey immediately thereafter (n=6). Cases were also deleted prior to randomization and resampled based on the first missed quality control check (although some participants might have missed multiple checks, numbers here represent unique cases): dishonesty or misrepresentation (n=14) or inattention (first attention check, n=20; second attention check, n=48). Some individuals quit the survey prior to randomization but did not miss any attention checks (n=11) and were removed and resampled. Finally, several individuals were randomized and accessed the intervention but did not provide any study data (n=8). These cases were also eliminated from analysis, but their arm assignment was not adjusted.A few individuals quit part way through the study but provided some data (n=9) after randomization; 15 individuals also fully completed the survey but did not submit a request for compensation. These individuals were retained in the arm to which they were assigned. Thus, the final total number of cases retained for analysis was 1526, of which 9 had partial data and 1517 had complete data, with 778 usable cases allocated to the intervention arm and 748 usable cases allocated to the control arm (CONSORT (Consolidated Standards of Reporting Trials) study diagram.Sample characteristics by study arm. | PMC10131812 |
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Hypothesis 1 | We hypothesized that overall trust in science and scientists [Main effects (arm, trust in science/scientists). | PMC10131812 |
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Hypotheses 2 Through 5 | μMain | We hypothesized that each of the 4 single-item measures of trust and credibility specific to the featured post and the scientist who conducted the study would be significantly lower in the intervention arm (cognitive plus normative language) than in the control arm (cognitive language alone) [Credibility of the scientist who conducted the study described in the post (μCredibility of the research described in the post (μTrusting scientific information if it came from this author (μTrusting this scientific information (μMain effects (arm, credibility of the scientist).Main effects (arm, credibility of the research).Main effects (arm, trust scientific information from this author).Main effects (arm, trust this scientific information). | PMC10131812 |
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Additional Preregistered Analyses | We preregistered additional analyses for this study focused on interactions between arm assignment and political orientation [ | PMC10131812 |
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Study Arm | In 4 of the 5 additional analyses, the study arm remained nonsignificant, including for overall trust in science and scientists (β=0.01, 95% CI –0.10 to 0.11; | PMC10131812 |
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Arm × Political Orientation Interaction | INTERACTION | The interaction between study arm and political orientation was nonsignificant for overall trust in science and scientists (β=0.00, 95% CI –0.02 to 0.02; Interaction (arm × political orientation, trust in science/scientists).Interaction (arm × political orientation, credibility of the scientist).Interaction (arm × political orientation, credibility of the research).Interaction (arm × political orientation, trust this scientific information).Interaction (arm × political orientation, trust scientific information from this author). | PMC10131812 |
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Political Orientation | Political orientation was strongly associated with each variable (more conservative orientation was associated with lower scores). This was true for overall trust in science and scientists (β=–0.13, 95% CI –0.15 to –0.12; | PMC10131812 |
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Exploratory Results | This study was not intended to study the covariates in detail, but we would be remiss in failing to mention an interesting feature of both the basic models and the models with the arm × political interaction (all outcome tables are available in | PMC10131812 |
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Discussion | PMC10131812 |
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Principal Findings | We conducted a large, preregistered, randomized controlled trial to test whether the addition of normative language to cognitive language about face masks in otherwise identical social media posts influenced 5 different measures of trust and credibility of science and scientists. As we outlined in our “Introduction” section as well as in our protocol paper [We also prespecified that we would conduct the same analyses while including an interaction term for study arm × political orientation. We made that decision because an association between political orientation and trust in science was observed in the validation and development study for the scale we used to measure overall trust in science and scientists (Nadelson et al [ | PMC10131812 |
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Interpretation | This study examined the effects of normative language using very specific parameters: a single exposure to normative plus cognitive language from a study in comparison to cognitive language alone, at a dose of at least 30 seconds. Further, the exposure specifically pertained to a topic that is highly politicized in US culture (COVID-19 face masks). In those specific circumstances, At the same time, we note that political orientation had an extremely strong, negative association with our measures in this study, regardless of the study arm. We also note that except in the case of the aggregated measure (overall trust in science and scientists), there was a clear, visible intersection (The shape of the data does cause us to wonder whether the following questions might be important to study:Are there very small differences (eg, smaller than we were able to test in this study) between how political liberals and political conservatives perceive normative language, such that single exposures increase trust and credibility among liberals and reduce it among conservatives?If the answer to the above question is yes, do such effects matter individually, and is there a cumulative effect of such exposures, such that the very small effect sizes observed for single exposures are summative or multiplicative in impact over time?Given the prima facie evidence that cognitive claims and normative claims are different, and the importance of understanding trust in science and scientists, and credibility thereof, we believe that additional probative studies (such as those described above) are important and may be useful. Debates about science communication are international in scope and can have high stakes. As an example, we point to a recently published postmortem review of Sweden’s COVID-19 policy, which lays out the complexity of scientific and policy interaction; although not its primary purpose, that document shows some ways in which cognitive and normative claims can be bundled together in high-stakes communication and decision making [However, after considering the totality of our study results, we note that substantive shifts in perceived trust or credibility appear unlikely to manifest in response to | PMC10131812 |
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Limitations and Conclusions | LGA | In addition to the caveats addressed throughout our manuscript, we note several additional considerations that are important when interpreting this work. First, although the study sample was nationally representative by cross sections of age, gender, and race/ethnicity, the Prolific service is an online program, which may raise some concerns about generalizability (eg, party affiliation is more often Democrat in our sample than in national Gallup polls [We thank Dr Judith Greenberg for edits and comments made on the protocol for this study.Authors' Contributions: JA and YX conceptualized this study. JA, YX, and LGA contributed to the study methodology. LGA and YX performed study validation. JA and LGA performed formal analysis. JA performed data curation, wrote the original draft, and was responsible for project administration. LGA contributed to data visualization. All authors contributed to the study investigation, acquisition of resources, and review and editing.Conflicts of Interest: None declared.CONSORT-eHEALTH checklist (V 1.6.1).Data, code, and syntax. | PMC10131812 |
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1. Introduction | Background: Cognitive functions decline with age. Declined cognitive functions negatively affect daily behaviors. Previous studies showed the positive effect of spices and herbs on cognition. In this study, we investigated the positive impact of wasabi, which is a traditional Japanese spice, on cognitive functions. The main bioactive compound of wasabi is 6-MSITC (6 methylsulfinyl hexyl isothiocyanate), which has anti-oxidant and anti-inflammatory functions. Anti-oxidants and anti-inflammatories have an important role in cognitive health. Therefore, 6-MSITC is expected to have positive effects on cognitive function. Previous studies showed the beneficial effects on cognitive functions in middle-aged adults. However, it is unclear that 6-MSITC has a positive effect on cognitive functions in healthy older adults aged 60 years and over. Here, we investigated whether 12 weeks’ 6-MSITC intervention enhances cognitive performance in older adults using a double-blinded randomized controlled trial (RCT). Methods: Seventy-two older adults were randomly assigned to 6-MSITC or placebo groups. Participants were asked to take a supplement (6-MSITC or a placebo) for 12 weeks. We checked a wide range of cognitive performances (e.g., executive function, episodic memory, processing speed, working memory, and attention) at the pre- and post-intervention periods. Results: The 6-MSITC group showed a significant improvement in working and episodic memory performances compared to the placebo group. However, we did not find any significant improvements in other cognitive domains. Discussion: This study firstly demonstrates scientific evidence that 6-MSITC may enhance working memory and episodic memory in older adults. We discuss the potential mechanism for improving cognitive functions after 6-MSITC intake.Cognitive performances decline with age [Nutrition is an important factor for cognitive health in older adults [Recent studies have also demonstrated that spices and herbs have health benefits [Wasabi (Eutrema japonicum) is a Japanese traditional spice. In Japan, wasabi is popular. The main bioactive compound of wasabi is Hexaraphane (6 methylsulfinyl hexyl isothiocyanate: 6-MSITC), which is an isothiocyanate family [Only two studies investigated beneficial effects of 6-MSITC on cognitive functions [In this study, we tested whether 12 weeks’ 6-MSITC intake would enhance cognitive performances in older adults. In this study, we made three main hypotheses. First, we hypothesized that 6-MSITC would improve episodic memory as well as working memory performances in older adults because a previous study on patients using 6-MSITC reported a significant improvement of the subjective severity of brain fog symptoms [ | PMC10648564 |
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2. Materials and Methods | PMC10648564 |
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2.1. Setting of Trial | This RCT was conducted in Sendai from October 2018 to March 2019. The study was approved by the Tohoku University Hospital Ethical Committee. This study was registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN 000032694).We investigated the positive effects of 6-MSITC on cognitive performances using a double-blinded RCT ( | PMC10648564 |
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2.2. Participants | FOOD ALLERGIES | To recruit participants, we posted advertisements in the local town paper in Sendai. The exclusion and inclusion criteria were written in the advertisements. Firstly, researchers checked whether the interested participants met eligibility based on the criteria, such as their basic information, medical history, and food allergies (please see | PMC10648564 |
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2.3. Inclusion and Exclusion Criteria | Based on previous studies [ | PMC10648564 |
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2.4. Sample Size Estimation | The sample size was calculated by G power [ | PMC10648564 |
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2.5. Randomization | We used a randomization program using the Graphpad (version 9) tool. We stratified participants based on sex with 1:1 [ | PMC10648564 |
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2.6. General Procedure of the Intervention | Participants in both groups were asked to take one tablet (6-MSITC or the placebo supplements) before going to bed every day for 12 weeks. Cognitive functions in all participants were assessed at the pre- and post-intervention period. Participants were also required to record their supplement intakes in the diary. After the intervention period, participants returned the remaining supplements and their diaries to the researchers. Then, we confirmed their adherence by checking the dairy and counting the remaining supplements.Previous studies using the 6-MSITC intervention set the intervention period at 8 weeks [ | PMC10648564 |
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2.7. 6-MSITC and Placebo Supplements | The 6-MSITC group took one 6-MSITC capsule that contained 100 mg wasabi extract powder containing 6-MSITC (0.8 mg) absorbed on α cyclodextrin and a 100 mg vehicle (calcium stearate, starch, and silicon dioxide) per day. The placebo group took one placebo capsule containing α 100 mg cyclodextrin and the vehicle per day. The main compositions in each capsule are summarized in We set the dose of 6-MSITC (0.8 mg) based on previous findings using 6-MSITC. There were two reasons. First, the dose of 6-MSITC differed among previous studies (from 0.8 to 9.6 mg). Previous studies with 4.8 mg or 9.6 mg of 6-MSITC were conducted using a pre–post intervention design without control groups [ | PMC10648564 |
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2.8. Cognitive Functions | We performed the screening tests at the baseline using the Japanese version of MMSE [To measure several cognitive domains (processing speed, attention, short-term memory, working memory, episodic memory, executive functions, and visual–spatial abilities), we used standardized cognitive assessments for healthy older adults. The detail of each test is shown in the These cognitive assessments are often used in RCTs in healthy older adults [ | PMC10648564 |
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2.9. Analysis | In this study, we used the intention to treat (ITT) principle. We calculated the change scores in each cognitive function (post–pre difference score). R (ver. 4.10) was used to conduct all analyses. A multiple imputation method with predictive mean matching was used to impute data (m = 20). All variables were included in the data imputation process. The multiple imputations were performed using the function of “mice” of the mice package in R [ | PMC10648564 |
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3. Results | We did not find any significant difference between the two groups at the baseline (We performed ANCOVAs for the change scores ( | PMC10648564 |
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4. Discussion | chronic fatigue | This study aimed to test whether 12 weeks’ 6-MSITC intervention has positive effects on cognitive performances in healthy older adults. We found two main findings. First, the 6-MSITC intervention improved working memory capacity as measured by DS-B compared to the placebo group. Second, the 6-MSITC intervention improved episodic memory performances as measured by LM and FSM. These findings support our first hypothesis. However, contrary to our second hypothesis, we did not find any significant improvements in inhibition. These findings suggest that the 12 weeks’ 6-MSITC intake selectively enhances working and episodic memory functions in healthy older adults.In this study, working memory performances, as measured by DS-B, were improved after the 12 weeks’ 6-MSITC intake compared to the placebo intake. This result is consistent with previous studies using Sulforaphane [The second finding is that the 12 weeks’ 6-MSITC intake improved episodic memory performances, as measured by LM and FSN, in healthy older adults. This finding is consistent with a previous patient study using 6-MSITC in middle-aged patients with chronic fatigue [In contrast to the third and fourth hypotheses, there are no significant changes in the inhibition and processing speed performances after the 6-MSITC intake in older adults. This is inconsistent with a previous study showing a beneficial effect of 6-MSITC on inhibition performance [It is important to consider a potential mechanism of the improvements in memory functions after 6-MSITC intake. Previous studies have demonstrated that 6-MSITC has anti-oxidant and anti-inflammatory functions [This study has some limitations. First, we did not measure any biomarkers of anti-oxidants or anti-inflammatories. To understand the biological mechanism of the benefit of 6-MSITC, it is important to investigate a change in the biomarkers before and after intervention periods. Second, we recruited only healthy older adults. To generalize the current findings, further investigation is needed on whether 6-MSITC would improve cognitive functions in young adults. Third, the number of female participants was larger than that of the male participants in this study, even though we recruited participants from the public using advertisements. We used sex as the covariate in all analyses. Therefore, the effect of sex would be reduced in this study. However, it is important to perform RCTs with a 1:1 sex ratio in future studies. | PMC10648564 |
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5. Conclusions | 6-MSITC is the main bioactive compound of wasabi. We investigated the benefits of 6-MSITC intake on cognitive health in older adults. The current RCT revealed that an intake of 0.8 mg of 6-MSITC for 12 weeks significantly improved memory functioning, including episodic and working memory, compared to the placebo group, but we did not find any significant improvements in other cognitive functions. This study is the first to demonstrate that 6-MSITC has a benefit on memory functioning in healthy older adults. | PMC10648564 |
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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10648564 |
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Author Contributions | H.N. | Conceptualization, R.N.; project administration, R.N.; methodology, R.N.; formal analysis, R.N.; investigation, R.N., N.Y.S.K., T.S., and H.N.; data curation, R.N. and H.N.; writing—original draft preparation, R.N.; writing—review and editing, R.N., N.Y.S.K., T.S., H.N., and R.K.; funding acquisition, R.N.; visualization, R.N.; supervision, R.K. All authors have read and agreed to the published version of the manuscript. | PMC10648564 |
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Institutional Review Board Statement | This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Tohoku University Graduate School of Medicine (ref. 2017-2-348-1 and 19 July 2017). | PMC10648564 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in this study. | PMC10648564 |
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Data Availability Statement | The datasets used and analyzed in this study are available from the corresponding author on reasonable request. | PMC10648564 |
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Conflicts of Interest | This study was supported by KINJIRUSHI Co., Ltd. The funding body had no role in the design of the study, collection, analyses, or interpretation of the data, writing of the manuscript, or the decision to publish the results. | PMC10648564 |
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Trial Registration | MAY | This trial was registered at The University Hospital Medical Information Network Clinical Trials Registry (UMIN 000032694). Registered 24 May 2018, | PMC10648564 |
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References | Depression | CONSORT diagram.Baseline data in both groups.Note: 6-MSITC, 6 mthylsulfinyl hexyl isothiocyanate; MMSE, Mini-Mental State examination; FAB, Frontal Assessment Battery at bedside; JART, Japanese Reading Ability Test; GDS, Geriatric Depression Scale; d, Cohen’s d (effect size).Compositions in each capsule.Note: 6-MSITC, 6 mthylsulfinyl hexyl isothiocyanate.Cognitive functions of both groups at the baseline.Note: 6-MSITC, 6 mthylsulfinyl hexyl isothiocyanate; SD, standard deviation; Cd, digit symbol coding; SS, symbol search; D-CAT, digit cancellation task; ST, Stroop task; rST, reverse Stroop task; CPM, Raven’s colored progressive matrices; DS-F, digit span forward; DS-B, digit span backward; LM, logical memory; FSN, face and second name test; MR, mental rotation test; d, Cohen’s d (effect size).Change scores of cognitive functions of both groups.Note: 6-MSITC, 6 mthylsulfinyl hexyl isothiocyanate; SD, standard deviation; Cd, digit symbol coding; SS, symbol search; D-CAT, digit cancellation task; ST, Stroop task; rST, reverse Stroop task; CPM, Raven’s colored progressive matrices; DS-F, digit span forward; DS-B, digit span backward; LM, logical memory; FSN, face and second name test; MR, mental rotation test. | PMC10648564 |
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Background | micropapillary bladder cancer | The present study aimed to construct and validate nomograms that can be used to predict cancer-specific survival (CSS) and overall survival (OS) in patients with micropapillary bladder cancer.
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Methods | micropapillary bladder cancer, bladder cancer | REGRESSION, BLADDER CANCER | The data of 627 patients diagnosed with micropapillary bladder cancer between 2000 and 2018 were obtained from the surveillance, epidemiology, and end results database. Patients were randomly divided into the training and internal validation sets (7:3). The Cox proportional hazards regression model was applied to evaluate the association between variables and survival and then nomograms were constructed to predict the survival of an individual patient. The performance of nomograms was validated by using calibration curves, concordance index, receiver operating characteristic curves with the calculated area under the curve and decision curve analysis in the training and internal validation set. Data from 41 micropapillary bladder cancer patients at Qilu Hospital of Shandong University from 2000 to 2022 were collected for external validation. | PMC9926703 |
Results | tumor | TUMOR | Several independent risk factors were taken into the two nomograms (CSS and OS), including age, marital status, AJCC TMN stage, surgical approach, lymph node ratio, and tumor size while the OS nomogram additionally contained race. The concordance index of the training set, internal validation set, and external verification set were all over 0.7. The calibration curve indicated good consistence between the nomogram prediction and actual survival. Area under the curve and decision curve analysis results indicated great clinical usefulness of nomograms. | PMC9926703 |
Conclusions | micropapillary bladder cancer | The nomograms predicting the survival outcome of patients with micropapillary bladder cancer would provide a valuable tool to help clinicians to evaluate the risk of patients and make individual treatment strategies. | PMC9926703 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12894-023-01183-z. | PMC9926703 |
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Keywords | PMC9926703 |
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Background | micropapillary bladder cancer, cancer prognosis [, MPBC, Micropapillary bladder cancer, AJCC, Cancer | CANCER | Micropapillary bladder cancer (MPBC) was first recognized in 1994 by Amin et al. [At present, the prognosis evaluation of the micropapillary bladder cancer patients mainly depends on American Joint Committee for Cancer (AJCC) tumor-node-metastasis (TNM) staging system [Nomograms can simplify the statistical prediction model into a visible tool, which is tailored for single patient and is widely used in the evaluation of cancer prognosis [ | PMC9926703 |
Methods | PMC9926703 |
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Data sources | Data were extracted from SEER using SEER*Stat software version 8.4.0 ( | PMC9926703 |
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Patient selection | cancer, micropapillary bladder cancer, Tumor | CANCER, DISEASES, TUMOR | We searched the SEER database including 17 cancer registries and covering 26.5% of the US population. The inclusion site code was C67.0-C67.9, and the histological code was 8131/2, 8131/3, according to the International Classification of Tumor Diseases, Third Edition (ICD-O-3). The exclusion criteria were (1) incomplete survival data; (2) patients in SEER database diagnosed before 2004 since their TNM stage information was not recorded; (3) lymph node examined and positive lymph node were unknown; (4) surgical approach, radiotherapy or chemotherapy was unknown. Patients with micropapillary bladder cancer in Qilu hospital of Shandong University were considered to be included in the external validation set. The exclusion criteria were similar to those of the SEER database. After selection, 627 patients were enrolled from the SEER database and 41 patients from the tertiary center. | PMC9926703 |
Variables | AJCC T stage, tumor, AJCC N stage, Cancer | TUMOR, CANCER | The information collected included age, sex, race, annual income, marital status, histologic type, grade, American Joint Committee on Cancer stage I-IV, AJCC T stage, AJCC N stage, AJCC M stage, surgery of primary site, lymph node examined and positive lymph node, radiotherapy, chemotherapy, tumor size, survival months and status. Age was regrouped into “< 80” and “> = 80”, annual income was regrouped into “< $60,000” and “> = $60,000”. Never married, Widowed, Separated and Divorced were classified as Single and the AJCC stage I | PMC9926703 |
Outcomes | death, micropapillary bladder cancer | SECONDARY | The primary outcome was CSS, defined as the time from the first diagnosis of micropapillary bladder cancer to cancer-specific death, and the secondary outcome was OS, defined as the time from the first diagnosis to death from any cause. | PMC9926703 |
Construction and validation of the nomogram | micropapillary bladder cancer, Micropapillary bladder cancer | REGRESSION | Eligible micropapillary bladder cancer patients from the SEER database were randomly divided into a training set and an internal validation set using a ratio of 7:3. Micropapillary bladder cancer patients from the tertiary center were designated as the external validation set. External validation was performed to further verify the accuracy of the nomograms.Univariate and multivariate Cox regression analyses were performed on patients in the training set to evaluate the variable’s impact on CSS and OS, presenting as a hazard ratio (HR) and corresponding 95% confidence interval (CI). Based on results of the multivariate Cox regression analysis, nomograms were created for predicting the probability of 1-, 3-, and 5-year CSS and OS. The internal validation of the nomogram was performed in the internal validation set and the external validation was conducted using external validation set. Validation of this nomogram was then performed using bootstrapping with 1000 resamples. The accuracy of nomograms was evaluated using a calibration curve through comparing nomogram-predicted survival with actual survival. The discriminatory ability of the nomogram was evaluated by the concordance index (C-index) and the receiver operating characteristic (ROC) curves with the calculated area under the curve (AUC). In addition, decision curve analysis (DCA) was applied to estimate the clinical net benefit of the nomogram by comparing the threshold probabilities range of the model to that of the AJCC staging system.All statistical analyses were conducted by R version 4.2.0 ( | PMC9926703 |
Results | PMC9926703 |
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Patients baseline characters | micropapillary bladder cancer | According to the inclusion criteria, a total of 668 micropapillary patients were retrospectively enrolled from SEER (n = 627) and tertiary centers (n = 41). By the end of follow-up, a total of 360 of the 627 people enrolled from SEER database had died, of which 280 died from micropapillary bladder cancer and the remaining 80 died from other causes. Details on the demographic information, clinicopathological parameters, and treatments in the training set, internal validation set, and external validation set were shown in Table Characteristics of patientsOtherIThe cancer-specific survival of micropapillary bladder cancer | PMC9926703 |
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Univariable and multivariable cox regression in the training set | tumor, AJCC TMN stage | REGRESSION, TUMOR | In univariable Cox regression analysis for CSS, eleven factors (age, sex, histologic grade, marital status, T stage, N stage, M stage, AJCC TMN stage, surgical approach, radiotherapy, lymph node ratio, and tumor size) reached statistical significance. Then, above eleven factors were included in the multivariate Cox analysis. The variables with Univariable and Multivariable Analyses of cancer-specific survival in the Ttraining setOtherIIn univariable Cox regression analysis for OS, twelve factors (age, race, histologic grade, marital status, T stage, N stage, M stage, AJCC TMN stage, surgical approach, radiotherapy, lymph node ratio, and tumor size) reached statistical significance. Then, above twelve factors were included in the multivariate Cox analysis. The variables with | PMC9926703 |
Nomogram construction | tumor, micropapillary bladder cancer | TUMOR, LYMPH NODE METASTASIS | Nomograms were established based on the above independent prognostic factors for predicting the 1-, 3-, 5-year CSS and OS (Fig. Nomograms predicting the 1-, 3-, 5-year CSS of micropapillary bladder cancer. I Each of the independent prognostic factors was given a point according to HR. The scores corresponding to independent prognostic factors were added to obtain the total score which is located onto the total points scale to obtain the probability of 1-, 3-, and 5- year CSS and OS. Nomograms can make individualized prediction based on patient information, improving the accuracy and efficiency of prediction. For example, if a 70-year old single patient was found no positive lymph node metastasis, the tumor size was 4 cm, and the AJCC stage was III after radical cystectomy, he would score 130 points, which means that this patient has approximately 86% possibility of cancer-special survival in the first year, approximately 62% possibility of cancer-special survival in the third year and approximately 52% possibility of cancer-special survival in the fifth year. | PMC9926703 |
Nomogram validation | PMC9926703 |
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Internal validation | micropapillary bladder cancer | Nomograms were validated internally in the training set and the internal validation set.In the training set, C-indices of the nomogram were 0.766 (95% CI 0.735–0.797), 0.742 (95% CI 0.726–0.758) for CSS and OS respectively, which were both higher than 0.7, suggesting that these two nomograms were relatively accurate and suitable for predicting CSS and OS for patients with micropapillary bladder cancer. In the internal validation set, C-indices of the nomogram were 0.753 (95% CI 0.699–0.808), and 0.738 (95% CI 0.715–0.761) for CSS and OS respectively.For micropapillary bladder cancer patients, the 1-, 3-, and 5-year CSS of the nomogram yielded AUC values of 0.812, 0.864, and 0.841 in the training set (Fig. ROC curves in the training set (The calibration curves of the nomogram were highly consistent with the standard curve, which indicated that the nomogram showed high reliability in predicting 1-, 3-, and 5-year CSS in the training (Fig. Calibration curves in the training set (DCA of the nomograms showed higher net benefits and demonstrated better clinical outcome values than those obtained using AJCC stage for CSS in the training (Fig. DCA curves in the training set ( | PMC9926703 |
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External validation | In the external validation set, C-indices of the nomograms were 0.813, 0.828 for CSS and OS respectively. The AUC values were 0.741, 0.929, and 0.968 for the 1-, 3-, and 5-year CSS (F | PMC9926703 |
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Discussion | papillary tumor, tumor, comorbidity, micropapillary breast cancer, cancer, urothelial carcinoma, micropapillary bladder cancer, bladder cancer, muscle-invasive bladder cancer, tumors, Micropapillary bladder cancer, AJCC | TUMOR, MICROPAPILLARY CARCINOMA, CANCER, UROTHELIAL CARCINOMA, BLADDER CANCER, INFILTRATING, TUMORS, METASTASES | Micropapillary carcinoma, a rare variant, is composed of infiltrating slender delicate filiform processes or small tight papillary tumor cell clusters that lie within lacunae [Although AJCC TNM staging system is popular for cancer prognosis, the rationality of its application in micropapillary bladder cancer has been much debated. Firstly, the TNM staging system is established mainly based on conventional urothelial carcinoma instead of micropapillary bladder cancer. Micropapillary bladder cancer has been reported to have a poorer prognosis than conventional bladder cancer, but a recent study showed that clinical outcomes were comparable to conventional bladder cancer after controlling for standard clinicopathologic predictors [Our study identified six independent prognostic factors for CSS, including age, marital status, AJCC stage, tumor size, surgery approach and positive lymph node ratio.Generally, older patients with decreased immunity and increased numbers of comorbidities are more likely to have poorer survival outcomes. Although age has not been reported to affect the prognosis of micropapillary bladder cancer, its effect on conventional bladder cancer and micropapillary breast cancer has been widely concerned [Marital status was used as a predictor of survival for various tumors, including bladder cancer [Similar to other tumors, clinicopathological features are also important prognostic indicators of micropapillary bladder cancer. Z Li et al. reported that micropapillary bladder cancer often presented at an advanced stage with lymphovascular invasion and distant metastases, and the prognosis was poor [In terms of surgical treatment, radical cystectomy is considered as the gold standard for muscle-invasive bladder cancer and refractory non-muscle-invasive bladder cancer. The optimal treatment of patients with cT1 remains controversial [However, there were several limitations in our study. First, this study was a retrospective analysis with inherent biases. Further efforts are needed to collect prospective data. Second, some important information is unavailable in the SEER database, such as blood test information, smoking history. Comorbidities information is also an important prognostic indicator, which can affect treatment choices and survival. Lack of comorbidity information is one of the limitations of this paper. Furthermore, although the C-indices of the two nomograms were greater than 0.7, indicating high accuracy in CSS and OS, about 30% of our predictions were wrong and nomograms need to be further improved.
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Conclusion | micropapillary bladder cancer | We established the visible nomograms to predict individual CSS and OS of micropapillary bladder cancer patients using demographic information, clinicopathological factors and treatment-related factors. The internal validation and external validation of the model proved its significant performance. The nomograms can be valuable in assisting patient counseling and guiding treatment decision making in areas such as prognostic evaluation, individualized therapy, and clinical trial design. | PMC9926703 |
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Acknowledgements | Not applicable. | PMC9926703 |
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Author contributions | PL: Conceptualization, Data Analysis, Investigation, Methodology, Project administration, Visualization, Writing; LX: Data Analysis, Investigation, Methodology, Visualization, Writing; GC: Data curation, Supervision, Writing; BS: Data curation, Supervision, Writing; QZ: Data curation, Supervision, Writing; SC: Conceptualization, Data curation, Supervision, Writing. All authors read and approved the final manuscript. | PMC9926703 |
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Funding | This work was supported by the Shandong Medical and Health Science and Technology Development Plan Project (2018WS333), the National Natural Science Foundation of China (Grant No. 81970661; 81900637) and the Tai Shan Scholar Foundation to Benkang Shi (ts201511092). | PMC9926703 |
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Availability of data and materials | The dataset supporting the conclusions of this article is available in the SEER*Stat software version 8.4.0 repository ( | PMC9926703 |
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Declarations | PMC9926703 |
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Ethics approval and consent to participate | Data were extracted from SEER using SEER*Stat software version 8.4.0 ( | PMC9926703 |
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Consent for publication | Not applicable. | PMC9926703 |
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Competing interests | The authors declare that they have no competing interests. | PMC9926703 |
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References | PMC9926703 |
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Background | COMPLICATIONS, VASOVAGAL REACTION | Vasovagal reactions (VVRs) are the most common acute complications of blood donation. Responsible for substantial morbidity, they also reduce the likelihood of repeated donations and are disruptive and costly for blood services. Although blood establishments worldwide have adopted different strategies to prevent VVRs (including water loading and applied muscle tension [AMT]), robust evidence is limited. The Strategies to Improve Donor Experiences (STRIDES) trial aims to reliably assess the impact of four different interventions to prevent VVRs among blood donors. | PMC10413586 |
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Methods | BLOOD | STRIDES is a cluster-randomised cross-over/stepped-wedge factorial trial of four interventions to reduce VVRs involving about 1.4 million whole blood donors enrolled from all 73 blood donation sites (mobile teams and donor centres) of National Health Service Blood and Transplant (NHSBT) in England. Each site (“cluster”) has been randomly allocated to receive one or more interventions during a 36-month period, using principles of cross-over, stepped-wedge and factorial trial design to assign the sequence of interventions. Each of the four interventions is compared to NHSBT’s current practices: (i) 500-ml isotonic drink before donation ( | PMC10413586 |
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Discussion | The STRIDES trial should yield novel information about interventions, singly and in combination, for the prevention of VVRs, with the aim of generating policy-shaping evidence to help inform blood services to improve donor health, donor experience, and service efficiency. | PMC10413586 |
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Trial registration | ISRCTN: 10412338. Registration date: October 24, 2019. | PMC10413586 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07473-z. | PMC10413586 |
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Keywords | PMC10413586 |
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Introduction | PMC10413586 |
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Background and rationale | hypovolaemic, fractures, pain | RECRUITMENT, COMPLICATIONS, COMPLICATION, BLOOD, VASOVAGAL REACTION | Vasovagal reactions (VVRs), the most common acute complication related to blood donation, are responsible for substantial morbidity, especially when accompanied by complications such as fall and fractures [Operating at different stages of blood donation, the principal mechanisms believed to underlie donation-related VVRs include the direct effects of removal of ~500mL of blood; the stress of giving blood (e.g. fear of needles, pain, sight of blood); and orthostatic effects superimposed on a relative hypovolaemic state after donation [A previous meta-analysis of randomised trials has, however, shown that there is limited evidence to support water loading or AMT [To evaluate the effects of four interventions for the prevention of VVRs among whole blood donors, we have designed the Strategies to Improve Donor Experiences (STRIDES) trial, a large cluster-randomised trial across all sites of the national blood service in England (National Health Service Blood and Transplant [NHSBT]). The trial aims to provide evidence-based policies to reduce VVRs among blood donors, leading to improvements in donor health, donor experience, and service efficiency. A subsidiary aim is to advance understanding of the determinants of VVRs and to develop prevention strategies for VVRs tailored to specific donor sub-populations.We confirm that recruitment into the trial was ongoing at the time this manuscript was submitted for publication. | PMC10413586 |
Objectives {7} | SECONDARY | The primary objective of STRIDES is to determine the optimum intervention(s) or combination of interventions to prevent VVRs in whole blood donors. A secondary objective is to advance understanding of the determinants of VVRs and to help develop prevention strategies for VVRs tailored to specific donor sub-populations (e.g. stratified by demographic, biological, psychosocial and other characteristics). | PMC10413586 |
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Hypothesis | We will test the hypothesis that the implementation of one or more interventions, singly or in combination, will reduce VVRs when compared to current practice in NHSBT. | PMC10413586 |
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Trial design {8} | PMC10413586 |
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Feasibility study | Prior to the initiation of STRIDES, a feasibility study was conducted in five blood donation sites (comprising 3 donor centres and 2 mobile teams) over a period of 15 weeks (25 March 2019 to 26 June 2019) to establish if the protocol for a cluster-randomised trial could be implemented successfully without disrupting routine blood collections. The feasibility study was also used to assess the acceptability of the interventions by blood donors. It showed that the implementation of the four different interventions under evaluation here−either individually or in combination−was practical and did not adversely affect routine blood collection (Supplementary Fig. | PMC10413586 |
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Main trial design | STRIDES is a cluster-randomised cross-over/stepped-wedge factorial trial of four interventions to reduce VVRs involving randomisation of all 73 blood donation sites (mobile teams and donor centres) of NHSBT in England. Four interventions were compared to current practice in NHSBT (i.e. | PMC10413586 |
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Methods: participants, interventions and outcomes | PMC10413586 |
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Study setting {9} | RECRUITMENT | NHSBT collects whole blood from donors at both static donation centres and mobile teams. Recruitment in STRIDES has been taking place in all 73 blood donation sites of NHSBT located across England (Fig. A map showing the locations of the blood donation sites. Mobile team points relate to the centre where the team is based, however, teams travel to different locations within their area for whole blood collections | PMC10413586 |
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Eligibility criteria {10} | All blood donors who were eligible to donate and attended a donation site during the study period (2 | PMC10413586 |
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Who will take informed consent? {26a} | fainting | We have followed the guidance of the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trial [To avoid biases that could undermine the interpretation of study results (e.g. greater awareness of fainting that could result in “social contagion” or other group triggers that lead to increasing fainting), we have not individually informed blood donors about the trial’s specific aim to investigate strategies to reduce VVRs [ | PMC10413586 |
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Additional consent provisions for collection and use of participant data and biological specimens {26b} | As noted above, the need for individual consent into the trial has been waived by the ethics committee. For the STRIDES BioResource sub-study, however, donors have needed to provide their individual and informed consent if they agree to join the NIHR BioResource and provide their surplus blood (taken from the satellite pouch of their routine donation) for research purposes. In particular, donors who have agreed to participate in the STRIDES BioResource have received NHSBT’s routine screening for donation eligibility, i.e. measurement of haemoglobin via copper sulphate test, followed by the Hemocue™ test for those that fail the initial test. Research nurses from NHSBT have, after providing an explanation of the STRIDES BioResource, sought consent from those donors invited to join the STRIDES BioResource. Donors wishing to participate have been asked to complete, with the assistance of a donor carer (if required), an electronic consent form using a tablet device. Alternatively, donors have been able to complete a paper version of the consent form, attached to the back of the Participant Information Sheet. | PMC10413586 |
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Interventions | PMC10413586 |
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Explanation for the choice of comparators {6b} | Interventions are tested versus current NHSBT practice (i.e. the standard of care). | PMC10413586 |
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Intervention description {11a} | orthostatic stress, hypovolemic, anxiety, pain | CONTRACTIONS | As noted above, our trial is evaluating different interventions: (1) 500ml of isotonic drink before donation; (2) 3-min rest on donation chair after donation; (3) modified applied muscle tension (AMT); and (4) a psychosocial intervention using preparatory materials. Table Details of the proposed interventions
Physical manoeuvres including tensing/releasing of skeletal muscles to combat orthostatic intoleranceStatic contractions of the skeletal muscles result in the emptying of large capacitance veins and increased venous return, blood pressure, and ultimately greater cerebral perfusionOther suggested mechanisms include anxiety reduction and distractionKeeping legs crossed throughout exerciseTensing legs and buttocks and including the abdomenInstructions to “breathe normally”5-s contractions and releaseTo exercise AMT following donation chair and leaving site, if symptomsKeeping legs crossed throughout exercise (current practice: crossing and uncrossing)Tensing legs and buttocks and including the abdomen (current practice: no abdomen)Instructions to breathe normally (current practice: no breathing instructions)5-s contractions and release (current practice: 10-s release)To exercise AMT following donation chair or leaving site, if symptoms (current practice; no such recommendation)Fear, pain, blood-related stimuli, lack of social support, and lack of a sense of control are associated with autonomic regulation, hemodynamic changes, blood pressure changes, and VVRsPreparation materials have been suggested to reduce VVRsFollowing the donation, the hypovolemic state combined with the orthostatic stress of suddenly standing leads to an increased risk of VVRsRecovery time in the donation chair in the upright position after removal of the donation needle has been suggested to attenuate orthostatic stress, reducing the amount of sudden blood pooling and consequent VVRs | PMC10413586 |
Criteria for discontinuing or modifying allocated interventions {11b} | MINOR | As this pragmatic trial was embedded into routine donation services, the study has been open to the following minor amendments. First, if a participant has not wished to receive the trial’s interventions, they have been able to receive NHSBT’s standard interventions (e.g. water loading rather than the isotonic drink evaluated in the trial). Second, the trial has been conducted during the COVID-19 pandemic, meaning that during the study NHSBT has routinely implemented service-wide revisions with the aim of enhancing donor and staff safety at donation sessions, including limiting the number of donors per session and removing hot drinks previously offered after donations. | PMC10413586 |
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