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PPG measurement method | inferior vena cava, TIPS | TIPS was established under local anesthesia using a transjugular approach. 4-Fr pigtail catheters were placed in the right atrium, inferior vena cava (at the level of the hepatic vein), and portal vein (where the spleen and superior mesenteric vein converge) to measure the pressure before and after stent placement. For all measurements, the pressure transducer was calibrated to 0 mmHg at the level of the patient's axillary midline. Each measurement was performed three times and then averaged. PPG is the pressure difference obtained by subtracting the IVC pressure from the PV pressure. | PMC10502141 | |
Statistical analysis | OHE | REGRESSION | The statistical analysis was performed by SPSS 26.0 (SPSS Inc, Chicago, USA) and R 4.0.3 (Institute of Statistics and Mathematics). The univariate or multivariate analysis was conducted at a test level of 0.01 or 0.05, respectively. Means of continuous variables were calculated and compared using Mann–Whitney U tests or Student's t tests. Statistically significant indicators in the univariate analysis were included in the multivariate analysis. The variables associated with OHE were assessed using logistic regression analyses. The nomogram prediction model was evaluated by establishing consistency index and evaluating calibration curve. We compared the predictive value of this new nomogram model with other predictive OHE scores. In order to determine the accuracy of this nomogram, a calibration chart with 1000 bootstrap samples was applied. DCA was used to measure clinical utility of this nomogram by calculating net benefit at different threshold probabilities. | PMC10502141 |
Ethical approval | The clinical data were approved by the Ethics Committee of Beijing Shijitan Hospital Affiliated to Capital Medical University. Patients sign informed consent. | PMC10502141 | ||
Results | PMC10502141 | |||
Constructing a nomogram prediction model for OHE after TIPS | OHE | Based on multivariate analysis, age, ICG-R15, percentage of PPG decline, creatinine, and blood ammonia were identified as independent risk factors for OHE after TIPS. By using rms package of R software, independent factors were incorporated into a nomogram prediction model for OHE after TIPS. The expected probability of OHE after TIPS is obtained by drawing a line to the point axis to obtain the points received by the value of each variable, and the sum of these points corresponds to the total point axis (Fig. In the training cohort, a novel nomogram was constructed by combining risk variables including age, ICG-R15, percentage of PPG decline, creatinine and blood ammonia. | PMC10502141 | |
The nomogram had a higher predictive power for OHE after TIPS in the training cohort | OHE | In the training cohort, this nomogram model achieved higher prediction accuracy than other conventional models. The C-index of our nomogram was 0.828 (95% CI 0.761–0.896), significantly higher than that of Child–Pugh score (0.665; 95% CI 0.576–0.755) or MELD score (0.657, 95% CI 0.559–0.755) (Fig. Prediction accuracy of OHE after TIPS was compared with traditional models (Child–Pugh score and MELD score) in (Calibration curves for developing a nomogram in ( | PMC10502141 | |
The nomogram had a higher predictive power for OHE after TIPS in the validation cohort | OHE | Our nomogram model was accurate in predicting OHE after TIPS in the validation cohort, with a C-index of 0.8464 (95% CI 0.7404–0.9524), higher than that of Child–Pugh score (0.6569, 95% CI 0.5129–0.8009) or MELD score (0.6616, 95% CI 0.5156–0.8076) (Fig. | PMC10502141 | |
DCA curve comparison of nomogram and conventional models for OHE after TIPS prediction accuracy | The DCA curves indicated that our nomogram prediction model was more valuable than MELD score or Child–Pugh score (Fig. In ( | PMC10502141 | ||
Discussion | TIPS, OHE, liver function injury | REGRESSION, POSTOPERATIVE COMPLICATIONS | With continuous improvement of hardware facilities and technical concepts, effects of TIPS on PHT therapy have becoming more and more remarkable, however, its postoperative complications remain challenging. For example, HE caused by biochemical disturbance of brain functions as a result of liver function injury and portal-systemic shunt greatly affects the quality of lifeIn this study, we have identified that age, creatinine, blood ammonia, ICG-R15, and percentage of PPG decline were independent risk factors for OHE after TIPS in PHT patients based on multivariate logistic regression models. Several risk factors were related to OHE after TIPS in previous studies. For example, age was associated with HE after TIPSCurrently, Child–Pugh scoring system and MELD scoring system have certain predictive value in predicting OHE after TIPS. However, some indicators in Child–Pugh score are subjective or interrelated, so Child–Pugh score cannot accurately predict OHE after TIPS. The MELD score may predict the mortality of patients after TIPS. Presently, MELD is the most widely applied index for evaluating liver function before liver transplantationThe nomogram is an intuitive statistical tool that can provide information for decision-making in clinical practice. Therefore, we combined 5 risk factors to illustrate a combinatory value in predicting OHE after TIPS. Compared with Child–Pugh score and MELD score, our novel model had a better predictive value for OHE after TIPS. The nomogram prediction model, Child–Pugh score and MELD ROC curves were drawn to calculate C-index values. The predictive ability of our nomogram model vs. conventional models in predicting OHE after TIPS was compared. The C-index value of our novel prediction model was the highest in training cohort and validation cohort, indicating that this nomogram prediction model had a better predictive capability. In terms of validation, Bootstrap self-sampling method was used to calculate consistency index. This prediction model had good accuracy. The calibration curve fit well with the ideal curve, indicating that this nomogram prediction model had a good prediction capability for OHE after TIPS. Traditionally, nomograms have been assessed by diagnostic performance indices, and its clinical value cannot be determined. DCA can assess the benefits of various patient-preferred diagnostic tests to identify the risks of undertreatment and overtreatment, in order to facilitate decision-making. The DCA demonstrated that our nomograms provided more benefits than other models in both training and validation cohorts. Therefore, our nomograms can be applied in clinical practice. However, this study still has some limitations: (1) this study used the change value of PPG as one of the model parameters, so the model cannot predict the occurrence of OHE before TIPS; (2) as a retrospective study, there is a certain selection bias; (3) this study only carried out internal verification, but lacked external verification.In conclusion, we have demonstrated that age, creatinine, ammonia, ICG-R15, and percentage of PPG decline are independent risk factors for predicting OHE after TIPS. When TIPS is performed for PHT patients, in order to reduce the incidence of postoperative OHE, in addition to routine preoperative assessment, attentions should be paid to age and renal function. Furthermore, blood ammonia and ICG-R15 results should be assessed before the surgery. Therapeutic effects attributed to decreased portal venous pressure and the possible increased risk of HE should be balanced during the surgery. In this study, we have proposed a novel predictive nomogram for HE after TIPS. The nomogram harbors good predictive performance and would be a conventional tool to facilitate clinical decision-making. | PMC10502141 |
Acknowledgements | We wish to particularly acknowledge the patients enrolled in this study for their participation. | PMC10502141 | ||
Author contributions | All authors contributed to the study conception and design. Data collection and analysis were performed by L.Z., J.-t.W., Z.-d.Y., Z.-h.F., Y.-f.W., Y.Z., C.-b.D., X.-q.W., T.C., M.-m.M., L.B., S.-b.C., F.-q.L., L.W. The first draft of the manuscript was written by Y.L. and all authors commented on previous versions of the manuscript. | PMC10502141 | ||
Funding | This work was supported by the National Natural Science Foundation of China General Program (Grant no. 81871461). | PMC10502141 | ||
Data availability | The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | PMC10502141 | ||
Competing interests | The authors declare no competing interests. | PMC10502141 | ||
References | PMC10502141 | |||
Background | mental disorders, depression, anxiety, Common mental disorders | Common mental disorders are the leading cause of workplace absences. The Prevail intervention programme aims to reduce stigma and to educate staff and managers about evidence-based low intensity psychological interventions for common mental disorders (depression, anxiety, stress, and distress). Prevail is innovative in taking a public health approach. It is designed to be given to all employees irrespective of their past or current mental health. Prevail was evaluated in three studies examining: (1) the acceptability of the intervention and perceived usefulness; (2) whether the intervention altered stigmatic attitudes and motivation to seek help; and (3) whether the intervention reduced sickness absence, both overall and due to mental health problems. | PMC10334530 | |
Methods | A two-armed cluster randomised control trial (RCT) evaluated the effectiveness of Prevail. Employees ( | PMC10334530 | ||
Results | Prevail was evaluated highly favourably by both the staff and their managers. Prevail produced significant reductions in self-stigma and anticipated stigma due to mental health difficulties. Crucially, sickness absence was significantly reduced by the Prevail Intervention. | PMC10334530 | ||
Discussion | Prevail achieved its goals of producing a palatable and engaging intervention that altered staff’s attitudes and stigmatic beliefs related to mental health and, crucially, produced a strong reduction in work-pace absenteeism. As the Prevail programme is aimed at common mental health problems and was not specialised to this particular workforce, the study provides the evidence-base for a mental health intervention programme that could be used by many organisations across the world. | PMC10334530 | ||
Trial Registration | mental disorder | ISRCTN12040087. Registered 04/05/2020. 10.1186/ISRCTN12040087. A full protocol for the randomised control trial was published: Gray NS, Davies H, Snowden RJ: Reducing stigma and increasing workplace productivity due to mental health difficulties in a large government organization in the UK: a protocol for a randomised control treatment trial (RCT) of a low intensity psychological intervention and stigma reduction programme for common mental disorder (Prevail). | PMC10334530 | |
Keywords | PMC10334530 | |||
Background | CMDs, depression, anxiety, Common mental disorders | ADULT DISEASE | Common mental disorders (CMDs, i.e. anxiety and depression) contribute around 16–17% of the burden of adult disease in the UK [ | PMC10334530 |
Previous intervention programmes | cognitive behavioural therapies | Most previous work aiming to look at the effects of therapies for CMDs on employment-related variables (e.g., sickness absence, return to work) have looked at standard treatments for CMDs such as cognitive behavioural therapies or medication. While such treatments have the expected (positive) effect on symptom reduction related to mental health problems, they do not have an impact on return to work and only modest effects on sick leave [Workplace interventions specifically target the problem as it affects the person’s ability to function in the workplace and involve the active involvement of the employee. However, such a process is likely to be challenging as the employee and employer may have different perspectives and aims [ | PMC10334530 | |
Prevail | CMD, presenteeism | Prevail is a multi-faceted programme aimed at reducing sickness absence and presenteeism due to CMDs. It involves two psychological interventions, both provided via group based intervention programmes. The first (Prevail Staff Intervention) is for all employees within the organization and its aims are to improve knowledge about mental health, including knowledge of best-practice in low intensity psychological inventions and the theoretical premises underpinning such interventions. It also aims to reduce stigma related to mental health issues, and in particular self-stigma [The second intervention (Prevail Managers Intervention) is aimed at the managerial level within the workplace and is designed to teach managers a formulation-based approach to evaluation and intervention. Formulation refers to a process of providing an explanation for the presenting problem and differs from a “diagnosis” which is more categorical and refers to identification and labelling of the actual CMD rather than an understanding of the causes, or trigger-factors, of the CMD for the individual. The focus here is on the understanding of the problem for the person, active problem-solving, and co-production (where both the employer and the employee share the responsibility to plan and deliver the intervention within the work-place and both make a contribution and commitment to this plan [Prevail was therefore devised as an intervention to improve the mental wellbeing of all employees via education in mental health literacy (including behaviours that improve mental wellbeing), low-level psychological interventions for less severe problems, and encouragement of help-seeking behaviours by destigmatising mental health issues. As such it was not specifically designed for this particular work setting (e.g., DVLA) but as a general programme of prevention/intervention to improve mental wellbeing, predicated upon established evidence-based practice, that could be used in many employment settings. However, in delivering the programme in this employment setting, we used specific examples related to the employer (using videos and case studies of their staff and work environment) so as to emphasise and illustrate the learning points and relevance to the specific workforce. | PMC10334530 | |
Aims and hypotheses | Our original aims were to: (1) measure mental health literacy (and mental health stigma in particular) before and after the intervention, (2) compare sick leave in the 12 months pre- and post-intervention, and (3) to measure quality of life, presenteeism, and current mental health 12 months post intervention [ | PMC10334530 | ||
Methods | The setting was the Driver and Vehicle Licencing Agency (DVLA). The DVLA is the executive agency part of the Department for Transport. DVLA maintain the registration and licensing of drivers and vehicles in Great Britain. It employs around 6,000 people mainly at its head office in Swansea, Wales, UK. All participants in this study were employed at the Head office. | PMC10334530 | ||
Participants | Sixty-seven managers across four divisions of the DVLA, stratified by division [Information Technology Services (ITS), the Contact Centre (CC), Casework and Enforcement Group (CAEG), and Input Services Group (ISG)] were chosen for the study. These were then randomised (using a random number sequence) into the two arms (active vs. control) with stratification to ensure equal numbers of managers from each division and similar gender profile being assigned to each group. These procedures were implemented by staff within the Human Resources department of the DVLA. The “random” split did not achieve a perfectly even split and 59% of the staff were allocated to the active arm of the study.The numbers in each phase of the study varied due to issues such as staff moving from the DVLA during the study, staff moving between teams/divisions within the DVLA, or not agreeing to consent to the study, etc. Numbers at each stage are illustrated in Fig.
Consort Representation of Study | PMC10334530 | ||
Power and statistical analysis | Our initial aim (see [A | PMC10334530 | ||
Prevail intervention | depression, CMD, anxiety | DISORDER, DISORDERS | The Prevail intervention programmes were conceptualised and written by two of the authors (NSG, RJS) who also served to train the trainers that delivered the Prevail Staff Intervention and to deliver the Prevail Managers intervention. NSG is a Consultant Clinical and Forensic Psychologist with over 25 years of experience working with people with mental health problems within both the NHS and with independent healthcare providers. She is a Professor of Psychology at Swansea University teaching courses to masters students on Clinical Psychology and mental health. She has over 100 peer reviewed publications in this area of research. RJS is a Professor of Psychology at Cardiff University with over 25 years of teaching and research in diverse areas of psychology, including mental health.The Prevail intervention consists of two parts. Part one, the Prevail Staff Intervention, is targeted at all staff. This involves attendance at a one-day intervention programme that incorporates a number of psychological techniques designed to: (1) improve knowledge about mental health and cover the basics of mental health literacy; (2) enhance the normalization of common mental disorder; (3) reduce stigma associated with common mental disorder, with an emphasis on self-stigma; and (4) assist staff to learn how to formulate a plan of managing common mental disorder within the workplace to reduce distress and workplace functional impairment. The Prevail Staff Intervention includes information about evidence-based low intensity psychological interventions for common mental health disorders. This includes intervention strategies for depression, anxiety, stress, and distress (including bereavement). The intervention also actively encourages disclosure of mental health difficulties and appropriate help seeking behaviour.Part two, The Prevail Managers Intervention, teaches managers the skills of active problem-solving interventions, formulation-based approaches to intervention, and co-production of solution-focussed management in order to support and intervene with staff currently experiencing, or at risk of developing, a CMD. The philosophy behind this managerial intervention is that mental health difficulties do not occur in a social vacuum and that if staff and their managers can be taught evidence-based active problem-solving interventions and the methodology of co-production [ | PMC10334530 |
Delivery of prevail | The Prevail Intervention programme consists of a series of nine modules taking a mainly didactic approach to learning, but with many interactive components and case study discussions to enhance participant engagement. The modules consist of lectures on specific topics (e.g. Module 5 “Stress and Emotional Stress”) that introduce the topic, give examples of these problems, and provides psychoeducation about the evidence-based approaches to reduce the problem or deal with more serious difficulties in this area. The lecture materials are complemented with video case study examples (produced within the DVLA in this instance), group activities, group discussions, and revision quiz(s). The Prevail Manager’s Intervention uses a similar approach.A Train the Trainer approach [Delivery of the Prevail Staff Intervention to those in the active group commenced on the 30th October 2019. Fifty-seven staff cohorts received the Prevail programme via group-based intervention (N = 571). The cohorts consisted of staff teams with other colleagues working in the same division, and where possible with the same manager. Where staff were unable to attend the allocated day of Prevail delivery they were individually re-scheduled to attend another session. Some staff teams were split over two days to accommodate working patterns.The Prevail Managers Intervention programme was delivered by the authors of Prevail (NSG, RJS) jointly with the Head of Talent and Learning at DVLA over three sessions to the 38 managers that had been allocated to the intervention arm of the study (commencing October 2019). It was important that there was a close association between the delivery of the Prevail Staff Intervention and the Prevail Managers Intervention as, if our intervention was successful in its aims of reducing stigma and enhancing help-seeking, the managers had to be ready and skilled to address the issues of staff as they arose. Eleven other senior managers also attended one of these sessions in order to become familiar with the intervention and aims of the Prevail programme. | PMC10334530 | ||
Results | PMC10334530 | |||
Part 1. Perceptions of the prevail training | depression, anxiety | Overall, 492 people completed the evaluation of the Prevail intervention. No demographic information was taken. A summary of the quantitative results for the Prevail Staff Intervention is given in Fig. Importantly, three questions in the quantitative evaluation aimed to examine if participants felt the intervention had equipped them with the knowledge and skills that had been intended: to be able to apply in practice what they had learnt; to be able to improve their own mental health; and to be able to help and assist others with their mental health difficulties. Again, these questions elicited very positive responses. 92% of participants endorsed that the aims of the intervention were met. 86% of people felt that they were able to immediately apply what they had learnt about mental health and evidence-based low intensity psychological interventions, and 81% of people felt that they were able to help others with their mental health difficulties (compared to 3% disagreeing for each of these latter two questions). Examination of the responses of those who did disagree identified the theme of “Thematic examination of responses to the question “What (if any) part(s) of the course did you find useful?” revealed four major themes. The most common theme (56 respondents) was termed “all of it” which is exemplified by the comments:
““
Quantitative Feedback from Prevail Staff InterventionThe theme “videos and case studies” was reported as being particularly useful by 50 respondents, where they expressed that seeing real people (and their colleagues in particular) talking about their mental health difficulties and well-being, enhanced their understanding of these issues (with one video and case study included for each of anxiety, depression, stress, and bereavement).For example:
“The theme “mental health as a continuum” was mentioned as being particularly useful by 22 respondents and as important in tackling stigma and self-stigma.For example:
“Finally, 16 people mentioned the section on “stress” as being particularly useful, with the theme emerging that this is often ignored and not treated as a real or significant problem impacting mental health and well-being in the workplace.For example:
“In total 49 people undertook the Prevail Managers training. This included the 38 managers in the active arm of the study alongside 11 other senior managers not directly involved in the main study. No demographic information was taken. A summary of the quantitative results for the Prevail Manager Intervention is given in Fig.
Quantitative Feedback from Prevail Managers InterventionThree questions aimed to examine if managers felt that the intervention programme had equipped them with the knowledge and skills that had been intended: to be able to apply in practice what they had learnt; to be able to improve their own mental health; and to be able to help and assist others with their mental health difficulties. Again, these questions elicited positive responses. Particularly encouraging were the responses to the question about being able to help others, as this was integral to the aims of the Prevail Managers programme. 94% of managers agreed that Prevail Managers had improved their ability to help others with their mental health difficulties, compared to 0% who disagreed. Examination of the responses of those who were neutral on this question (neither agreeing nor disagreeing) showed very few comments with no common theme.Thematic examination of responses to the question “What (if any) part(s) of the intervention did you find useful?” revealed one theme mentioned by eight respondents. This consisted of comments stating that they found the section of the intervention programme related to The feedback for both the Prevail Staff Intervention and the Prevail Manager Intervention programmes has shown an overwhelming endorsement by staff and managers that the aims of the intervention programme have been met, the content of the intervention is fit for purpose, and the delivery of the programme is satisfactory.We thought it useful to summarise with two comments from delegates:
“
| PMC10334530 | |
Part two. Changes in mental health literacy | The descriptive statistics for the sample, stratified by condition (active vs. control) and wave (pre-assessment or Wave 1 vs. post-assessment or Wave 2) are presented in Table
Demographic Information on RCT participantsThe psychometric properties for the SASS scales were highly similar to a previous report of the properties of SASS in a workplace population [ | PMC10334530 | ||
Part three. Sickness absence | PMC10334530 | |||
Statistical methods | mental disorder | Chi-square analysis was performed to compare the active and control arms on demographic characteristics including age, gender, and directorate. Chi-square analysis and unadjusted odds ratios (OR) with 95% confidence intervals (95% CI) were used to compare the treatment arms on the number of “all sickness” and “mental disorder” days taken as sick leave between two time periods. Finally, Cochran-Mantel-Haenszel tests were employed to compare men and women on their respective “all sickness” and “mental disorder” days taken as sick leave from work. Frequency and percentage statistics were reported for each of the analyses in a cross-tabulation format. Statistical significance was assumed at an alpha value of 0.05 and all analyses were performed using SPSS Version 29 (Armonk, NY: IBM Corp.). | PMC10334530 | |
Statistical results | The results of the demographic variable comparisons are presented in Table
Demographics and chi-square analysis for the participants in the RCT for sickness absenceFor the analysis of summary sickness absences, there was a significantly higher proportion of “all sickness” absence days in the control group during the second period of observation (
Analysis of Summary Absences (days taken as sick leave)For the comparison of gender related to absences, significant conditional independence was detected between females and males for “all absences,”
Gender Analyses of Absences (days taken as sick leave) | PMC10334530 | ||
Discussion | In order to evaluate the Prevail intervention we assessed, (1) whether the people who underwent Prevail thought that the intervention achieved its aims, (2) whether Prevail produced changes in people’s mental health literacy (including stigma reduction), and (3) whether Prevail changed their ability to work (reduced absenteeism) as indicated by the number of days taken as sickness absence. We found strong evidence that Prevail achieved all three aims. | PMC10334530 | ||
Evaluation of the prevail intervention | Prevail Staff Intervention was administered to staff via a one-day group intervention. Most participants evaluated the duration and pace of the intervention as appropriate and that they were able to understand the Prevail content. Crucially, they also thought that they would be able to improve their own mental health, and be able to help other people with their mental health. Hence, Prevail has strong face value in its objectives and was found to be palatable and valuable to the workforce. This is important as the perceived value of any intervention is going to be an important factor as to whether people physically attend, and psychologically engage, with the intervention [ | PMC10334530 | ||
Changes in mental health literacy | The Prevail Intervention led to clear reductions in levels of self-stigma and anticipated stigma. These two scales are those most strongly associated with mental health [ | PMC10334530 | ||
Changes in sickness absence | anxiety | DISORDERS, DISEASE, FLU | Producing an intervention that is valued by the workforce and which is able to change people’s attitudes and intentions to seek help is a good achievement. However, actually being able to change people’s future behaviour is a far more difficult task [While the results of the Prevail intervention appear robust there are two surprising elements to the results that we did not expect: (1) the levels of sickness absence at the pre-intervention period were lower for the control group compared to the active group; and (2) levels of sickness absence increased for those in the control group between the pre- and post- intervention periods. We address each of these points in turn.One of the purposes of conducting a RCT is to ensure that the effects of extraneous factors (such as levels of sickness absence pre-intervention) is equated across the two groups (active vs. control) - [While we predicted reductions in sickness absence for those in the active arm of the study, it was expected that those in the control arm would have no change in the levels of sickness absence from pre- to post-intervention (as essentially nothing had happened with the control group and it was work practice as usual). However, levels of sickness absence actually increased. Hence, it would appear that there were factors at play that caused increased levels of sickness absence in the post-intervention period (Dec 2019-Feb 2020) compared to the pre-intervention period (Dec 2018-Feb 2019). While there may be other factors (e.g., increased rates of flu or other seasonal disorders) that were different between these time periods, the most salient factor is the onset of the COVID-19 pandemic. Although the first recorded case in Wales was at the end of our data collection period, in late February 2020, concerns about the on-coming pandemic and the impact of this internationally were evident much earlier as the disease spread across the world. This may have impacted anxiety levels and decisions to try and avoid busy workplaces at such a worrying time.While the causes of the increase in rates of sickness absence in the control arm of the study are, at best, speculation, these unexpected increases in sick leave show the value of the RCT and of collecting pre-and post-intervention data to help with the interpretation of effects. If it is indeed the case that rates of sickness absence were higher in the data collection period post-intervention for the workforce as a whole (mimicking the effects in the control group), then the | PMC10334530 |
Limitations to the RCT | LEAKAGE | The main limitation to the study were the unexpected differences in baseline levels of sickness absence between the two arms of the study (see discussion above). The study was also curtailed in some of its aims due to the onset of restrictions due to the COVID-19 pandemic that severely altered work practices and limited access of the researchers to the employees of the DVLA. Finally, the data on sickness absences could only be provided to the research team at the level of “groups” rather than individuals due to Data Protection issues. Hence, we were unable to examine the relationship between mental health literacy and stigma (as measured by the SASS) and sickness absence, or to data at the individual level. Future studies may benefit from research designs that are able to tie sickness rates to specific demographics such as history of mental health problems, gender, ethnicity, time in current employment, etc.The study was also unable to prevent any “leakage” and contamination of the Prevail programme from people in the active arm of the study to those in the control arm despite efforts to do so via using cluster randomisation. However, it should be emphasised that any such leakage would have served to reduce the differences between the active and control arms the study and thus be conservative to our hypotheses.Our original protocol for the study [Finally, while our data are supportive of the efficacy of Prevail they are not able to distinguish which parts of the Prevail intervention are effective (and which may not be). Indeed, part of the effect of Prevail may be accounted for by “placebo effects” in that merely taking part in any intervention that brings mental health and mental wellbeing to the forefront of peoples’ attention may be beneficial to mental wellbeing and therefore have effects on attitudes to mental health and in reduced sickness absences. Indeed, participants taking the Prevail intervention commented that the open acknowledgement of mental health challenges and stressors in the workplace led to feelings of validation and value by the employer. | PMC10334530 | |
Acknowledgements | Thanks to all members of the project team at the DVLA for their help with this project and for the support we received from the DVLA Executive Board who approved and supported the Prevail Intervention programme and three-stage evaluation. We are particularly grateful to Louise White and Andrew Falvey as Executive Directors of the DVLA, both of whom drove this project forward. Our sincere thanks go to Amanda Payne for the organisation of the train-the-trainers programme at DVLA and for the oversight and management of the intervention delivery process. We are indebted to the Prevail trainers at the DVLA: Rebecca Roach, Hayley Morgan, Clare Moses, Vicki Davies, and Abigail Williams. The future success of Prevail will undoubtedly be due to the professionalism, hard work, and excellent coaching skills of the Prevail trainers, all of which were very ably led by Amanda Payne to whom we are grateful. We are indebted to Kirsten Howell and Melissa Lewis for supervision of the data entry, veracity checks on data quality, and processing of the qualitative feedback data on Prevail. We also thank Alys Docksey for preparatory work in development of the SASS measure which she completed as part of her Research Masters at Swansea University. We also thank Dr. Eric Heidel (University of Tennessee), an Accredited Professional Statistician, who acted as the statistical consultant on the project. | PMC10334530 | ||
Authors’ contributions | The conception of the Prevail programme was completed by NSG in collaboration with HD. NSG and RJS wrote the Prevail intervention programme. HD arranged for a cross-section of DVLA staff to give feedback on draft versions of the psychological intervention and gave advice on practical implementation of the programme to staff and managers. RJS and NSG designed the RCT, registered the trial, wrote the protocol, and analysed the data. RB gave expert advice on Data Protection issues and helped with writing the Data Protection Impact Assessment for this project. RB gathered and provided data from Human Resources about sick leave. All authors read and approved the final manuscript. | PMC10334530 | ||
Funding | The development of Prevail, its implementation to the DVLA, and the costs of the RCT were funded by the DVLA via a research grant to Swansea University (Ref number: PSC1046). The funders helped in the implementation of the RCT via selecting appropriate managers and their teams, randomising these managers/teams to the active and control arms of the study, delivering the Prevail intervention via a train-the-trainer programme, and tabulating data on sickness absence from their official records. All data entry, statistical analysis, and writing of the manuscript was done independently of the funders, although the funders had sight of the report and were invited to give comments and suggestions. | PMC10334530 | ||
Data Availability | mental disorder | The datasets generated during this research and/or analysed following completion of the current study are stored in a publicly available repository (Mendeley). Snowden, Robert (2022), “Reducing stigma and increasing workplace productivity due to mental health difficulties: A randomised control treatment trial (RCT) of a low intensity psychological intervention and stigma reduction programme for common mental disorder (Prevail).”, Mendeley Data, V1, doi: 10.17632/4ph3dr3vg5.1 The data shared are: (1) Results from the survey of opinions about the Prevail course. Data are at a group level. (2) an anonymised SPSS database that contains the item by item scores from the psychometric measures as well as the scale scores and demographic information, (3) an excel database containing data on number of sick days taken. These are at a group level only. The data was published at the time of provisional acceptance of this paper and will remain available indefinitely. Access will be open to anyone via the usual access to Mendeley. | PMC10334530 | |
Declarations | PMC10334530 | |||
Ethical approval and consent to participate | All methods were carried out in accordance with relevant guidelines and regulations (e.g., the Declaration of Helsinki). This trial has received ethical approval by Ethics committee of Swansea University, 25/09/2019 Ref: 1521. Participants selected for the Prevail intervention programme undertook this programme as part of their work duties mandated by the DVLA. Sickness absence data from Human Resources at the DVLA were provided at a group level (active vs. control) with no individuating information included, and so individual consent was not required. Completion of the psychometric questionnaire data was voluntary, as participation in the attitudinal evaluation was not deemed part of employees’ work duties. Thus, written informed consent was taken from all staff for completion of the psychometric measures. Staff who did not wish to engage in the evaluation of Prevail were allowed to leave the information/evaluation sessions without the need to justify their decision. All data was anonymous and was analysed on a group basis. Any data relating to sub-groups (e.g. by DVLA division, age, and mental health status) that fell under a group number of 10 was withheld from the researchers in order to comply with the UK Data Protection Act (2018) and GDPR regulation via a detailed Data Protection Impact Assessment. | PMC10334530 | ||
Consent for publication | Not applicable. | PMC10334530 | ||
Competing interests | NSG and RJS are the authors of the Prevail intervention and may receive commission or financial reward for the future use of this programme. The other authors have no competing interests. | PMC10334530 | ||
References | PMC10334530 | |||
The present study | personality traits | SECONDARY | The goal of this study was to test the effects of a 7-week digital self-control intervention to increase physical activity using a two-arm randomized controlled trial. The self-control treatment group showed greater increases in self-reported physical activity (MET’s) than the comparison group. Both groups significantly increased their daily steps and self-control. Participants with higher initial levels of conscientiousness were better able to increase their daily steps during the intervention and participants who increased more in self-control showed greater increases in MET’s. These moderation effects were more pronounced in the self-control treatment group as compared to the comparison group. This study shows that the effects of physical activity interventions may depend on personality characteristics and outcomes may be improved when individual differences are considered and targeted.An active lifestyle has broad benefits for cognitive, physical, and psychological health (Self-control refers to the ability to suppress or control impulsive actions, emotions, and desires in favor of desired alternatives and enables people to reach long-term goals (such as sticking to regular exercise) despite the presence of short-term desires and distractions (The modification of personality facets such as self-control through interventions to promote healthy aging is a research priority of the US National Institute of Aging (The overall goal of this study was to explore the effects of a digital self-control coaching intervention to increase physical activity among sedentary adults who are at risk for poor health. To measure physical activity, we focused on the richness and complementary information that self-report and objective measurements can offer (The specific aims of the study were threefold. The first aim was to test the effects of a digital self-control intervention to increase physical activity by comparing the two conditions (i.e. treatment group vs comparison group). It was expected that those who received the self-control intervention, would show greater increases in physical activity compared to people in the comparison group, who did not receive the self-control intervention. As part of the first study aim, it was also expected that the effects in the treatment group would last longer compared to the changes in the comparison group. Also, based on prior research, which found that higher conscientiousness was associated with greater increases in daily steps during an intervention (The second aim was to compare changes in self-control between the treatment group and the comparison group. We expected that participants in the self-control treatment group would show greater increases in self-control compared to participants in the comparison group and that self-control changes in the treatment group would last longer compared to changes in the comparison group.The third aim was to examine whether participants who increased more in self-control also showed greater increases in their physical activity and if this effect was moderated by their condition. We expected that those who showed greater increases in self-control would also show greater increases in physical activity.In addition, we explored whether participants changed in the secondary outcome measures (Big Five personality traits, exercise self-efficacy, satisfaction with life, sense of control, and cognitive performance) across time and whether these changes differed between conditions. | PMC10466994 |
Method | This study has been approved by the University’s Institutional Review Board at Brandeis University and the protocol has been registered at ClinicalTrials.gov (CT04522141) and is published ( | PMC10466994 | ||
Participants | A total of 86 middle-aged adults were enrolled in the study between October 2020 and April 2021. Participants were recruited from across the US, with a majority in the Northeast, by posting advertisements on public boards and online. Advertisements specified: “Do you want to be more active, but find yourself making excuses to avoid exercise?” Participants received a Fitbit Charge 4 step counter and a $25 gift card for completing all aspects of the study.Interested participants were asked to complete a screening questionnaire. Participants were included if they indicated they wanted to become more physically active, were between 35 and 65 years, fluent in English, fit enough to walk for at least 20 minutes at a time, and own a smartphone with a data plan. Participants were excluded if they experienced a fall or heart problem/condition in the last 6 months before the start of the study, were already participating in an exercise program or using a Smartwatch (e.g. Fitbit, Garmin, Apple Watch etc.), already exercised (all types of exercise as defined by the person) at least 3 times per week for more than 30 minutes at a time, and/or if a doctor had advised them to not walk due to health conditions.As shown in | PMC10466994 | ||
Study design and procedure | BLIND | This study used a two-arm randomized controlled trial design with a pretest (baseline), weekly assessments at the end of every week (weeks 1–7), a posttest (week 8), and a follow-up assessment (week 12). Participants were randomly assigned to one of the two conditions: the treatment group or the comparison group. The allocation was computer generated when participants declared interest for study participation and block randomization was used to ensure that the two groups are comparable in terms of sample size. Participants were blind to which condition they were in. The CONSORT flow diagram of the study is shown in On the first study day, all participants were asked to complete an online pretest on Qualtrics and to wear their Fitbit Charge 4 every day for at least 8 weeks from when they wake up to when they go to bed. During the first study week, participants were only asked to wear the Fitbit to establish their baseline activity. Across the study, participants also completed weekly assessments of self-control. After 8 weeks (1 baseline week and 7 study weeks), participants were asked to complete an online posttest and after 12 weeks an online follow-up assessment. | PMC10466994 | |
Self-control treatment group | The treatment group used the MindHike coaching application, which supports and guides people who would like to train their self-control with the help of a digital coach. The app delivered the same dialogs to all participant in the treatment group. There was no bi-directional communication, but participants clicked on predesignated responses to advance the chatbot dialog. The original MindHike coaching app targets self-control without focusing on the domain of physical activity (Participants were contacted by the app twice each day for 8 weeks (one baseline week and seven intervention weeks). During the baseline week, the first daily message was a push notification which reminded them to wear their Fitbit at customized times in the morning. The second daily push notification reminded participants to sync their step data and charge the Fitbit at customized times in the evening. During the seven intervention weeks, participants received an additional short daily chatbot-based self-control coaching input.As part of the self-control intervention, participants set their own physical activity goal because physical activity interventions are more effective when individuals can choose their preferred activities ( | PMC10466994 | ||
Comparison group | The comparison group used a minimal app version across the eight study weeks, which sent them two daily reminders. At customized times in the morning, they were reminded to wear the Fitbit and at customized times in the evening, they were reminded to sync their step data with the Fitbit app and to charge their Fitbit device. The reminder in the evening was chatbot-based to make sure the comparison group used the app at the same frequency as the treatment group. | PMC10466994 | ||
Primary outcome measures | The study included Qualtrics online questionnaires at the pretest, weekly assessments (weeks 1–7), a posttest (week 8), and a follow-up assessment (week 12). | PMC10466994 | ||
Self-control | Self-control was assessed in two ways. First, we assessed overall self-control at pretest, at posttest, and follow-up assessment using the Brief Self-control Scale (BSCS; Second, to measure weekly self-control, we asked participants to indicate to what extent the same 13 items from the BSCS applied to them with respect to | PMC10466994 | ||
Self-reported physical activity (MET’s) | Self-reported physical activity was assessed at pretest, posttest, and follow-up using the short version of the International Physical Activity Questionnaire (IPAQ; | PMC10466994 | ||
Objectively assessed physical activity | Fitbit Charge 4 activity trackers ( | PMC10466994 | ||
Daily steps | As there were likely times when participants walked without wearing their Fitbit device, we only included days with more than 500 steps as valid days in our analyses. This is in line with prior studies using step data ( | PMC10466994 | ||
MVPA | Daily steps and MVPA can be correlated, but MVPA can pick up on activity that is more strenuous than regular walking. Fitbit categorizes active time into four categories: sedentary, lightly active, fairly active, and very active. In this study, MVPA was calculated by adding up fairly active and very active minutes each day ( | PMC10466994 | ||
Secondary outcome measures | PMC10466994 | |||
Conscientiousness | At pretest, posttest, and follow-up assessment, participants completed the 60-item BFI-2 to assess conscientiousness ( | PMC10466994 | ||
Covariates | Age, sex (0 = female, 1 = male), education in years, race (0 = White, 1 = Non-White), self-reported functional health (SF-36( | PMC10466994 | ||
Data analysis | Details on the power analyses are reported in We used longitudinal multilevel models and the lme4 package in R (To test if participants showed significant changes in our outcome measures, we tested the main effects of time using multilevel models. In additional multilevel models, we tested if there was differential change between the two groups by adding a time by condition interaction term as a Level 2 predictor. Moreover, we tested if both groups were able to maintain their levels of physical activity and self-control until the follow-up assessment 4 weeks after the end of the intervention (main effect of time) and if there were differential maintenance effects between the two groups (time by condition interaction).To explore if T1 conscientiousness predicted changes in physical activity, we used a time by T1 conscientiousness interaction term as a Level 2 predictor in our multilevel models. To test for any differences between the two conditions, we used a time by T1 conscientiousness by condition interaction term as a Level 2 predictor.To test if participants who showed greater increases in self-control were better able to increase their physical activity, we added a time by change in self-control (follow-up minus pretest) interaction term as a Level 2 predictor in the multilevel models. Also, we used a time by change in self-control by condition interaction term as a Level 2 predictor to test for any group differences. | PMC10466994 | ||
Results | Randomization check and attrition analyses are reported in | PMC10466994 | ||
Association between changes in self-control and changes in physical activity | We tested a Time by Change in Self-control interaction to examine if participants who showed greater increases in self-control were better able to increase their physical activity across time. The results suggest that participants who showed greater increases in self-control showed greater increases in MET’s (Associations between changes in self-control and changes in MET’s from pretest to follow-up by condition.X-axis: 1 = pretest, 2 = posttest, 3 = follow-up; Shaded areas represent 95% CIs.The results of all multilevel analyses with covariates mirrored the findings of the models without covariates. | PMC10466994 | ||
Discussion | Three important findings emerged from the present study. First, the results suggest significant overall increases in physical activity and self-control in both conditions. Also, both groups maintained their levels of physical activity and self-control until 4 weeks after the end of the intervention. Second, participants of the treatment group showed greater increases in MET’s as compared to participants in the comparison group. Third, participants with higher initial levels of conscientiousness were better able to increase their daily steps during the intervention and participants who increased more in self-control showed greater increases in MET’s. These effects were more pronounced in the treatment group as compared to the comparison group. However, it should be noted that these three-way interactions involve relatively small numbers and should be interpreted with caution.We found significant group differences in terms of changes in MET’s. However, changes in self-control, daily steps, and MVPA did not differ between the two conditions. The increases of the comparison group suggest that daily reminders and activity feedback on the Fitbit device alone are helpful micro interventions to support people on their journey of becoming more self-controlled and more active. In fact, a recent meta-analysis (The results differed somewhat depending on the activity outcome which was used (i.e. MET’s, daily steps or MVPA). That is, the treatment group showed greater increases in MET’s, but not in daily steps or MVPA, when compared to the comparison group. It is important to note that participants could choose what type of exercise they wanted to implement in their daily life and could set their own activity goal. The IPAQ was used to measure MET’s, which is a valid measure, has acceptable measurement properties, and shows good test-retest stability (The results also suggest that those of the treatment group with higher initial levels in conscientiousness or greater increases in self-control were better able to increase their physical activity as compared to those of the comparison group. Previous research also found that participants with higher conscientiousness were better able to increase their levels of physical activity when taking part in a physical activity intervention ( | PMC10466994 | ||
Limitations and future directions | Based on the present findings, it is not entirely clear which micro interventions are most effective in changing self-control and physical activity. Future research is needed to disentangle the specific active ingredients of the intervention. The results on increasing self-control and physical activity in the comparison group, which received only daily app-based reminders and feedback on the Fitbit device, suggest the effectiveness of these micro interventions for physical activity promotion. Second, although the allocation into the two conditions was computer generated to ensure that the conditions were fully randomized with respect to participants’ baseline characteristics, the two conditions differed in some of the baseline characteristics. In our analyses, we controlled for these characteristics to statistically adjust those group differences. Third, the 1-week baseline before the beginning of the intervention might have been too short to track participants’ usual activity behavior. During the first week, participants might be highly motivated to be more active than they were previously just because of the new Fitbit device. In the future, a longer timespan to track usual pre-intervention activity behavior may be worthwhile before testing the effects of the intervention. Fourth, the sample size of this study is relatively small which limits generalizability of our findings. Future research is needed to replicate the findings in larger samples that would allow for further analyses (e.g. to identify for which participants the intervention is most effective). Finally, the 4-week follow-up period after the end of the intervention was relatively short. Future research is needed to replicate the current findings as well as to include longer follow-up periods to test the ideal timing of such an intervention. | PMC10466994 | ||
Conclusion | This study constitutes the first to test whether a digital self-control coaching intervention has an effect on physical activity. The results suggest that a digital intervention targeting self-control can help people increase their MET levels for physical activity. Also, individuals with higher levels of conscientiousness and those who show greater increases in self-control are more likely to become more physically active. This intervention study highlights the notion that the effects of behavior change interventions may depend on personality characteristics and outcomes may be improved when individual differences are considered and targeted. | PMC10466994 | ||
Supplemental Material | PMC10466994 | |||
sj-docx-9-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.Supplemental material, sj-docx-9-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
sj-pdf-1-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.sj-pdf-1-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
sj-pdf-2-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.sj-pdf-2-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
sj-pdf-3-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.sj-pdf-3-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
sj-pdf-4-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.sj-pdf-4-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
sj-sav-5-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.sj-sav-5-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
sj-sav-6-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.sj-sav-6-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
sj-sav-7-hpq-10.1177_13591053231166756 – Supplemental material for Effects of a digital self-control intervention to increase physical activity in middle-aged adults | Click here for additional data file.j-sav-7-hpq-10.1177_13591053231166756 for Effects of a digital self-control intervention to increase physical activity in middle-aged adults by Mirjam Stieger, Mathias Allemand and Margie E Lachman in Journal of Health Psychology | PMC10466994 | ||
References | PMC10466994 | |||
Methods | Autoimmune and Autoinflammatory Disorders, Sarah Alice, T1D | AUTOIMMUNE DISORDERS, TYPE 1 DIABETES | Edited by: Sarah Alice Long, Benaroya Research Institute, United StatesReviewed by: Howard Davidson, University of Colorado, United States; Helena Reijonen, City of Hope National Medical Center, United StatesThis article was submitted to Autoimmune and Autoinflammatory Disorders: Autoimmune Disorders, a section of the journal Frontiers in ImmunologyGAD-alum given into lymph nodes to Type 1 diabetes (T1D) patients participating in a multicenter, randomized, placebo-controlled double-blind study seemed to have a positive effect for patients with DR3DQ2 haplotype, who showed better preservation of C-peptide than the placebo group. Here we compared the immunomodulatory effect of GAD-alum administered into lymph nodes of patients with T1D versus placebo with focus on patients with DR3DQ2 haplotype.GAD autoantibodies, GADA subclasses, GAD | PMC9933867 |
Results | Higher GADA, GADA subclasses, GAD | PMC9933867 | ||
Conclusion | Patients with DR3DQ2 haplotype had a distinct early cellular immune response to GAD-alum injections into the lymph node, and predominant GAD | PMC9933867 | ||
Introduction | T1D, chronic disorder | CHRONIC DISORDER, DISEASE PROGRESSION, ADVERSE EVENTS, DISEASE, TYPE 1 DIABETES | Type 1 diabetes (T1D) is a chronic disorder requiring lifelong treatment. Despite intensive treatment, the disease causes substantial morbidity and mortality. Several clinical intervention trials with different approaches to delay or halt disease progression have shown limited efficacy, sometimes accompanied with adverse events (Use of 65-kD isoform of glutamic acid decarboxylase (GADHere we describe treatment effect on the immune response of patients who participated in the DIAGNODE-2 trial, comparing the effect in the GAD-alum treated patients in relation to the placebo group, as well as focusing on the immunomodulatory effect of GAD-alum in the patients both according to the presence or absence of the DR3DQ2 haplotype and according to the preservation of beta cell function. | PMC9933867 |
Materials and methods | PMC9933867 | |||
Study design | diabetes | TOLERANCE, DIABETES | DIAGNODE-2 study was a two-arm, multicenter, randomized, double-blind, placebo-controlled trial (NCT03345004) performed at 18 diabetes clinics in the Czech Republic, the Netherlands, Spain, and Sweden as described before (Three intralymphatic injection with 4 μg GAD-alum (Diamyd Medical, Stockholm, Sweden) on days 30, 60, and 90 and 2,000 IE oral vitamin D daily from day 1 to 120.Three intralymphatic injection of placebo on days 30, 60, and 90 and oral placebo for vitamin D daily from day 1 to 120.Patients received 3 injections (1 month apart) of GAD-alum or Placebo into an inguinal lymph node administrated by using ultrasound needle guide, and in addition vitamin D or placebo if serum level of vitamin D was <100 nmol/L (40 ng/mL) at screening.All patients were evaluated on day 1 (baseline), 1, 2, 3, 6 and 15 months with clinical examination and blood samples. Mixed Meal Tolerance Test (MMTT) (HLA genotyping for all patient was included as an amendment to the original clinical study protocol ahead of treatment unblinding. Individuals genotyping for HLA DR3DQ2 (defined as DRB1 * 03, DQB1 * 02: 01) haplotype at screening were performed centrally by Synlab Pharma Institute (Munich, Germany), using a sequence-specific oligonucleotides kit (One Lambda) (The study was approved by the relevant regulatory authorities and research ethics boards of the participating sites and countries. All participants and their parents/caregivers gave their consent after oral and written information. | PMC9933867 |
Blood samples | For the immunological analysis, blood and serum were collected at all visits. Samples were drawn during the morning hours, and peripheral blood mononuclear cells (PBMCs) were isolated within 24 hours using Leucosep (Greiner Bio One), according to the manufacturer’s instructions at Linköping University, Sweden. | PMC9933867 | ||
GAD autoantibodies and IgG subclasses | GAD autoantibodies | Serum GAD autoantibodies (GADA) levels were assessed by means of enzyme-linked immunosorbent assay (ELISA) by Synlab Pharma Institute (Munich, Germany).GADA IgG 1, 2, 3, and 4 subclasses were measured by radio-binding assays using IgG subclass-specific biotin-labelled mouse-anti-human monoclonal antibodies bound on Streptavidin Sepharose High Performance beads (GE Healthcare Life Sciences, Freiburg, Germany) ( | PMC9933867 | |
Lymphocyte proliferation assay | PROLIFERATIVE | Proliferative response was analyzed in PBMCs cultured in triplicates in AIM-V medium with β-mercaptoethanol at 37°C in 5% CO | PMC9933867 | |
Cytokine secretion assay | Cytokines were quantified both in serum samples and in PBMCs supernatants. PBMCs were cultured in AIM-V medium with β-mercaptoethanol for 7 days at 37°C in 5% CO | PMC9933867 | ||
Statistics and software analysis | Immunological data was presented as median with 95% CI following non-normal distribution, and nonparametric tests were applied. For determining differences between groups, the Mann-Whitney test was used, and Wilcoxon test was applied for differences within groups. A probability level of < 0.05 was considered statistically significant. Calculations were performed using GraphPad Prism 8.0.1 for Windows (GraphPad Software, La Jolla, CA, USA).Clustering heatmap of immune cytokine secretion data were constructed using ClustVis software (Fast and stimulated C-peptide values were calculated during the clinical trial ( | PMC9933867 | ||
Results | PMC9933867 | |||
Immune response in GAD-alum treated patients | PROLIFERATION | GADA levels increased in GAD-alum treated patients at 2 months, after the first injection, and remained higher through the study compared to the placebo group (Immune response from day 1 to 15 months in GAD-alum (smooth line, n=56) and Placebo (dashed line, n=52) individuals. GADFurther stratification of the GAD-alum and placebo groups according to the presence or absence of DR3DQ2 haplotype showed a similar pattern as for the whole cohort. Thus, GADA, GADA IgG1, 2, 3 and 4 subclasses, GAD-induced proliferation and cytokine secretion were higher in GAD-alum treated patients with and without DR3DQ2 compared to placebo individuals with the same haplotype (Levels of all analyzed cytokines were similar in PBMC supernatants from placebo and GAD-alum treated subjects, both when cells were cultured in medium alone or in the presence of CD3/CD28. No differences were observed when patients were stratified according DR3DQ2 haplotype. Analysis of cytokines in serum samples did not reveal any difference for any comparison. The same was true for CD3/CD28 induced proliferation (data not shown). | PMC9933867 | |
Changes associated to the DR3DQ2 haplotype | Comparison of the immune response in individuals who received GAD-alum stratified according to the DR3DQ2 haplotype showed that GADImmune response from day 1 to 15 months in GAD-alum treated patients with (black, n=29) and without (light blue, n=27) DR3DQ2 haplotype. | PMC9933867 | ||
Immune response in relation to clinical outcome | To search for immune surrogate markers of clinical efficacy, we looked for the association between remaining C-peptide secretion at 15 months (Immune responses in GAD-alum treated patients in relation to Clinical outcome. Patients who received GAD-alum were stratified into Good Responders (GR, n=23, loss < 30% AUC) and Poor Responders (PR, n=32, loss ≥ 30% AUC) according to their C-peptide preservation at 15 months. Comparison of the immunological data between GR and PR revealed that GADTo further search for signatures related to the presence or absence of DR3DQ2 haplotype, GR and PR were stratified according to their haplotype ( | PMC9933867 | ||
Discussion | T1D | DISEASE, TYPE 1 DIABETES, OTHER AUTOIMMUNE DISEASE | The DIAGNODE-2 study constituted the first placebo-controlled trial in which an autoantigen was administrated into the lymph nodes of patients with Type 1 diabetes, and immunological changes observed in GAD-alum treated patients with respect to placebo have not been previously described. Modifications following therapy included an increment of GADA, GADA subclasses, and GADAlthough no significant treatment effect was seen in the whole study cohort during the clinical trial, a statistically significant preservation of beta cell function was found in the prespecified subgroup of GAD-alum patients with DR3DQ2 haplotype (The increasing consensus on the heterogenicity of T1D, that can reflect diverse immunological pathways to disease, brings focus to the matter that, as in many other autoimmune diseases, many of the patients participating in T1D clinical trials benefit from the treatments, while others do not (In an attempt to find biomarkers for clinical response, GAD-alum treated individuals were classified according to their preservation of C-peptide. Comparison of the immunological response revealed that patients displaying a better beta cell preservation had a more pronounced GADIn a previous study we have shown that administration of GAD-alum subcutaneously induced an early Th2-skewed immune response associated to clinical benefit (Although better preservation of C-peptide and an improvement in several clinical parameters was observed in GAD-alum treated patients with DR3DQ2 haplotype (In conclusion, here we show that patients with DR3DQ2 haplotype had an early immune response to GAD-alum injections into the lymph node, and predominant GAD | PMC9933867 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC9933867 | ||
Ethics statement | The studies involving human participants were reviewed and approved by the relevant regulatory authorities and research ethics boards of the participating sites and countries. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. | PMC9933867 | ||
Author contributions | RC designed the experiments. SP-M, FD, and PA performed experiments. SP-M and HB analyzed the data. SP-M and RC interpreted the results and wrote the manuscript. JL conceived DIAGNODE-2 study, recruited, and followed patients. All authors contributed to the article and approved the submitted version. | PMC9933867 |
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