A systematic review of inequalities in the uptake of , adherence to and effectiveness of behavioural weight management interventions

Background: It has been suggested that interventions focusing on individual behaviour change, such as behavioural weight management interventions, may exacerbate health inequalities. These intervention-generated inequalities may occur at different stages, including intervention uptake, adherence and effectiveness. We conducted a systematic review to synthesise evidence on how different measures of inequality moderate the uptake of, adherence to and effectiveness of behavioural weight management interventions in adults. Methods: We updated a previous systematic literature review from the US Preventive Services Taskforce to identify trials of behavioural weight management interventions in adults that could be conducted in or recruited from primary care. Medline, Cochrane database (CENTRAL) and PsycINFO were searched. Only randomised controlled trials and cluster-randomised controlled trials were included. Two investigators independently screened articles for eligibility and conducted risk of bias assessment. We curated publication families for eligible trials. The PROGRESS-Plus acronym (place of residence, race/ethnicity, occupation, gender, religion, education, socioeconomic status, social capital, plus other discriminating factors) was used to consider a comprehensive range of health inequalities. Data on trial uptake, intervention adherence, weight change, and PROGRESS-Plus related-data were extracted. Results: Data extraction in currently underway. A total of 108 studies are included in the review. Data will be synthesised narratively and through the use of Harvest Plots. A Harvest plot for each PROGRESS-Plus criterion will be presented, showing whether each trial found a negative, positive or no health inequality gradient. We will also identify potential sources of unpublished original research data on these factors which can be synthesised through a future individual participant data metaanalysis. Conclusions and implications: The review findings will contribute towards the consideration of intervention-generated inequalities by researchers, policy makers and healthcare and public health practitioners. Authors of trials included in the completed systematic review may be invited to collaborate on a future IPD meta-analysis. PROSPERO registration number: CRD42020173242 Page 3 of 11 A systematic review of inequalities in the uptake of, adherence to and effectiveness of behavioural weight management interventions Jack M. Birch1, Rebecca A. Jones1, Julia Mueller1, Rebecca Richards1, Michael P. Kelly2, Simon J. Griffin1,2, Amy L. Ahern1 1 MRC Epidemiology Unit, University of Cambridge. 2 Primary Care Unit, University of Cambridge PROSPERO registration:CRD42020173242 Contact: jack.birch@mrc-epid.cam.ac.uk • Two phase search strategy: Phase 1 • Articles included in United States Preventive Services Taskforce (USPSTF) report published in 2018. [4]; AND • Replication of USPSTF search completed on 5th March 2020 in Medline, Cochrane CENTRAL and PsycInfo. • Articles were dual-screened using Covidence. Phase 2 • ‘Parent’ publication from each study identified and ‘publication families’ curated. • Publications relating to the parent publication were identified through searching Medline, Cochrane CENTRAL and PsycInfo. • Databases were searched using first or last author of parent publication and a study identifier (such as study name). • Each publication family is considered as one study. Search strategy & sources Data extraction • Data extracted using a modified version of Cochrane Public Health Group’s extraction form. • Risk of bias assessed using Cochrane’s Risk of Bias (RoB 2.0) tool. • Data extraction and RoB performed by one investigator and checked by another. Data synthesis • We anticipate that there will be insufficient data to conduct meta-analyses. • We will conduct narrative synthesis to identify and describe inequalities in the uptake of, adherence to, and effectiveness of BWMIs. • Harvest plots will be produced to synthesise evidence of differential effectiveness by PROGRESS-Plus criteria in a visual display. Data extraction & synthesis Results to date • This review will identify and describe where inequalities in BWMIs occur (i.e. by PROGRESS-Plus criteria) and at what stage (uptake, adherence and/or effectiveness). • The protocol was reviewed by a PPI representative, and received positive feedback on the review aims and plans. • Findings will contribute towards the consideration of intervention-generated inequalities by researchers, policy makers and healthcare and public health practitioners. • We anticipate the review will be completed by September 2021, with PPI support informing research dissemination. • Authors of the 17 UK-based studies in the review will be invited to collaborate on an individual participant data (IPD) meta-analysis. Discussion • JMB, RAJ, SJG and ALA are supported by the Medical Research Council (MRC) (Grant MC_UU_00006/6). Acknowledgements • Health inequalities occur by Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital plus factors such as age and sexual orientation (PROGRESS-Plus). [1] • Interventions requiring high personal agency, such as behavioural weight management interventions (BWMIs), are likely to be inequitable. [2,3] • Some evidence suggests that if interventions are targeted (e.g. for low-income groups), they may reduce health inequalities. [4] • Previous systematic reviews have focused on mean weight loss [5] and have not considered whether uptake, adherence or effectiveness differs by PROGRESS-Plus criteria. • This systematic review synthesises the literature on inequalities in trials of BWMIs. The full protocol is published in BMJ Open [6] and is accessible via the QR code. Background (Cluster) Randomised controlled trials. Adults aged 18 years and over with overweight or obesity (BMI >25kg/m2). Study conducted in/recruited from/could feasibly be implemented in primary care. Minimum 12-month follow up. Ꭓ Population not selected on basis of weight status. Ꭓ Population with a chronic disease where weight loss is part of disease management. Eligibility criteria Investigating the causes and prevention of diabetes and obesity www.mrc-epid.cam.ac.uk 4. HILLIER-BROWN, F. C., BAMBRA, C. L., CAIRNS, J. M., et al. 2014. A systematic review of the effectiveness of individual, community and societal-level interventions at reducing socio-economic inequalities in obesity among adults. Int J Obes (Lond), 38, 1483-90. 5. LEBLANC, E. S., PATNODE, C. D., WEBBER, E. M., et al. 2018. Behavioral and Pharmacotherapy Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. Jama, 320, 1172-1191. 6. BIRCH, J. M., GRIFFIN, S. J., KELLY, M. P. & AHERN, A. L. 2020. Inequalities in the uptake of, adherence to and effectiveness of behavioural weight management interventions: systematic review protocol. BMJ Open. References 1. O'NEILL, J., TABISH, H., WELCH, V., et al. 2014. Applying an equity lens to interventions: using PROGRESS ensures consideration of socially stratifying factors to illuminate inequities in health. J Clin Epidemiol, 67, 56-64. 2. WHITE, M., ADAMS, J. & HEYWOOD, P. 2009. How and why do interventions that increase health overall widen inequalities within populations? . In: BABONES, S. J. (ed.) Social inequality and public health. Bristol: Policy Press. 3. ADAMS, J., MYTTON, O., WHITE, M. & MONSIVAIS, P. 2016. Why Are Some Population Interventions for Diet and Obesity More Equitable and Effective Than Others? The Role of Individual Agency. PLOS Medicine, 13, e1001990. • To identify and describe inequalities in the uptake of, adherence to and effectiveness of behavioural weight management interventions. Aim Records identified through database searching (n=4643) Records for title/abstract screening (n=4637) Records for full text screening (n=163) Eligible studies from USPSTF report (n=89) Studies for inclusion (n=14) Total studies included in review (n=103)

Background: It has been suggested that interventions focusing on individual behaviour change, such as behavioural weight management interventions, may exacerbate health inequalities. These intervention-generated inequalities may occur at different stages, including intervention uptake, adherence and effectiveness. We conducted a systematic review to synthesise evidence on how different measures of inequality moderate the uptake of, adherence to and effectiveness of behavioural weight management interventions in adults. Methods: We updated a previous systematic literature review from the US Preventive Services Taskforce to identify trials of behavioural weight management interventions in adults that could be conducted in or recruited from primary care. Medline, Cochrane database (CENTRAL) and PsycINFO were searched. Only randomised controlled trials and cluster-randomised controlled trials were included. Two investigators independently screened articles for eligibility and conducted risk of bias assessment. We curated publication families for eligible trials. The PROGRESS-Plus acronym (place of residence, race/ethnicity, occupation, gender, religion, education, socioeconomic status, social capital, plus other discriminating factors) was used to consider a comprehensive range of health inequalities. Data on trial uptake, intervention adherence, weight change, and PROGRESS-Plus related-data were extracted. Results: Data extraction in currently underway. A total of 108 studies are included in the review. Data will be synthesised narratively and through the use of Harvest Plots. A Harvest plot for each PROGRESS-Plus criterion will be presented, showing whether each trial found a negative, positive or no health inequality gradient. We will also identify potential sources of unpublished original research data on these factors which can be synthesised through a future individual participant data metaanalysis. Conclusions and implications: The review findings will contribute towards the consideration of intervention-generated inequalities by researchers, policy makers and healthcare and public health practitioners. Authors of trials included in the completed systematic review may be invited to collaborate on a future IPD meta-analysis. PROSPERO registration number: CRD42020173242 • Articles were dual-screened using Covidence.

Phase 2
• 'Parent' publication from each study identified and 'publication families' curated.
• Publications relating to the parent publication were identified through searching Medline, Cochrane CENTRAL and PsycInfo.
• Databases were searched using first or last author of parent publication and a study identifier (such as study name).
• Each publication family is considered as one study.

Data extraction
• Data extracted using a modified version of Cochrane Public Health Group's extraction form.
• Risk of bias assessed using Cochrane's Risk of Bias (RoB 2.0) tool.
• Data extraction and RoB performed by one investigator and checked by another.

Data synthesis
• We anticipate that there will be insufficient data to conduct meta-analyses.
• We will conduct narrative synthesis to identify and describe inequalities in the uptake of, adherence to, and effectiveness of BWMIs.
• Harvest plots will be produced to synthesise evidence of differential effectiveness by PROGRESS-Plus criteria in a visual display.

Results to date
• This review will identify and describe where inequalities in BWMIs occur (i.e. by PROGRESS-Plus criteria) and at what stage (uptake, adherence and/or effectiveness).
• The protocol was reviewed by a PPI representative, and received positive feedback on the review aims and plans.
• Findings will contribute towards the consideration of intervention-generated inequalities by researchers, policy makers and healthcare and public health practitioners.
• We anticipate the review will be completed by September 2021, with PPI support informing research dissemination.
• Authors of the 17 UK-based studies in the review will be invited to collaborate on an individual participant data (IPD) meta-analysis. • Interventions requiring high personal agency, such as behavioural weight management interventions (BWMIs), are likely to be inequitable. [2,3] • Some evidence suggests that if interventions are targeted (e.g. for low-income groups), they may reduce health inequalities.

Discussion
[4] • Previous systematic reviews have focused on mean weight loss [5] and have not considered whether uptake, adherence or effectiveness differs by PROGRESS-Plus criteria.
• This systematic review synthesises the literature on inequalities in trials of BWMIs. The full protocol is published in BMJ Open [6] and is accessible via the QR code.
Adults aged 18 years and over with overweight or obesity (BMI >25kg/m 2 ).
Study conducted in/recruited from/could feasibly be implemented in primary care.
Minimum 12-month follow up.
Ꭓ Population not selected on basis of weight status.
Ꭓ Population with a chronic disease where weight loss is part of disease management.

Eligibility criteria
Investigating the causes and prevention of diabetes and obesity www.mrc-epid.cam.ac. • To identify and describe inequalities in the uptake of, adherence to and effectiveness of behavioural weight management interventions.

Conflicts of interest and funding sources:
BW has received research grants and/or honoria from Alexion, Merck Serono, Biogen, Teva, Novartis, Sanofi Genzyme, Bayer Healthcare, and research grants from the Dietmar Hopp Foundation, the Klaus Tschira Foundation and the Deutsche Forschungsgemeinschaft (DFG). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abstract:
Background: The role of B cells in multiple sclerosis (MS) is increasingly recognized. B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby memory B cells accumulate in the CSF. While B-cell trafficking across the bloodbrain barrier has been intensely investigated, cellular diapedesis through the blood-CSF barrier (BCSFB) is incompletely understood. Objectives: To investigate how B cells interact with the choroid plexus to transmigrate into the CSF, we isolated circulating B cells from healthy donors (HC) and MS patients, utilized an inverted cell culture filter system of human choroid plexus papilloma (HIBCPP) cells to determine transmigration rates of B-cell subsets, immunofluorescence, and electron microscopy to analyze migration routes, and qRT-PCR to determine cytokines/chemokines mediating B-cell diapedesis.
We also screened the transcriptome of intrathecal B cells from MS patients. Results: We found that spontaneous transmigration of HC-and MS-derived B cells was scant yet increased significantly in response to B-cell specific chemokines CXCL-12/CXCL-13, was further boosted upon pre-activation and occurred via paracellular and transcellular pathways. Migrating cells exhibited upregulation of several genes involved in B-cell activation/migration and enhanced expression of chemokine receptors CXCR4/CXCR5 and were predominantly of isotype class switched memory phenotype. This antigen-experienced migratory subset displayed more pronounced chemotactic activities in MS than in HC and was retrieved in intrathecal B cells from patients with active MS. Trafficking of class-switched memory B cells was downscaled in a small cohort of natalizumab-exposed MS patients and the proportions of these phenotypes were reduced in peripheral blood yet were enriched intrathecally in patients who experienced recurrence of disease activity after withdrawal of natalizumab. Conclusion: Our findings highlight the relevance of the BCSFB as an important gate for the entry of potentially harmful activated B cells into the CSF. Objective The role of B lymphocytes in MS immunopathogenesis is increasingly recognized. B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby antigen-experienced memory B cells accumulate in the CSF. While B cell trafficking across the blood-brain barrier has been intensively investigated, cellular diapedesis through the blood-CSF barrier (BCSFB) is incompletely understood. We therefore investigated the interaction of B cells with the choroid plexus to transmigrate into the CSF.

Conclusion
Our findings elucidate in more detail how antigen-experienced B cell phenotypes and the BCSFB act together to facilitate aberrant B cell accumulation in the CSF of patients with multiple sclerosis.   In our work, we present a computational framework that uses patient-specific data to investigate cancer metabolism and provide personalised survival predictions and cancer development outcomes. The proposed model integrates patient-specific multi-omics data (i.e., genomic, metabolomic and clinical data) into a metabolic model of cancer to produce a list of metabolic reactions affecting cancer progression. Quantitative and predictive analysis, through survival analysis and machine learning techniques, is then performed on the list of selected reactions.

Chemotactic activities of MS-derived memory B cells were higher when compared with HC-derived cells
Since our model performs an analysis of patient-specific data, the outcome of our pipeline provides a personalised prediction of survival outcome and cancer development based on a subset of identified multi-omics features (genomic, metabolomic and clinical data).
In particular, our work aims to develop a computational pipeline for clinicians that relates the omic profile of each patient to their survival probability, based on a combination of machine learning and metabolic modelling techniques. The model provides patient-specific predictions on cancer development and survival outcomes towards the development of personalised medicine.
Then: 1)To assess vaccine stability •Samples reduced, denatured and separated using gel electrophoresis.
•The band intensity of treated samples was expressed as a % of its negative control (sample containing trimer only) •This gives a read out of proteolytic digestion of the trimer.

2)To assess vaccine immunogenicity )
•It was thought that proteases may attack specific antibody epitopes within Env •ELISA assay performed to assess antibody-Env binding. •Antibody-trimer binding maintained following commercially -sourced elastase •The same was true following supernatant treatment.
•HIV-1 infection can be prevented by blocking viral entry into cells via the action of neutralising antibodies, targeting Env 1 .
•In these trials, adjuvant was used.
•Studies have shown that adjuvants trigger neutrophil infiltration 2 .  43-53 (1975). With thanks to the Sattentau group at the Dunn School of Pathology, University of Oxford, for their assistance in this project, particularly Rebecca Moore and Quentin Sattentau for their mentorship.

References and Acknowledgements
Why is Env stability so different in the presence of commercially sourced proteases Vs supernatant, containing the same protease?

Future Directions
•Chemical cross-linking and HS stabilise Env trimer antigens in vitro.
•Further work is required to determine the effect of HS on elastase potency in vivo, as well as the effect of other components of the immune system on trimer stability.
•The potential for adjuvant-induced protease release should be taken into consideration when selecting adjuvants.

Conflicts of interest and funding sources:
AV undertakes paid part-time work on an ad hoc basis at Outcomes Based Healthcare (OBH) -a health data analytics organisation providing insights for population health management.

Abstract:
"Overdiagnosis" -when people are labelled with or treated for a disease that would never cause them harm -is increasingly highlighted as a significant issue within contemporary healthcare, yet one which to date, has received little attention outside of the medical context. As a society, our collective enthusiasm to diagnose and treat disease has paradoxically been shown to potentially do more harm than good, impacting individuals whilst simultaneously increasing financial costs to the health system. As health systems across the world continue to face unprecedented pressures, tackling this phenomenon represents an important step in reducing the proliferation of low-value care inherent within the practice of modern medicine, and contributing towards the development of sustainable health systems. This research represents the first interdisciplinary analysis of the factors contributing towards overdiagnosis within modern healthcare systems. The analysis finds that individual disciplines of a medical and non-medical origin elude to important insights in relation to the drivers of overdiagnosis which are not necessarily reflected across multiple disciplines. Drivers identified within literature which lies beyond the medical context likely represent new knowledge in relation to the causes of overdiagnosis, and collectively provide a starting point from which to consider the role of patients and clinicians in influencing overdiagnosis, the nature of the interaction between the drivers of overdiagnosis, and the role of the different models of health in providing a unique perspective of the wider phenomenon. These findings highlight the importance of interdisciplinarity within health research and contribute towards efforts to reduce the rise of low value care within modern healthcare, fostering the development of sustainable health systems.