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Objectives: To determine if genetic variation in genes in the hypothalamic-pituitary-adrenal (HPA) axis, the primary stress response system, influences susceptibility to developing musculoskeletal pain.Methods: Pain and comorbidity data was collected at three time points in a prospective population-based cohort study. Pairwise tagging single nucleotide polymorphisms (SNPs) were selected and genotyped for seven genes. Genetic association analysis was carried out using zero-inflated negative binomial regression to test for association between SNPs and the maximum number of pain sites across the three time points in participants reporting pain, reported as proportional changes with 95% CIs. SNPs were also tested for association with chronic widespread pain (CWP) using logistic regression reporting odds ratios and 95% CI.Results: A total of 75 SNPs were successfully genotyped in 994 participants including 164 cases with persistent CWP and 172 pain-free controls. Multiple SNPs in SERPINA6 were associated with the maximum number of pain sites; for example, each copy of the T allele of rs941601 was associated with having 16% (proportional change=1.16, 95% CI 1.04 to 1.28, p=0.006) more pain sites compared to participants with the CC genotype. SERPINA6 gene SNPs were also associated with CWP. Significant associations between the maximum number of pain sites and SNPs in the CRHBP and POMC genes were also observed and a SNP in MC2R was also associated with CWP. Associations between SNPs and comorbidity of poor sleep quality and depression explained some of the associations observed.Conclusions: Genetic variation in HPA axis genes was associated with musculoskeletal pain; however, some of the associations were explained by comorbidities. Replication of these findings is required in independent cohorts. [ABSTRACT FROM AUTHOR]

Chronic widespread pain (CWP) is associated with poor health-related quality of life (HRQoL). It is unclear whether pain itself is the cause of poor HRQoL or other factors play a role. We hypothesised that new onset of CWP was associated with poor physical and mental HRQoL but that psychosocial risk markers for CWP onset would explain this relationship. A prospective population-based survey measured pain and psychosocial status at baseline. Subjects free of CWP at baseline were followed up 15 months later, when pain status, threatening life events and HRQoL (SF-12) were assessed. The risk associated with the new onset of CWP and reporting poor SF12-MCS and SF12-PCS was quantified using multinomial logistic regression (relative risk ratios (RRRs) with 95% confidence intervals (95% CI)), adjusted for age and gender. 3000 subjects (77%) free of CWP at baseline participated at follow-up. 2650 subjects (88%) provided full SF-12 and pain data and formed the cohort for this analysis. 9.4% of subjects (n=248) reported new CWP. New CWP was associated with an increased risk of having the poorest SF12-MCS (RRR=2.3; 95% CI 1.6-3.2) and SF12-PCS (RRR=8.0; 95% CI 5.4-11.8) scores. After adjusting for baseline psychosocial status, the relationship between CWP onset and SF12-MCS was attenuated (RRR=1.2; 95% CI 0.8-1.8), although the association with SF12-PCS remained (RRR=4.8% CI 3.1-7.47). New onset of CWP is associated with poor mental and physical HRQoL. However, the relationship with mental HRQoL is explained by psychosocial risk markers. [ABSTRACT FROM AUTHOR]

Background: It remains unclear how to meaningfully classify people living with multimorbidity (multiple long-term conditions (MLTCs)), beyond counting the number of conditions. This paper aims to identify clusters of MLTCs in different age groups and associated risks of adverse health outcomes and service use., Methods: Latent class analysis was used to identify MLTCs clusters in different age groups in three cohorts: Secure Anonymised Information Linkage Databank (SAIL) (n = 1,825,289), UK Biobank (n = 502,363), and the UK Household Longitudinal Study (UKHLS) (n = 49,186). Incidence rate ratios (IRR) for MLTC clusters were computed for: all-cause mortality, hospitalisations, and general practice (GP) use over 10 years, using <2 MLTCs as reference. Information on health outcomes and service use were extracted for a ten year follow up period (between 01 st Jan 2010 and 31st Dec 2019 for UK Biobank and UKHLS, and between 01 st Jan 2011 and 31st Dec 2020 for SAIL)., Findings: Clustering MLTCs produced largely similar results across different age groups and cohorts. MLTC clusters had distinct associations with health outcomes and service use after accounting for LTC counts, in fully adjusted models. The largest associations with mortality, hospitalisations and GP use in SAIL were observed for the " Pain+ " cluster in the age-group 18-36 years (mortality IRR = 4.47, hospitalisation IRR = 1.84; GP use IRR = 2.87) and the " Hypertension, Diabetes & Heart disease " cluster in the age-group 37-54 years (mortality IRR = 4.52, hospitalisation IRR = 1.53, GP use IRR = 2.36). In UK Biobank, the " Cancer, Thyroid disease & Rheumatoid arthritis " cluster in the age group 37-54 years had the largest association with mortality (IRR = 2.47). Cardiometabolic clusters across all age groups, pain/mental health clusters in younger groups, and cancer and pulmonary related clusters in older age groups had higher risk for all outcomes. In UKHLS, MLTC clusters were not significantly associated with higher risk of adverse outcomes, except for the hospitalisation in the age-group 18-36 years., Interpretation: Personalising care around MLTC clusters that have higher risk of adverse outcomes may have important implications for practice (in relation to secondary prevention), policy (with allocation of health care resources), and research (intervention development and targeting), for people living with MLTCs., Funding: This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)-NIHR202020)., Competing Interests: SJS is Clinical Lead for National Respiratory Audit Programme–Pulmonary Rehabilitation and also a National Institute for Health Research (NIHR) Senior Investigator. This work was supported by the NIHR Leicester Biomedical Research Centre (BRC). KJ declares funding from NIHR Applied Research Collaboration West Midlands and Sub-committee chair for NIHR Programme Grants for Applied Health Research (payment to institution). BIN declares receiving funding from NIHR, vs. Arthritis, NIHR-EPSRC, Glasgow Knowledge Exchange Fund and for external PhD examination. RAE declares receipt of speaker fees (Boeringher June 2021; Moderna April 2023) and ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary (unpaid), and ATS Pulmonary Rehabilitation Assembly Chair (unpaid). SD declares NIHR Applied Research Collaboration: South West Peninsula (PenARC; payment to institution), receipt of the following NIHR grants (payment to institution): NIHR151938; NIHR204099; RP-PG-0514-20,002; NIHR201038; NIHR201070; NIHR200428, receipt of grants (payment to institution): Gillings Family foundation (ID 943008); The Stroke Association (ID 901902); NIHR School for Primary Care Research—Exeter internal fund (ID 856766); Academic Health Science Network South West (ID 1355693), receipt of textbook royalties (John Wiley & Sons), support for meeting attendance from NIHR (p-PG-0514- 20,002) and Health Research Council New Zealand (21/826; 18/254), and membership of NIHR Programme Grant for Applied Research funding panel committee and The Stroke Association research funding panel. SJK declares receipt of conference funding from School of Health and Wellbeing, University of Glasgow. SAS declares presidency of the UK Society of Behavioural Medicine, membership of HTA Clinical Evaluations and Trials Committee (2016–2020), membership of Commissioning Panel for the National Institute of Health Research (NIHR) Policy Research Programme (2019–2022), and membership of Chief Scientist Office HIPS committee (2018–2023). FSM declares grants from NIHR during the conduct of the study; grants from Wellcome, grants from Innovate UK, grants from Innovative Medicines Initiative (IMI2), grants from UKRI, grants from EPSRC, grants from MRC, grants from Chief Scientist office Scotland, outside the submitted work; and MRC CARP Panel membership. Dr Greaves reports grants from National Institute for Health Research (NIHR) during the conduct of the study., (© 2024 The Authors.)

Frailty, social isolation, and loneliness have individually been associated with adverse health outcomes. This study examines how frailty in combination with loneliness or social isolation is associated with socioeconomic deprivation and with all-cause mortality and hospitalisation rate in a middle-aged and older population. Baseline data from 461,047 UK Biobank participants (aged 37-73) were used to assess frailty (frailty phenotype), social isolation, and loneliness. Weibull models assessed the association between frailty in combination with loneliness or social isolation and all-cause mortality adjusted for age/sex/smoking/alcohol/socioeconomic-status and number of long-term conditions. Negative binomial regression models assessed hospitalisation rate. Frailty prevalence was 3.38%, loneliness 4.75% and social isolation 9.04%. Frailty was present across all ages and increased with age. Loneliness and social isolation were more common in younger participants compared to older. Co-occurrence of frailty and loneliness or social isolation was most common in participants with high socioeconomic deprivation. Frailty was associated with increased mortality and hospitalisation regardless of social isolation/loneliness. Hazard ratios for mortality were 2.47 (2.27-2.69) with social isolation and 2.17 (2.05-2.29) without social isolation, 2.14 (1.92-2.38) with loneliness and 2.16 (2.05-2.27) without loneliness. Loneliness and social isolation were associated with mortality and hospitalisation in robust participants, but this was attenuated in the context of frailty. Frailty and loneliness/social isolation affect individuals across a wide age spectrum and disproportionately co-occur in areas of high deprivation. All were associated with adverse outcomes, but the association between loneliness and social isolation and adverse outcomes was attenuated in the context of frailty. Future interventions should target people living with frailty or loneliness/social isolation, regardless of age., (© 2024. The Author(s).)

Background: In the United Kingdom (UK), cancer screening invitations are based on general practice (GP) registrations. We hypothesize that GP electronic medical records (EMR) can be utilised to calculate a lung cancer risk score with good accuracy/clinical utility., Methods: The development cohort was Secure Anonymised Information Linkage-SAIL (2.3 million GP EMR) and the validation cohort was UK Biobank-UKB (N = 211,597 with GP-EMR availability). Fast backward method was applied for variable selection and area under the curve (AUC) evaluated discrimination., Results: Age 55-75 were included (SAIL: N = 574,196; UKB: N = 137,918). Six-year lung cancer incidence was 1.1% (6430) in SAIL and 0.48% (656) in UKB. The final model included 17/56 variables in SAIL for the EMR-derived score: age, sex, socioeconomic status, smoking status, family history, body mass index (BMI), BMI:smoking interaction, alcohol misuse, chronic obstructive pulmonary disease, coronary heart disease, dementia, hypertension, painful condition, stroke, peripheral vascular disease and history of previous cancer and previous pneumonia. The GP-EMR-derived score had AUC of 80.4% in SAIL and 74.4% in UKB and outperformed ever-smoked criteria (currently the first step in UK lung cancer screening pilots)., Discussion: A GP-EMR-derived score may have a role in UK lung cancer screening by accurately targeting high-risk individuals without requiring patient contact., (© 2023. The Author(s).)

Background: Components of social connection are associated with mortality, but research examining their independent and combined effects in the same dataset is lacking. This study aimed to examine the independent and combined associations between functional and structural components of social connection and mortality., Methods: Analysis of 458,146 participants with full data from the UK Biobank cohort linked to mortality registers. Social connection was assessed using two functional (frequency of ability to confide in someone close and often feeling lonely) and three structural (frequency of friends/family visits, weekly group activities, and living alone) component measures. Cox proportional hazard models were used to examine the associations with all-cause and cardiovascular disease (CVD) mortality., Results: Over a median of 12.6 years (IQR 11.9-13.3) follow-up, 33,135 (7.2%) participants died, including 5112 (1.1%) CVD deaths. All social connection measures were independently associated with both outcomes. Friends/family visit frequencies < monthly were associated with a higher risk of mortality indicating a threshold effect. There were interactions between living alone and friends/family visits and between living alone and weekly group activity. For example, compared with daily friends/family visits-not living alone, there was higher all-cause mortality for daily visits-living alone (HR 1.19 [95% CI 1.12-1.26]), for never having visits-not living alone (1.33 [1.22-1.46]), and for never having visits-living alone (1.77 [1.61-1.95]). Never having friends/family visits whilst living alone potentially counteracted benefits from other components as mortality risks were highest for those reporting both never having visits and living alone regardless of weekly group activity or functional components. When all measures were combined into overall functional and structural components, there was an interaction between components: compared with participants defined as not isolated by both components, those considered isolated by both components had higher CVD mortality (HR 1.63 [1.51-1.76]) than each component alone (functional isolation 1.17 [1.06-1.29]; structural isolation 1.27 [1.18-1.36])., Conclusions: This work suggests (1) a potential threshold effect for friends/family visits, (2) that those who live alone with additional concurrent markers of structural isolation may represent a high-risk population, (3) that beneficial associations for some types of social connection might not be felt when other types of social connection are absent, and (4) considering both functional and structural components of social connection may help to identify the most isolated in society., (© 2023. BioMed Central Ltd., part of Springer Nature.)

selfBACK is an artificial intelligence based self-management app for low back pain (LBP) recently reported to reduce LBP-related disability. The aim of this study was to examine if age, gender, or education modify the effectiveness of the selfBACK intervention using secondary analysis of the selfBACK randomized controlled trial. Persons seeking care for LBP were recruited from primary care in Denmark and Norway and an outpatient clinic (Denmark). The intervention group (n = 232) received the selfBACK app adjunct to usual care. The control group (n = 229) received usual care only. Analyses were stratified by age (18-34, 35-64, ≥65 years), gender (male, female), and education (≤12, >12 years) to investigate differences in effect at three and nine months follow-up on LBP-related disability (Roland-Morris Disability Questionnaire [RMDQ]), LBP intensity and pain self-efficacy. Overall, there was no effect modification for any of the sociodemographic factors. However, data on LBP-related disability suggest that the effect of the intervention was somewhat more beneficial in older than in younger participants. The difference between the intervention and control group due to interaction was 2.6 (95% CI: 0.4 to 4.9) RMDQ points for those aged ≥65 years as compared to those aged 35-64 years. In conclusion, age, gender, or education did not influence the effect of the selfBACK intervention on LBP-related disability. However, older participants may have an additional long-term positive effect compared to younger participants. Trial registration: ClinicalTrials.gov Identifier: NCT03798288., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bardal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: selfBACK provides individually tailored self-management support for low back pain (LBP) via an artificial intelligence-based smartphone app. We explore whether those with depressive/stress symptoms can benefit from this technology., Methods: Secondary analysis of the selfBACK randomized controlled trial (n = 461). Participants with LBP were randomized to usual care (n = 229), or usual care plus selfBACK (n = 232)., Primary Outcome: LBP-related disability (Roland-Morris Disability Questionnaire, RMDQ) over 9 months., Secondary Outcomes: global perceived effect (GPE)/pain self-efficacy (PSEQ)/satisfaction/app engagement. Baseline depressive symptoms were measured using the patient health questionnaire (PHQ-8) and stress with the perceived stress scale (PSS). Outcomes stratified by baseline PHQ-8/PSS scores to assess associations across the whole cohort, and intervention versus control groups., Results: Participants with higher levels of depressive/stress symptoms reported more baseline LBP-related disability (RMDQ 3.1; 1.6 points higher in most vs least depressed/stressed groups respectively); lower self-efficacy (PSEQ 8.1; 4.6 points lower in most vs least depressive/stressed groups respectively). LBP-related disability improved over time; relative risk of improvement in those with greatest depressive/stress symptoms versus nil symptom comparators at 9 months: 0.8 (95% CI: 0.6 to 1.0) and 0.8 (95% CI: 0.7 to 1.0) respectively. No evidence that different baseline levels of depressive/perceived stress symptoms are associated with different RMDQ/GPE/PSEQ outcomes. Whilst participants with higher PHQ-8/PSS were less likely to be satisfied or engage with the app, there was no consistent association among PHQ-8/PSS level, the intervention and outcomes., Conclusions: The selfBACK app can improve outcomes even in those with high levels of depressive/stress symptoms and could be recommended for patients with LBP., Significance: We have demonstrated that an app supporting the self-management of LBP is helpful, even in those with higher levels of baseline depression and stress symptoms. selfBACK offers an opportunity to support people with LBP and provides clinicians with an additional tool for their patients, even those with depression or high levels of stress. This highlights the potential for digital health interventions for chronic pain., (© 2023 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Purpose: We aimed to classify individuals with RA and ≥2 additional long-term conditions (LTCs) and describe the association between different LTC classes, number of LTCs and adverse health outcomes., Methods: We used UK Biobank participants who reported RA (n=5,625) and employed latent class analysis (LCA) to create classes of LTC combinations for those with ≥2 additional LTCs. Cox-proportional hazard and negative binomial regression were used to compare the risk of all-cause mortality, major adverse cardiac events (MACE), and number of emergency hospitalisations over an 11-year follow-up across the different LTC classes and in those with RA plus one additional LTC. Persons with RA without LTCs were the reference group. Analyses were adjusted for demographic characteristics, smoking, BMI, alcohol consumption and physical activity., Results: A total of 2,566 (46%) participants reported ≥2 LTCs in addition to RA. This involved 1,138 distinct LTC combinations of which 86% were reported by ≤2 individuals. LCA identified 5 morbidity-classes. The distinctive condition in the class with the highest mortality was cancer (class 5; HR 2.66 95%CI (1.91-3.70)). The highest MACE (HR 2.95 95%CI (2.11-4.14)) and emergency hospitalisations (rate ratio 3.01 (2.56-3.54)) were observed in class 3 which comprised asthma, COPD & CHD. There was an increase in mortality, MACE and emergency hospital admissions within each class as the number of LTCs increased., Conclusions: The risk of adverse health outcomes in RA varied with different patterns of multimorbidity. The pattern of multimorbidity should be considered in risk assessment and formulating management plans in patients with RA., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: There has been conflicting evidence on the association between multimorbidity and blood pressure (BP) control. This study aimed to investigate this associations in people with hypertension attending primary care in Canada, and to assess whether individual long-term conditions are associated with BP control., Methods: This was a cross-sectional study in people with hypertension attending primary care in Toronto between January 1, 2017 and December 31, 2019. Uncontrolled BP was defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. A list of 11 a priori selected chronic conditions was used to define multimorbidity. Multimorbidity was defined as having ≥1 long-term condition in addition to hypertension. Logistic regression models were used to estimate the association between multimorbidity (or individual long-term conditions) with uncontrolled BP., Results: A total of 67 385 patients with hypertension were included. They had a mean age of 70, 53.1% were female, 80.6% had multimorbidity, and 35.7% had uncontrolled BP. Patients with multimorbidity had lower odds of uncontrolled BP than those without multimorbidity (adjusted OR = 0.72, 95% CI 0.68-0.76). Among the long-term conditions, diabetes (aOR = 0.73, 95%CI 0.70-0.77), heart failure (aOR = 0.81, 95%CI 0.73-0.91), ischemic heart disease (aOR = 0.74, 95%CI 0.69-0.79), schizophrenia (aOR = 0.79, 95%CI 0.65-0.97), depression/anxiety (aOR = 0.91, 95%CI 0.86-0.95), dementia (aOR = 0.87, 95%CI 0.80-0.95), and osteoarthritis (aOR = 0.89, 95%CI 0.85-0.93) were associated with a lower likelihood of uncontrolled BP., Conclusion: We found that multimorbidity was associated with better BP control. Several conditions were associated with better control, including diabetes, heart failure, ischemic heart disease, schizophrenia, depression/anxiety, dementia, and osteoarthritis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract: The risk of COVID-19 in those with chronic pain is unknown. We investigated whether self-reported chronic pain was associated with COVID-19 hospitalisation or mortality. UK Biobank recruited 502,624 participants aged 37 to 73 years between 2006 and 2010. Baseline exposure data, including chronic pain (>3 months, in at least 1 of 7 prespecified body sites) and chronic widespread pain (>3 months, all over body), were linked to COVID-19 hospitalisations or mortality. Univariable or multivariable Poisson regression analyses were performed on the association between chronic pain and COVID-19 hospitalisation and Cox regression analyses of the associations with COVID-19 mortality. Multivariable analyses adjusted incrementally for sociodemographic confounders, then lifestyle risk factors, and finally long-term condition count. Of 441,403 UK Biobank participants with complete data, 3180 (0.7%) were hospitalised for COVID-19 and 1040 (0.2%) died from COVID-19. Chronic pain was associated with hospital admission for COVID-19 even after adjustment for all covariates (incidence rate ratio 1.16; 95% confidence interval [CI] 1.08-1.24; P < 0.001), as was chronic widespread pain (incidence rate ratio 1.33; 95% CI 1.06-1.66; P = 0.012). There was clear evidence of a dose-response relationship with number of pain sites (fully adjusted global P -value < 0.001). After adjustment for all covariates, there was no association between chronic pain (HR 1.01; 95% CI 0.89-1.15; P = 0.834) but attenuated association with chronic widespread pain (HR 1.50, 95% CI 1.04-2.16, P -value = 0.032) and COVID-19 mortality. Chronic pain is associated with higher risk of hospitalisation for COVID-19, but the association with mortality is unclear. Future research is required to investigate these findings further and determine whether pain is associated with long COVID., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: Low back pain (LBP) is one of the most common reasons for disability globally. Digital interventions are a promising means of supporting people to self-manage LBP, but implementation of digital interventions has been suboptimal. An artificial intelligence-driven app, selfBACK, was developed to support self-management of LBP as an adjunct to usual care. To better understand the process of implementation from a participant perspective, we qualitatively explored factors influencing embedding, integrating, and sustaining engagement with the selfBACK app, and the self-perceived effects, acceptability, and satisfaction with the selfBACK app., Methods: Using a qualitative interview study and an analytic framework approach underpinned by Normalization Process Theory (NPT), we investigated the experiences of patients who participated in the selfBACK randomized controlled trial (RCT). Interviews focused on the motivation to participate in the RCT, experiences of using the selfBACK app, and views about future intended use and potential of using digital health interventions for self-management of LBP. Participants were purposively sampled to represent diversity in age, sex, and implementation reflected by a proxy measure of number of app-generated self-management plans during the first three months of RCT participation., Results: Twenty-six participants aged 21-78, eleven females and fifteen men, with two to fourteen self-management plans, were interviewed between August 2019 and April 2020. A broad range of factors influencing implementation of selfBACK within all constructs of NPT were identified. Key facilitating factors were preferences and beliefs favoring self-management, a friendly, motivational, and reassuring supporter, tailoring and personalization, convenience and ease of use, trustworthiness, perceiving benefits, and tracking achievements. Key impeding factors were preferences and beliefs not favoring self-management, functionality issues, suboptimal tailoring and personalization, insufficient time or conflicting life circumstances, not perceiving benefits, and insufficient involvement of health care practitioners. Self-perceived effects on pain and health, behavior/attitude, and gaining useful knowledge varied by participant., Conclusions: The high prevalence of LBP globally coupled with the advantages of providing help through an app offers opportunities to help countless people. A range of factors should be considered to facilitate implementation of self-management of LBP or similar pain conditions using digital health tools., (© 2022. The Author(s).)

Objective: Multimorbidity (the coexistence of two or more long-term conditions) is highly prevalent in people who have rheumatoid arthritis (RA). The present work systematically reviewed the literature to determine the effect of multimorbidity on all-cause mortality, functional status, and quality of life in RA., Methods: Six electronic databases were searched: CINAHL, The Cochrane Library, Embase, Medline, PsycINFO, and Scopus. Full-text longitudinal observational studies in English were selected. Quality appraisal of studies was undertaken using the Cochrane-developed QUIPS tool and a narrative synthesis of findings conducted., Results: The search strategy identified 5,343 articles, with 19 studies meeting the inclusion criteria. Nine studies had mortality as an outcome, 9 reported functional status and/or quality of life, and 1 study reported both mortality and functional status. The number of participants ranged from 183 to 18,485, with studies conducted between 1985 and 2018. The mean age of participants ranged from 52.0 to 66.6 years, and 60.0-88.0% were female. Nine studies showed a significant association between multimorbidity and higher risk of mortality in people with RA. Ten studies reported significant associations between multimorbidity and reduced functional status in RA. Three studies also showed a further association with reduced quality of life. Only one study investigated the influence of mental health comorbidities on outcomes., Conclusion: Our review findings indicate that multimorbidity is a significant predictor for higher mortality and poorer functional status/quality of life in people with RA and should be considered in clinical management plans., (© 2021 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Frailty, a state of reduced physiological reserve, is common in people with chronic obstructive pulmonary disease (COPD). Frailty can occur at any age; however, the implications in younger people (eg, aged <65 years) with COPD are unclear. We assessed the prevalence of frailty in UK Biobank participants with COPD; explored relationships between frailty and forced expiratory volume in 1 second (FEV1) and quantified the association between frailty and adverse outcomes., Methods: UK Biobank participants (n=3132, recruited 2006-2010) with COPD aged 40-70 years were analysed comparing two frailty measures (frailty phenotype and frailty index) at baseline. Relationship with FEV1 was assessed for each measure. Outcomes were mortality, major adverse cardiovascular event (MACE), all-cause hospitalisation, hospitalisation with COPD exacerbation and community COPD exacerbation over 8 years of follow-up., Results: Frailty was common by both definitions (17% frail using frailty phenotype, 28% moderate and 4% severely frail using frailty index). The frailty phenotype, but not the frailty index, was associated with lower FEV1. Frailty phenotype (frail vs robust) was associated with mortality (HR 2.33; 95% CI 1.84 to 2.96), MACE (2.73; 1.66 to 4.49), hospitalisation (incidence rate ratio 3.39; 2.77 to 4.14) hospitalised exacerbation (5.19; 3.80 to 7.09) and community exacerbation (2.15; 1.81 to 2.54), as was frailty index (severe vs robust) (mortality (2.65; 95% CI 1.75 to 4.02), MACE (6.76; 2.68 to 17.04), hospitalisation (3.69; 2.52 to 5.42), hospitalised exacerbation (4.26; 2.37 to 7.68) and community exacerbation (2.39; 1.74 to 3.28)). These relationships were similar before and after adjustment for FEV1., Conclusion: Frailty, regardless of age or measure, identifies people with COPD at risk of adverse clinical outcomes. Frailty assessment may aid risk stratification and guide-targeted intervention in COPD and should not be limited to people aged >65 years., Competing Interests: Competing interests: FM is the principal supervisor of PH (first author) who is funded by a MRC Clinical Research Training Fellowship (Grant reference: MR/S021949/1) which supported PH to do this work. FM is also a principal investigator or co-investigator on grants funded by the MRC, NIHR, Wellcome, CSO, and EPSRC to undertake multimorbidity research. The funds go to FM’s institution, the University of Glasgow., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Infection with SARS-CoV-2 virus (COVID-19) impacts disadvantaged groups most. Lifestyle factors are also associated with adverse COVID-19 outcomes. To inform COVID-19 policy and interventions, we explored effect modification of socioeconomic-status (SES) on associations between lifestyle and COVID-19 outcomes., Methods: Using data from UK-Biobank, a large prospective cohort of 502,536 participants aged 37-73 years recruited between 2006 and 2010, we assigned participants a lifestyle score comprising nine factors. Poisson regression models with penalised splines were used to analyse associations between lifestyle score, deprivation (Townsend), and COVID-19 mortality and severe COVID-19. Associations between each exposure and outcome were examined independently before participants were dichotomised by deprivation to examine exposures jointly. Models were adjusted for sociodemographic/health factors., Results: Of 343,850 participants (mean age > 60 years) with complete data, 707 (0.21%) died from COVID-19 and 2506 (0.76%) had severe COVID-19. There was evidence of a nonlinear association between lifestyle score and COVID-19 mortality but limited evidence for nonlinearity between lifestyle score and severe COVID-19 and between deprivation and COVID-19 outcomes. Compared with low deprivation, participants in the high deprivation group had higher risk of COVID-19 outcomes across the lifestyle score. There was evidence for an additive interaction between lifestyle score and deprivation. Compared with participants with the healthiest lifestyle score in the low deprivation group, COVID-19 mortality risk ratios (95% CIs) for those with less healthy scores in low versus high deprivation groups were 5.09 (1.39-25.20) and 9.60 (4.70-21.44), respectively. Equivalent figures for severe COVID-19 were 5.17 (2.46-12.01) and 6.02 (4.72-7.71). Alternative SES measures produced similar results., Conclusions: Unhealthy lifestyles are associated with higher risk of adverse COVID-19, but risks are highest in the most disadvantaged, suggesting an additive influence between SES and lifestyle. COVID-19 policy and interventions should consider both lifestyle and SES. The greatest public health benefit from lifestyle focussed COVID-19 policy and interventions is likely to be seen when greatest support for healthy living is provided to the most disadvantaged groups., (© 2022. The Author(s).)

Objective: To assess the prevalence of frailty in rheumatoid arthritis (RA) and its association with baseline and longitudinal disease activity, all-cause mortality and hospitalisation., Participants: People with RA identified from the Scottish Early Rheumatoid Arthritis (SERA) inception cohort (newly diagnosed, mean age 58.2 years) and UK Biobank (established disease identified using diagnostic codes, mean age 59 years). Frailty was quantified using the frailty index (both datasets) and frailty phenotype (UK Biobank only). Disease activity was assessed using Disease Activity Score in 28 joints (DAS28) in SERA. Associations between baseline frailty and all-cause mortality and hospitalisation was estimated after adjusting for age, sex, socioeconomic status, smoking and alcohol, plus DAS28 in SERA., Results: Based on the frailty index, frailty was common in SERA (12% moderate, 0.2% severe) and UK Biobank (20% moderate, 3% severe). In UK Biobank, 23% were frail using frailty phenotype. Frailty index was associated with DAS28 in SERA, as well as age and female sex in both cohorts. In SERA, as DAS28 lessened over time with treatment, mean frailty index also decreased. The frailty index was associated with all-cause mortality (HR moderate/severe frailty vs robust 4.14 (95% CI 1.49 to 11.51) SERA, 1.68 (95% CI 1.26 to 2.13) UK Biobank) and unscheduled hospitalisation (incidence rate ratio 2.27 (95% CI 1.45 to 3.57) SERA 2.74 (95% CI 2.29 to 3.29) UK Biobank). In UK Biobank, frailty phenotype also associated with mortality and hospitalisation., Conclusion: Frailty is common in early and established RA and associated with hospitalisation and mortality. Frailty in RA is dynamic and, for some, may be ameliorated through controlling disease activity in early disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: SELFBACK, an artificial intelligence (AI)-based app delivering evidence-based tailored self-management support to people with low back pain (LBP), has been shown to reduce LBP-related disability when added to usual care. LBP commonly co-occurs with multimorbidity (≥ 2 long-term conditions) or pain at other musculoskeletal sites, so this study explores if these factors modify the effect of the SELFBACK app or influence outcome trajectories over time., Methods: Secondary analysis of a randomized controlled trial with 9-month follow-up. Primary outcome is as follows: LBP-related disability (Roland Morris Disability Questionnaire, RMDQ). Secondary outcomes are as follows: stress/depression/illness perception/self-efficacy/general health/quality of life/physical activity/global perceived effect. We used linear mixed models for continuous outcomes and logistic generalized estimating equation for binary outcomes. Analyses were stratified to assess effect modification, whereas control (n = 229) and intervention (n = 232) groups were pooled in analyses of outcome trajectories., Results: Baseline multimorbidity and co-occurring musculoskeletal pain sites did not modify the effect of the SELFBACK app. The effect was somewhat stronger in people with multimorbidity than among those with LBP only (difference in RMDQ due to interaction, - 0.9[95 % CI - 2.5 to 0.6]). Participants with a greater number of long-term conditions and more co-occurring musculoskeletal pain had higher levels of baseline disability (RMDQ 11.3 for ≥ 2 long-term conditions vs 9.5 for LBP only; 11.3 for ≥ 4 musculoskeletal pain sites vs 10.2 for ≤ 1 additional musculoskeletal pain site); along with higher baseline scores for stress/depression/illness perception and poorer pain self-efficacy/general health ratings. In the pooled sample, LBP-related disability improved slightly less over time for people with ≥ 2 long-term conditions additional to LBP compared to no multimorbidity and for those with ≥4 co-occurring musculoskeletal pain sites compared to ≤ 1 additional musculoskeletal pain site (difference in mean change at 9 months = 1.5 and 2.2, respectively). All groups reported little improvement in secondary outcomes over time., Conclusions: Multimorbidity or co-occurring musculoskeletal pain does not modify the effect of the selfBACK app on LBP-related disability or other secondary outcomes. Although people with these health problems have worse scores both at baseline and 9 months, the AI-based selfBACK app appears to be helpful for those with multimorbidity or co-occurring musculoskeletal pain., Trial Registration: NCT03798288 . Date of registration: 9 January 2019., (© 2022. The Author(s).)

Background: International guidelines consistently endorse the promotion of self-management for people with low back pain (LBP); however, implementation of these guidelines remains a challenge. Digital health interventions, such as those that can be provided by smartphone apps, have been proposed as a promising mode of supporting self-management in people with chronic conditions, including LBP. However, the evidence base for digital health interventions to support self-management of LBP is weak, and detailed descriptions and documentation of the interventions are lacking. Structured intervention mapping (IM) constitutes a 6-step process that can be used to guide the development of complex interventions., Objective: The aim of this paper is to describe the IM process for designing and creating an app-based intervention designed to support self-management of nonspecific LBP to reduce pain-related disability., Methods: The first 5 steps of the IM process were systematically applied. The core processes included literature reviews, brainstorming and group discussions, and the inclusion of stakeholders and representatives from the target population. Over a period of >2 years, the intervention content and the technical features of delivery were created, tested, and revised through user tests, feasibility studies, and a pilot study., Results: A behavioral outcome was identified as a proxy for reaching the overall program goal, that is, increased use of evidence-based self-management strategies. Physical exercises, education, and physical activity were the main components of the self-management intervention and were designed and produced to be delivered via a smartphone app. All intervention content was theoretically underpinned by the behavior change theory and the normalization process theory., Conclusions: We describe a detailed example of the application of the IM approach for the development of a theory-driven, complex, and digital intervention designed to support self-management of LBP. This description provides transparency in the developmental process of the intervention and can be a possible blueprint for designing and creating future digital health interventions for self-management., (©Malene Jagd Svendsen, Louise Fleng Sandal, Per Kjær, Barbara I Nicholl, Kay Cooper, Frances Mair, Jan Hartvigsen, Mette Jensen Stochkendahl, Karen Søgaard, Paul Jarle Mork, Charlotte Rasmussen. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 24.01.2022.)

Objectives: Chronic pain is often experienced alongside other long-term conditions (LTCs), yet our understanding of this, particularly in relation to multimorbidity (≥2 LTCs) is poor. We aimed to examine associations between the presence/extent of chronic pain with type/number of LTCs experienced., Methods: We examined the relationship between number/type of LTCs (N = 45) in UK Biobank participants (n = 500,295) who self-reported chronic pain lasting ≥3 months in seven body sites or widespread. Relative risk ratios (RRR) for presence/extent of chronic pain sites were compared using logistic regression adjusted for sociodemographic (sex/age/socioeconomic status) and lifestyle factors (smoking/alcohol intake/BMI/physical activity)., Results: 218,648 participants self-reported chronic pain. Of these, 69.1% reported ≥1 LTC and 36.2% reported ≥2 LTCs. In 31/45 LTCs examined, >50% of participants experienced chronic pain. Chronic pain was common with migraine/headache and irritable bowel syndrome where pain is a primary symptom, but also with mental health conditions and diseases of the digestive system. Participants with >4 LTCs were over three times as likely to have chronic pain (RRR 3.56, 95% confidence intervals (CIs) 3.44-3.68) and 20 times as likely to have widespread chronic pain (RRR 20.13, 95% CI 18.26-22.19) as those with no LTCs., Conclusions: Chronic pain is extremely common across a wide range of LTCs. People with multimorbidity were at higher risk of having a greater extent of chronic pain. These results show that chronic pain is a key factor for consideration in the management of patients with LTCs or multimorbidity., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Chronic kidney disease (CKD) typically co-exists with multimorbidity (presence of 2 or more long-term conditions: LTCs). The associations between CKD, multimorbidity and hospitalisation rates are not known. The aim of this study was to examine hospitalisation rates in people with multimorbidity with and without CKD. Amongst people with CKD, the aim was to identify risk factors for hospitalisation., Methods: Two cohorts were studied in parallel: UK Biobank (a prospective research study: 2006-2020) and Secure Anonymised Information Linkage Databank (SAIL: a routine care database, Wales, UK: 2011-2018). Adults were included if their kidney function was measured at baseline. Nine categories of participants were used: zero LTCs; one, two, three and four or more LTCs excluding CKD; and one, two, three and four or more LTCs including CKD. Emergency hospitalisation events were obtained from linked hospital records., Results: Amongst 469,339 UK Biobank participants, those without CKD had a median of 1 LTC and those with CKD had a median of 3 LTCs. Amongst 1,620,490 SAIL participants, those without CKD had a median of 1 LTC and those with CKD had a median of 5 LTCs. Compared to those with zero LTCs, participants with four or more LTCs (excluding CKD) had high event rates (rate ratios UK Biobank 4.95 (95% confidence interval 4.82-5.08)/SAIL 3.77 (3.71-3.82)) with higher rates if CKD was one of the LTCs (rate ratios UK Biobank 7.83 (7.42-8.25)/SAIL 9.92 (9.75-10.09)). Amongst people with CKD, risk factors for hospitalisation were advanced CKD, age over 60, multiple cardiometabolic LTCs, combined physical and mental LTCs and complex patterns of multimorbidity (LTCs in three or more body systems)., Conclusions: People with multimorbidity have high rates of hospitalisation. Importantly, the rates are two to three times higher when CKD is one of the multimorbid conditions. Further research is needed into the mechanism underpinning this to inform strategies to prevent hospitalisation in this very high-risk group., (© 2021. The Author(s).)

Background/aims: Upper gastrointestinal cancers (oesophageal/stomach) have high mortality rates and are often diagnosed after the disease has progressed, making it important to identify populations at greater risk of upper gastrointestinal (UGI) cancer to promote earlier diagnosis. This study aims to determine if there is an association between a broad range of long-term conditions (LTCs) and incidence of UGI cancers., Method: A prospective-based cohort of 487,798 UK Biobank participants (age 37-73 years) after excluding previous UGI cancer. Least Absolute Shrinkage and Selection Operator (LASSO) regression used to identify candidate LTCs as predictors for UGI cancer. Strength of association was studied using Cox's regression adjusting for demographics and lifestyle factors., Results: After median follow-up period of 86 months, 598 participants developed oesophageal cancer; 397 developed stomach cancer. In fully adjusted models, participants with alcohol addiction (Hazard Ratio-HR 4.11, 95% Confidence Interval-CI 2.01-8.43), Barrett's oesophagus (HR 5.68, 95% CI 3.36-9.58), bronchiectasis (HR 2.72, 95% CI 1.01-7.31), diabetes (HR 1.38, 95% CI 1.06-1.81), hiatus hernia (HR 1.69, 95% CI 1.16-2.45), Parkinson's disease (HR 3.86, 95% CI 1.60-9.37) and psoriasis/eczema (HR 1.53, 95% 1.08-2.17) were observed to have a higher risk of oesophageal cancer. Stomach cancer incidence was higher among participants with anorexia/bulimia (HR 8.86, 95% CI 1.20-65.14), Barrett's oesophagus (HR 3.37, 95% 1.39-8.14), chronic fatigue syndrome (HR 3.36, 95% CI 1.25-9.03), glaucoma (HR 2.06, 95% CI 1.16-3.67), multiple sclerosis (HR 4.60, 95% CI 1.71-12.34), oesophageal stricture (HR 1.04, 95% CI 1.46-74.46) and pernicious anaemia (HR 6.93, 95% CI 3.42-14.03)., Conclusion: Previously unrecognised LTCs may have a role in symptom appraisal and risk assessment of UGI cancer in primary care. Further research should explore mechanisms underpinning these findings and determine whether they are replicable in other populations., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Importance: Lower back pain (LBP) is a prevalent and challenging condition in primary care. The effectiveness of an individually tailored self-management support tool delivered via a smartphone app has not been rigorously tested., Objective: To investigate the effectiveness of selfBACK, an evidence-based, individually tailored self-management support system delivered through an app as an adjunct to usual care for adults with LBP-related disability., Design, Setting, and Participants: This randomized clinical trial with an intention-to-treat data analysis enrolled eligible individuals who sought care for LBP in a primary care or an outpatient spine clinic in Denmark and Norway from March 8 to December 14, 2019. Participants were 18 years or older, had nonspecific LBP, scored 6 points or higher on the Roland-Morris Disability Questionnaire (RMDQ), and had a smartphone and access to email., Interventions: The selfBACK app provided weekly recommendations for physical activity, strength and flexibility exercises, and daily educational messages. Self-management recommendations were tailored to participant characteristics and symptoms. Usual care included advice or treatment offered to participants by their clinician., Main Outcomes and Measures: Primary outcome was the mean difference in RMDQ scores between the intervention group and control group at 3 months. Secondary outcomes included average and worst LBP intensity levels in the preceding week as measured on the numerical rating scale, ability to cope as assessed with the Pain Self-Efficacy Questionnaire, fear-avoidance belief as assessed by the Fear-Avoidance Beliefs Questionnaire, cognitive and emotional representations of illness as assessed by the Brief Illness Perception Questionnaire, health-related quality of life as assessed by the EuroQol-5 Dimension questionnaire, physical activity level as assessed by the Saltin-Grimby Physical Activity Level Scale, and overall improvement as assessed by the Global Perceived Effect scale. Outcomes were measured at baseline, 6 weeks, 3 months, 6 months, and 9 months., Results: A total of 461 participants were included in the analysis; the population had a mean [SD] age of 47.5 [14.7] years and included 255 women (55%). Of these participants, 232 were randomized to the intervention group and 229 to the control group. By the 3-month follow-up, 399 participants (87%) had completed the trial. The adjusted mean difference in RMDQ score between the 2 groups at 3 months was 0.79 (95% CI, 0.06-1.51; P = .03), favoring the selfBACK intervention. The percentage of participants who reported a score improvement of at least 4 points on the RMDQ was 52% in the intervention group vs 39% in the control group (adjusted odds ratio, 1.76; 95% CI, 1.15-2.70; P = .01)., Conclusions and Relevance: Among adults who sought care for LBP in a primary care or an outpatient spine clinic, those who used the selfBACK system as an adjunct to usual care had reduced pain-related disability at 3 months. The improvement in pain-related disability was small and of uncertain clinical significance. Process evaluation may provide insights into refining the selfBACK app to increase its effectiveness., Trial Registration: ClinicalTrials.gov Identifier: NCT03798288.

Introduction: The aim of this study was to determine risk of being SARS-CoV-2 positive and severe infection (associated with hospitalization/mortality) in those with family history of diabetes., Methods: We used UK Biobank, an observational cohort recruited between 2006 and 2010. We compared the risk of being SARS-CoV-2 positive and severe infection for those with family history of diabetes (mother/father/sibling) against those without., Results: Of 401,268 participants in total, 13,331 tested positive for SARS-CoV-2 and 2282 had severe infection by end of January 2021. In unadjusted models, participants with ≥2 family members with diabetes were more likely to be SARS-CoV-2 positive (risk ratio-RR 1.35; 95% confidence interval-CI 1.24-1.47) and severe infection (RR 1.30; 95% CI 1.04-1.59), compared to those without. The excess risk of being tested positive for SARS-CoV-2 was attenuated but significant after adjusting for demographics, lifestyle factors, multimorbidity and presence of cardiometabolic conditions. The excess risk for severe infection was no longer significant after adjusting for demographics, lifestyle factors, multimorbidity and presence of cardiometabolic conditions, and was absent when excluding incident diabetes., Conclusion: The totality of the results suggests that good lifestyle and not developing incident diabetes may lessen risks of severe infections in people with a strong family of diabetes., (© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background: Multimorbidity [the presence of two or more long-term conditions (LTCs)] is associated with a heightened risk of mortality, but little is known about its relationship with the risk of kidney events., Methods: Associations between multimorbidity and major adverse kidney events [MAKE: the need for long-term kidney replacement therapy, doubling of serum creatinine, fall of estimated glomerular filtration rate (eGFR) to <15 mL/min/1.73 m 2 or 30% decline in eGFR] were studied in 68 505 participants from the UK Biobank cohort. Participants were enrolled in the study between 2006 and 2010. Associations between LTC counts and MAKE were tested using survival analyses accounting for the competing risk of death., Results: Over a median follow-up period of 12.0 years, 2963 participants had MAKE. There were associations between LTC count categories and the risk of MAKE [one LTC adjusted subhazard ratio (sHR) = 1.29, 95% confidence interval (CI) 1.15-1.45; two LTCs sHR = 1.74 (95% CI 1.55-1.96); and three or more LTCs sHR = 2.41 (95% CI 2.14-2.71)]. This finding was more pronounced when only cardiometabolic LTCs were considered [one LTC sHR = 1.58 (95% CI 1.45-1.73); two LTCs sHR = 3.17 (95% CI 2.80-3.59); and three or more LTCs sHR = 5.24 (95% CI 4.34-6.33)]. Combinations of LTCs associated with MAKE were identified. Diabetes, hypertension and coronary heart disease featured most commonly in high-risk combinations., Conclusions: Multimorbidity, and in particular cardiometabolic multimorbidity, is a risk factor for MAKE. Future research should study groups of patients who are at high risk of progressive kidney disease based on the number and type of LTCs., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception., Competing Interests: The authors have declared that no competing interests exist.

Background: Alcohol consumption is a leading contributor to death and disability worldwide, but previous research has not examined the effects of different patterns of alcohol consumption. The study objective was to understand the relationship between different alcohol consumption patterns and adverse health outcomes risk, adjusting for average amount consumed among regular drinkers., Methods: This was a prospective cohort study of UK Biobank (UKB) participants. Abstainers, infrequent alcohol consumers or those with previous cancer, myocardial infarction (MI), stroke or liver cirrhosis were excluded. We used beverage type, consumption with food and consumption frequency as exposures and adjusted for potential confounding. All-cause mortality, major cardiovascular events-MACE (MI/stroke/cardiovascular death), accidents/injuries, liver cirrhosis, all-cause and alcohol-related cancer incidence over 9-year median follow-up period were outcomes of interest., Results: The final sample size for analysis was N = 309,123 (61.5% of UKB sample). Spirit drinking was associated with higher adjusted mortality (hazard ratio (HR) 1.25; 95% confidence intervals (CI) 1.14-1.38), MACE (HR 1.31; 95% CI 1.15-1.50), cirrhosis (HR 1.48; 95% CI 1.08-2.03) and accident/injuries (HR 1.10; 95% CI 1.03-1.19) risk compared to red wine drinking, after adjusting for the average weekly alcohol consumption amounts. Beer/cider drinkers were also at a higher risk of mortality (HR 1.18; 95% CI 1.10-1.27), MACE (HR 1.16; 95% CI 1.05-1.27), cirrhosis (HR 1.36; 95% CI 1.06-1.74) and accidents/injuries (HR 1.11; 95% CI 1.06-1.17). Alcohol consumption without food was associated with higher adjusted mortality (HR 1.10; 95% CI 1.02-1.17) risk, compared to consumption with food. Alcohol consumption over 1-2 times/week had higher adjusted mortality (HR 1.09; 95% CI 1.03-1.16) and MACE (HR 1.14; 95% CI 1.06-1.23) risk, compared to 3-4 times/week, adjusting for the amount of alcohol consumed., Conclusion: Red wine drinking, consumption with food and spreading alcohol intake over 3-4 days were associated with lower risk of mortality and vascular events among regular alcohol drinkers, after adjusting for the effects of average amount consumed. Selection bias and residual confounding are important possible limitations. These findings, if replicated and validated, have the potential to influence policy and practice advice on less harmful patterns of alcohol consumption.

Objectives: Low back pain (LBP) is a leading contributor to disability globally. Self-management is a core component of LBP management. We aimed to synthesise published qualitative literature concerning digital health interventions (DHIs) to support LBP self-management to: (1) determine engagement strategies, (2) identify barriers and facilitators affecting patient uptake/utilisation and (3) develop a preliminary conceptual model of barriers and facilitators to uptake/utilisation., Design: Systematic review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines., Data Sources: MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Library, DoPHER, TRoPHI, Web of Science and OT Seeker, from January 2000 to December 2018, using the concepts: LBP, DHI and self-management., Eligibility Criteria: Peer-reviewed qualitative study (or component) examining engagement with, or barriers and/or facilitators to the uptake/utilisation of an interactive DHI for self-management of LBP in adults (community, primary or secondary care settings)., Data Extraction and Synthesis: Standardised data extraction form was completed. COREQ (Consolidated criteria for Reporting Qualitative research) checklist was used to assess methodology. Data was synthesised narratively for engagement strategies, thematically for barriers/facilitators to uptake/utilisation and normalisation process theory was applied to produce a conceptual model., Results: We identified 14 191 citations, of which 105 full-text articles were screened, and five full-text articles from four studies included. These were from community and primary care contexts in Europe and the USA, and involved 56 adults with LBP and 19 healthcare professionals. There was a lack of consideration on how to sustain engagement with DHIs. Examination of barriers and facilitators for uptake/utilisation identified four major themes: IT (information technology) usability-accessibility; quality-quantity of content; tailoring-personalisation; and motivation-support. These themes informed the development of a preliminary conceptual model for uptake/utilisation of a DHI for LBP self-management., Conclusions: We highlight key barriers and facilitators that should be considered when designing DHIs for LBP self-management. Our findings are in keeping with reviews of DHIs for other long-term conditions, implying these findings may not be condition specific., Systematic Review Registration: A protocol for this systematic review was registered with https://www.crd.york.ac.uk/PROSPERO/ (CRD42016051182) on 10 November 2016. https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?ID=CRD42016051182., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To explore the prevalence of multimorbidity as well as individual and combinations of long-term conditions (LTCs) in people with type 2 diabetes (T2D) attending Australian general practice, using electronic health record (EHR) data. We also examine the association between multimorbidity condition count (total/concordant(T2D related)/discordant(unrelated)) and glycaemia (glycated haemoglobin, HbA1c)., Design: Cross-sectional study., Setting: Australian general practice., Participants: 69 718 people with T2D with a general practice encounter between 2013 and 2015 captured in the MedicineInsight database (EHR Data from 557 general practices and >3.8 million Australian patients)., Primary and Secondary Outcome Measures: Prevalence of multimorbidity, individual and combinations of LTCs. Multivariable linear regression models used to examine associations between multimorbidity counts and HbA1c (%)., Results: Mean (SD) age 66.42 (12.70) years, 46.1% female and mean (SD) HbA1c 7.1 (1.4)%. More than 90% of participants with T2D were living with multimorbidity. Discordant conditions were more prevalent (83.4%) than concordant conditions (69.9 %). The three most prevalent discordant conditions were: painful conditions (55.4%), dyspepsia (31.6%) and depression (22.8%). The three most prevalent concordant conditions were hypertension (61.4%), coronary heart disease (17.1%) and chronic kidney disease (8.5%). The three most common combinations of conditions were: painful conditions and hypertension (38.8%), painful conditions and dyspepsia (23.1%) and hypertension and dyspepsia (22.7%). We found no associations between any multimorbidity counts (total, concordant and discordant) or combinations and HbA1c., Conclusions: Multimorbidity was common in our cohort of people with T2D attending Australian general practice, but was not associated with glycaemia. Although we did not explore mortality in this study, our results suggest that the increased mortality in those with multimorbidity and T2D observed in other studies may not be linked to glycaemia. Interestingly, discordant conditions were more prevalent than concordant conditions with painful conditions being the second most common comorbidity. Better understanding of the implications of different patterns of multimorbidity in people with T2D will allow more effective tailored care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate how the type and number of long-term conditions (LTCs) impact on all-cause mortality and major adverse cardiovascular events (MACE) in people with rheumatoid arthritis (RA)., Design: Population-based longitudinal cohort study., Setting: UK Biobank., Participants: UK Biobank participants (n=502 533) aged between 37 and 73 years old., Primary Outcome Measures: Primary outcome measures were risk of all-cause mortality and MACE., Methods: We examined the relationship between LTC count and individual comorbid LTCs (n=42) on adverse clinical outcomes in participants with self-reported RA (n=5658). Risk of all-cause mortality and MACE were compared using Cox's proportional hazard models adjusted for lifestyle factors (smoking, alcohol intake, physical activity), demographic factors (sex, age, socioeconomic status) and rheumatoid factor., Results: 75.7% of participants with RA had multimorbidity and these individuals were at increased risk of all-cause mortality and MACE. RA and > 4 LTCs showed a threefold increased risk of all-cause mortality (HR 3.30, 95% CI 2.61 to 4.16), and MACE (HR 3.45, 95% CI 2.66 to 4.49) compared with those without LTCs. Of the comorbid LTCs studied, osteoporosis was most strongly associated with adverse outcomes in participants with RA compared with those without RA or LTCs: twofold increased risk of all-cause mortality (HR 2.20, 95% CI 1.55 to 3.12) and threefold increased risk of MACE (HR 3.17, 95% CI 2.27 to 4.64). These findings remained in a subset (n=3683) with RA diagnosis validated from clinical records or medication reports., Conclusion: Those with RA and other LTCs, particularly comorbid osteoporosis, are at increased risk of adverse outcomes, although the role of corticosteroids could not be evaluated in this study. These results are clinically relevant for the monitoring and management of RA across the healthcare system, and future clinical guidelines for RA should acknowledge the importance of multimorbidity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Frailty has been associated with worse prognosis following COVID-19 infection. While several studies have reported the association between frailty and COVID-19 mortality or length of hospital stay, there have been no community-based studies on the association between frailty and risk of severe infection. Considering that different definitions have been identified to assess frailty, this study aimed to compare the association between frailty and severe COVID-19 infection in UK Biobank using two frailty classifications: the frailty phenotype and the frailty index., Methods: A total of 383,845 UK Biobank participants recruited 2006-2010 in England (211,310 [55.1%] women, baseline age 37-73 years) were included. COVID-19 test data were provided by Public Health England (available up to 28 June 2020). An adapted version of the frailty phenotype derived by Fried et al. was used to define frailty phenotype (robust, pre-frail, or frail). A previously validated frailty index was derived from 49 self-reported questionnaire items related to health, disease and disability, and mental wellbeing (robust, mild frailty, and moderate/severe frailty). Both classifications were derived from baseline data (2006-2010). Poisson regression models with robust standard errors were used to analyse the associations between both frailty classifications and severe COVID-19 infection (resulting in hospital admission or death), adjusted for sociodemographic and lifestyle factors., Results: Of UK Biobank participants included, 802 were admitted to hospital with and/or died from COVID19 (323 deaths and 479 hospitalisations). After analyses were adjusted for sociodemographic and lifestyle factors, a higher risk of COVID-19 was observed for pre-frail (risk ratio (RR) 1.47 [95% CI 1.26; 1.71]) and frail (RR 2.66 [95% CI 2.04; 3.47]) individuals compared to those classified as robust using the frailty phenotype. Similar results were observed when the frailty index was used (RR mildly frail 1.46 [95% CI 1.26; 1.71] and RR moderate/severe frailty 2.43 [95% CI 1.91; 3.10])., Conclusions: Frailty was associated with a higher risk of severe COVID-19 infection resulting in hospital admission or death, irrespective of how it was measured and independent of sociodemographic and lifestyle factors. Public health strategies need to consider the additional risk that COVID-19 poses in individuals with frailty, including which additional preventive measures might be required.

Aims: To explore associations between multimorbidity condition counts (total; concordant (diabetes-related); discordant (unrelated to diabetes)) and glycaemia (HbA1c; glycaemic variability (GV); time in range (TIR)) using data from a randomised controlled trial examining effectiveness of continuous glucose monitoring (CGM) in people with type 2 diabetes (T2D)., Methods: Cross-sectional study: 279 people with T2D using baseline data from the General Practice Optimising Structured MOnitoring To Improve Clinical outcomes (GP-OSMOTIC) trial from 25 general practices in Australia. Number of long-term conditions (LTCs) in addition to T2D used to quantify total/concordant/discordant multimorbidity counts. GV (measured by coefficient of variation (CV)) and TIR derived from CGM data. Multivariable linear regression models used to examine associations between multimorbidity counts, HbA1c (%), GV and TIR., Results: Mean (SD) age of participants 60.4 (9.9) years; 40.9% female. Multimorbidity was present in 89.2% of participants. Most prevalent comorbid LTCs: hypertension (57.4%), painful conditions (29.8%), coronary heart disease (22.6%) and depression (19.0%). No evidence of associations between multimorbidity counts, HbA1c, GV and TIR., Conclusions: While multimorbidity was common in this T2D cohort, it was not associated with HbA1c, CV or TIR. Future studies should explore factors other than glycaemia that contribute to the increased mortality observed in those with multimorbidity and T2D., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Implementation and process evaluation is vital for understanding how interventions function in different settings, including if and why interventions have different effects or do not work at all., Objective: This paper presents the protocol for an implementation and process evaluation embedded in a multicenter randomized controlled trial conducted in Denmark and Norway (the selfBACK project). selfBACK is a data-driven decision support system that provides participants with weekly self-management plans for low back pain. These plans are delivered through a smartphone app and tailored to individual participants by using case-based reasoning methodology. In the trial, we compare selfBACK in addition to usual care with usual care alone., Methods: The aim of this study is to conduct a convergent mixed-methods implementation and process evaluation of the selfBACK app by following the reach, effectiveness, adoption, implementation, and maintenance framework. We will evaluate the process of implementing selfBACK and investigate how participants use the intervention in daily life. The evaluation will also cover the reach of the intervention, health care provider willingness to adopt it, and participant satisfaction with the intervention. We will gather quantitative measures by questionnaires and measures of data analytics on app use and perform a qualitative exploration of the implementation using semistructured interviews theoretically informed by normalization process theory. Data collection will be conducted between March 2019 and October 2020., Results: The trial opened for recruitment in February 2019. This mixed-methods implementation and evaluation study is embedded in the randomized controlled trial and will be collecting data from March 2019 to October 2020; dissemination of trial results is planned thereafter. The results from the process evaluation are expected 2021-2022., Conclusions: This study will provide a detailed understanding of how self-management of low back pain can be improved and how a digital health intervention can be used as an add-on to usual care to support patients to self-manage their low back pain. We will provide knowledge that can be used to explore the possibilities of extending the generic components of the selfBACK system and key drivers that could be of use in other conditions and diseases where self-management is an essential prevention or treatment strategy., Trial Registration: ClinicalTrials.gov NCT03798288; https://www.clinicaltrials.gov/ct2/show/NCT03798288., International Registered Report Identifier (irrid): DERR1-10.2196/20308., (©Charlotte Diana Nørregaard Rasmussen, Malene Jagd Svendsen, Karen Wood, Barbara I Nicholl, Frances S Mair, Louise Fleng Sandal, Paul Jarle Mork, Karen Søgaard, Kerstin Bach, Mette Jensen Stochkendahl. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 29.10.2020.)

Background: It is now well recognised that the risk of severe COVID-19 increases with some long-term conditions (LTCs). However, prior research primarily focuses on individual LTCs and there is a lack of data on the influence of multimorbidity (≥2 LTCs) on the risk of COVID-19. Given the high prevalence of multimorbidity, more detailed understanding of the associations with multimorbidity and COVID-19 would improve risk stratification and help protect those most vulnerable to severe COVID-19. Here we examine the relationships between multimorbidity, polypharmacy (a proxy of multimorbidity), and COVID-19; and how these differ by sociodemographic, lifestyle, and physiological prognostic factors., Methods and Findings: We studied data from UK Biobank (428,199 participants; aged 37-73; recruited 2006-2010) on self-reported LTCs, medications, sociodemographic, lifestyle, and physiological measures which were linked to COVID-19 test data. Poisson regression models examined risk of COVID-19 by multimorbidity/polypharmacy and effect modification by COVID-19 prognostic factors (age/sex/ethnicity/socioeconomic status/smoking/physical activity/BMI/systolic blood pressure/renal function). 4,498 (1.05%) participants were tested; 1,324 (0.31%) tested positive for COVID-19. Compared with no LTCs, relative risk (RR) of COVID-19 in those with 1 LTC was no higher (RR 1.12 (CI 0.96-1.30)), whereas those with ≥2 LTCs had 48% higher risk; RR 1.48 (1.28-1.71). Compared with no cardiometabolic LTCs, having 1 and ≥2 cardiometabolic LTCs had a higher risk of COVID-19; RR 1.28 (1.12-1.46) and 1.77 (1.46-2.15), respectively. Polypharmacy was associated with a dose response higher risk of COVID-19. All prognostic factors were associated with a higher risk of COVID-19 infection in multimorbidity; being non-white, most socioeconomically deprived, BMI ≥40 kg/m2, and reduced renal function were associated with the highest risk of COVID-19 infection: RR 2.81 (2.09-3.78); 2.79 (2.00-3.90); 2.66 (1.88-3.76); 2.13 (1.46-3.12), respectively. No multiplicative interaction between multimorbidity and prognostic factors was identified. Important limitations include the low proportion of UK Biobank participants with COVID-19 test data (1.05%) and UK Biobank participants being more affluent, healthier and less ethnically diverse than the general population., Conclusions: Increasing multimorbidity, especially cardiometabolic multimorbidity, and polypharmacy are associated with a higher risk of developing COVID-19. Those with multimorbidity and additional factors, such as non-white ethnicity, are at heightened risk of COVID-19., Competing Interests: JPP is a member of the Scientific Advisory Committee of UK Biobank. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no potential, perceived, or real conflicts of interest.

Background: Saudi Arabia is continuously working on developing its health care system, however with the high prevalence of type 2 diabetes and comorbidities, such as cardiovascular diseases, self-management education programmes are essential. As part of a planned series of studies to develop a culturally sensitive type 2 diabetes self-management programme, this study explores the need versus barriers and facilitators relevant to implementing a national programme for type 2 diabetes self-management education within the community and health care system in Saudi Arabia., Methods: A qualitative methodology was used to explore the views of a multidisciplinary group of diabetes health professionals and adult patients with type 2 diabetes. The views of nine health professionals working at a specialised diabetes care centre were gathered at two focus groups (four and five) that included doctors, nutritionists, health educators and nurses. Individual interviews with 12 patients with type 2 diabetes (six females and six males) attending the centre were also carried out. Recurring themes through the translated transcripts were studied and treated by the research group under pre-set protocols., Results: Focus groups with health professionals revealed three main themes. 1. Resources: availability of resources and how they impacted on performance and patients' care; 2.Familiarity with self-management education programmes: educating patients and raising awareness among them; and 3. Lifestyle: patients' lifestyle and how it could affect their compliance with self-management programmes. Interviews with patients also revealed three main themes. 1. Habits: post diagnosis changes in patients' attitudes and behaviours towards diet and physical activity; 2. Health education: awareness of managing type 2 diabetes through health centre advice or self-education; and 3. Culture and society: a lack of cultural or social support created by some social practices or conventions., Conclusion: The findings from this study highlight a gap in type 2 diabetes care system that can be breached through the development of a Saudi specific self-management programme for type 2 diabetes. The identified barriers and facilitators can be used for adapting a self-management programme to the Saudi context. However, initial training is needed for local health professionals to understand the mechanisms of self-management programmes. Such programmes will need to infiltrate to the society, and the patients' families, in particular to tackle the rising prevalence of type 2 diabetes in Saudi Arabia and provide a friendlier, more supportive environment for the current patients to self-manage their diabetes., Competing Interests: The authors have declared that no competing interests exist.

Background: Understanding of the role of ethnicity and socioeconomic position in the risk of developing SARS-CoV-2 infection is limited. We investigated this in the UK Biobank study., Methods: The UK Biobank study recruited 40-70-year-olds in 2006-2010 from the general population, collecting information about self-defined ethnicity and socioeconomic variables (including area-level socioeconomic deprivation and educational attainment). SARS-CoV-2 test results from Public Health England were linked to baseline UK Biobank data. Poisson regression with robust standard errors was used to assess risk ratios (RRs) between the exposures and dichotomous variables for being tested, having a positive test and testing positive in hospital. We also investigated whether ethnicity and socioeconomic position were associated with having a positive test amongst those tested. We adjusted for covariates including age, sex, social variables (including healthcare work and household size), behavioural risk factors and baseline health., Results: Amongst 392,116 participants in England, 2658 had been tested for SARS-CoV-2 and 948 tested positive (726 in hospital) between 16 March and 3 May 2020. Black and south Asian groups were more likely to test positive (RR 3.35 (95% CI 2.48-4.53) and RR 2.42 (95% CI 1.75-3.36) respectively), with Pakistani ethnicity at highest risk within the south Asian group (RR 3.24 (95% CI 1.73-6.07)). These ethnic groups were more likely to be hospital cases compared to the white British. Adjustment for baseline health and behavioural risk factors led to little change, with only modest attenuation when accounting for socioeconomic variables. Socioeconomic deprivation and having no qualifications were consistently associated with a higher risk of confirmed infection (RR 2.19 for most deprived quartile vs least (95% CI 1.80-2.66) and RR 2.00 for no qualifications vs degree (95% CI 1.66-2.42))., Conclusions: Some minority ethnic groups have a higher risk of confirmed SARS-CoV-2 infection in the UK Biobank study, which was not accounted for by differences in socioeconomic conditions, baseline self-reported health or behavioural risk factors. An urgent response to addressing these elevated risks is required.

Background: There is emerging interest in multimorbidity in type 2 diabetes (T2D), which can be either concordant (T2D related) or discordant (unrelated), as a way of understanding the burden of disease in T2D. Current diabetes guidelines acknowledge the complex nature of multimorbidity, the management of which should be based on the patient's individual clinical needs and comorbidities. However, although associations between multimorbidity, glycated haemoglobin (HbA1c), and mortality in people with T2D have been studied to some extent, significant gaps remain, particularly regarding different patterns of multimorbidity, including concordant and discordant conditions. This study explores associations between multimorbidity (total condition counts/concordant/discordant/different combinations of conditions), baseline HbA1c, and all-cause mortality in T2D., Methods and Findings: We studied two longitudinal cohorts of people with T2D using the UK Biobank (n = 20,569) and the Taiwan National Diabetes Care Management Program (NDCMP) (n = 59,657). The number of conditions in addition to T2D was used to quantify total multimorbidity, concordant, and discordant counts, and the effects of different combinations of conditions were also studied. Outcomes of interest were baseline HbA1c and all-cause mortality. For the UK Biobank and Taiwan NDCMP, mean (SD) ages were 60.2 (6.8) years and 60.8 (11.3) years; 7,579 (36.8%) and 31,339 (52.5%) were female; body mass index (BMI) medians (IQR) were 30.8 (27.7, 34.8) kg/m2 and 25.6 (23.5, 28.7) kg/m2; and 2,197 (10.8%) and 9,423 (15.8) were current smokers, respectively. Increasing total and discordant multimorbidity counts were associated with lower HbA1c and increased mortality in both datasets. In Taiwan NDCMP, for those with four or more additional conditions compared with T2D only, the mean difference (95% CI) in HbA1c was -0.82% (-0.88, -0.76) p < 0.001. In UK Biobank, hazard ratios (HRs) (95% CI) for all-cause mortality in people with T2D and one, two, three, and four or more additional conditions compared with those without comorbidity were 1.20 (0.91-1.56) p < 0.001, 1.75 (1.35-2.27) p < 0.001, 2.17 (1.67-2.81) p < 0.001, and 3.14 (2.43-4.03) p < 0.001, respectively. Both concordant/discordant conditions were significantly associated with mortality; however, HRs were largest for concordant conditions. Those with four or more concordant conditions had >5 times the mortality (5.83 [4.28-7.93] p <0.001). HRs for NDCMP were similar to those from UK Biobank for all multimorbidity counts. For those with two conditions in addition to T2D, cardiovascular diseases featured in 18 of the top 20 combinations most highly associated with mortality in UK Biobank and 12 of the top combinations in the Taiwan NDCMP. In UK Biobank, a combination of coronary heart disease and heart failure in addition to T2D had the largest effect size on mortality, with a HR (95% CI) of 4.37 (3.59-5.32) p < 0.001, whereas in the Taiwan NDCMP, a combination of painful conditions and alcohol problems had the largest effect size on mortality, with an HR (95% CI) of 4.02 (3.08-5.23) p < 0.001. One limitation to note is that we were unable to model for changes in multimorbidity during our study period., Conclusions: Multimorbidity patterns associated with the highest mortality differed between UK Biobank (a population predominantly comprising people of European descent) and the Taiwan NDCMP, a predominantly ethnic Chinese population. Future research should explore the mechanisms underpinning the observed relationship between increasing multimorbidity count and reduced HbA1c alongside increased mortality in people with T2D and further examine the implications of different patterns of multimorbidity across different ethnic groups. Better understanding of these issues, especially effects of condition type, will enable more effective personalisation of care., Competing Interests: The authors have declared that no competing interests exist.

Background: There is evidence that type 2 diabetes self-management programmes may have a positive impact on health outcomes of adults living in Gulf countries. However, none of the programmes evaluated were developed using evidence about the specific needs of adults with Type 2 diabetes living in the Gulf countries. This study is part of a wider programme of research, which uses a cultural adaptation framework to generate information on how to tailor type 2 diabetes self-management to the Saudi context., Methods: Secondary data analysis of the Saudi Health Interview Survey (SHIS) (N = 10,821) was conducted. Bivariate and multivariate logistic regression modelling assessed factors associated with type 2 diabetes and its control / self-management including sociodemographic factors (e.g. age, gender), lifestyle (e.g. diet, physical activity), and health seeking behaviours (e.g. chronic illnesses, health services)., Results: 7% (N = 808) of all participants had type 2 diabetes (59% male), however it represents 35% at or above 55 years. In multivariate analysis at older age, being overweight or obese, male, having hypertension, and reporting a reduction in health status in the 12 months prior to questionnaire completion, were significantly associated with having type 2 diabetes. Participants who reported walking for more than 10 min per day were less likely to report type 2 diabetes. Unexpectedly there was a significant association between type 2 diabetes and lower frequency of fast food intake, while increased fruit and vegetable intake was associated with poor glycaemic control., Conclusions: Being overweight and/or hypertensive are concomitant with type 2 diabetes in Saudi Arabia. Any self-management programmes for type 2 diabetes patients with either of these conditions should be tailored accordingly. Walking behaviours should be prioritised in Saudi self-management programmes. Prediabetes management programmes may be of special importance to the Saudi community.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by articular inflammation and systemic complications. Multimorbidity (the presence of two or more long-term health conditions) is highly prevalent in people with RA but the effect of multimorbidity on mortality and other health-related outcomes is poorly understood., Objective: To determine what is known about the effect, if any, of multimorbidity on mortality and health-related outcomes in individuals with RA., Design: Systematic review of the literature. The following electronic medical databases will be searched: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, The Cochrane Library and Scopus. Included studies will be quality appraised using the Quality in Prognostic Studies tool developed by the Cochrane Prognosis Methods Group. A narrative synthesis of findings will be undertaken and meta-analyses considered, if appropriate. This protocol adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols 2015 guidelines, ensuring the quality of the review., Conclusions: Understanding the influence of multimorbidity on mortality and other health-related outcomes in RA will provide an important basis of knowledge with the potential to improve future clinical management of RA. PROSPERO registration number: CRD42019137756., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Purpose: Anticholinergic burden (ACB), the cumulative effect of anticholinergic medications, is associated with adverse outcomes in older people but is less studied in middle-aged populations. Numerous scales exist to quantify ACB. The aims of this study were to quantify ACB in a large cohort using the 10 most common anticholinergic scales, to assess the association of each scale with adverse outcomes, and to assess overlap in populations identified by each scale., Methods: We performed a longitudinal analysis of the UK Biobank community cohort (502,538 participants, baseline age: 37-73 years, median years of follow-up: 6.2). The ACB was calculated at baseline using 10 scales. Baseline data were linked to national mortality register records and hospital episode statistics. The primary outcome was a composite of all-cause mortality and major adverse cardiovascular event (MACE). Secondary outcomes were all-cause mortality, MACE, hospital admission for fall/fracture, and hospital admission with dementia/delirium. Cox proportional hazards models (hazard ratio [HR], 95% CI) quantified associations between ACB scales and outcomes adjusted for age, sex, socioeconomic status, body mass index, smoking status, alcohol use, physical activity, and morbidity count., Results: Anticholinergic medication use varied from 8% to 17.6% depending on the scale used. For the primary outcome, ACB was significantly associated with all-cause mortality/MACE for each scale. The Anticholinergic Drug Scale was most strongly associated with mortality/MACE (HR = 1.12; 95% CI, 1.11-1.14 per 1-point increase in score). The ACB was significantly associated with all secondary outcomes. The Anticholinergic Effect on Cognition scale was most strongly associated with dementia/delirium (HR = 1.45; 95% CI, 1.3-1.61 per 1-point increase)., Conclusions: The ACB was associated with adverse outcomes in a middle- to older-aged population. Populations identified and effect size differed between scales. Scale choice influenced the population identified as potentially requiring reduction in ACB in clinical practice or intervention trials., (© 2020 Annals of Family Medicine, Inc.)

Chronic pain is a complex trait that is moderately heritable and genetically, as well as phenotypically, correlated with major depressive disorder (MDD). Use of the conditional false discovery rate (cFDR) approach, which leverages pleiotropy identified from existing GWAS outputs, has been successful in discovering novel associated variants in related phenotypes. Here, genome-wide association study outputs for both von Korff chronic pain grade and for MDD were used to identify variants meeting a cFDR threshold for each outcome phenotype separately, as well as a conjunctional cFDR (ccFDR) threshold for both phenotypes together. Using a moderately conservative threshold, we identified a total of 11 novel single nucleotide polymorphisms (SNPs), six of which were associated with chronic pain grade and nine of which were associated with MDD. Four SNPs on chromosome 14 were associated with both chronic pain grade and MDD. SNPs associated only with chronic pain grade were located within SLC16A7 on chromosome 12. SNPs associated only with MDD were located either in a gene-dense region on chromosome 1 harbouring LINC01360, LRRIQ3, FPGT and FPGT-TNNI3K, or within/close to LRFN5 on chromosome 14. The SNPs associated with both outcomes were also located within LRFN5. Several of the SNPs on chromosomes 1 and 14 were identified as being associated with expression levels of nearby genes in the brain and central nervous system. Overall, using the cFDR approach, we identified several novel genetic loci associated with chronic pain and we describe likely pleiotropic effects of a recently identified MDD locus on chronic pain.

Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype 'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches., Competing Interests: The authors have declared that no competing interests exist.