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Introduction Frailty and multimorbidity are common in type 2 diabetes (T2D), including people Methods Analysis of UK Biobank participants (n = 20,566) with T2D aged 40-72 years comparing two frailty measures (frailty phenotype and frailty index) and two multimorbidity measures (Charlson comorbidity index and a simply count of 40 long-term conditions (LTCs)). Outomes: mortality (all-cause, cardiovascular- and cancer-related mortality), Major Adverse Cardiovascular Event (MACE), hospitalization with hypoglycaemia or fall/fracture. Results Measure choice influenced the population identified: 42% of participants were identified as frail/multimorbid by at least one measure; only 2.2% were identified by all four measures. Both frailty and multimorbidity, by all measures, were prevalent throughout the age range studied. Each measure was associated with mortality, MACE, hypoglycaemia and falls. The absolute 5-year mortality risk was higher in older versus younger participants with a given level of frailty (e.g. 1.9%, and 9.9% in men aged 45 and 65, respectively, using frailty phenotype) or multimorbidity (e.g. 1.3%, and 7.8% in men with 4 LTCs aged 45 and 65, respectively). Using frailty phenotype, the relationship between higher HbA1c and mortality was stronger in frail compared with pre-frail or robust participants. Conclusion Assessment of frailty/multimorbidity should be embedded within routine management of middle-aged and older people with T2D. Method of identification as well as features such as age impact baseline risk and should influence clinical decisions (e.g. glycaemic control).

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.

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.

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.

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.

To assess the prevalence of frailty in rheumatoid arthritis (RA) and its association with baseline and longitudinal disease activity, all-cause mortality and hospitalisation.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.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.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.

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., Our aim was to determine risk of severe SARS‐CoV‐2 (infection associated with hospitalization/mortality) in those with family history of diabetes. Using UK Biobank data, the findings suggest that having ≥2 family members with diabetes is associated with higher risk of SARS‐CoV‐2 infection and severe infection, but that such risk may be attenuated by better lifestyle, and by avoiding development of diabetes.

This paper presents the design of a Clinician Dashboard to promote co-decision making between patients and clinicians. Targeted patients are those with non-specific low back pain, a leading cause of discomfort, disability and absence from work throughout the world. Targeted clinicians are those in primary care, including general practitioners, physiotherapists, and chiropractors. Here, the functional specifications for the Clinical Dashboard are delineated, and wireframes illustrating the system interface and flow of control are shown. Representative scenarios are presented to exemplify how the system could be used for co-decision making by a patient and clinician. Also included are a discussion of potential barriers to implementation and use in clinical practice and a look ahead to future work. This work has been conducted as part of the Horizon 2020 selfBACK project, which is funded by the European Commission. © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

Frailty and multimorbidity are common in type 2 diabetes (T2D), including people

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.

Objective:\ud Multimorbidity (the co‐existence of two or more long‐term conditions (LTCs)) is highly prevalent in people with rheumatoid arthritis (RA). This work systematically reviewed the literature to determine the effect of multimorbidity on all‐cause mortality, functional status and quality of life in RA.\ud \ud Methods:\ud Six electronic databases were searched: CINAHL, 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.\ud \ud Results:\ud 5,343 papers were identified by the search strategy, with 19 studies meeting the inclusion criteria. Nine studies had mortality as an outcome, nine reported functional status and/or quality of life and one study reported both mortality and functional status. The number of participants ranged from 183‐18,485, with studies conducted between 1985‐2018. Mean age of participants ranged from 53.5‐66.6 years; with 60.0‐84.2% female. Nine studies reported 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 reported a further association with reduced quality of life. Only one study investigated the influence of mental health comorbidities on outcomes.\ud \ud Conclusion:\ud 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.

[This corrects the article DOI: 10.1371/journal.pone.0238091.].

This randomized clinical trial examines a decision support tool that provides lower back pain information and self-management recommendations that are specific to an individual’s characteristics, symptoms, and symptom progression., Key Points Question Is selfBACK, an evidence-based, individually tailored self-management support system that is delivered through an artificial intelligence–based app and in conjunction with usual care, effective for pain-related disability in adults with lower back pain? Findings In this randomized clinical trial involving 461 participants in Denmark and Norway, those who received the selfBACK intervention had reduced pain-related disability compared with those who received usual care alone. However, the effect may be too small to be clinically meaningful. Meaning The findings of this trial and process evaluation may inform and encourage further development of the selfBACK intervention to increase its effectiveness., 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

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.

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.

ObjectivesLow 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.DesignSystematic review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.Data sourcesMEDLINE, 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 criteriaPeer-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 synthesisStandardised 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.ResultsWe 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.ConclusionsWe 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 registrationA 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_record.php?ID=CRD42016051182

ObjectivesTo 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).DesignCross-sectional study.SettingAustralian general practice.Participants69 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 measuresPrevalence of multimorbidity, individual and combinations of LTCs. Multivariable linear regression models used to examine associations between multimorbidity counts and HbA1c (%).ResultsMean (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.ConclusionsMultimorbidity 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.

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.

ObjectiveTo 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).DesignPopulation-based longitudinal cohort study.SettingUK Biobank.ParticipantsUK Biobank participants (n=502 533) aged between 37 and 73 years old.Primary outcome measuresPrimary outcome measures were risk of all-cause mortality and MACE.MethodsWe 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.Results75.7% 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.ConclusionThose 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.

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

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., Author summary Chronic pain is a highly prevalent and debilitating condition, which is more common in women than in men. Sex differences in this condition may be a result of several factors, including differences between the sexes in genetic variation related to chronic pain and gene expression differences related to sex. To explore sex differences in chronic pain from a genetic perspective, we looked for genetic variants associated with chronic pain in men and women separately in a large general-population cohort, and compared the variants we identified between the sexes. We assessed the degree of overlap between genetic variants associated with chronic pain in each sex and those associated with a wide range of other traits, including major depression, body-mass index and suicidality. We also investigated gene expression patterns across a range of tissues for genes associated with chronic pain in each sex, in particular examining expression in neural and non-neural human and mouse tissues and assessing the degree of Dorsal Root Ganglion (DRG) enrichment, an important peripheral nervous system component involved in chronic pain. This work contributes to understanding of chronic pain as a trait and of sex differences in chronic pain at the levels of genetics and gene expression.

ObjectivesTo investigate severe COVID-19 risk by occupational group.MethodsBaseline UK Biobank data (2006–10) for England were linked to SARS-CoV-2 test results from Public Health England (16 March to 26 July 2020). Included participants were employed or self-employed at baseline, alive and aged ResultsOf 120 075 participants, 271 had severe COVID-19. Relative to non-essential workers, healthcare workers (RR 7.43, 95% CI 5.52 to 10.00), social and education workers (RR 1.84, 95% CI 1.21 to 2.82) and other essential workers (RR 1.60, 95% CI 1.05 to 2.45) had a higher risk of severe COVID-19. Using more detailed groupings, medical support staff (RR 8.70, 95% CI 4.87 to 15.55), social care (RR 2.46, 95% CI 1.47 to 4.14) and transport workers (RR 2.20, 95% CI 1.21 to 4.00) had the highest risk within the broader groups. Compared with white non-essential workers, non-white non-essential workers had a higher risk (RR 3.27, 95% CI 1.90 to 5.62) and non-white essential workers had the highest risk (RR 8.34, 95% CI 5.17 to 13.47). Using SOC 2000 major groups, associate professional and technical occupations, personal service occupations and plant and machine operatives had a higher risk, compared with managers and senior officials.ConclusionsEssential workers have a higher risk of severe COVID-19. These findings underscore the need for national and organisational policies and practices that protect and support workers with an elevated risk of severe COVID-19.

ObjectivesTo investigate severe COVID-19 risk by occupational group.MethodsBaseline UK Biobank data (2006-10) for England were linked to SARS-CoV-2 test results from Public Health England (16 March to 26 July 2020). Included participants were employed or self-employed at baseline, alive and aged less than 65 years in 2020. Poisson regression models adjusted sequentially for baseline demographic, socioeconomic, work-related, health, and lifestyle-related risk factors to assess risk ratios (RRs) for testing positive in hospital or death due to COVID-19 by three occupational classification schemes (including Standard Occupation Classification 2000).ResultsOf 120,075 participants, 271 had severe COVID-19. Relative to non-essential workers, healthcare workers (RR 7.43, 95% CI:5.52,10.00), social and education workers (RR 1.84, 95% CI:1.21,2.82) and other essential workers (RR=1.60, 95% CI:1.05,2.45) had higher risk of severe COVID-19. Using more detailed groupings, medical support staff (RR 8.70, 95% CI:4.87,15.55), social care (RR 2.46, 95% CI:1.47,4.14) and transport workers (RR= 2.20, 95% CI:1.21,4.00) had highest risk within the broader groups. Compared to white non-essential workers, non-white non-essential workers had a higher risk (RR 3.27, 95% CI: 1.90,5.62) and non-white essential workers had the highest risk (RR 8.34, 95% CI:5.17,13.47). Using SOC2000 major groups, associate professional and technical occupations, personal service occupations and plant and machine operatives had higher risk, compared to managers and senior officials.ConclusionsEssential workers have higher risk of severe COVID-19. These findings underscore the need for national and organizational policies and practices that protect and support workers with elevated risk of severe COVID-19.Trial registration-N/AWhat is already known on this topicEssential workers have a higher exposure to the SARS-CoV-2 virus due to the nature of their work.In comparison to non-essential workers, healthcare workers appear to have a higher risk of SARS-CoV-2 infection.What this study addsHealthcare workers had a more than seven-fold higher risk of severe COVID-19; those working in social care and transport occupations had a two-fold higher risk.Adjusting for potential confounding and mediating variables did not fully account for the differences in the observed risk amongst most occupational groups.Non-white essential workers had the highest risk of severe COVID-19 infection.How might this impact on policy or clinical practice in the foreseeable future?Our findings reinforce the need for adequate health and safety arrangements and provision of PPE, particularly in the health and social care sectors, and highlight the need for national and organizational policies and practices that protect and support workers with elevated risk of SARS-CoV-2 infection.

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. CLINICALTRIAL ClinicalTrials.gov NCT03798288; https://www.clinicaltrials.gov/ct2/show/NCT03798288 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/20308

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, Jason Chiang and colleagues reveal the relationship between multimorbidity, HbA1c and all-cause mortality in 2 large cohorts., Author summary Why was this study done? People with type 2 diabetes (T2D) commonly have other coexisting chronic medical conditions (‘multimorbidity’). These conditions can be either concordant (T2D related) or discordant (T2D unrelated). Multimorbidity is associated with higher mortality and hypoglycaemia; however, the effect of multimorbidity on glycaemia (measured by glycated haemoglobin [HbA1c]) is mixed. Significant knowledge gaps remain, particularly regarding the prevalence and impacts of different patterns of multimorbidity, including concordant and discordant conditions, and their associations with HbA1c and mortality. What did the researchers do and find? We assessed the associations between different counts of multimorbidity, including concordant and discordant conditions, and HbA1c and the effects of different combinations of conditions on all-cause mortality in people with T2D. In two large community cohorts of people with T2D (UK Biobank and Taiwan National Diabetes Care Management Program [NDCMP]), we found that increasing multimorbidity is significantly associated with increased mortality and with lower HbA1c. The combinations of conditions with the greatest association with mortality differed between UK Biobank, a population predominantly comprising people of European descent, and the Taiwan NDCMP, a predominantly ethnic Chinese population. What do these findings mean? To our knowledge, this is the first study to assess and compare the relationship between total, concordant, and discordant multimorbidity counts; HbA1c; and all-cause mortality in people with T2D or to look at the effects of such a range of combinations of comorbid conditions. Our findings suggest the need for further research to explore the effects of different combinations of conditions on outcomes in those with T2D across different ethnic groups. Our findings suggest that poor glycaemic control is unlikely to explain the increased mortality seen in those with increasing multimorbidity count.

BackgroundUnderstanding 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.MethodsThe 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.ResultsAmong 428,225 participants in England, 1,474 had been tested and 669 tested positive between 16 March and 13 April 2020. Black, south Asian and white Irish people were more likely to have confirmed infection (RR 4.01 (95%CI 2.92-5.12); RR 2.11 (95%CI 1.43-3.10); and RR 1.60 (95% CI 1.08-2.38) respectively) and were more likely to be hospital cases compared to the White British. While they were more likely to be tested, they were also more likely to test positive. 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 2.26 (95%CI 1.76-2.90); and RR 1.91 (95%CI 1.53-2.38) respectively).ConclusionsSome 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, measured baseline health or behavioural risk factors. An urgent response to addressing these elevated risks is required.

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.\ud \ud 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.\ud \ud 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).\ud \ud 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.

Background Low back pain (LBP) is prevalent across all social classes, in all age groups, and across industrialized and developing countries. From a global perspective, LBP is considered the leading cause of disability and negatively impacts everyday life and well-being. Self-management is a recommended first-line treatment, and mobile apps are a promising platform to support self-management of conditions like LBP. In the selfBACK project, we have developed a digital decision support system made available for the user via an app intended to support tailored self-management of nonspecific LBP. Objective The trial aims to evaluate the effectiveness of using the selfBACK app to support self-management in addition to usual care (intervention group) versus usual care only (control group) in people with nonspecific LBP. Methods This is a single-blinded, randomized controlled trial (RCT) with two parallel arms. The selfBACK app provides tailored self-management plans consisting of advice on physical activity, physical exercises, and educational content. Tailoring of plans is achieved by using case-based reasoning (CBR) methodology, which is a branch of artificial intelligence. The core of the CBR methodology is to use data about the current case (participant) along with knowledge about previous and similar cases to tailor the self-management plan to the current case. This enables a person-centered intervention based on what has and has not been successful in previous cases. Participants in the RCT are people with LBP who consulted a health care professional in primary care within the preceding 8 weeks. Participants are randomized to using the selfBACK app in addition to usual care versus usual care only. We aim to include a total of 350 participants (175 participants in each arm). Outcomes are collected at baseline, 6 weeks, and 3, 6, and 9 months. The primary end point is difference in pain-related disability between the intervention group and the control group assessed by the Roland-Morris Disability Questionnaire at 3 months. Results The trial opened for recruitment in February 2019. Data collection is expected to be complete by fall 2020, and the results for the primary outcome are expected to be published in fall 2020. Conclusions This RCT will provide insights regarding the benefits of supporting tailored self-management of LBP through an app available at times convenient for the user. If successful, the intervention has the potential to become a model for the provision of tailored self-management support to people with nonspecific LBP and inform future interventions for other painful musculoskeletal conditions. Trial Registration ClinicalTrial.gov NCT03798288; https://clinicaltrials.gov/ct2/show/NCT03798288 International Registered Report Identifier (IRRID) DERR1-10.2196/14720

Background Multimorbidity is common in stroke, but the risk factors and effects on mortality remain poorly understood. Objective To examine multimorbidity and its associations with sociodemographic/lifestyle risk factors and all-cause mortality in UK Biobank participants with stroke or transient ischaemic attack (TIA). Design Data were obtained from an anonymized community cohort aged 40–72 years. Overall, 42 comorbidities were self-reported by those with stroke or TIA. Relative risk ratios demonstrated associations between participant characteristics and number of comorbidities. Hazard ratios demonstrated associations between the number and type of comorbidities and all-cause mortality. Results were adjusted for age, sex, socioeconomic status, smoking, and alcohol intake. Data were linked to national mortality data. Median follow-up was 7 years. Results Of 8,751 participants (mean age 60.9±6.7 years) with stroke or TIA, the all-cause mortality rate over 7 years was 8.4%. Over 85% reported ≥1 comorbidities. Age, socioeconomic deprivation, smoking and less frequent alcohol intake were associated with higher levels of multimorbidity. Increasing multimorbidity was associated with higher all-cause mortality. Mortality risk was double for those with ≥5 comorbidities compared to those with none. Having cancer, coronary heart disease, diabetes, or chronic obstructive pulmonary disease significantly increased mortality risk. Presence of any cardiometabolic comorbidity significantly increased mortality risk, as did any non-cardiometabolic comorbidity. Conclusions In stroke survivors, the number of comorbidities may be a more helpful predictor of mortality than type of condition. Stroke guidelines should take greater account of comorbidities, and interventions are needed that improve outcomes for people with multimorbidity and stroke.

BackgroundThis study investigated differences in cognitive performance between middle-aged adults with and without a lifetime history of mood disorder features, adjusting for a range of potential confounders.MethodsCross-sectional analysis of baseline data from the UK Biobank cohort. Adults aged 40–69 (n = 143,828) were assessed using measures of reasoning, reaction time and memory. Self-reported data on lifetime features of major depression and bipolar disorder were used to construct groups for comparison against controls. Regression models examined the association between mood disorder classification and cognitive performance, adjusting for sociodemographic, lifestyle and clinical confounders.ResultsInverse associations between lifetime history of bipolar or severe recurrent depression features and cognitive performance were attenuated or reversed after adjusting for confounders, including psychotropic medication use and current depressive symptoms. Participants with a lifetime history of single episode or moderate recurrent depression features outperformed controls to a small (but statistically significant) degree, independent of adjustment for confounders. There was a significant interaction between use of psychotropic medication and lifetime mood disorder features, with reduced cognitive performance observed in participants taking psychotropic medication.ConclusionsIn this general population sample of adults in middle age, lifetime features of recurrent depression or bipolar disorder were only associated with cognitive impairment within unadjusted analyses. These findings underscore the importance of adjusting for potential confounders when investigating mood disorder-related cognitive function.

Introduction: Multimorbidity (MM) is common in people with T2D (PwT2D) who in Australia, receive medical care predominantly in family practice (FP). We explored the association between MM condition count and HbA1c in PwT2D attending Australian FP, using electronic health record (EHR) data. Methods: Cross-sectional study of 69,718 PwT2D who had a FP encounter between 2013-15 captured in the NPS MedicineInsight dataset (EHR data from >500 family practices and 3.5 million patients across Australia). MM condition count was based on coded and free text conditions in the reason for visit, prescription or medical history fields. Primary outcome: HbA1c. Multivariable mixed-effects linear regression examined associations between MM counts (total, concordant (T2D-related) and discordant (unrelated)) and HbA1c (%). Results: We found statistically significant associations between HbA1c and total and discordant MM counts. Mean HbA1c (95% CI) was lower for those having 1, 2, 3 and 4+ total conditions compared to T2D only, -0.065 (-0.089, -0.041), -0.097 (-0.128, -0.066), -0.089 (-0.133, -0.046), and -0.097 (-0.146, -0.047) respectively, and for discordant conditions -0.085 (-0.108, -0.061), -0.100 (-0.134, -0.065), -0.141 (-0.195, -0.087), and -0.204 (-0.276, -0.133). There was no statistically significant association between HbA1c and increasing concordant count. Conclusions: While EHR counts of MM and discordant conditions are associated with lower HbA1c, this is not likely to be clinically significant, suggesting the impact of MM on HbA1c remains unclear. The NPS dataset uses routine data entered by clinicians for the purpose of patient care, rather than epidemiological studies and may thus underestimate the number of conditions experienced by PwT2D. While clinicians need to consider the MM burden of PwT2D, the NPS MedicineInsight dataset needs further validation, eg through combining with other data sources, in the study of MM. Disclosure J.I. Chiang: None. J. Furler: Research Support; Self; Abbott, Sanofi. B.D. Jani: None. F.S. Mair: None. S. Thuraisingam: None. B.I. Nicholl: None. J.E. Manski-Nankervis: Research Support; Self; Australian National Health and Medical Research Council, Boehringer Ingelheim International GmbH, Diabetes Australia, Eli Lilly and Company. Speaker’s Bureau; Self; RACGP. Funding Royal Australian College of General Practitioners

Background Multimorbidity is associated with higher mortality, but the relationship with cancer and cardiovascular mortality is unclear. The influence of demographics and type of condition on the relationship of multimorbidity with mortality remains unknown. We examine the relationship between multimorbidity (number/type) and cause of mortality and the impact of demographic factors on this relationship. Methods Data source: the UK Biobank; 500,769 participants; 37-73 years; 53.7% female. Exposure variables: number and type of long-term conditions (LTCs) (N = 43) at baseline, modelled separately. Cox regression models were used to study the impact of LTCs on all-cause/vascular/cancer mortality during median 7-year follow-up. All-cause mortality regression models were stratified by age/sex/socioeconomic status. Results All-cause mortality is 2.9% (14,348 participants). Of all deaths, 8350 (58.2%) were cancer deaths and 2985 (20.8%) vascular deaths. Dose-response relationship is observed between the increasing number of LTCs and all-cause/cancer/vascular mortality. A strong association is observed between cardiometabolic multimorbidity and all three clinical outcomes; non-cardiometabolic multimorbidity (excluding cancer) is associated with all-cause/vascular mortality. All-cause mortality risk for those with ≥ 4 LTCs was nearly 3 times higher than those with no LTCs (HR 2.79, CI 2.61–2.98); for ≥ 4 cardiometabolic conditions, it was > 3 times higher (HR 3.20, CI 2.56–4.00); and for ≥ 4 non-cardiometabolic conditions (excluding cancer), it was 50% more (HR 1.50, CI 1.36–1.67). For those with ≥ 4 LTCs, morbidity combinations that included cardiometabolic conditions, chronic kidney disease, cancer, epilepsy, chronic obstructive pulmonary disease, depression, osteoporosis and connective tissue disorders had the greatest impact on all-cause mortality. In the stratified model by age/sex, absolute all-cause mortality was higher among the 60–73 age group with an increasing number of LTCs; however, the relative effect size of the increasing number of LTCs on higher mortality risk was larger among those 37–49 years, especially men. While socioeconomic status was a significant predictor of all-cause mortality, mortality risk with increasing number of LTCs remained constant across different socioeconomic gradients. Conclusions Multimorbidity is associated with higher all-cause/cancer/vascular mortality. Type, as opposed to number, of LTCs may have an important role in understanding the relationship between multimorbidity and mortality. Multimorbidity had a greater relative impact on all-cause mortality in middle-aged as opposed to older populations, particularly males, which deserves exploration. Electronic supplementary material The online version of this article (10.1186/s12916-019-1305-x) contains supplementary material, which is available to authorized users.

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., Author summary Chronic pain is common worldwide and imposes a significant burden from a public health and socioeconomic perspective. The reasons why some individuals develop chronic pain and others do not are not fully understood. In this study we searched for genetic variants associated with chronic pain in a large general-population cohort. We also assessed how this genetic variation was correlated with a range of other diseases and traits, such as depression and BMI, and we tested for causal relationships between depression and chronic pain. We found that chronic pain was associated with several genes involved in brain function and development and was correlated with mental health and autoimmune traits (including depression, PTSD and asthma). We also found evidence for causal relationships between chronic pain and major depressive disorder. This work provides new insights into the genetics and underlying biology of chronic pain and may help to inform new treatment strategies.

Chronic pain is highly prevalent worldwide, contributing 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 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. We have here made use of a measure of the number of sites of chronic pain in individuals within the general UK population. This measure, termed Multisite Chronic Pain (MCP), is also a complex trait, but its genetic architecture has not previously been investigated. To address this, a large-scale genome-wide association study (GWAS) of MCP was carried out in ~380,000 UK Biobank participants to identify associated genetic variants. Findings were consistent with MCP having a significant polygenic component with a SNP heritability of 10.2%, and 76 independent lead single nucleotide polymorphisms (SNPs) at 39 risk loci were identified. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as being 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 BMI. Furthermore, in Mendelian randomisation (MR) analyses a bi-directional causal relationship was observed between MCP and MDD. 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. These findings support the proposition that chronic pain involves a strong nervous system component and have implications for our understanding of the physiology of chronic pain and for the development of novel treatment strategies.

Chronic pain is highly prevalent worldwide, with a significant socioeconomic burden, and also contributes to excess mortality. 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 as a quasi-quantitative trait 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.Author SummaryGenetic variants explaining variation in complex traits can often be associated with more than one trait at once (‘pleiotropy’). Taking account of this pleiotropy in genetic studies can increase power to find sites in the genome harbouring trait-associated variants. In this study we used the suspected underlying pleiotropy between chronic pain and major depressive disorder to discover novel variants associated with chronic pain, and to investigate genetic variation that may be shared between the two disorders.

Summary: Background: Combinations of lifestyle factors interact to increase mortality. Combinations of traditional factors such as smoking and alcohol are well described, but the additional effects of emerging factors such as television viewing time are not. The effect of socioeconomic deprivation on these extended lifestyle risks also remains unclear. We aimed to examine whether deprivation modifies the association between an extended score of lifestyle-related risk factors and health outcomes. Methods: Data for this prospective analysis were sourced from the UK Biobank, a prospective population-based cohort study. We assigned all participants an extended lifestyle score, with 1 point for each unhealthy lifestyle factor (incorporating sleep duration and high television viewing time, in addition to smoking, excessive alcohol, poor diet [low intake of oily fish or fruits and vegetables, and high intake of red meat or processed meats], and low physical activity), categorised as most healthy (score 0–2), moderately healthy (score 3–5), or least healthy (score 6–9). Cox proportional hazards models were used to examine the association between lifestyle score and health outcomes (all-cause mortality and cardiovascular disease mortality and incidence), and whether this association was modified by deprivation. All analyses were landmark analyses, in which participants were excluded if they had an event (death or cardiovascular disease event) within 2 years of recruitment. Participants with non-communicable diseases (except hypertension) and missing covariate data were excluded from analyses. Participants were also excluded if they reported implausible values for physical activity, sleep duration, and total screen time. All analyses were adjusted for age, sex, ethnicity, month of assessment, history of hypertension, systolic blood pressure, medication for hypercholesterolaemia or hypertension, and body-mass index categories. Findings: 328 594 participants aged 40–69 years were included in the study, with a mean follow-up period of 4·9 years (SD 0·83) after the landmark period for all-cause and cardiovascular disease mortality, and 4·1 years (0·81) for cardiovascular disease incidence. In the least deprived quintile, the adjusted hazard ratio (HR) in the least healthy lifestyle category, compared with the most healthy category, was 1·65 (95% CI 1·25–2·19) for all-cause mortality, 1·93 (1·16–3·20) for cardiovascular disease mortality, and 1·29 (1·10–1·52) for cardiovascular disease incidence. Equivalent HRs in the most deprived quintile were 2·47 (95% CI 2·04–3·00), 3·36 (2·36–4·76), and 1·41 (1·25–1·60), respectively. The HR for trend for one increment change towards least healthy in the least deprived quintile compared with that in the most deprived quintile was 1·25 (95% CI 1·12–1·39) versus 1·55 (1·40–1·70) for all-cause mortality, 1·30 (1·05–1·61) versus 1·83 (1·54–2·18) for cardiovascular disease mortality, and 1·10 (1·04–1·17) versus 1·16 (1·09–1·23) for cardiovascular disease incidence. A significant interaction was found between lifestyle and deprivation for all-cause and cardiovascular disease mortality (both pinteraction