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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.

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.

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.

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

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.

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.

BackgroundThere 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 findingsWe 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 ConclusionsMultimorbidity 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.

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.

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.

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

Summary: Background: Frailty is associated with older age and multimorbidity (two or more long-term conditions); however, little is known about its prevalence or effects on mortality in younger populations. This paper aims to examine the association between frailty, multimorbidity, specific long-term conditions, and mortality in a middle-aged and older aged population. Methods: Data were sourced from the UK Biobank. Frailty phenotype was based on five criteria (weight loss, exhaustion, grip strength, low physical activity, slow walking pace). Participants were deemed frail if they met at least three criteria, pre-frail if they fulfilled one or two criteria, and not frail if no criteria were met. Sociodemographic characteristics and long-term conditions were examined. The outcome was all-cause mortality, which was measured at a median of 7 years follow-up. Multinomial logistic regression compared sociodemographic characteristics and long-term conditions of frail or pre-frail participants with non-frail participants. Cox proportional hazards models examined associations between frailty or pre-frailty and mortality. Results were stratified by age group (37–45, 45–55, 55–65, 65–73 years) and sex, and were adjusted for multimorbidity count, socioeconomic status, body-mass index, smoking status, and alcohol use. Findings: 493 737 participants aged 37–73 years were included in the study, of whom 16 538 (3%) were considered frail, 185 360 (38%) pre-frail, and 291 839 (59%) not frail. Frailty was significantly associated with multimorbidity (prevalence 18% [4435/25 338] in those with four or more long-term conditions; odds ratio [OR] 27·1, 95% CI 25·3–29·1) socioeconomic deprivation, smoking, obesity, and infrequent alcohol consumption. The top five long-term conditions associated with frailty were multiple sclerosis (OR 15·3; 99·75% CI 12·8–18·2); chronic fatigue syndrome (12·9; 11·1–15·0); chronic obstructive pulmonary disease (5·6; 5·2–6·1); connective tissue disease (5·4; 5·0–5·8); and diabetes (5·0; 4·7–5·2). Pre-frailty and frailty were significantly associated with mortality for all age strata in men and women (except in women aged 37–45 years) after adjustment for confounders. Interpretation: Efforts to identify, manage, and prevent frailty should include middle-aged individuals with multimorbidity, in whom frailty is significantly associated with mortality, even after adjustment for number of long-term conditions, sociodemographics, and lifestyle. Research, clinical guidelines, and health-care services must shift focus from single conditions to the requirements of increasingly complex patient populations. Funding: CSO Catalyst Grant and National Health Service Research for Scotland Career Research Fellowship.

BackgroundThis study aimed to evaluate whether prompting general practitioners (GPs) to routinely assess and manage anxiety and depression in patients consulting with osteoarthritis (OA) improves pain outcomes.Methods and findingsWe conducted a cluster randomised controlled trial involving 45 English general practices. In intervention practices, patients aged ≥45 y consulting with OA received point-of-care anxiety and depression screening by the GP, prompted by an automated electronic template comprising five questions (a two-item Patient Health Questionnaire-2 for depression, a two-item Generalized Anxiety Disorder-2 questionnaire for anxiety, and a question about current pain intensity [0-10 numerical rating scale]). The template signposted GPs to follow National Institute for Health and Care Excellence clinical guidelines for anxiety, depression, and OA and was supported by a brief training package. The template in control practices prompted GPs to ask the pain intensity question only. The primary outcome was patient-reported current pain intensity post-consultation and at 3-, 6-, and 12-mo follow-up. Secondary outcomes included pain-related disability, anxiety, depression, and general health. During the trial period, 7,279 patients aged ≥45 y consulted with a relevant OA-related code, and 4,240 patients were deemed potentially eligible by participating GPs. Templates were completed for 2,042 patients (1,339 [31.6%] in the control arm and 703 [23.1%] in the intervention arm). Of these 2,042 patients, 1,412 returned questionnaires (501 [71.3%] from 20 intervention practices, 911 [68.0%] from 24 control practices). Follow-up rates were similar in both arms, totalling 1,093 (77.4%) at 3 mo, 1,064 (75.4%) at 6 mo, and 1,017 (72.0%) at 12 mo. For the primary endpoint, multilevel modelling yielded significantly higher average pain intensity across follow-up to 12 mo in the intervention group than the control group (adjusted mean difference 0.31; 95% CI 0.04, 0.59). Secondary outcomes were consistent with the primary outcome measure in reflecting better outcomes as a whole for the control group than the intervention group. Anxiety and depression scores did not reduce following the intervention. The main limitations of this study are two potential sources of bias: an imbalance in cluster size (mean practice size 7,397 [intervention] versus 5,850 [control]) and a difference in the proportion of patients for whom the GP deactivated the template (33.6% [intervention] versus 27.8% [control]).ConclusionsIn this study, we observed no beneficial effect on pain outcomes of prompting GPs to routinely screen for and manage comorbid anxiety and depression in patients presenting with symptoms due to OA, with those in the intervention group reporting statistically significantly higher average pain scores over the four follow-up time points than those in the control group.Trial registrationISRCTN registry ISRCTN40721988.

This study aimed to systematically review intervention studies on self-management of type 2 diabetes in Gulf Cooperation Council (GCC) countries to determine the most effective self-management strategies for individuals with type 2 diabetes in this region.A search strategy was developed using multiple databases: Medline and Embase (via Ovid), CINAHL (via EBSCO), and PubMed. Study and intervention characteristics, intervention structure, content, cultural adaptation, and outcomes were extracted from the included studies. To be included in the review the studies should have met the following criteria: have examined the effectiveness of at least one intervention involving a type 2 DSME programme, have involved participants over 18 years old diagnosed with type 2 diabetes, have taken place to in a GCC country, have a study design that was observational, quasi-experimental or controlled, have reported at least one individual and have a quantitative outcome. A narrative data synthesis was used to describe the studies and comment on their methodological quality.Of the 737 retrieved papers, only eight met the inclusion criteria. Only one study was a randomised controlled trial. A statistically significant improvement in HbA1c was reported in five of the eight studies. There was a significant improvement in physical activity levels as reported in four of the eight studies. Only three studies referred to aspects of cultural design or adaptation of the intervention implemented.Self-management interventions may have a positive impact on HbA1 levels in patients with type 2 diabetes in the GCC area. A greater emphasis placed on culturally appropriate self-management programmes may improve the effectiveness of self-management interventions for adults with type 2 diabetes in the GCC.

BackgroundChronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study.Methods and findingsUsing family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum β = 6.18x10-2, 95% CI 2.84 x10-2 to 9.35 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 5.68 x 10-2, 95% CI 4.70x10-2 to 6.65x10-2, p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum β = 6.62x10-2, 95% CI 2.82 x10-2 to 9.76 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 2.56x10-2, 95% CI 1.62x10-2 to 3.63x10-2, p < 3x10-4). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes.ConclusionsGenetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.

Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area.

Background: The relative contribution of demographic, lifestyle and medication factors to the association between affective disorders and cardiometabolic diseases is poorly understood., Aims: To assess the relationship between cardiometabolic disease and features of depresion and bipolar disorder within a large population sample., Method: Cross-sectional study of 145 991 UK Biobank participants: multivariate analyses of associations between features of depression or bipolar disorder and five cardiometabolic outcomes, adjusting for confounding factors., Results: There were significant associations between mood disorder features and 'any cardiovascular disease' (depression odds ratio (OR) = 1.15, 95% CI 1.12-1.19; bipolar OR = 1.28, 95% CI 1.14-1.43) and with hypertension (depression OR = 1.15, 95% CI 1.13-1.18; bipolar OR = 1.26, 95% CI 1.12-1.42). Individuals with features of mood disorder taking psychotropic medication were significantly more likely than controls not on psychotropics to report myocardial infarction (depression OR = 1.47, 95% CI 1.24-1.73; bipolar OR = 2.23, 95% CI 1.53-3.57) and stroke (depression OR = 2.46, 95% CI 2.10-2.80; bipolar OR = 2.31, 95% CI 1.39-3.85)., Conclusions: Associations between features of depression or bipolar disorder and cardiovascular disease outcomes were statistically independent of demographic, lifestyle and medication confounders. Psychotropic medication may also be a risk factor for cardiometabolic disease in individuals without a clear history of mood disorder., (© The Royal College of Psychiatrists 2016.)