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Abstract Hip pain is a common musculoskeletal complaint that leads many people to seek medical attention. We conducted a primary genome-wide association study (GWAS) on the hip pain phenotype within the UK Biobank cohort. Sex-stratified GWAS analysis approach was also performed to explore sex specific variants associated with hip pain. We found seven different loci associated with hip pain at GWAS significance level, with the most significant single nucleotide polymorphism (SNP) being rs77641763 within the EXD3 (p value = 2.20 × 10–13). We utilized summary statistics from the FinnGen cohort and a previous GWAS meta-analysis on hip osteoarthritis as replication cohorts. Four loci (rs509345, rs73581564, rs9597759, rs2018384) were replicated with a p value less than 0.05. Sex-stratified GWAS analyses revealed a unique locus within the CUL1 gene (rs4726995, p = 2.56 × 10–9) in males, and three unique loci in females: rs1651359966 on chromosome 7 (p = 1.15 × 10–8), rs552965738 on chromosome 9 (p = 2.72 × 10–8), and rs1978969 on chromosome 13 (p = 2.87 × 10–9). This study has identified seven genetic loci associated with hip pain. Sex-stratified analysis also revealed sex specific variants associated with hip pain in males and females. This study has provided a foundation for advancing research of hip pain and hip osteoarthritis.

Introduction Exposure to adverse childhood experiences (ACEs) is associated with a range of poor long-term health outcomes, including multimorbidity and chronic pain. Epidemiological evidence underpins much of this relationship; however, psychophysical testing methods, such as quantitative sensory testing (QST), may provide valuable insights into potential mechanisms. Previous studies have shown inconsistent links between ACEs and QST, but the QST profiles of people with multimorbidity have not been reported. We hypothesise that exposure to ACEs is associated with lowered QST thresholds (ie, experience of pain with milder stimuli) and that this association is stronger in adults with multimorbidity and/or chronic pain. The ACE-MAP study is a cross-sectional feasibility study with the primary aim of assessing the feasibility and acceptability of the proposed study procedures. The secondary aim is to generate preliminary data to understand the impact of ACEs on QST thresholds.Methods and analysis We plan to recruit 40 participants, with 10 in each of the following groups: (1) chronic pain with multimorbidity; (2) chronic pain without multimorbidity; (3) multimorbidity without chronic pain; and (4) controls. Participants will complete a series of questionnaires (including on ACEs, chronic pain and long-term conditions) and will then take part in QST assessments. The primary study outcomes will include measures of feasibility and acceptability of the proposed study design. The secondary study outcomes will include exploratory analysis on the relationship between ACEs and QST thresholds.Ethics and dissemination The study was approved by the Scotland B Research Ethics Committee (reference: 24/SS/0031). Results from the study will be presented at scientific conferences, published in a peer-reviewed journal and shared with patients and members of the public through other media streams.Trial registration number ISRCTN10049430.

Abstract Background Adverse childhood experiences (ACEs) have been implicated in the aetiology of a range of health outcomes, including multimorbidity. In this systematic review and meta-analysis, we aimed to identify, synthesise, and quantify the current evidence linking ACEs and multimorbidity. Methods We searched seven databases from inception to 20 July 2023: APA PsycNET, CINAHL Plus, Cochrane CENTRAL, Embase, MEDLINE, Scopus, and Web of Science. We selected studies investigating adverse events occurring during childhood (

ABSTRACT The escalating burden of lifestyle‐related diseases stands as a critical global public health challenge, contributing substantially to the prevalence of chronic conditions and a large portion of premature mortality. Despite this, concise evidence‐based lifestyle interventions targeting physical inactivity, nutrition, alcohol and smoking continue to be underutilised. Although good evidence exists for addressing the four lifestyle‐related risk factors independently, rarely do these present in isolation. Evidence is lacking regarding how to integrate interventions targeting multiple risk factors. Consequently, this paper aims to provide an overview of the evidence for delivering multiple interventions in primary healthcare settings. Different lifestyle factors are inter‐related, with decisions around ordering of the delivery of multiple lifestyle interventions an important consideration. There is evidence supporting the effectiveness of addressing some lifestyle factors simultaneously (e.g., physical activity and nutrition), although smoking cessation may be delivered best in a sequential approach. While the World Health Organisation highlights four key lifestyle factors (nutrition, physical activity, alcohol and smoking), incorporating additional elements such as sleep, mental well‐being and social connectedness offers a holistic framework for promoting well‐being. Despite the presentation of multiple behaviour risk factors being commonplace in healthcare settings, the evidence (outlined in the paper) for how best to deliver interventions to address this is limited, with further research and subsequent clinical guidance required. In order to address the barriers to delivering lifestyle interventions in primary care, innovation will be required. The use of non‐medical personnel, social prescribers and health coaches has the potential to alleviate time constraints, whilst mounting evidence exists for group consultations for addressing lifestyle‐related non‐communicable diseases (NCDs). If the challenges to implementation can be addressed, and if healthcare systems can adapt for the promotion of healthy lifestyles, the impact of NCDs can be mitigated.

Abstract Purpose In order to deliver appropriate and timely care planning and minimise avoidable late diagnoses, clinicians need to be aware of which patients are at higher risk of receiving a late cancer diagnosis. We aimed to determine which demographic and clinical factors are associated with receiving a ‘late’ cancer diagnosis (within the last 12 weeks of life). Method Retrospective cohort study of 2,443 people who died from cancer (‘cancer decedents’) in 2013–2015. Demographic and cancer registry datasets linked using patient-identifying Community Health Index numbers. Analysis used binary logistic regression, with univariate and adjusted odds ratios (SPSS v25). Results One third (n = 831,34.0%) received a late diagnosis. Age and cancer type were significantly associated with late cancer diagnosis (p 85 years had higher odds of late diagnosis (95%CI OR3.45 (OR2.63 to 4.55)), compared to those aged

ABSTRACTVibrio is a genus of halophilic, gram-negative bacteria found in estuaries around the globe. Integral parts of coastal cultures often involve contact with vectors of pathogenic Vibrio spp. (e.g., consuming raw shellfish). High rates of mortality from certain Vibrio spp. infections demonstrate the need for an improved understanding of Vibrio spp. dynamics in estuarine regions. Our study assessed meteorological, hydrographic, and biological correlates of Vibrio parahaemolyticus and V. vulnificus at 10 sites in the Eastern Mississippi Sound System (EMSS) from April to October 2019. During the sampling period, median abundances of V. parahaemolyticus and V. vulnificus were 2.31 log MPN/L and 2.90 log MPN/L, respectively. Vibrio spp. dynamics were largely driven by site-based variation, with sites closest to freshwater inputs having the highest abundances. The E-W wind scalar, which affects Ekman transport, was a novel Vibrio spp. correlate observed. A potential salinity effect on bacterial-particle associations was identified, where V. vulnificus was associated with larger particles in conditions outside of their optimal salinity. Additionally, V. vulnificus abundances were correlated to those of harmful algal species that did not dominate community chlorophyll. Correlates from this study may be used to inform the next iteration of regionally predictive Vibrio models and may lend additional insight to Vibrio spp. ecology in similar systems.IMPORTANCEVibrio spp. are bacteria found in estuaries worldwide; some species can cause illness and infections in humans. Relationships between Vibrio spp. abundance, salinity, and temperature are well documented, but correlations to other environmental parameters are less understood. This study identifies unique correlates (e.g., E-W wind scalar and harmful algal species) that could potentially inform the next iteration of predictive Vibrio models for the EMSS region. Additionally, these correlates may allow existing environmental monitoring efforts to be leveraged in providing data inputs for future Vibrio risk models. An observed correlation between salinity and V. vulnificus/particle-size associations suggests that predicted environmental changes may affect the abundance of Vibrio spp. in certain reservoirs, which may alter which vectors present the greatest vibrio risk.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract Background Opioids can be effective analgesics, but long-term use may be associated with harms. In 2013, the first national, comprehensive, evidence-based pain management guideline was published, from the Scottish Intercollegiate Guideline Network (SIGN 136: Management of Chronic Pain) with key recommendations on analgesic prescribing. This study aimed to examine the potential impact on national opioid prescribing rates in Scotland. Methods Trends in national and regional community opioid prescribing data for Scotland were analysed from quarter one (Q1) 2005 to Q2 2020. Interrupted time series regression examined the association of SIGN 136 publication with prescribing rates for opioid-containing drugs. Gabapentinoid prescribing was used as a comparison drug. Results After a positive prescribing trend pre-publication, the timing of SIGN 136 publication was associated with a negative change in the trend of opioid prescribing rates (−2.82 items per 1000 population per quarter [PTPPQ]; P < 0.01). By Q2 2020, the relative reduction in the opioid prescribing rate was −20.67% (95% CI: −23.61, −17.76). This persisted after correcting for gabapentinoid prescribing and was mainly driven by the reduction in weak opioids, whereas strong opioid prescribing rates continued to rise. Gabapentinoid prescribing showed a significant rise in level (8.00 items per 1000 population; P = 0.01) and trend (0.27 items PTPPQ; P = 0.01) following SIGN 136 publication. Conclusions The publication of SIGN 136 was associated with a reduction in opioid prescribing rates. This suggests that changes in clinical policy through evidence-based national clinical guidelines may affect community opioid prescribing, though this may be partially replaced by gabapentinoids, and other factors may also contribute.

Abstract. Chronic pain (CP) is a common and often debilitating disorder that has major social and economic impacts. A subset of patients develop CP that significantly interferes with their activities of daily living and requires a high level of healthcare support. The challenge for treating physicians is in preventing the onset of refractory CP or effectively managing existing pain. To be able to do this, it is necessary to understand the risk factors, both genetic and environmental, for the onset of CP and response to treatment, as well as the pathogenesis of the disorder, which is highly heterogenous. However, studies of CP, particularly pain with neuropathic characteristics, have been hindered by a lack of consensus on phenotyping and data collection, making comparisons difficult. Furthermore, existing cohorts have suffered from small sample sizes meaning that analyses, especially genome-wide association studies, are insufficiently powered. The key to overcoming these issues is through the creation of large consortia such as DOLORisk and PAINSTORM and biorepositories, such as UK Biobank, where a common approach can be taken to CP phenotyping, which allows harmonisation across different cohorts and in turn increased study power. This review describes the approach that was used for studying neuropathic pain in DOLORisk and how this has informed current projects such as PAINSTORM, the rephenotyping of UK Biobank, and other endeavours. Moreover, an overview is provided of the outputs from these studies and the lessons learnt for future projects.

Abstract The objective to provide an overview of the literature on the barriers and facilitators to physical activity (PA) promotion in primary care, as experienced by practitioners and patients. Method A search strategy of the English‐language literature was conducted in EMBASE, MEDLINE and the COCHRANE LIBRARY. Search terms were primary care OR general practice OR family medicine OR family practitioner AND physical activity OR exercise AND barriers OR facilitators. Databases were searched from inception until 21 October 2022. Results After screening, 63 articles were included within the summary and content analysis of this review. Analysis of the barriers to the implementation of PA highlighted four main themes perceived by practitioners: time, knowledge/skills, resources/support and financial implications. Analysis of the patient perspective identified themes which were categorised into individual (pre‐existing health conditions, knowledge of benefits of PA, time/capacity), societal (social support and cultural norms) and environmental (availability of facilities and weather). Conclusions As the importance of PA increases through the manifestation of sedentary behaviour‐related disease, a combined primary care and public health approach to increase PA is required. By identifying the main barriers to PA promotion in primary care, resources and funding can be directed to address this. This is particularly relevant in the United Kingdom, with the re‐negotiation of the primary care contract and the changes to healthcare delivery as a consequence of the Covid‐19 pandemic. Throughout this review, we have explored ways of addressing the identified barriers through evidence‐based interventions.

Abstract Background People who die from cancer (‘cancer decedents’) may latterly experience unpleasant and distressing symptoms. Prescribing medication for pain and symptom control is essential for good-quality palliative care; however, such provision is variable, difficult to quantify and poorly characterised in current literature. This study aims to characterise trends in prescribing analgesia, non-analgesic palliative care medication and non-palliative medications, to cancer decedents, in their last year of life, and to assess any associations with demographic or clinical factors. Methods This descriptive study, analysed all 181,247 prescriptions issued to a study population of 2443 cancer decedents in Tayside, Scotland (2013–2015), in the last year of life, linking prescribing data to demographic, and cancer registry datasets using the unique patient-identifying Community Health Index (CHI) number. Anonymised linked data were analysed in Safe Haven using chi-squared test for trend, binary logistic regression and Poisson regression in SPSSv25. Results In their last year of life, three in four cancer decedents were prescribed strong opioids. Two-thirds of those prescribed opioids were also prescribed laxatives and/or anti-emetics. Only four in ten cancer decedents were prescribed all medications in the ‘Just in Case’ medication categories and only one in ten was prescribed breakthrough analgesia in the last year of life. The number of prescriptions for analgesia and palliative care drugs increased in the last 12 weeks of life. The number of prescriptions for non-palliative care medications, including anti-hypertensives, statins and bone protection, decreased over the last year, but was still substantial. Cancer decedents who were female, younger, or had lung cancer were more likely to be prescribed strong opioids; however, male cancer decedents had higher odds of being prescribed breakthrough analgesia. Cancer decedents who had late diagnoses had lower odds of being prescribed strong opioids. Conclusions A substantial proportion of cancer decedents were not prescribed strong opioids, breakthrough medication, or medication to alleviate common palliative care symptoms (including ‘Just in Case’ medication). Many patients continued to be prescribed non-palliative care medications in their last days and weeks of life. Age, gender, cancer type and timing of diagnosis affected patients’ odds of being prescribed analgesic and non-analgesic palliative care medication.

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Abstract Background To improve the treatment of painful Diabetic Peripheral Neuropathy (DPN) and associated co-morbidities, a better understanding of the pathophysiology and risk factors for painful DPN is required. Using harmonised cohorts (N = 1230) we have built models that classify painful versus painless DPN using quality of life (EQ5D), lifestyle (smoking, alcohol consumption), demographics (age, gender), personality and psychology traits (anxiety, depression, personality traits), biochemical (HbA1c) and clinical variables (BMI, hospital stay and trauma at young age) as predictors. Methods The Random Forest, Adaptive Regression Splines and Naive Bayes machine learning models were trained for classifying painful/painless DPN. Their performance was estimated using cross-validation in large cross-sectional cohorts (N = 935) and externally validated in a large population-based cohort (N = 295). Variables were ranked for importance using model specific metrics and marginal effects of predictors were aggregated and assessed at the global level. Model selection was carried out using the Mathews Correlation Coefficient (MCC) and model performance was quantified in the validation set using MCC, the area under the precision/recall curve (AUPRC) and accuracy. Results Random Forest (MCC = 0.28, AUPRC = 0.76) and Adaptive Regression Splines (MCC = 0.29, AUPRC = 0.77) were the best performing models and showed the smallest reduction in performance between the training and validation dataset. EQ5D index, the 10-item personality dimensions, HbA1c, Depression and Anxiety t-scores, age and Body Mass Index were consistently amongst the most powerful predictors in classifying painful vs painless DPN. Conclusions Machine learning models trained on large cross-sectional cohorts were able to accurately classify painful or painless DPN on an independent population-based dataset. Painful DPN is associated with more depression, anxiety and certain personality traits. It is also associated with poorer self-reported quality of life, younger age, poor glucose control and high Body Mass Index (BMI). The models showed good performance in realistic conditions in the presence of missing values and noisy datasets. These models can be used either in the clinical context to assist patient stratification based on the risk of painful DPN or return broad risk categories based on user input. Model’s performance and calibration suggest that in both cases they could potentially improve diagnosis and outcomes by changing modifiable factors like BMI and HbA1c control and institute earlier preventive or supportive measures like psychological interventions.

Background: Adverse childhood experiences and chronic pain are complex problems affecting millions of people worldwide, and result in significant healthcare utilisation. Our review aimed to determine known associations between adversity in childhood and chronic pain in adulthood. Methods: We performed a prospectively registered systematic review (PROSPERO ID: 135625). Six electronic databases (Pubmed, Medline, Cochrane, Scopus, APA PsycNet, Web of Science) were searched from January 1, 2009 until May 30, 2022. Titles and abstracts were screened, and all original research studies examining associations between adverse childhood experiences and chronic pain in adulthood were considered for inclusion. Full texts were reviewed, and a narrative synthesis was used to identify themes from extracted data. Ten percent of studies were dual reviewed to assess inter-rater reliability. Quality assessment of study methodology was undertaken using recognised tools. Results: Sixty-eight eligible studies describing 196 130 participants were included. Studies covered 15 different types of childhood adversity and 10 different chronic pain diagnoses. Dual reviewed papers had a Cohen's kappa reliability rating of 0.71. Most studies were of retrospective nature and of good quality. There were consistent associations between adverse childhood experiences and chronic pain in adulthood, with a ‘dose’-dependent relationship. Poor mental health was found to mediate the detrimental connection between adverse childhood experiences and chronic pain. Conclusion: A strong association was found between adverse childhood experiences and chronic pain in adulthood. Adverse childhood experiences should be considered in patient assessment, and early intervention to prevent adverse childhood experiences may help reduce the genesis of chronic pain. Further research into assessment and interventions to address adverse childhood experiences is needed.

Abstract. Introduction:. The World Health Organization recognizes chronic pain as a global public health concern; however, there is a bias towards research conducted in relatively affluent nations. There is a dearth of large-scale epidemiological studies in Nepal using rigorously validated, cross-culturally adapted instruments. Objectives:. The aim of this study was to examine the prevalence of both chronic pain and chronic pain of predominantly neuropathic origin and their associations with a range of sociodemographic and psychosocial characteristics. Methods:. We conducted a cross-sectional study of adults (≥18 years) in all households in Ranipani, Baluwa Village Development Committee, Nepal. All adults (n = 887) were approached, and those consenting, who met the inclusion criteria (n = 520, 58.6%), participated. Questionnaires validated in Nepali were used to examine several constructs: demographics; chronic pain; neuropathic pain; pain catastrophizing; resilience, pain intensity; pain interference; sleep disturbance; and depression. Results:. The point prevalence of chronic pain was 53.3% (n = 277). The point prevalence of chronic pain of predominantly neuropathic origin was 12.7% (n = 66). Chronic pain was associated with female gender, older age, and manual labour occupations. Using standardized scoring techniques, compared with available population estimates from other countries, those with chronic pain were associated with lower pain intensity and resilience scores and higher pain catastrophizing, pain interference, and depression scores. Conclusion:. These findings are broadly comparable to epidemiological studies from other countries, and these indicate areas for targeting interventions (eg, occupational and mental health). For comparison, more data are needed, from larger population samples in this region.

Abstract. Introduction:. Previous epidemiological studies of neuropathic pain have reported a range of prevalences and factors associated with the disorder. Objectives:. This study aimed to verify these characteristics in a large UK cohort. Methods:. A cross-sectional analysis was conducted of 148,828 UK Biobank participants who completed a detailed questionnaire on chronic pain. The Douleur Neuropathique en Quatre Questions (DN4) was used to distinguish between neuropathic pain (NeuP) and non-neuropathic pain (non-NeuP) in participants with pain of at least 3 months' duration. Participants were also identified with less than 3 months' pain or without pain (NoCP). Multivariable regression was used to identify factors associated with NeuP compared with non-NeuP and NoCP, respectively. Results:. Chronic pain was present in 76,095 participants (51.1%). The overall prevalence of NeuP was 9.2%. Neuropathic pain was significantly associated with worse health-related quality of life, having a manual or personal service type occupation, and younger age compared with NoCP. As expected, NeuP was associated with diabetes and neuropathy, but also other pains (pelvic, postsurgical, and migraine) and musculoskeletal disorders (rheumatoid arthritis, osteoarthritis, and fibromyalgia). In addition, NeuP was associated with pain in the limbs and greater pain intensity and higher body mass index compared with non-NeuP. Female sex was associated with NeuP when compared with NoCP, whereas male sex was associated with NeuP when compared with non-NeuP. Conclusion:. This is the largest epidemiological study of neuropathic pain to date. The results confirm that the disorder is common in a population of middle- to older-aged people with mixed aetiologies and is associated with a higher health impact than non-neuropathic pain.

Abstract Background This consensus statement was developed because there are concerns about the appropriate use of opioids for acute pain management, with opposing views in the literature. Consensus statement on policies for system-level interventions may help inform organisations such as management structures, government agencies and funding bodies. Methods We conducted a multi-stakeholder survey using a modified Delphi methodology focusing on policies, at the system level, rather than at the prescriber or patient level. We aimed to provide consensus statements for current developments and priorities for future developments. Results Twenty-five experts from a variety of fields with experience in acute pain management were invited to join a review panel, of whom 23 completed a modified Delphi survey of policies designed to improve the safety and quality of opioids prescribing for acute pain in the secondary care setting. Strong agreement, defined as consistent among> 75% of panellists, was observed for ten statements. Conclusions Using a modified Delphi study, we found agreement among a multidisciplinary panel, including patient representation, on prioritisation of policies for system-level interventions, to improve governance, pain management, patient/consumers care, safety and engagement.

Abstract Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

Many undergraduate students encounter struggle as they navigate academic, financial, and social contexts of higher education. The transition to emergency online instruction during the Spring of 2020 due to the COVID-19 pandemic exacerbated these struggles. To assess college students’ struggles during the transition to online learning in undergraduate biology courses, we surveyed a diverse collection of students (n = 238) at an R2 research institution in the Southeastern United States. Students were asked if they encountered struggles and whether they were able to overcome them. Based on how students responded, they were asked to elaborate on (1) how they persevered without struggle, (2) how they were able to overcome their struggles, or (3) what barriers they encountered that did not allow them to overcome their struggles. Each open-ended response was thematically coded to address salient patterns in students’ ability to either persevere or overcome their struggle. We found that during the transition to remote learning, 67% of students experienced struggle. The most reported struggles included: shifts in class format, effective study habits, time management, and increased external commitments. Approximately, 83% of those struggling students were able to overcome their struggle, most often citing their instructor’s support and resources offered during the transition as reasons for their success. Students also cited changes in study habits, and increased confidence or belief that they could excel within the course as ways in which they overcame their struggles. Overall, we found no link between struggles in the classroom and any demographic variables we measured, which included race/ethnicity, gender expression, first-generation college students, transfer student status, and commuter student status. Our results highlight the critical role that instructors play in supporting student learning during these uncertain times by promoting student self-efficacy and positive-growth mindset, providing students with the resources they need to succeed, and creating a supportive and transparent learning environment.

ABSTRACT The global spread of the novel coronavirus first reported in December 2019 led to drastic changes in the social and economic dynamics of everyday life. Nationwide, racial, gender, and geographic disparities in symptom severity, mortality, and access to health care evolved, which impacted stress and anxiety surrounding COVID-19. On university campuses, drastic shifts in learning environments occurred as universities shifted to remote instruction, which further impacted student mental health and anxiety. Our study aimed to understand how students from diverse backgrounds differ in their worry and stress surrounding COVID-19 upon return to hybrid or in-person classes during the Fall of 2020. Specifically, we addressed the differences in COVID-19 worry, stress response, and COVID-19-related food insecurity related to race/ethnicity (Indigenous American, Asian/Asian American, black/African American, Latinx/Hispanic, white, or multiple races), gender (male, female, and gender expressive), and geographic origin (ranging from rural to large metropolitan areas) of undergraduate students attending a regional-serving R2 university, in the southeastern U.S. Overall, we found significance in worry, food insecurity, and stress responses with females and gender expressive individuals, along with Hispanic/Latinx, Asian/Asian American, and black/African American students. Additionally, students from large urban areas were more worried about contracting the virus compared to students from rural locations. However, we found fewer differences in self-reported COVID-related stress responses within these students. Our findings can highlight the disparities among students’ worry based on gender, racial differences, and geographic origins, with potential implications for mental health of university students from diverse backgrounds. Our results support the inclusion of diverse voices in university decisioning making around the transition through the COVID-19 pandemic.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Purpose Neuropathic pain is a common disorder of the somatosensory system that affects 7%–10% of the general population. The disorder places a large social and economic burden on patients as well as healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset.Participants DOLORisk Dundee has been constructed by rephenotyping two pre-existing Scottish population cohorts for neuropathic pain using a standardised ‘core’ study protocol: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) (n=5236) consisting of predominantly type 2 diabetics from the Tayside region, and Generation Scotland: Scottish Family Health Study (GS:SFHS; n=20 221). Rephenotyping was conducted in two phases: a baseline postal survey and a combined postal and online follow-up survey. DOLORisk Dundee consists of 9155 participants (GoDARTS=1915; GS:SFHS=7240) who responded to the baseline survey, of which 6338 (69.2%; GoDARTS=1046; GS:SFHS=5292) also responded to the follow-up survey (18 months later).Findings to date At baseline, the proportion of those with chronic neuropathic pain (Douleur Neuropathique en 4 Questions questionnaire score ≥3, duration ≥3 months) was 30.5% in GoDARTS and 14.2% in Generation Scotland. Electronic record linkage enables large scale genetic association studies to be conducted and risk models have been constructed for neuropathic pain.Future plans The cohort is being maintained by an access committee, through which collaborations are encouraged. Details of how to do this will be available on the study website (http://dolorisk.eu/). Further follow-up surveys of the cohort are planned and funding applications are being prepared to this effect. This will be conducted in harmony with similar pain rephenotyping of UK Biobank.

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.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Abstract Background Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

Background: Headache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. Methods: We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. Results: We identified 3343 SNPs which reached the genome-wide significance level of P

Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

Health-related traits are known to vary geographically. Here, Amador and colleagues show that regional variation of obesity-related traits in a Scottish population is influenced more by lifestyle differences than it is by genetic differences.

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p

Background: Neuropathic pain is an increasingly prevalent condition and has a major impact on health and quality of life. However, the risk factors for the development and maintenance of neuropathic pain are poorly understood. Clinical, genetic and psychosocial factors all contribute to chronic pain, but their interactions have not been studied in large cohorts. The DOLORisk study aims to study these factors. Protocol: Multicentre cross-sectional and longitudinal cohorts covering the main causes leading to neuropathic pain (e.g. diabetes, surgery, chemotherapy, traumatic injury), as well as rare conditions, follow a common protocol for phenotyping of the participants. This core protocol correlates answers given by the participants on a set of questionnaires with the results of their genetic analyses. A smaller number of participants undergo deeper phenotyping procedures, including neurological examination, nerve conduction studies, threshold tracking, quantitative sensory testing, conditioned pain modulation and electroencephalography. Ethics and dissemination: All studies have been approved by their regional ethics committees as required by national law. Results are disseminated through the DOLORisk website, scientific meetings, open-access publications, and in partnership with patient organisations. Strengths and limitations: Large cohorts covering many possible triggers for neuropathic pain Multi-disciplinary approach to study the interaction of clinical, psychosocial and genetic risk factors High comparability of the data across centres thanks to harmonised protocols One limitation is that the length of the questionnaires might reduce the response rate and quality of responses of participants

Background: Stressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable and genetic risk for SLEs is associated with risk for MDD. We sought to investigate the genetic and environmental contributions to SLEs in a family-based sample, and quantify genetic overlap with MDD and neuroticism. Methods: A subset of Generation Scotland: the Scottish Family Health Study (GS), consisting of 9618 individuals with information on MDD, past 6 month SLEs, neuroticism and genome-wide genotype data was used in the present study. We estimated the heritability of SLEs using GCTA software. The environmental contribution to SLEs was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression (LDSC) we analysed the genetic overlap between MDD, neuroticism and SLEs. Results: Past 6-month life events were positively associated with lifetime MDD status (β=0.21, r2=1.1%, p=2.5 x 10-25) and neuroticism (β =0.13, r2=1.9%, p=1.04 x 10-37) at the phenotypic level. Common SNPs explained 8% of the phenotypic variance in personal life events (those directly affecting the individual) (S.E.=0.03, p= 9 x 10-4). A significant effect of couple environment was detected accounting for 13% (S.E.=0.03, p=0.016) of the phenotypic variation in SLEs. PRS analyses found that reporting more SLEs was associated with a higher polygenic risk for MDD (β =0.05, r2=0.3%, p=3 x 10-5), but not a higher polygenic risk for neuroticism. LDSC showed a significant genetic correlation between SLEs and both MDD (rG=0.33, S.E.=0.08 ) and neuroticism (rG=0.15, S.E.=0.07). Conclusions: These findings suggest that SLEs should not be regarded solely as environmental risk factors for MDD as they are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work is needed to determine the causal direction and source of these associations.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Neuropathic pain is defined as pain arising as a direct consequence of a lesion or a disease affecting the somatosensory system and it affects around 1 in 4 diabetic patients in the UK. The purpose of this genome-wide association study (GWAS) was to identify genetic contributors to this disorder. Cases of neuropathic pain were defined as diabetic patients with a multiple prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain. Controls were diabetic individuals who were not prescribed any of these drugs, nor amitriptyline, carbamazepine, or nortriptyline. Overall, 961 diabetic neuropathic pain cases and 3260 diabetic controls in the Genetics of Diabetes Audit and Research Tayside (GoDARTS) cohort were identified. We found a cluster in the Chr1p35.1 (ZSCAN20-TLR12P) with a lowest P value of 2.74 × 10−7 at rs71647933 in females and a cluster in the Chr8p23.1, next to HMGB1P46 with a lowest P value of 8.02 × 10−7 at rs6986153 in males. Sex-specific narrow sense heritability was higher in males (30.0%) than in females (14.7%). This GWAS on diabetic neuropathic pain provides evidence for the sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with the disorder, indicating the need for further research.

Background: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants. Methods: In the present analysis, three cohort studies (ntotal = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions. Results: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator (DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer’s disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10-7), was the butyrylcholinesterase (BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognitive ability merits further investigation. Conclusions: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.

[This corrects the article DOI: 10.1371/journal.pgen.1006528.].

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Significant research effort has gone towards the development of powered lower limb prostheses that control power during gait. These devices use forward prediction based on electromyography (EMG), kinetics and kinematics to command the prosthesis which locomotion activity is desired. Unfortunately these predictions can have substantial errors, which can potentially lead to trips or falls. It is hypothesized that one reason for the significant prediction errors in the current control systems for powered lower-limb prostheses is due to the inter- and intra-subject variability of the data sources used for prediction. Environmental data, recorded from a depth sensor worn on a belt, should have less variability across trials and subjects as compared to kinetics, kinematics and EMG data, and thus its addition is proposed. The variability of each data source was analyzed, once normalized, to determine the intra-activity and intra-subject variability for each sensor modality. Then measures of separability, repeatability, clustering and overall desirability were computed. Results showed that combining Vision, EMG, IMU (inertial measurement unit), and Goniometer features yielded the best separability, repeatability, clustering and desirability across subjects and activities. This will likely be useful for future application in a forward predictor, which will incorporate Vision-based environmental data into a forward predictor for powered lower-limb prosthesis and exoskeletons.

Correction to: Molecular Psychiatry, published online 2 May 2023 In this article Honami Arai, Irene Bollettini, Rosa Calvo Escalona, Ana Coelho, Federica Colombo, Leila Darwich, Martine Fontaine, Toshikazu Ikuta, Jonathan C. Ipser, Asier Juaneda-Seguí, Hitomi Kitagawa, Gerd Kvale, Mafalda Machado-Sousa, Astrid Morer, Takashi Nakamae, Jin Narumoto, Joseph O’Neill, Sho Okawa, Eva Real, Veit Roessner, Joao R. Sato, Cinto Segalàs, Roseli G. Shavitt, Dick J. Veltman, Kei Yamada were missing from the author list indexed under the ENIGMA-OCD Working Group. Additionally, there was an error regarding Tokiko Yoshida’s name, where the first name and last name were written in the wrong order. The original article has been corrected.

BackgroundDepression and chronic pain are the two most important causes of disability (Global Burden of Disease Study 2013). They occur together more frequently than expected and both conditions have been shown to be co-morbid with cardiovascular disease. Although shared socio-demographic risk factors (e.g. gender, deprivation) might explain the co-morbidity of these three conditions, we hypothesised that these three long-term, highly prevalent conditions co-occur and may be due to shared familial risk, and/or genetic factors.Methods and findingsWe employed three different study designs in two independent cohorts, namely Generation Scotland and TwinsUK, having standardised, validated questionnaire data on the three traits of interest. First, we estimated the prevalence and co-occurrence of chronic pain, depression and angina among 24,024 participants of a population-based cohort of extended families (Generation Scotland: Scottish Family Health Study), adjusting for age, gender, education, smoking status, and deprivation. Secondly, we compared the odds of co-morbidity in sibling-pairs with the odds in unrelated individuals for the three conditions in the same cohort. Lastly, examination of similar traits in a sample of female twins (TwinsUK, n = 2,902), adjusting for age and BMI, allowed independent replication of the findings and exploration of the influence of additive genetic (A) factors and shared (C) and non-shared (E) environmental factors predisposing to co-occurring chronic widespread pain (CWP) and cardiovascular disease (hypertension, angina, stroke, heart attack, elevated cholesterol, angioplasty or bypass surgery). In the Generation Scotland cohort, individuals with depression were more than twice as likely to have chronic pain as those without depression (adjusted OR 2·64 [95% CI 2·34-2·97]); those with angina were four times more likely to have chronic pain (OR 4·19 [3·64-4·82]); those with depression were twice as likely to have angina (OR 2·20 [1·90-2·54]). Similar odds were obtained when the outcomes and predictors were reversed and similar effects seen among sibling pairs; depression in one sibling predicted chronic pain in the other (OR 1·34 [1·05-1·71]), angina predicted chronic pain in the other (OR 2·19 [1·63-2·95]), and depression, angina (OR 1·98 [1·49-2·65]). Individuals with chronic pain and angina showed almost four-fold greater odds of depression compared with those manifesting neither trait (OR 3·78 [2·99-4·78]); angina showed seven-fold increased odds in the presence of chronic pain and depression (OR 7·76 [6·05-9·95]) and chronic pain nine-fold in the presence of depression and angina (OR 9·43 [6·85-12·98]). In TwinsUK, the relationship between CWP and depression has been published (R = 0.34, pConclusionWe found an increased co-occurrence of chronic pain, depression and cardiovascular disease in two independent cohorts (general population-based cohort, twins cohort) suggesting a shared genetic contribution. Adjustment for known environmental influences, particularly those relating to socio-economic status (Generation Scotland: age, gender, deprivation, smoking, education; Twins UK: age,BMI) did not explain the relationship observed between chronic pain, depression and cardiovascular disease. Our findings from two independent cohorts challenge the concept of traditional disease boundaries and warrant further investigation of shared biological mechanisms.

Pheochromocytomas and extra-adrenal paragangliomas are catecholamine-secreting tumors that rarely occur in pregnancy. The diagnosis of these tumors in pregnancy can be challenging given that many of the signs and symptoms are commonly attributed to preeclampsia or other more common diagnoses. Early diagnosis and appropriate management are essential in optimizing maternal and fetal outcomes. We report a rare case of a catecholamine-secreting tumor in which diagnosis occurring at the time labor was being induced for concomitant preeclampsia with severe features. Her initial presentation in hypertensive crisis with other symptoms led to diagnostic workup for secondary causes of hypertension and led to eventual diagnosis of paraganglioma. Obtaining this diagnosis prior to delivery was essential, as this led to prompt multidisciplinary care, changed the course of her clinical management, and ultimately enabled good maternal and fetal outcomes. This case highlights the importance of maintaining a high index of suspicion for secondary causes of hypertension and in obstetric patients and providing timely multidisciplinary care.

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.

The global spread of the novel coronavirus first reported in December 2019 led to drastic changes in the social and economic dynamics of everyday life. Nationwide, racial, gender, and geographic disparities in symptom severity, mortality, and access to health care evolved, which impacted stress and anxiety surrounding COVID-19. On university campuses, drastic shifts in learning environments occurred as universities shifted to remote instruction, which further impacted student mental health and anxiety. Our study aimed to understand how students from diverse backgrounds differ in their worry and stress surrounding COVID-19 upon return to hybrid or in-person classes during the Fall of 2020. Specifically, we addressed the differences in COVID-19 worry, stress response, and COVID-19-related food insecurity related to race/ethnicity (Indigenous American, Asian/Asian American, black/African American, Latinx/Hispanic, white, or multiple races), gender (male, female, and gender expressive), and geographic origin (ranging from rural to large metropolitan areas) of undergraduate students attending a regional-serving R2 university, in the southeastern U.S. Overall, we found significance in worry, food insecurity, and stress responses with females and gender expressive individuals, along with Hispanic/Latinx, Asian/Asian American, and black/African American students. Additionally, students from large urban areas were more worried about contracting the virus compared to students from rural locations. However, we found fewer differences in self-reported COVID-related stress responses within these students. Our findings can highlight the disparities among students' worry based on gender, racial differences, and geographic origins, with potential implications for mental health of university students from diverse backgrounds. Our results support the inclusion of diverse voices in university decisioning making around the transition through the COVID-19 pandemic.